Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)N)[CH2:22][CH2:21]1)(=[O:19])[CH3:18].C([N:35](CC)CC)C.O>CN1C(=O)CCC1>[C:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]([C:11]3[CH:12]=[C:2]([F:1])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([NH2:35])[C:10]=3[N+:14]([O-:16])=[O:15])[CH:30]=[CH:31][CH:32]=2)[CH2:22][CH2:21]1)(=[O:19])[CH3:18]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(F)cc(-c2cccc(N3CCN(C(C)=O)CC3)c2)c([N+](=O)[O-])c1N
Temperature: 80 °C

Procedure:
A mixture of ethyl 2,4-difluoro-5-nitrobenzoate (22) (1.0 g; 4.33 mmol), 4f (0.95 g; 4.33 mmol) and triethylamine (0.6 ml; 0.33 mmol) in anhydrous NMP (10 ml) was heated to 80° C. for one hour. The cooled mixture was poured into water and extracted with ethyl acetate. The organic extract was dried over magnesium sulphate, concentrated under reduced pressure and purified by column-chromatography on silica gel using ethyl acetate as the eluent. Yield: 1.53 g (82%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C1(C)C=CC=CC=1>[S:16]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][Cl:1])(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCOCCCl
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(2-chloroethoxy)ethanol (15.3 g, 123 mmol) in toluene (100 ml) kept at 5° C. was added triethylamine (50 g, 500 mmol). A solution of methanesulfonyl chloride (28 g, 245 mmol) in toluene (50 ml) was carefully added keeping the temperature around 5° C. When addition was complete the reaction mixture was stirred at 5° C. for 45 minutes and then 75 minutes at ambient temperature. Water (100 ml) was added and the mixture was stirred for 15 minutes. The phases were separated and the organic phase was washed with water, brine and dried over magnesium sulphate. The solvent was evaporated in vacuo to give crude 2-(2-chloroethoxy)ethyl mesylate as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[C:4](=[O:11])[N:3]1[C:12]1[CH:39]=[CH:38][C:15]([CH2:16][C@@H:17]([C:35]([OH:37])=[O:36])[NH:18][C:19]([C:21]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=1>C(O)C.C(O)(C(F)(F)F)=O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:21]2([C:19]([NH:18][C@H:17]([C:35]([OH:37])=[O:36])[CH2:16][C:15]3[CH:38]=[CH:39][C:12]([N:3]4[C:2](=[O:1])[CH:10]5[CH:5]([CH2:6][NH:7][CH2:8][CH2:9]5)[C:4]4=[O:11])=[CH:13][CH:14]=3)=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(N4C(=O)c5ccncc5C4=O)cc3)C(=O)O)CCCC2)cc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(N4C(=O)C5CCNCC5C4=O)cc3)C(=O)O)CCCC2)cc1
Reaction time: 0.58 h
Yield: 13.8 %

Procedure:
A solution of 4-(2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-c]pyridin-2-yl)-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (30 mg, 0.057 mmol) in ethanol (4 mL) containing a few drops of TFA was hydrogenated over 10% Pd(C) (6 mg) for 18 hours. The mixture was filtered and evaporated and the residue was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 35 min. The peak eluting at 59.5% acetonitrile was concentrated and mixture was lyophilized to give N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-[(3aRS, 7aRS)-(octahydro-1,3-dioxo-1H-pyrrolo[3,4-c]pyridin-2-yl)]-L-phenylalanine (4.2 mg), HR FABMS: obs. mass 534.2602. Calcd. mass 534.2604 (M+H). The peak eluting at 62% acetonitrile was concentrated and the mixture lyophilzed to give 4-[(RS)-2,3,5,6,7,7a-hexahydro-1,3-dioxo-1H-pyrrolo[3,4-c]pyridin-2-yl]-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (4.9 mg), HR FABMS:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].[C:32]([O:36][C:37]([NH:39][C@@:40]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:45]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=2)[C@H:44](O)[C@@H:43]2[C@H:41]1[C@H:42]2[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:38])([CH3:35])([CH3:34])[CH3:33].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)C>[C:32]([O:36][C:37]([NH:39][C@@:40]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:45]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=2)[C@@H:44]([O:28][C:27]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=2)=[O:29])[C@@H:43]2[C@H:41]1[C@H:42]2[C:57]([O:59][C:60]([CH3:62])([CH3:61])[CH3:63])=[O:58])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
Triphenylphosphine (12.66 g, 48.26 mmol) and 4-nitrobenzoic acid (8.19 g, 48.26 mmol) are added to di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (14.20 g, 24.13 mmol) and tetrahydrofuran (241.28 mL, 2.97 moles) at room temperature. Cool the mixture in an ice bath. Diisopropyl azodicarboxylate (9.57 mL, 9.76 g, 48.26 mmol) in tetrahydrofuran (20 mL) is added and the reaction mixture is gradually warmed to room temperature overnight. Dilute with diethyl ether, and then wash with aqueous sodium carbonate. Extract the aqueous layer again with diethyl ether. Combine all ether extracts, wash with water, brine, dry over magnesium sulfate, and concentrate under reduced pressure to give a residue. The residue is purified by flash chromatography, eluting with 10-100% ethyl acetate in hexanes to give the title compound (9 g, 12.2 mmol, 51%): MS (m/z): 759 (M+1).
Reaction SMILES: [C:1]1([C:6](Cl)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][C:25]1=[O:33])[CH3:23]>O>[CH2:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:6](=[O:7])[C:1]3[S:5][CH:4]=[CH:3][CH:2]=3)=[CH:30][CH:31]=2)[CH2:26][C:25]1=[O:33])[CH3:23]
Reactant: O=C(Cl)c1cccs1
Reactant: CCN1C(=O)Cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN1C(=O)Cc2cc(C(=O)c3cccs3)ccc21
Temperature: 100 °C
Yield: 47.7 %

Procedure:
To a mixture of 27.3 g. (19.9 mmoles) of 2-thenoyl chloride, 30 ml. of nitrobenzene and 32.95 g. of aluminum chloride was gradually added 10 g. (62 mmoles) of 1-ethyloxindole, and the resulting reaction mixture heated at 100° C. for 75 minutes. The reaction was cooled to room temperature and poured into 2 l. of ice and water. The product was extracted with methylene chloride and the dried extract concentrated to dryness, 11.05 g. The product was recrystallized from methylene chloride-hexane, 8.03 g. (47.7% yield)m, m.p. 158°-160° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:8][CH2:9][CH2:10][NH:11][C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCO[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 52.8 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butyldimethylsilyloxy)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.211 g, 0.301 mmol) in THF (2 mL) was added TBAF (1M in THF) (0.601 mL, 0.601 mmol). The mixture was stirred at rt for 2.75 h then was diluted with water (10 mL) and was extracted with dichloromethane (3×10 mL). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was adsorbed to silica gel and was purified by flash chromatography using a 0-25% EtOAc in hexanes gradient. The title compound (93.4 mg, 0.159 mmol, 52.9% yield), was isolated as a colorless film. LCMS: m/e 588.6 (M+H)+, 1.98 min (method 2). 1H NMR (500 MHz, CHLOROFORM-d) d ppm 7.91 (d, J=8.24 Hz, 2H), 7.18 (d, J=8.24 Hz, 2H), 5.27 (d, J=4.58 Hz, 1H), 4.70 (d, J=1.83 Hz, 1H), 4.59 (s, 1H), 3.89 (s, 3H), 3.54-3.64 (m, 2H), 2.52-2.69 (m, 3H), 2.09 (dd, J=17.09, 6.41 Hz, 1H), 1.68 (s, 3H), 1.07 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H), 0.93-2.05 (m, 21H), 0.91 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(Br)cc1Br
Reactant: CCOC(=O)C1CCCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Br)cc2Br)CCC1

Procedure:
using isopropyl 2,4-dibromo-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate in toluene there is obtained isopropyl 2,4-dibromo-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 157°-158° C.,
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[CH2:4][C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([F:15])=[N:10][C:11]=2[NH2:14])[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:34][CH2:35][CH2:36][C:37]#[CH:38])(=O)=O>CN(C=O)C>[F:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([CH2:4][C:3]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:2]=3[Br:1])[N:6]2[CH2:38][CH2:37][CH2:36][C:35]#[CH:34])=[C:11]([NH2:14])[N:10]=1
Reactant: COc1cc(Br)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)c(OC)cc2Br)nc2c(N)nc(F)nc21

Procedure:
A solution of 8-(2-bromo-4,5-dimethoxy-benzyl)-2-fluoroadenine (13 mg, 0.034 mmol), Cs2CO3 (11 mg, 0.034 mmol), pent-4-ynyl tosylate (10 mg, 9 L, 0.044 mmol) in anhydrous DMF (80 L) was stirred at 60° C. for 30 min. Following solvent removal, the product (8.2 mg, 53.6%) was collected through silica gel column purification (CHC13:EtOAc:hexanes:i-PrOH at 20:10:20:1). 1HNMR (400 MHz, CDC13) 7.06 (s, 1H), 6.67 (s, 1H), 5.92 (bs, 2H), 4.31 (s, 2H), 4.14 (t, J=7.4 Hz, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 2.25-2.20 (m, 2H), 1.99 (t, J=2.6 Hz, 1H), 1.96-1.89 (m, 2H); 13C NMR (100 MHz, CDC13) 160.0, 158.3, 156.7, 153.4, 151.3, 149.4, 127.2, 117.3, 115.9, 114.5, 113.2, 82.7, 70.2, 56.62, 56.56, 42.7, 34.3, 30.1, 28.5, 16.3; MS m/z 447.9 (M+H)+. HPLC: (a) 99.0% (60% water-40% acetonitrile); (b) 98.8% (35% to 55% acetonitrile).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 135 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methyl sulfinyl)benzo[d]oxazole (330 mg, 0.84 mmol), (1R,2R)-2-aminocyclohexanol (192 mg, 1.27 mg) and DIEA (327 mg, 2.54 mmol) in DMA (15 mL) was stirred at 135° C. for 1 h. The reaction mixture was cooled to rt, poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:6 petroleum ether/ethyl acetate to give (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a light yellow solid (373 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.38 (s, 1H), 7.13 (s, 1H), 5.48 (s, 2H), 4.68 (s, 3H), 3.37 (br s, 2H), 1.92 (br s, 2H), 1.62 (br s, 2H), 1.23 (br s, 4H). LCMS (ESI) m/z 441 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:19])[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(OCC)C>C1(C)C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH3:19])[C:7](=[O:20])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 100 °C
Yield: 23.7 %

Procedure:
8-Cyclopentyl-6-methyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 3.43 mmol) was added to 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.91 g, 6.86 mmol) in toluene (5 ml). The mixture was heated to 100° C. over 18 hours then treated with diethyl ether to produce a precipitate. This precipitate was collected by filtration then dried in vacuo to provide 4-[6-(8-cyclopentyl-6-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.411 g). MS (APCI) M++1: Calc'd, 506.28, Found 506.2.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4]1\[CH2:5][N:6]([C:11]2[N:16]=[C:15]3[N:17]([CH:25]4[CH2:27][CH2:26]4)[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[C:20](=[O:21])[C:14]3=[CH:13][C:12]=2[F:28])[CH2:7][CH:8]\1[CH2:9][NH2:10].C(Cl)Cl.[C:32]([OH:37])(=[O:36])[CH:33]([CH3:35])[OH:34]>C(O)C>[CH3:1][O:2]/[N:3]=[C:4]1\[CH2:5][N:6]([C:11]2[N:16]=[C:15]3[N:17]([CH:25]4[CH2:27][CH2:26]4)[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[C:20](=[O:21])[C:14]3=[CH:13][C:12]=2[F:28])[CH2:7][CH:8]\1[CH2:9][NH2:10].[C:32]([O-:37])(=[O:36])[CH:33]([CH3:35])[OH:34]
Reactant: CC(O)C(=O)O
Agent: CO/N=C1\CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1CN
Solvent: ClCCl
Solvent: CCO
Product: CC(O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Gemifloxacin free base (3 gm) is added to methylene dichloride (65 ml) at 25-30° C., ethanol (20 ml) is added to form a clear solution. To the solution, lactic acid (0.6ml) is added at 25-30° C., stirred for 1 hour and then cooled to 10° C. Filtered the solid and dried at 50-l 55° C. to give 3 gm of gemifloxacin lactate (HPLC Purity: 99.93%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[N:37](C(OC(C)(C)C)=O)[CH:38]=[CH:39][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:37][CH:38]=[CH:39][CH:40]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc[nH]2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1, 100 mg, 0.224 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (131 mg, 0.448 mmol), Pd(PPh3)2Cl2 (15.73 mg, 0.022 mmol), Na2CO3 (95 mg, 0.896 mmol), DME (951 μL), water (272 μL) and EtOH (136 μL) in a MW vial was sealed, evacuated/purged 3 times with argon and stirred at 80° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW irradiation at 150° C. for 5 min, diluted with DME (3 mL) and treated with Si-Thiol (Silicycle, 1.44 mmol/g, 93 mg, 0.134 mmol) overnight. The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) to afford the title compound as a grey solid. UPLC-MS (Condition 3) tR 1.02 min, m/z=433.4 [M+H]+, m/z=477.3 [M+formic acid-H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.77 (m, 1H) 1.77-1.88 (m, 1H) 2.97 (d, J=11.80 Hz, 1H) 3.23-3.32 (m, 2H) 3.39-3.49 (m, 1H) 4.15-4.24 (m, 1H) 4.79-4.89 (m, 1H) 6.06-6.13 (m, 2H) 6.76-6.84 (m, 1H) 7.34 (d, J=8.28 Hz, 2H) 7.82-7.92 (m, 2H) 8.02 (d, J=2.51 Hz, 1H) 8.69 (d, J=2.51 Hz, 1H) 10.17 (s, 1H) 11.14 (d, J=1.76 Hz, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N+:9]([O-])=[CH:10]2)=[CH:5][CH:4]=1.BrC1C=C2C(=CC=1)C([Cl:25])=NC=C2>>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[Cl:25])=[CH:5][CH:4]=1
Reactant: [O-][n+]1ccc2ccc(Br)cc2c1
Reactant: Clc1nccc2cc(Br)ccc12
Agent: Cl
Product: Clc1nccc2ccc(Br)cc12

Procedure:
Compound 37b was prepared from 37a using the procedure described for 1b. 1H-NMR 200 MHz (CDCl3) δ: 7.57-7.88 (3H, m), 8.32 (1H, d, J=6 Hz), 8.51-8.54 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cncc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cncc(Br)c1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
To the stirred solution (5-bromo-pyridin-3-yl)-methanol (3.0 g, 16 mmol) in CH2Cl2 (30 mL) is added triethylamine (2.4 g, 24 mmol). The reaction mixture is cooled to 0° C., methanesulfonyl chloride (2.2 g, 19 mmol) is added slowly at 0° C. Then the reaction mixture is warmed up to room temperature for 3 hrs. Ice cold water is added and the mixture is extracted with CH2Cl2. Organic layers are combined, dried over Na2SO4 and concentrated to give 3.0 g of the crude methanesulfonic acid 5-bromo-pyridin-3-ylmethyl ester which is used without purification.
Reaction SMILES: [CH2:1]=[O:2].[C:3]1(O)C=CC=CC=1.S(=O)(=O)(O)O.[C:15]1([CH3:22])[CH:20]=[CH:19][CH:18]=[C:17](C)[CH:16]=1>>[C:15]1([CH3:22])[CH:16]=[CH:17][CH:18]=[C:19]([CH:1]=[O:2])[C:20]=1[CH3:3]
Reactant: Cc1cccc(C)c1
Reactant: Oc1ccccc1
Reactant: C=O
Agent: O=S(=O)(O)O
Product: Cc1cccc(C=O)c1C

Procedure:
A 2-liter separable flask equipped with a thermometer, a reflux condenser, and a stirrer was charged with 480 parts of 50% formalin, 110 parts of phenol, 202 parts of 98% industrial sulfuric acid, and 424 parts of m-xylene. The resulting mixture was allowed to react at 84 to 88° C. for 4 hours. After completion of the reaction, the reaction mixture was allowed to stand to separate a resin phase and a sulfuric acid aqueous phase. After the resin phase was washed with water 3 times, unreacted m-xylene was removed under the conditions of 20 to 30 mmHg and 120 to 130° C. for 20 minutes. As a result, 480 parts of a phenol-modified xylene-formaldehyde resin having a viscosity of 1,050 mPa·s (25° C.) was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[C:7]([NH2:10])(=[S:9])[CH3:8]>>[ClH:1].[Cl:1][CH2:2][C:3]1[N:10]=[C:7]([CH3:8])[S:9][CH:5]=1
Reactant: CC(N)=S
Reactant: O=C(CCl)CCl
Product: Cc1nc(CCl)cs1
Product: Cl
Reaction time: 2 h

Procedure:
25.4 g of 1,3-dichloroacetone (0.2 mol) and 15 g of thioacetamide (0.2 mol), dissolved in 200 ml of absolute alcohol are stirred at 60°-70° for two hours. Subsequently, the solution is filtered and after evaporation in vacuo the residue is treated with 200 ml of ether. The 4-chloromethyl-2-methylthiazole, hydrochloride (32.8 g=89%) is filtered off and recrystallized from absolute alcohol (refrigerator); m.p. 168°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: CCCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCOc1cc(C(=O)O)cc(C(=O)OC)c1
Yield: 52.9 %

Procedure:
A suspension of 5-butoxy-isophthalic acid dimethyl ester (2.0 g, 7.5 mmol) in THF/MeOH/water (5.0 mL each) is treated with lithium hydroxide (0.22 g, 9.0 mmol) at room temperature for 1.0 h. The reaction mixture is acidified with 1.0 M HCl and the product is extracted with EtOAc (30 mL), washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as solid (1.0 g, 53%). LC-ES/MS m/e 270.3 (M+18), 251.3 (M−1).
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:27]([OH:29])=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:38]>ClCCl>[C:1]([NH:18][C@H:19]([C:27]([F:38])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)F)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
FMOC-L-Phenylalanine (17 g, 44 mmol) (Bachem) was dissolved in dichloromethane (100 mL). Pyridine (3.55 mL, 44 mmol) (Aldrich) and cyanuric fluoride (6 g, 44 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 3.5 hours. Ice cold water (300 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford FMOC-L-phenylalanyl fluoride as a white powder. (Yield 13.6 g, 80%).