Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([NH2:24])=O)=[CH:16][CH:15]=1>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][NH2:24])=[CH:16][CH:15]=1
Reactant: COc1ccc(CCC(N)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCCN)cc1
Yield: 47.6 %

Procedure:
Lithium aluminium hydride (0.01 mol) and tetrahydrofuran (500 ml) were placed in a 1 liter flask fitted with a soxhlet extractor, with 3-(4-methoxyphenyl)propanamide (0.056 mol) in the extraction thimble. The reaction was refluxed 3 hours, was cooled and water (3.5 ml) was carefully added. After the mixture was sequentially extracted with 10% aqueous sodium hydroxide (3.5 ml) and water (10.5 ml), the mixture was filtered and concentrated. The crude product was distilled (Kugelrohr) to yield 4.4 g (48%) of a colorless oil which was stored under N2.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:20][CH2:21][CH2:22]C#N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH:44]([OH:46])=[O:45]>>[CH2:1]([O:17][CH2:18][CH:19]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:20][CH2:21][CH2:22][C:44]([OH:46])=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=CO
Reactant: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCC#N
Agent: Cl
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCC(=O)O
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 1,3-di-O-(n-hexadecyl)-2-O-(2-cyanoethyl)-glycerol (4.8 g., 8.1 mmoles), concentrated hydrochloric acid (50 ml.) and formic acid (50 ml.) was stirred for 16 hours at reflux, then cooled and extracted with ether (3×100 ml.). The combined ether extract was washed with water (200 ml.), dried (MgSO4), filtered and evaporated in vacuo to yield 1,3-di-O-(n-hexadecyl)-2-O-(2-carboxyethyl)-glycerol solids (4.5 g.), which were purified by silica gel chromatography (elution with toluene:ethanol) [3.5 g., 71% yield, m.p. 43°-45° C., ir (CHCl3) 1740 cm-1, n.m.r. (CDCl3) δ 3.93 (t, J=6 Hz, 2, --OCH2CH2COOH) and 2.65 (t, J=6 Hz, 2, --OCH2CH2COOH)].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(O[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])(=O)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)OCCOCOC(C)=O
Product: CC(=O)OCCOCn1cnc2c(Cl)nc(Cl)nc21
Temperature: 138 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
2,6-dichloro purine 5.5 g and 2-oxa-1,4-butanediol diacetate 513 g were placed in a flask and partially evacuated and then heated to 138° C., initially the mixture was too thick to stir but gradually gave rise to a melt which was stirred, and after 20 minutes was completely melted and the reaction mixture heated for 10 minutes more (total heat time=30 minutes). The mixture was then cooled to room temperature and para-toluenesulphonic acid 150 mg was added, the vacuum reapplied and heating resumed with stirring. After 20 minutes heating vigorous bubbling was noted, cooled to room temperature, chloroform was added and the solution extracted once with saturated aqueous sodium bicarbonate and once with water. The chloroform phase was dried over anhydrous sodium sulphate and evaporated. The residual oil dissolved in benzene applied to column of 200 g. of silica gel in benzene. Benzene elution removed acetate by products. Ether elution gave 9 isomer yield of 64%. Recrystallisation from benzene to give lustrous white flakes m.p. 96°-99° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].Br[C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([Cl:17])[CH:16]=1)[C:13](=[O:18])[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=1)[CH2:11]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.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.[Cu]I>[Cl:17][C:15]1[CH:16]=[C:8]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:9]=[C:10]2[C:14]=1[C:13](=[O:18])[N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:24][CH:25]=1)[CH2:11]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of dimethyl-prop-2-ynyl-amine (0.036 mL, 0.32 mmol), 5-bromo-7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.120 g, 0.28 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-5-(3-dimethylamino-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.095 g, 79%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 6H), 3.46 (s, 2H), 4.23 (s, 2H), 4.76 (s, 2H), 6.93-7.38 (m, 10H), 7.43 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1nccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2nccnc2Cl)cc1
Reaction time: 17.5 h
Yield: 43.6 %

Procedure:
Couple 2,3-dichloropyrazine (0.302 g, 2.03 mmol) and 4-chlorophenylboronic acid (0.320 g, 2.05 mmol), using tetrakis(triphenylphosphine)palladium(0) (0.124 g, 0.107 mmol), and potassium fluoride (0.355 g, 6.11 mmol) in toluene (19 mL) and water (5 mL), at 100° C. for 17.5 hr. Cool the reaction, partition the layers and extract the aqueous layer with ethyl acetate. Wash the combined organic layers with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 35:65 ethyl acetate:hexanes), to give 2-chloro-3-(4-chlorophenyl)-pyrazine (0.199 g, 44%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:26]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of ethyl 4-(4-aminopiperidin-1-yl)benzoate (3.0 g, 12.1 mmol) in CH2Cl2 under nitrogen was added Et3N (2.45 g, 24.2 mmol), followed by benzoyl chloride (1.70 g, 12.1 mmol). The mixture was stirred at room temperature overnight, washed with brine (200 mL), dried over anhydrous MgSO4, filtered, and concentrated. The resulting solids were triturated with hexanes to afford ethyl 4-(4-benzamidopiperidin-1-yl)benzoate as a yellow solid (4.2 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)Cl>CC(C)=O>[CH2:21]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[C:3]([O:13][CH3:14])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(CCC(=O)O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cc(CCC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Yield: 180.5 %

Procedure:
A mixture of 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid (5.1 g, 25.99 mmol), anhydrous K2CO3 (25 g, 180.88 mmol) and benzyl bromide (7.5 ml, 63.14 mmol) in anhydrous acetone (100 ml) was stirred at reflux for 7.5 h under nitrogen. After cooling, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (CH2Cl2) gave the title compound (8.83 g, 23.45 mmol, 90%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[O:4][C:3]=1[C@H:13]([OH:16])[CH2:14][OH:15].N1C=CN=C1.[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5](=[O:12])[O:4][C:3]=1[C@H:13]([OH:16])[CH2:14][O:15][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=c1oc([C@H](O)CO)c(Br)c2ccccc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H](O)c1oc(=O)c2ccccc2c1Br)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
A solution of 4-bromo-3-[(1R)-1,2-dihydroxyethyl]-1H-2-benzopyran-1-one (145 mg, 0.509 mmol) and imidazole (51.9 mg, 0.763 mmol) in N,N-Dimethylformamide (DMF) (2.4 mL) was treated with tert-butyldiphenylchlorosilane (159 μl, 0.610 mmol). After 20 min, the reaction mixture was poured into water and extracted with EtOAc. The organic phase was dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate-hexanes 0-50%) to afford the title compound (169 mg, 0.323 mmol, 64% yield) as a white foam: Rt=1.24 min, ES+ MS: 546 (M+23).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][C@H:12]([CH3:43])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH3:28])[CH:23]=[N:22][C:21]=2[N:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35]C(OCCCC)=O)[C:18]1=[O:19])(=[O:10])[CH3:9]>ClCCl>[C:8]([O:11][C@H:12]([CH3:43])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH3:28])[CH:23]=[N:22][C:21]=2[N:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:18]1=[O:19])(=[O:10])[CH3:9]
Reactant: CCCCOC(=O)NCCCCCCn1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)c2c1ncn2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCN)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Trifluoroacetic acid (30 ml) was added to a solution of (R)-1-(5-acetoxyhexyl)-3-(N-1-butyloxycarbonyl-6-aminohexyl)-7-methylxanthine (1.37 g) in dichloromethane (30 ml). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml). The solution was washed with saturated aqueous sodium bicarbonate solution (20 ml), with water (20 ml), with saturated aqueous sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine (1.073 g).
Reaction SMILES: C(N(CC)CC)C.C([C:11]1[CH:16]=[C:15](C(C)C)[CH:14]=[C:13]([CH:20]([CH3:22])C)[C:12]=1S(Cl)(=O)=O)(C)C.C[CH2:28][O:29]CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:13]1([CH2:20][C@H:22]2[CH2:28][O:29]2)[CH2:12][CH2:11][CH2:16][CH2:15][CH2:14]1
Reactant: CCOCC
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C1CCC(C[C@H]2CO2)CC1
Temperature: 0 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a solution of the product from Example 15B in CH2Cl2 was added triethylamine (6.6 mL), 2,4,6-triisopropylbenzenesulfonyl chloride (11.5 g), and DMAP (0.386 g). After 14 hours, the reaction was diluted with ether, chilled to 0° C., filtered through celite, and concentrated. The residue was dissolved in ethanol (100 mL) and 1M NaOH (32 mL) was added. After 30 minutes, the reaction was carefully concentrated, diluted with water (100 mL), and extracted into ether (3×50 mL). The organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated to provide a colorless aromatic oil which was purified first by passage through a plug of silica gel eluting with 5% EtOAc/hexanes, then by bulb-to-bulb distillation under reduced pressure to provide 3.3 g (75%) of the title compound as a colorless aromatic oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:42][CH2:41]C[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:41][CH2:42][CH2:37][CH2:38][CH2:39]2)=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCCC1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)OC1CCCCC1
Yield: 86.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclohexanol (47 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (120 mg, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([S:11]CC2C=CC(OC)=CC=2)=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:3]=1[F:29].[C:30](O)(C(F)(F)F)=O.C(O)=O.C(C(O)=O)CCCC>CC(O)=O>[NH2:1][C:2]1[C:10]([SH:11])=[CH:9][C:5]([C:6]([O:8][CH3:30])=[O:7])=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:3]=1[F:29]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CSc2cc(C(=O)[O-])c(Nc3ccccc3F)c(F)c2N)cc1
Solvent: CC(=O)O
Solvent: CCCCCC(=O)O
Solvent: O=CO
Product: COC(=O)c1cc(S)c(N)c(F)c1Nc1ccccc1F

Procedure:
4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate can be deprotected in the presence of acid (such as CF3COOH, HCOOH, CH3COOH and n-C5H11COOH, prefer CF3COOH) at certain temperature (20-75° C., prefer 25-75° C.) in appropriate aromatic aliphatic ether (such as anisole and phenetole, prefer anisole) for some time (1-12 h, prefer 3-10 h). Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate is obtained after conventional workup.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:22])=[CH:19][CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.C(N(CC)CC)C>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](=[O:28])[NH:11][C@@H:10]3[CH2:9][CH2:8][C:7]4[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=4[N:5]4[CH:1]=[CH:2][N:3]=[C:4]34)[CH2:25][CH2:26]2)=[O:22])=[CH:19][CH:18]=1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(Cl)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(Cl)cc1
Temperature: -20 °C
Yield: 93.58 %

Procedure:
Concentrate the ethanolic solution of (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine to dryness prior to use in the coupling reaction. Dissolve 15.0 g (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine and 18.03 g 1-[(4-Chlorobenzoyl)amino]cyclopropanecarboxylic acid in 120 ml of dichloromethane and 32 ml triethylamine. After cooling to −20° C., add 53.0 ml (1.2 eq.) of T3P within 40 minutes maintaining a temperature of −19° C. Allow the reaction to warm to room temperature over night. Test by HPLC for complete consumption of starting materials. After aqueous quench (75 ml of water) at 0 to 6° C. and further dilution with dichloromethane (precipitating solids dissolved after adding additional 180 ml of dichloromethane), separate the phases. Wash the organic layer two times with 75 ml of water and then back-extract the combined aqueous layers once with 75 ml of dichloromethane. Concentrate the organic extract phases (420 ml) removing 290 ml of solvents (beginning precipitation of solids). Add 240 ml of isopropyl acetate and then remove a further 250 ml of solvents. Warm the resulting thick suspension to 70° C., add 30 ml of n-heptane and slowly cool the suspension to room temperature over night. Filter the suspension via glass filter nutsch and wash the filter cake with n-heptane. After drying with a rotavap, results in a pale brown solid, 29.65 g (93.58% yield, HPLC (achiral). LC-MS (mass spectrometry) (m/z): 421.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[S:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[S:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1sc(Nc2cccc(Br)c2)nc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
A solution of 8.6 g (0.05 mol) of 3-bromoaniline in 100 ml of dimethylformamide is added dropwise to a solution of 12.0 g (0.06 mol) of 2,4-dichloro-5-nitrothiazole in 100 ml of dimethylformamide at 0° C. to 5° C. in the course of about 2 hours and the mixture is subsequently stirred at the same temperature for a further 4 hours. It is then stirred into 1,000 ml of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred in 80 ml of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 16.0 g (95.7% of theory) of 2-(3bromophenylamino)-4-chloro-5-nitrothiazole of melting point 191° C. to 192° C. (decomposition) are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]2[C:20](=O)[C:19]3[C:6](=[CH:7][C:8]4[C:9](=O)[C:10]5[C:15]([C:16](=O)[C:17]=4[CH:18]=3)=[CH:14][C:13]([Cl:26])=[CH:12][CH:11]=5)[C:5](=O)[C:4]=2[CH:3]=1.[BH4-].[Na+].CO.Cl>COCCOCCOC.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]2[C:4](=[CH:5][C:6]3[C:19]([CH:20]=2)=[CH:18][C:17]2[C:8](=[CH:9][C:10]4[C:15]([CH:16]=2)=[CH:14][C:13]([Cl:26])=[CH:12][CH:11]=4)[CH:7]=3)[CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2c(=O)c2cc3c(=O)c4ccc(Cl)cc4c(=O)c3cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOCCOC
Solvent: O
Product: Clc1ccc2cc3cc4cc5cc(Cl)ccc5cc4cc3cc2c1
Temperature: 23 °C
Reaction time: 14 h
Yield: 46.4 %

Procedure:
A mixture of 2.0 grams (5.9 mmol, leq) of 2,9-dichloropentacene-5,7,12,14-tetrone and 3.0 g (322 mmol, 54 eq) of sodium borohydride in 46 mL of 2-methoxyethylether was stirred at 23° C. in a nitrogen atmosphere for 14 hours. To this reaction mixture was added 23 mL of methanol in a dropwise fashion to keep the reaction temperature below 50° C. A solution of 18 grams (96 mmol, 16 eq) of stannous chloride in 19.7 grams of water and 7.3 grams of 12M hydrochloric acid was added at such a rate as to keep the reaction temperature between 23° C. and 40° C. The mixture was stirred for an additional 30 minutes. The reaction mixture was filtered and the residue washed with 46 mL of 12M hydrochloric acid followed by 120 mL of acetone and 40 mL of THF. The solid was dried in air to give 0.95 grams of the desired product. IR KBr 1618 cm−1, 906 cm−1.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][C:8]([CH2:13][OH:14])(CO)[CH2:7][CH2:6]1.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:21][S:22]([O:14][CH3:13])(=[O:24])=[O:23].[CH3:21][S:22]([O:14][CH3:13])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COCOC1CCC(CO)(CO)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCOC1CCCCC1
Product: COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
6.84 g of 4-(methoxymethoxy)cyclohexane-1,1-dimethanol was dissolved in 110 ml of dichloromethane and 13.56 g of pyridine was added thereto and ice-cooled. 7.79 ml of methanesulfonyl chloride was added thereto and the resulting mixture was stirred at room temperature for 17 hours. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 11.91 g of the title compound as a colorless oily substance.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=3)[N:9]([CH3:18])[C:8]=2[CH3:19])=[O:6])[CH2:3][CH2:2]1.B(Br)(Br)Br>>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[N:9]([CH3:18])[C:8]=2[CH3:19])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1ccc2c(C(=O)NC3CC3)c(C)n(C)c2c1
Agent: BrB(Br)Br
Product: Cc1c(C(=O)NC2CC2)c2ccc(O)cc2n1C
Yield: 21.3 %

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid cyclopropylamide 20a (655 mg, 2.5 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give 130 mg (21%) of a white solid. 1H NMR (DMSO-d6) δ9.06 (1H, s), 7.51 (1H, d, J=4.0 Hz), 7.41 (1H, d, J=8.5 Hz), 6.73 (1H, d, J=1.8 Hz), 6.60 (1H, dd, J=1.8, 8.5 Hz), 3.56 (3H, s), 2.82 (1H, m), 2.50 (3H, s), 0.62 (2H, m), 0.52 (2H, m).
Reaction SMILES: C(SCC(NCCC(O)=O)=O)(=O)C.O[C:15](C)([C:21]([OH:23])=[O:22])[C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17].C(N(CC)CC)C>CN(C)C=O>[NH2:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][C:21]([OH:23])=[O:22]
Reactant: CC(O)(C(=O)O)[C@H](N)C(=O)O
Agent: CC(=O)SCC(=O)NCCC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 2.5 h

Procedure:
Compound 8 (1.0 g; 3.07 mmoles) was dissolved in dimethylformamide (7 ml). β-Hydroxy,β-methyl-aspartic acid (0.5 g; 3.07 mmoles) was added to the solution. Triethylamine (0.64 ml; 4.5 mmoles) was added to the stirred suspension. Stirring was continued for 2.5 hours, after which a clear solution was obtained. The solvent was then evaporated in vacuo. The residue was dissolved in water and the aqueous solution was subsequently extracted three times with ethyl acetate in order to remove the p-nitrophenol. Following acidification of the aqueous solution to pH 1-2 by addition of 5% (w/w) aqueous potassium bisulfate, the solution was extracted four times with dichloromethane-butanol-2 (3:2; v/v). The combined organic extracts were evaporated in vacuo to give compound 9 as a syrup. The product was purified by column chromatography on silica(R) ("Merck" 40-63 μm) using butanol-1-acetic acid-water (4:1:1; v/v) as the eluent. Fractions containing pure 9 were combined and evaporated in vacuo. The residue was dissolved in water upon which the product was isolated by lyophilization (450 mg; 42%).