Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-].[Na+].[CH3:18][C:19]([C:21](Cl)=[O:22])=[CH2:20].Cl>O.C(OCC)(=O)C>[C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:22])[C:19]([CH3:20])=[CH2:18]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In 9 l of water at 30° C. were dissolved 218 g of 12-aminododecanoic acid and 100 g of sodium hydroxide (purity: 93%), and 102 ml of methacryl chloride was added thereto over 1 hour while stirring. The reaction mixture was stirred for 2 hours and then heated to 60° C., at which 3 l of ethyl acetate and 300 ml of concentrated hydrochloric acid were added thereto successively. The mixture was filtered while hot (60° C.) to remove any insoluble matter, followed by liquid-liquid separation. The organic layer was dried over 30 g of magnesium sulfate and, after removal of the magnesium sulfate, cooled to 10° C., at which 6 l of n-hexane was added, whereupon a precipitate was formed. The precipitate was collected by filtration and thoroughly washed with 1 l of n-hexane. Recrystallization of the precipitate from 500 ml of ethyl acetate yielded 128 g of 12-methacryloylaminododecanoic acid.
Reaction SMILES: C(O[C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])=O)(C)(C)C.CCO.[CH2:22]([O:24][C:25](=[O:35])[CH2:26][C:27](=CN(C)C)[C:28](=O)[CH3:29])[CH3:23]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:22]([O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:6]=[N:8][N:9]([CH2:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[OH:18])[C:28]=1[CH3:29])[CH3:23]
Reactant: CCOC(=O)CC(=CN(C)C)C(C)=O
Reactant: CC(C)(C)OC(=O)NNCc1cc(Br)ccc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)Cc1cnn(Cc2cc(Br)ccc2O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A suspension of N′-(5-bromo-2-hydroxy-benzyl)-hydrazinecarboxylic acid tert-butyl ester 1 1 g (3.1 mmol) in a mixture of CH2Cl2 (8 mL) and TFA (8 mL) was stirred at RT for 2 hours. The volatiles were removed in vacuo. The residue was dissolved in abs. EtOH (7 mL) and added to 3-[1-dimethylamino-methylidene]-4-oxo-pentanoic acid ethyl ester (4.8 mmol) at RT. The resulting mixture was stirred at RT for 1 hour, refluxed for 2 h, let cool down and stirred at RT for 16 h. The oily residue obtained after removing the volatiles in vacuo was purified by MPLC (10 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) to give 0.18 g of [1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-4-yl]-acetic acid ethyl ester, 2.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.O[N:35]=[C:36]([NH2:44])[CH2:37][S:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:44]=[C:36]([CH2:37][S:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[N:35]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC(CSc1cccs1)=NO
Product: CON=C1C[C@@H](c2nc(CSc3cccs3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and N′-hydroxy-2-(2-thienylsulfanyl) ethanimidamide, the title compound was obtained in 81% purity by HPLC. MS(ESI+): m/z=491.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=O)[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>O=P(Cl)(Cl)Cl>[Cl:15][C:6]1[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:13])([CH3:1])[N:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1(C)NC(=O)c2ccccc2O1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)N=C(Cl)c2ccccc2O1
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a solution of 2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one (100 g, 0.56 mol) in POCl3 (500 mL) was added PCl5 (170 g, 0.84 mol) at the room temperature. The mixture was hearted at 60° C. overnight. The solvent was removed by distillation under atmospheric pressure and the residue was distilled under reduced pressure (85-86° C., 2.5 mmHg) to give 4-chloro-2,2-dimethyl-2H-benzo[e][1,3]oxazine (50 g, 45%). 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J=1.6, 8.4 Hz, 1H), 7.38 (dt, J=1.6, 8.0 Hz 1H), 6.95 (t, J=6.8 Hz 1H), 6.79 (d, J=8.0 Hz 1H), 1.61 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:15]([O:17][CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:42][CH2:41][NH:40][CH2:39]2)[CH2:32][CH2:31]1)[CH3:16]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([N:40]1[CH2:41][CH2:42][C:38]([CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][CH:30]([NH:29][C:21]3[N:20]([CH2:19][CH2:18][O:17][CH2:15][CH3:16])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=3)[CH2:31][CH2:32]2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:39]1)=[O:7]
Reactant: COc1ccc(C#N)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C#N)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-cyanobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.Cl.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1NCc1ccccc1
Yield: 57.1 %

Procedure:
To a solution of benzyl-(2-nitro-phenyl)-amine (1068) (2.5 g, 10.43 mmol) in ethanol (150 mL) and water (10 mL) was added iron (8.7 g, 155.7 mmol) followed by 30 drops of concentrated HCl, and the resulting mixture was heated overnight at reflux. The reaction mixture was quenched with water, diluted with DCM and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to give a brown oily residue. Further purification by column chromatography (SiO2, 20% ethyl acetate/hexanes) afforded N-benzyl-benzene-1,2-diamine (1069) as a dark yellow oil (1.18 g, 57%). 1H NMR (400 MHz, CDCl3) 7.41-7.24 (m, 5H), 6.82-6.67 (m, 4H), 4.32 (s, 2H), 3.56 (b, 3H, NH).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[C:20]([C:36]#[N:37])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=[O:17])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[NH2:8][C@H:9]([CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[C:20]([C:36]#[N:37])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=[O:17])[C:10]([OH:12])=[O:11].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(C(=O)NCC[C@@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-2-(tert-Butoxycarbonylamino)-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)butanoic acid (40 mg, 0.06 mmol) was dissolved in TFA (4 mL) and CH2Cl2 (4 mL). The resulting mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was dissolved again in CH2Cl2 (4 mL). The volatiles were removed again in vacuo to give the title compound as its TFA salt in 19 mg. MS: (−) m/z 405.27 (M−1).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CO.[Pd]>[CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]([OH:10])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of tert-butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (0.63 g, 2.5 mmol) and triethylamine (0.65 mL, 5 mmol) in methanol (15 mL) was added Pd/C (0.1 g), and the mixture was hydrogenated under 30 psi pressure at rt overnight. The mixture was filtered and the filtrate was concentrated to give tert-butyl (2S,3R)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.44 g, 70%). 1H NMR (400 MHz, CDCl3): 4.48 (brs, 1H), 3.78 (m, 2H), 2.30 (brs, 1H), 1.82 (m, 1H), 1.66 (m, 4H), 1.45 (s, 9H), 1.40-1.00 (m, 6H), 1.10 (d, J=6.4 Hz, 3H), 1.00-0.70 (m, 2H); MS (E/Z): 272 (M+H+).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([S:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.O.[NH2:25][CH2:26][CH2:27][CH2:28][NH2:29]>>[NH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:2]1[C:6]2[CH:7]=[C:8]([S:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: NCCCN
Reactant: COc1ccc(CNS(=O)(=O)c2ccc3snc(Cl)c3c2)cc1
Solvent: O
Product: COc1ccc(CNS(=O)(=O)c2ccc3snc(NCCCN)c3c2)cc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A solution of 3-chloro-N-(4-methoxybenzyl)benzo[d]isothiazole-5-sulfonamide (52 mg, 0.1 mmol) in 1,3-diaminopropane (1 mL) was allowed to stir at room temperature for 80 min. The dark brown reaction mixture was then poured over water (10 mL) and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 3-(3-aminopropylamino)-N-(4-methoxybenzyl)benzo[d]isothiazole-5-sulfonamide (57 mg) as an orange oil. 1H NMR (300 MHz, CD3OD): 8.22 (dd,1H), 7.54 (dd, 1H), 7.29 (dd, 1H), 7.04 (d, 2H), 6.64 (d, 2H), 4.00 (s, 2H), 3.64 (s, 3H), 3.36 (t, 2H), 2.82 (d, 2H), 1.94-2.02 ppm (m, 2H). MW=406 confirmed by LC-MS, tr=7.95 min (Method Y) MH+=407.
Reaction SMILES: [C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ncccc1C(=O)Cl
Reactant: C1COCCN1
Product: CC(=O)c1ncccc1CN1CCOCC1

Procedure:
Following the procedures of Example 14, 2-acetylnicotinic acid chloride (1.0 g, 5.5 mmol) and morpholine (0.6 g, 6.7 mmol) are reacted together to give 4-(2-acetylnicotinyl)morpholine, which compound (1.0 g, 4.2 mmol) is then reacted with 4-(3-fluorophenyl)semicarbazide (0.7 g, 4.2 mmol) to give 4-(2-acetylnicotinyl)morpholine 4-(3-fluorophenyl)semicarbazone, m.p. 193°-195° (compound 150).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[Na].C[O-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:11]([C:6]1[N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[N:3]=[C:2]([O:1][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:12]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1c(O)nc(C(F)(F)F)nc1CC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCc1c(CC)nc(C(F)(F)F)nc1OCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 50 °C
Yield: 9 %

Procedure:
4-Hydroxy-6-ethyl-5-propyl-2-(trifluoromethyl)pyrimidine (1.2 g, 5 mmole) was converted to the sodium salt with sodium methoxide (275 mg). The sodium salt was dissolved in DMF and mixed with 2.8 g (5 mmole) of 5-(4'-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole [U.S. Pat. No. 4,870,186], and the mixture heated at 50° C. for 18 hours. The solvent was evaporated to dryness and the residue was triturated with excess water to give a gum which was extracted into EtoAc. The organic layer was washed with H2O twice, dried over Na2SO4 and evaporated to a thick oil (4 g). One gram of this oil was treated with dry HCl saturated methanol for 3 hours then evaporated to dryness. The residue was triturated with hexane twice and decanted to afford a gum. The rest of the material was treated in the same way to provide a total of 2 g of crude product. Flash chromatography through silica gel and elution with CHCl3 contg. 4% MeOH gave 210 mg of the desired compound as a white solid. TLC, Silica gel (CHCl3 -MeOH-NH4OH,7:3:2%) Rf 0.55 MS (DCI) [M+H]+ 469
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>O>[F:18][C:19]1[CH:20]=[C:21]([C:25](=[CH:14][C:13]2[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=2)[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1cccc(F)c1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ccc(C=C(C(=O)O)c2cccc(F)c2)cc1
Temperature: 120 °C
Yield: 39.1 %

Procedure:
A mixture of acetic anhydride (60 mL), 4-(methylthio)benzaldehyde (4.99 g, 33 mmol), 3-fluorophenylacetic acid (5.08 g, 33 mmol), and triethylamine (3.98 g, 39 mmol) was heated to reflux for 4 hours. The reaction was cooled to 120° C., and water (120 mL) was added through an addition funnel. A yellow precipitate formed and, after further cooling to room temperature, was collected by filtration, washed with water, and recrystallized from toluene to give the desired intermediate as a yellow solid (3.72 g, 39%): mp 184°-187° C. 1H NMR (CDCl3) 300 MHz 7.92 (s,1H), 7.35 (m, 1H), 7.26 (d, J=6.3 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H) 7.00 (m, 5H), 2.44 and 2.36 (s, 3H); 19F NMR (CDCl3) -112.61 (m). Mass spectrum M+H=289.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:17])=[O:16])[CH2:11][CH2:10]1)(C)(C)C.Cl>O1CCOCC1.C(Cl)(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][S:15]([N:12]2[CH2:11][CH2:10][CH:9]([CH2:8][NH2:7])[CH2:14][CH2:13]2)(=[O:16])=[O:17])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.4 g of {1-[2-(4-fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-carbamic acid tert-butyl ester and 5 mL of 4N HCl in dioxane was stirred at room temperature for 3 h, then diluted with 50 mL of chloroform, washed with 50 mL of saturated sodium carbonate, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The product was a white solid:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:26])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH:21]([CH3:25])[CH2:20]4)[C:16]=3F)[C:11](=[O:27])[C:10]([C:28]([OH:30])=[O:29])=[CH:9]2)[CH2:7][CH2:6]1>CO>[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:26])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH:21]([CH3:25])[CH2:20]4)[C:16]=3[O:2][CH3:1])[C:11](=[O:27])[C:10]([C:28]([OH:30])=[O:29])=[CH:9]2)[CH2:7][CH2:6]1
Reactant: C[O-]
Reactant: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 70.5 h

Procedure:
To a solution of sodium methoxide prepared from sodium (0.4 g) and absolute methanol (20 ml) was added 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (1.12 g), and, the mixture in sealed tube was stirred for 70.5 hours at 140° to 150° C. and then concentrated. The residue was dissolved in small amount of water, the resulting solution was adjusted to pH 7 with acetic acid and concentrated. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1) and recrystallized from methanol to give the title compound (0.33 g) as pale yellow prisms, mp 162° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:5][C:4]=2[N:3]=1.[H-].[Na+].Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1)C2
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(N)nc2c1C(=NOCCN(C)C)CC(c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 30, (109 mg, 0.38 mmol) in DMF (2 ml) under nitrogen was added sodium hydride (60% dispersion in oil) (18 mg, 0.44 mmol) and the mixture was stirred at ambient temperature for 10 min. 2-Dimethylaminoethylchloride hydrochloride (54 mg, 0.38 mmol) and triethylamine (52 μl, 0.38 mmol) were added to the reaction mixture, which was stirred and heated at 80° C. until complete disappearance of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime was observed by LC-MS. Ethyl acetate (5 ml) was added to the mixture and the solution was washed three times with water (3×5 ml). The organic phase was dried with MgSO4, filtered and the solvent removed under reduced pressure to furnish the title compound as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=[O:18])C.Cl.[Cl:21][CH2:22][CH2:23]Cl>O>[Cl:21][CH2:22][CH2:23][CH2:11][CH2:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)=[O:18]
Reactant: CCCCc1ccc(Cl)cc1
Reactant: CC(=O)Cl
Reactant: ClCCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(CCCCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 250 ml round-bottomed flask were added 5.0 g (29.65 mmol) 4-chlorophenylbutane and 10 ml 1,2-dichloroethane. To the stirred solution was added a solution of 4.35 g (32.62 mmol) aluminum chloride and 4.22 ml (59.31 mmol) acetyl chloride in 50 ml 1,2-dichloroethane. The solution evolved HCl as it was stirred at room temperature for 1 hour. It was then poured into water, the layers were separated, and the organic layer was washed with 1N HCl, aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated to an oil, 6.7 g (>100%). NMR (CDCl3): 1.76 (m, 4H), 2.54 (m, 3H), 2.66 (m, 2H), 3.50 (m, 2H), 7.2 and 7.85 (m, 4H). IR (cm.-1, neat): 1678 (C=O).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](Cl)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:24]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28]N[CH2:26][CH2:25]1.[CH:38](N(CC)C(C)C)(C)C>CC(O)C>[CH3:21][C@H:13]1[C:14]2[C:19]([CH:38]3[CH2:28][CH2:29][CH2:30][N:24]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:26]3)=[N:18][CH:17]=[N:16][C:15]=2[C@H:11]([O:10][C:8](=[O:9])[C:7]2[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:12]1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(C3CCCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 80 °C
Yield: 80.6 %

Procedure:
(5R,7R)-4-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (65 mg, 0.195 mmol) was dissolved in i-PrOH (5 mL), and then tert-butyl 1,4-diazepane-1-carboxylate (51 mg, 0.253 mmol) was added. N,N-Diisopropylethylamine (49 mg, 0.350 mmol) was added, and the reaction mixture was heated to 80° C. for 12 hours, after which the solvents were removed under reduced pressure. The resulting residue was taken up into EtOAc and then washed twice with water and once with brine. The organic portion was dried over magnesium sulfate, filtered, and then concentrated. The resulting residue was purified via silica gel chromatography to give tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azepane-1-carboxylate (78 mg, 81%). LCMS (APCI+) M+=498.1, Rt=3.81 min.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([Br:26])[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:3]>CO.Cl.O1CCOCC1>[Br:26][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=1)[NH:11][CH:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indol-3-yl]-1-piperidinecarboxylate (1.56 g, 3.7 mmol) in methanol (10 mL), HCl in dioxane (4M, 35.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the resulting residue was partitioned between ethyl acetate (50 mL) and 5% of aqueous NaOH (50 mL). The aqueous layer was washed with ethyl acetate (2×50 mL) and the combined organic phases were dried with MgSO4 and concentrated under reduced pressure to give the desired product (685 mg, 58%), which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:32])=[C:8]2[C:16]([C:17]#[N:18])=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+].CO>>[C:17]([C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:3])[C:7]=2[OH:32])[N:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)#[N:18]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(-c2ccc(F)cc2)n(-c2ccccc2)c2c(C#N)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3,7-dicyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 454 (M−1)−.