Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(C)=CC=CC=1C.[F:9][C:10]([F:23])([F:22])[S:11]([O:14]S(C(F)(F)F)(=O)=O)(=[O:13])=[O:12].[Cl:24][C:25]1[CH:33]=[C:29]([C:30]([OH:32])=[O:31])[C:28](O)=[C:27]([N+:35]([O-:37])=[O:36])[CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([N+:35]([O-:37])=[O:36])[C:28]([O:14][S:11]([C:10]([F:23])([F:22])[F:9])(=[O:13])=[O:12])=[C:29]([CH:33]=1)[C:30]([OH:32])=[O:31]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Yield: 95.2 %

Procedure:
2,6-Lutidine (1.83 ml, 15.7 mmol) and trifluoro-methanesulfonic anhydride (3.67 g, 13 mmol) were added dropwise in turn to a solution of methyl ester of 5-chloro-3-nitrosalicylic acid (2.32 g, 10.0 mmol) in methylene chloride (25 ml) with stirring under ice cooling and the mixture was stirred under ice cooling for 0.5 hrs. Methylene chloride (20 ml) and ice water (30 ml) were added to the reaction mixture and the aqueous layer was separated and extracted with methylene chloride. The organic layers were combined, washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10) to give methyl ester of 5-chloro-2-trifluoromethanesulfonyloxy-3-nitrobenzoic acid (3.33 g, 91%) as a pale yellow oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[H-].[Na+]>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(OCCCCCn2ccnc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCCCCCn2ccnc2)cc1

Procedure:
To a solution of 2.46 g p-[5-(1-imidazolyl)pentyloxy]phenol and 1.2 ml ethyl bromoacetate in 25 ml anhydrous N,N-dimethylformamide, was added under ice cooling and with stirring 440 mg of 60% sodium hydride in oil, and stirring was continued at room temperature for ten minutes. The solvent was distilled off, the residue was dissolved in chloroform, and the solution was washed with water and dried over anhydrous sodium sulfate. After distilling off, the chloroform, the residue was purified by silical gel column chromatography, affording 2.7 g of ethyl p-[5-(1-imidazolyl)pentyloxy]phenoxyacetate as oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:33][CH2:34][CH3:35]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:33][CH2:34][CH3:35])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a stirred solution of 1.0 g (0.0033 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) and 10 mL of dimethylformamide was added 3.23 g (0.0099 mole) cesium carbonate followed by 0.8 mL (0.0099 mole) of 1-iodopropane. The mixture was stirred at room temperature for 18 hours, then water was added. After 15 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium metabisulfite solution and then brine. The aqueous layers were reextracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexanes-dichloromethane to give 1.0 g of 2-Chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:32][C:33]1[C:34]([CH3:50])=[CH:35][C:36]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:37]([CH:41]=1)[C:38](O)=[O:39]>CN(C)C=O>[Br:32][C:33]1[C:34]([CH3:50])=[CH:35][C:36]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:37]([CH:41]=1)[C:38]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:39]
Reactant: Nc1cccnc1
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)c(C(=O)Nc2cccnc2)cc1Br
Reaction time: 8 h

Procedure:
3-Aminopyridine (193 mg, 2.06 mmol), and HATU (852 mg, 2.24 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 9; 600 mg, 1.87 mmol) in N,N-dimethylformamide (10 ml). The reaction was stirred overnight and the solid was filtered. Solvent was removed in vacuo and water was added. The solid was filtered and washed with ethyl acetate (10 ml) to give a white solid. The products were combined to yield the title compound as an off white solid. 508 mg.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+].[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[C:22]([O:28][CH2:29][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C@@H:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc([C@@H](C)c2nccn2COC(=O)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the compound of Example 1 (120 mg, 0.6 mmol) and potassium carbonate (246 mg, 1.8 mmol) in dimethylformamide (4 ml) was added chloromethyl pivalate (215 μl, 1.5 mmol) and the reaction mixture stirred at room temperature overnight. Water (10 ml) was added and the mixture then extracted with ethyl acetate (2×10 ml). The organic layers were combined, washed with water (10 ml) and brine (10 ml), dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([NH:13][C:14]2[N:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([O:18]CC)=[O:17])=[CH:11][C:10]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:9]1.O.[OH-].[Li+].Cl>C(O)C.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([NH:13][C:14]2[N:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([OH:18])=[O:17])=[CH:11][C:10]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[N:9]1
Reactant: CCOC(=O)c1cccnc1Nc1cc(-c2ccc(F)cc2)nn1-c1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccnc1Nc1cc(-c2ccc(F)cc2)nn1-c1ccccc1Cl
Temperature: 40 °C
Yield: 98.9 %

Procedure:
To a solution of ethyl 2-{[1-(2-chlorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}nicotinate (410 mg, 0.94 mmol) in a mixture of ethanol (4 mL) and THF (4 mL) was added lithium hydroxide monohydrate (115 mg, 2.74 mmol) in water (8 mL), and the mixture was then heated to 40° C. for 1 h. The reaction mixture was cooled to rt, and the pH of the solution was adjusted to 5 by addition of 0.5 N hydrochloric acid solution (the mixture turned cloudy). The solid was filtered off and washed with more water. The solid was dried in a vacuum oven at 60° C. to give 380 mg of the desired product (99%). 1H NMR (300 MHz, CD2Cl2) δ 10.18 (s, 1H), 8.45 (dd, 1H), 8.24 (dd, 1H), 7.87 (dd, 2H), 7.47-7.62 (m, 4H), 7.23 (s, 1H), 7.12 (t, 2H), 6.85 (dd, 1H); ES-MS m/z 351.2 (MH+); HPLC RT (min) 2.58.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14]C1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Sn](C)(C)(C)C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Sn](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])cc2ccoc12
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
7-Iodo-5-nitro-benzofuran (6.5 g, 22.1 mmol), Pd(OAc)2 (1 g, 3.9 mmol), P(o-tolyl)3, Me4Sn, Et3N were dissolved in DMF (40 mL) and portioned out in 13 tubes and heated at 100° C. for 10 min each using controlled microwave energy. The reaction mixtures were combined and filtered and the solvent was evaporated. The crude material was purified using flash chromatography (using a gradient of isohexane—10% EtOAc in isohexane). Yield: 2.82 g (70%) of 7-methyl-5-nitro-1-benzofuran. 1H NMR (400 MHz, CDCl3) δ ppm 2.51-2.64 (m, 3H) 6.90 (d, J=2.3 Hz, 1H) 7.77 (d, J=2.3 Hz, 1H) 8.04 (d, J=1.3 Hz, 1H) 8.37 (d, J=2.3 Hz, 1H); HPLC 96% Rt=2.31 min (System A; 10-97% in 3 min ACE column). MS (ESI+) for C9H7NO3 m/z 178 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14](=[O:49])[C@H:15]([CH2:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1)[NH:16][C:17](=[O:37])[C@H:18]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1>>[CH3:12][O:13][C:14](=[O:49])[C@H:15]([CH2:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1)[NH:16][C:17](=[O:37])[C@H:18]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:22]=1
Reactant: COC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(N)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: COC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C#N)cc2)c1
Yield: 56 %

Procedure:
By coupling 4-cyanobenzoic acid with N-[N-(m-aminobenzoyl)-3-(t-butoxycarbonyl)-L-alanyl]-3-(1-naphthyl)-L-alanine methyl ester there is obtained N-[3-(t-butoxycarbonyl)-N-[m-(p-cyanobenzamido)benzoyl]-L-alanyl]-3-(1-naphthyl)-L-alanine methyl ester, yield: 56% of theory, MS: 649 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(NC(C)C)(C)C.[Li]CCCC.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:24]([CH3:26])([CH3:25])[CH3:23])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1ccccc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc(Br)c1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
2-Bromobenzoic acid (30.15 g, 150 mmol), THF (400 mL), and diisopropyl amine (33.4 g, 330 mmol) were stirred under nitrogen and cooled to −78° C. 10M n-BuLi in hexanes (31 mL, 0.31 mol) was then added dropwise, followed by the dropwise addition of TMSCl (17.4 g, 160 mmol). The mixture was allowed to slowly warm to −30° C., stirred for 1 h, then was poured into 25% citric acid (100 mL) and stirred for 15 min. The mixture was extracted with two 100 mL portions of ether, which were ombined and washed three times with sat aq NaHCO3 olution. The bicarbonate solution was acidified with 5% citric acid and extracted with three 100 mL portions of ether. These extracts were combined, dried (MgSO4), and concentrated. The crude product was purified by recrystallization from ether/hexanes, and the desired product was recovered as a white solid in 35% yield. m.p. 139-141° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C(=O)(OC)OC>[CH3:21][S:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COC(=O)OC
Product: COc1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 75.8 %

Procedure:
15.0 g (83.2 mmol) of 4-hydroxy-3-tert-butylanisole and 10.5 g (104 mmol) of triethylamine were dissolved in 250 ml of dimethyl carbonate (solvent), and 11.9 g (104 mmol) of methanesulfonyl chloride was dropwise added thereto, taking 25 minutes and controlling the inner temperature at 5° C. or lower. After the addition, this was stirred at 25° C. for 1.5 hours, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution, the aqueous layer was separated, the organic layer was washed twice with water, and then the organic layer was separated and concentrated. The concentrate was purified through distillation (139° C./32 pa) to give 16.3 g of 2-tert-butyl-4-methoxyphenyl methanesulfonate (yield, 76%).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].C([O-])(=O)C.[Na+].Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)(=O)C>[OH:20][C:13]1[CH:12]=[CH:1][CH:2]=[C:3]([CH3:4])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: C/C=C/C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)cccc1O
Temperature: 25 °C
Yield: 65 %

Procedure:
A stirred mixture of crotonaldehyde (21.0 g, 0.30 mol) and anhydrous sodium acetate (25.0 g, 0.30 mol) in glacial acetic acid is heated to reflux temperature under N2, treated dropwise with ethyl chloroacetoacetate (41.1 g, 95%, 0.25 mol) over a 2.25 hr. period, heated at reflux temperature for 16 hr., cooled to room temperature and concentrated in vacuo to give a residue. The residue is partitioned between ethyl acetate and water. The organic phase is diluted with hexanes, washed sequentially with water and aqueous NaHCO3 and concentrated in vacuo to give the title product as an oil, 41.0 g, 71.4% purity (65% yield), characterized by NMR analysis.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:17])([CH3:16])[O:4][C:5]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:6]=12.[Na].[S:19]1(=[O:25])(=[O:24])[CH2:23][CH2:22][CH2:21][NH:20]1.O>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([N:20]2[CH2:21][CH2:22][CH2:23][S:19]2(=[O:25])=[O:24])[C:6]2[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][C:3]1([CH3:17])[CH3:16]
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2C2OC21
Reactant: O=S1(=O)CCCN1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N2CCCS2(=O)=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
To a solution of 3,4-dihydro-3,4-epoxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (1.5 g) in dimethyl sulfoxide (30 ml) was added sodium salt of isothiazolidine 1,1-dioxide (1.7 g). The mixture was stirred at room temperature overnight. Water was carefully added to the reaction mixture and the whole was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (50 g) with a mixture of chloroform and methanol (50:1) as eluents to give trans-3,4-dihydro-3-hydroxy-4-(1,1-dioxoisothiazolidin-2-yl)-6-mesyl-2,2-dimethyl-2H-1-benzopyran (0.47 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.OS(O)(=O)=O.CCOC(C)=O>C1COCC1.O>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
To 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzonitrile (460 mg, 1.88 mmol, reference example 117) dissolved in THF (2 mL) was added 10% H2SO4 (4 mL) and the reaction was stirred for 24 h at room temperature. TLC (40% EtOAc in hexanes) shows a small amount of starting material, but mainly a more polar product. The reaction was diluted with water, extracted with dichloromethane (3×), washed with saturated aqueous NaCl solution, dried with Na2SO4, filtered and evaporated. The crude product was chromatographed on silica gel (20-40% EtOAc in hexanes) to afford the title compound (315 mg, 84%). 1H NMR (CDCl3): δ 7.52 (d, 2H), 6.88 (d, 2H), 3.72 (t, 4H), 2.57 (t, 4H). MS (ion spray) m/z 200 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10](Cl)=[N:9][C:8]=2[CH:13]=1)(=[O:3])[CH3:2].[SH2:14].[K].Cl>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10](=[S:14])[NH:9][C:8]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: S
Reactant: CC(=O)c1ccc2sc(Cl)nc2c1
Agent: Cl
Agent: [K]
Solvent: CCO
Product: CC(=O)c1ccc2sc(=S)[nH]c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A mixture of 5-acetyl-2-chlorobenzothiazole (137 mg, 0.65 mmol), potassium hydrogen sulfide (94 mg, 1.30 mmol) and ethanol (3.3 mL) in a capped flask was stirred in an oil bath at 80° C. for two hours. The mixture was cooled in ice, acidified with 1N hydrochloric acid (1.35 mL) and evaporated in vacuo. The residue was partitioned between water (25 mL) and ethyl acetate (50, 25 mL). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to a solid (133 mg). This material was triturated with ether and dried to provide 5-acetyl-2-thioxo-2,3-dihydrobenzothiazole (110 mg) as a pale yellow solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:17]2[CH2:16][CH2:15][C@@:12]2(C=O)[C@H:8]3[C@@H]3C[C@@H]3[CH2:11]2)[CH2:3]1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[O:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>C(OCC)C>[CH2:41]1[C@@H:43]2[C@H:44]([OH:40])[C@:12]3([CH2:15][CH2:16][C@H:17]4[C@@H:7]([CH2:6][CH:5]=[C:4]5[C@:18]4([CH3:21])[CH2:19][CH2:20][C@H:2]([OH:1])[CH2:3]5)[C@@H:8]3[C@H:42]12)[CH3:11]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@H]1[C@@H]3[C@@H]4C[C@@H]4C[C@@]3(C=O)CC[C@@H]12
Reactant: C1CCOC1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1[C@@H]1C[C@@H]1[C@@H]2O

Procedure:
A solution of 21 g of 3β-hydroxy-15β,16β-methylene-5-androsten-18-one in 210 ml of tetrahydrofuran was stirred with 21 g of lithium tri-tert.-butoxyaluminohydride for 1 hour at room temperature. The mixture was then diluted with diethyl ether, washed with 2N sulfuric acid and water, dired, and evaporated, thus obtaining 19 g of 15β,16β-methylene-5-androstene-3β,17β-diol, used without further purification in the subsequent stage.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([Cl:12])=[O:11])=[N:2]1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH2:24][CH2:23]2)=[N:14]1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[ClH:12].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:10]([C:3]3[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[S:1][N:2]=3)=[O:11])[CH2:26][CH2:27]2)=[N:14]1
Reactant: NCCCCN1CCN(c2nsc3ccccc23)CC1
Reactant: O=C(Cl)c1nsc2ccccc12
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(NCCCCN1CCN(c2nsc3ccccc23)CC1)c1nsc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
A mixture of 1,2-benzisothiazole-3-carboxylic acid chloride (2.6 g), 1-(1,2-benzisothiazol-3-yl)-4-(4-aminobutyl)piperazine (3.45 g), and triethylamine (5 ml), in sieve-dried toluene (100 ml) was heated to 80° C., with stirring, overnight. After 24 hr, the reaction mixture was cooled to room temperature and added to water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The ethyl acetate extracts and the toluene phase were combined and dried anhydrous over magnesium sulfate. The organic phase was filtered and the filtrate concentrated in vacuo. The residue was chromatographed on silica using ethyl acetate. The appropriate fractions were collected and concentrated in vacuo. The residue was taken up in ether and hydrogen chloride in ether was added. The precipitate was recrystallized from dichloromethane/ether and dried (0.1 mm mercury, refluxing isopropanol alcohol temperature) to provide 1.60 g (27.1%) of product, mp 203°-205° C.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[NH:18][C:17](=[O:22])[C:16]3[NH:23][CH:24]=[CH:25][C:15]=3[C:14]=2[CH:13]=1.Cl.[CH2:27]([C:29]([OH:31])=[O:30])[CH3:28].C(N(CC)CC)C>CN(C)C=O>[CH:1]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[NH:18][C:17](=[O:22])[C:16]3[NH:23][CH:24]=[CH:25][C:15]=3[C:14]=2[CH:13]=1)=[O:2].[CH2:27]([C:29]([O-:31])=[O:30])[CH3:28]
Reactant: O=CO
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCC(=O)O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)[O-]
Product: O=CNc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
74 μL (1.95 mmol) of formic acid is added slowly to 153 μL (1.63 mmol) of acetic anhydride cooled on an ice bath, then the reaction mixture is stirred for 2 hours at 60° C. The mixture is cooled to room temperature then added to a solution of 500 mg (1.63 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) dissolved in 5 mL of anhydrous dimethylformamide and 460 μL (3.25 mmol) of triethylamine. The reaction mixture is stirred for 2 hours at 60° C. The solvent is evaporated and the residue is triturated in hot methanol to give 359 mg (74%) of 8-formylamino-4-oxo-4,5-dihydro-3H -pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a pale pink solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:40]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:43])[NH:41][NH2:42].O>CN(C)C=O.C(OCC)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:24][C:25]([NH:42][NH:41][C:40]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)N1CCN(c2ccc(CCc3cccc(CC(=O)O)c3)nc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(CCc3cccc(CC(=O)NNC(=O)OC(C)(C)C)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
To a suspension of (3-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)acetic acid (213.4 mg, 0.581 mmol) in anhydrous N,N-dimethylformamide (3 ml) was added 1,1′-carbonyldiimidazole (188.9 mg, 1.165 mmol), and the mixture was stirred at room temperature for 1.5 hrs. tert-Butyl carbazate (460.3 mg, 3.483 mmol) was added, and the mixture was stirred at room temperature for 14 hrs. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred, stood still and partitioned. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified 3 times by silica gel column chromatography (ethyl acetate→methanol: dichloromethane=1:15, methanol:dichloromethane=1:20, methanol:dichloromethane=1:20) to give tert-butyl 2-[(3-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)acetyl]hydrazinecarboxylate (219.4 mg, yield 78.4%) as a white solid.