Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:46])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:23][OH:24])[CH:17]=[C:16]([C:31]([O:33]CC)=[O:32])[C:15]3=[O:36])=[C:8]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[CH:7]=1)[CH3:2].[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([NH:3][C:4](=[O:46])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:23][OH:24])[CH:17]=[C:16]([C:31]([OH:33])=[O:32])[C:15]3=[O:36])=[C:8]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:43])[F:44])[N:41]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C(CO)C2CCOCC2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C(CO)C2CCOCC2)cn1
Temperature: 100 °C
Yield: 26.2 %

Procedure:
To a solution of ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 103, 107 mg, 0.16 mmol, 1 equiv.) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2 M lithium hydroxide (0.162 mL, 0.32 mmol). The reaction mixture was heated to 100° C. for 15 min in a microwave. The reaction mixture was cooled to room temperature and diluted with water. The reaction mixture was filtered, and the filtrate was dried. Purification via reverse phase HPLC (C18, acetonitrile/water 0-95% gradient) and concentrated under reduced pressure to provide 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol--yl)pyridin-3-yl)-1-(2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a light yellow solid (26.5 mg, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[CH2:8][CH3:9].C([Li])CCC.CCCCCC.B(OC)(OC)OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51](I)=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:51]2[CH:52]=[CH:53][C:48]([Cl:47])=[CH:49][CH:50]=2)[S:4][C:3]=1[CH2:8][CH3:9]
Reactant: CCc1sc(Br)cc1Br
Reactant: Clc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COB(OC)OC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1sc(-c2ccc(Cl)cc2)cc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 3,5-dibromo-2-ethyl-thiophene (3.28 g, 12.15 mmol) in diethyl ether (50 ml) at −78° C. under N2 is added, slowly, 2.5M butyl lithium in hexane solution (4.86 ml, 12.15 mmol) over 10 minutes and the reaction stirred at −78° C. for a further 30 minutes. The reaction is then cooled to −78° C. before the dropwise addition of trimethyl borate (1.64 ml, 14.6 mmol) over 5 minutes. The reaction is stirred at −78° C. for 30 minutes, then allowed to warm to room temperature and stirred for a further 60 minutes. Palladium acetate (68 mg, 0.3 mmol), triphenylphosphine (314 mg, 1.2 mmol) and 4-chloro-iodobenzene (4.9 g, 12.15 mmol) is then added to the reaction, followed by THF (50 ml) and 1N sodium carbonate solution (20 ml) and the reaction is heated to reflux for 3 hours. The cooled reaction mixture is partitioned between ether (250 ml) and water (300 ml). The organic layer is separated, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is therefore purified by flash chromatography on silica gel to give 3-bromo-5-(4-chlorophenyl)-2-ethyl-thiophene as a white solid (2.75 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH:9]([OH:24])[CH2:10][NH:11][CH:12]([CH2:14][CH2:15][N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])[CH:6]=[CH:5][C:4]=1[OH:25].C(OO)(=[O:28])C.C(Cl)(Cl)Cl.CO.N>CO>[CH3:23][N:16]([CH2:15][CH2:14][CH:12]([NH:11][CH2:10][CH:9]([C:7]1[CH:6]=[CH:5][C:4]([OH:25])=[C:3]([S:2]([CH3:1])=[O:28])[CH:8]=1)[OH:24])[CH3:13])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CSc1cc(C(O)CNC(C)CCN(C)c2ccccc2)ccc1O
Reactant: CC(=O)OO
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(CCN(C)c1ccccc1)NCC(O)c1ccc(O)c(S(C)=O)c1

Procedure:
To 2-methylthio-4-(2-[4-(methylanilino)-2-butylamino]-1-hydroxyethyl)phenol (1.8 g=5 mmol) in 50 ml methanol add a solution of 40% peracetic acid (5.0 mmol) in 10 ml methanol. Stir one-half hour and concentrate to obtain a gum. Chromatograph on 100 g silica gel using chloroform/methanol/ammonia as eluant and combine appropriate fractions and concentrate to obtain 4-(2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl)-2-methylsulfinylphenol. Dissolve this in ether and treat with ethereal hydrogen chloride to obtain the title product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][CH2:35][N:36]([CH3:79])[C:37](=[O:78])[C:38]1[CH:77]=[CH:76][CH:75]=[C:40]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54]C[CH2:52][CH2:51]3)=[CH:46][C:45]=2[C:56]2[CH:61]=[C:60]([C:62](=[O:74])[NH:63][C@@H:64]3[C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH2:67][CH2:66][CH2:65]3)[CH:59]=[CH:58][N:57]=2)=[O:42])[CH:39]=1)=[O:28].C(N(CC)C1C=CC(NC(=O)C2C=CC=C(C(N(C)CC=O)=O)C=2)=C(C2C=C(C(=O)N[C@@H]3C4C(=CC=CC=4)CCC3)C=CN=2)C=1)C>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][CH2:35][N:36]([CH3:79])[C:37](=[O:78])[C:38]1[CH:77]=[CH:76][CH:75]=[C:40]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]([CH2:55][CH3:54])[CH2:51][CH3:52])=[CH:46][C:45]=2[C:56]2[CH:61]=[C:60]([C:62](=[O:74])[NH:63][C@@H:64]3[C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH2:67][CH2:66][CH2:65]3)[CH:59]=[CH:58][N:57]=2)=[O:42])[CH:39]=1)=[O:28]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCNC(=O)[C@@H]1CCCN1CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CC=O)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N1-(2-((S)-2-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-ylcarbamoyl)pyrrolidin-1-yl)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide Example 195, using (S)—N1-(4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(2-oxoethyl)isophthalamide in place of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide. MS (ES, m/z): 1082.52 [M+H]+.
Reaction SMILES: C(OC(=O)C)(=O)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.O=C(C)CC[N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41]>CCOC(C)=O>[C:32]1(=[O:41])[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39](=[O:40])[NH:31]1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 70 °C
Yield: 22.3 %

Procedure:
To a stirred solution of acetic anhydride (5.0 mL, 53.0 mmol) and 7.7 wt % phosphorus pentoxide in methanesulfonic acid (Eaton's Reagent) (5.0 mL, 4.60 mmol) was added 2-(3-oxobutyl)isoindoline-1,3-dione (1.0 g, 4.60 mmol). The reaction was heated at 70° C. and for 8 h. The reaction was allowed to cool to room temperature and maintained overnight. The reaction was diluted with EtOAc, washed with ice cold water, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Analogix, SF40-115 g, 20-100% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness and triturated with 10% EtOAc in hexanes, filtered and evaporated to dryness to give 2-(2,6-dimethyl-4-oxo-4H-pyran-3-yl)methyl)isoindoline-1,3-dione (290 mg, 1.024 mmol, 22.24% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.74 (m, 4 H), 6.06 (s, 1 H), 4.54 (s, 2 H), 2.43 (s, 3 H), 2.22 (s, 3 H). MS(ES) [M+H]+ 284.0.
Reaction SMILES: C1CC[CH:4]([N:7]=C=NC2CCCCC2)CC1.[NH2:16][C@H:17]([C:25]([OH:27])=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(NC(=O)[O-])C1C=CC=CC=1.ON1C(=O)CCC1=O>C1COCC1>[CH3:4][NH:7][C:25](=[O:27])[C@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:16]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])NCc1ccccc1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 16 h

Procedure:
DCC (3.02 g) was added to a solution of L-phenylalanine-N-benzylcarbamate (4.00 g) and N-hydroxysuccinimide (1.69 g) in dry THF (35 ml) at 0° C. The mixture was stirred at that temperature for 16 h and filtered through Celite. To the filtrate was added aqueous methylamine (40% aq., 5 ml) and the mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo and the crude material (6.01 g) was dissolved in ethanol (250 ml). A suspension of 10% palladium on carbon in H2O (ca 2 ml) was added to the ethanol solution in a bomb. The mixture was stirred in the presence of hydrogen at 724 kPa (105 psi) for 18 h. The solution was filtered through Celite and the filtrate was evaporated in vacuo. The residue was partioned between 1N hydrochloric acid (110 ml) and dichloromethane (50 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (50 ml). The aqueous layer was basified with 3N sodium hydroxide solution to pH ~14 and extracted with dichloromethane (3×50 ml). The latter extracts were combined, dried (Na2SO4), filtered and evaporated, to give the title compound as a colourless viscous oil which solidified under high vacuum (2.24 g).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+].O>CS(C)=O.C1COCC1>[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: ICC1CCc2ccccc2C1
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(O)c1cccc(OCC2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.3 %

Procedure:
A mixture of 4.0 g (0.018 mol) 2-(iodomethyl)-1,2,3,4-tetrahydronaphthalene, 3.4 g (0.018 mol) 3-(1-hydroxyhexyl)phenol and 3.4 ml NaOH (5N) in 50 ml DMSO and 20 ml THF was stirred at room temperature for a period of 48 hours. The reaction mixture was concentrated under reduced pressure. The concentrated reaction mixture was poured into water and extracted with ether. The ether extract was washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue was passed through a silica gel comumn using hexane/ethyl acetate (3:1) as eluent. Evaporation of eluent gave an oily product (1.3 g).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[O:26])=[C:16](OS(CC)(=O)=O)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40]>C1COCC1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[O:26])=[C:16]([N:41]([CH2:42][CH3:43])[CH2:39][CH3:40])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: CCS(=O)(=O)OC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: C1CCOC1
Product: CCN(CC)C1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
p-Methoxybenzyl 7-phenoxyacetamido-3-diethylamino-3-cephem-4-carboxylate is prepared with p-methoxybenzyl 7-phenoxyacetamido-3-ethylsulfonyloxy-3-cephem-4-carboxylate and diethylamine in THF.
Reaction SMILES: [CH2:1]1[CH2:5]O[CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]=O)[C:11]([S:19][CH3:20])=[CH:10]2.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Ti](Cl)(Cl)Cl.[Zn].C(Cl)(Cl)Cl>[CH3:3][C:2]1[CH:8]=[C:9]2[C:14](=[CH:5][CH:1]=1)[CH:13]=[C:12]([CH:17]=[CH:17][C:12]1[C:11]([S:19][CH3:20])=[CH:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([CH3:6])[CH:8]=3)[CH:13]=1)[C:11]([S:19][CH3:20])=[CH:10]2
Reactant: C1CCOC1
Reactant: CSc1cc2cc(C)ccc2cc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CSc1cc2cc(C)ccc2cc1C=Cc1cc2ccc(C)cc2cc1SC
Temperature: 25 °C
Reaction time: 19 h
Yield: 62 %

Procedure:
Air in a 200 ml three-neck flask equipped with a dropping funnel and a reflux tube was replaced with nitrogen, and THF (31 ml) was added into the three-neck flask. While the flask was being cooled in ice bath, TiCl4 (0.35 ml, 3.2 mmol) was dropped into the flask, and subsequently zinc powder (209 mg, 3.2 mmol) was added therein. An obtained reaction solution was refluxed for 2 hours. After that, an anhydrous THF (15 ml) solution of 6-methyl-3-methylthio-2-naphthaldehyde (230 mg, 1.1 mmol) was slowly dropped into the reaction solution, and the reaction solution was refluxed for 20 hours. The reaction solution was then cooled down to a room temperature, a saturated sodium carbonate aqueous solution and chloroform were added thereto and stirred for 19 hours, and the reaction solution was filtrated so that an insoluble solid was removed. An obtained filtrate solution was extracted with chloroform, and a resultant organic layer was dried with anhydrous magnesium sulfate. A solvent was then removed therefrom by use of a rotary evaporator. An obtained yellow solid was separated and purified by silica gel column chromatography (methylene chloride solvent, column diameter: 3 cm, column length: 20 cm) so as to obtain 1,2-bis(6-methyl-3-methylthio-2-naphthyl)ethylene (131 mg, 0.33 mmol, 62%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[C:31]([C:33]([O:35]CC)=[O:34])[CH:30]=[CH:29][C:28]=2[N:38]2[CH:42]=[CH:41][C:40]([CH3:43])=[N:39]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[C:31]([C:33]([OH:35])=[O:34])[CH:30]=[CH:29][C:28]=2[N:38]2[CH:42]=[CH:41][C:40]([CH3:43])=[N:39]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: CCOC(=O)c1ccc(-n2ccc(C)n2)c([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2ccc(C(=O)O)cc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 23) using the LiOH general method provides the title compound as a white solid.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:5]=1[C:6](C1C=CC=CC=1)=[O:7]>S(=O)(=O)(O)O>[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:5]=1[C:6]([OH:7])=[O:1]
Reactant: O=C(c1ccccc1)c1cc(F)c(F)cc1Cl
Reactant: OO
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 7 h
Yield: 58.9 %

Procedure:
32 g of 20% hydrogen peroxide solution are added dropwise over 30 min to a solution of 37.8 g (0.15 mol) of 2-chloro-4,5-difluorobenzophenone in 400 g of 100% sulfuric acid in such a way that the temperature remains below 35° C. The reaction is complete after 7 h. The reaction mixture is then poured on to 1200 g of ice. Extraction of the mother liquor with methyl tert-butyl ether, isolation of the crude product from the extract and crystallization from water gives 17.0 g (0.0883 mol, 88%) of colorless 2-chloro-4,5-difluorobenzoic acid melting at 104.4°-105.8° C.
Reaction SMILES: [N+](C1C=CC([C:10]2[CH:22]=[C:21]([C:23]([O-:25])=O)[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:26])[CH:18]=4)[N:13]([CH3:27])[C:12]=3[C:11]=2[O:28][CH3:29])=CC=1)([O-])=O.[Cl:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([Cl:38])[C:36]=1[NH2:37].[H-].[Na+]>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([Cl:38])[C:36]=1[NH:37][C:23]([C:21]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:26])[CH:18]=3)[N:13]([CH3:27])[C:12]=2[C:11]([O:28][CH3:29])=[CH:10][CH:22]=1)=[O:25]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1c(-c2ccc([N+](=O)[O-])cc2)cc(C(=O)[O-])c2c3cc(Cl)ccc3n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(Cl)ccc3n(C)c12
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 4-nitrophenyl-6-chloro-1-methoxy-9-methyl-9H-4-carbazole carboxylate (160 mg, 0.4255 mmoles), and 3,5-dichloro-4-amino pyridine (69.36 mg, 0.4255 mmoles) in dry DMF (7 mL) at 25° C., sodium hydride 55% (34 mg, 0.8510 mmoles) was added and stirred under nitrogen atmosphere for 1 hr. The reaction mixture was quenched in ice cold water (25 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with bicarbonate (2×25 mL), followed by 1N HCl (2×25 mL) and with brine (25 mL), dried over sodium sulphate and concentrated to give the 90 mg of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8](Cl)[N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H].O.O.O.C([O-])(=O)C.[Na+]>CO.[Pd]>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1ncc(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1

Procedure:
A solution of 21.8 g (47.5 mmol) of tert-butyl 2-[4-(2-butyl-4-chloro-5-formyl-imidazol-1-yl-methyl)phenyl]-2-cyclopentyl-acetate in 200 ml of methanol is hydrogenated at a hydrogen pressure of about 2 bar for 1 h at 25° C. in the presence of 2.18 g of palladium on active carbon (5% strength) and 6.47 g (47.5 mmol) of sodium acetate trihydrate. The solution is then filtered off from the catalyst and concentrated, and the residue is chromatographed on silica gel 60 using ethyl acetate/petroleum ether (1:1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N+:6]([O-])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([OH:3])=[O:2].[C-]#N.[Na+].[CH2:20]([N:22](CC)CC)C.Cl[Si](C)(C)C>CN(C)C=O>[C:1]([C:4]1[C:9]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][C:7]([C:20]#[N:22])=[N:6][CH:5]=1)([OH:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1c[n+]([O-])ccc1C1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C2CCCCC2)c(C(=O)O)cn1

Procedure:
4-Cyclohexylnicotinic acid hydrochloride (4.5 g, 0.018 mol) is dissolved in methylene chloride (40 ml). This solution is mixed with a cold solution of metachloroperbenzoic acid (10.82 g, 0.063 mol) in CH2Cl2 (80 ml), and the resulting mixture is stirred at room temperature overnight. The precipitate obtained is filtered and the filtrate evaporated to dryness. The residue is suspended in ether. The precipitate is filtered, washed with ether and dried to yield 3-carboxy-4-cyclohexyl-pyridine N-oxide, m.p. 168°-169°. (c) To a solution of 3-carboxy-4-cyclohexyl-pyridine N-oxide (3.09 g, 0.014 mol), sodium cyanide (2.47 g, 0.05 mol) and triethylamine (7.08 g, 0.07 mol) in absolute dimethylformamide (50 ml), chlorotrimethylsilane (7.6 g, 0.07 mol) is added. The reaction mixture is then heated for 28 h at 85°. After cooling, the inorganic salts are filtered, washed with diethyl ether, and the filtrate is evaporated at 50° in vacuo. The dark residue is purified by chromatography on Florisil® (ethyl acetate/methanol 4:1) to yield 5-carboxy-2-cyano-4-cyclohexyl-pyridine; m.p. 225°-230°, Rf =0.55.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(N(CC)CC)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:9]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:10])[CH:12]=1
Reactant: CC(Nc1ccc(Cl)cc1)c1cccnc1
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCC(=O)N(c1ccc(Cl)cc1)C(C)c1cccnc1

Procedure:
To a stirred solution of 7.5 g. of N-(4-chlorophenyl)-[1-(3-pyridyl)ethyl]amine in 200 ml. of toluene containing 5.0 g. of triethylamine were added dropwise over thirty minutes 4.5 g. of hexanoyl chloride. Following the complete addition, the solid precipitate which had formed was removed by filtration, and the solvent was removed from the filtrate by evaporation under reduced pressure. The product thus formed was chromatographed over a silica gel column to provide, after removal of the solvent from the appropriate factions, 650 mg. of N-[1-(3-pyridyl)ethyl]-N-(4-chlorophenyl)hexanamide. Oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]2[OH:17])[CH:3]=1.O.[C:19]1(C)[CH:24]=CC(S(O)(=O)=O)=C[CH:20]=1.COC(OC)(C)C>CO>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[C@@H:10]3[O:17][C:19]([CH3:24])([CH3:20])[O:16][C@@H:11]3[C@@H:12]([CH2:14][OH:15])[CH2:13]2)[CH:3]=1
Reactant: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: COC(C)(C)OC
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(Cl)ncn3)[C@@H]2O1
Yield: 45.9 %

Procedure:
A solution of (1R,2S,3R,5R)-3-[(6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diol (255 mg, 0.982 mmol), p-toluenesulfonic acid monohydrate (187 mg, 0.982 mmol) and 2,2-dimethoxypropane (0.670 mL, 0.545 mmol) in MeOH (5.00 mL) was stirred overnight. The reaction was quenched via addition of saturated aqueous NaHCO3 solution (10 mL) and MeOH was removed in vacuo. The aqueous mixture was extracted with DCM (4×20 mL) and the combined organics were concentrated in vacuo. The crude mixture was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (135 mg, 45.8%). LC/MS: Rt=1.77 min, ES+ 300. (AA standard).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccccc1Nc1nc(Cl)nc2ccccc12
Product: COc1ccccc1N(C)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (72% yield). 1H NMR (CDCl3): 7.72 (d, J=8.1 Hz, 1H), 7.54 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.20 (dd, J=8.4 and 1.8 Hz, 1H), 6.87-7.04 (m, 4H), 3.67 (s, 3H), 3.56 (s, 3H).