Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][S:3]([CH3:6])(=O)=O.[F:7][C:8]([F:19])([F:18])[CH:9]([C:11]1[CH:16]=[CH:15]C(S)=[CH:13][CH:12]=1)[OH:10]>CCO.C1COCC1>[F:7][C:8]([F:18])([F:19])[CH:9]([C:11]1[CH:16]=[CH:15][C:1]([S:2][S:3][CH3:6])=[CH:13][CH:12]=1)[OH:10]
Reactant: OC(c1ccc(S)cc1)C(F)(F)F
Reactant: CSS(C)(=O)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CSSc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
Methanethiosulfonic acid S-methyl ester (0.02 ml, 0.22 mmol) was dissolved in an EtOH (0.46 mL) and saturated NaCO3/H2O (pH 8) solution (0.8 mL) under argon at 0° C. A solution of 2,2,2-trifluoro-1-(4-mercapto-phenyl)-ethanol (5) (22 mg, 0.11 mmol) dissolved in THF (1.5 mL) under argon was added dropwise. After 10 minutes, the reaction temperature was raised to room temperature. After 36 hours, the reaction was extracted with ethyl acetate (3×30 mL) and H2O (30 mL). The combined organic phases were dried over Na2SO4 and under reduced pressure. Flash chromatography on silica gel using 0-30% acetone/hexane gave Compound 15 as a yellow oil (23 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 7.5 (m, 4H), 5.02 (q, J=6.7 Hz, 1H), 2.45 (s, 3H); 19F NMR (376 Hz, CDCl3) δ −78.79 (d); 13C NMR (100 MHz, CH3OD): δ 137.6, 134.2, 128.8, 126.4, 124.6 (q, JCF=281.7 Hz), 71 (q, JCF=31.5 Hz), 21.5.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][CH2:14][CH2:15][CH2:16][CH3:17].[Li+].[OH-]>C1COCC1.CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:18])=[O:2])=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=1
Reactant: CCCCNc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCNc1cc(F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid methyl ester (145 mg, 0.58 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 N LiOH (4 mL). The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure, and then acidified with 3 N HCl. The mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid (120 mg, 88%) after purification by crystallization form EtOAc and hexane. To a mixture of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid (52 mg, 0.22 mmol), (R)-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)ethylamine hydrochloride (64 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33 mmol) in THF (5 mL) was added 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.5 mg, 4%) after trituration with ethyl ether. 2:1).
Reaction SMILES: C(OC(=O)[NH2:7])(C)(C)C.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.N1[C:27]2[C:18](=[CH:19][CH:20]=[C:21]3[C:26]=2N=CC=C3)[CH:17]=[CH:16]C=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[N:9]1([C:20]2[CH:19]=[C:18]([C@@H:17]([NH2:7])[CH3:16])[CH:27]=[CH:26][CH:21]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(N)=O
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: C[C@H](N)c1cccc(-n2ccnc2)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
A mixture of (S)-1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (500 mg, 1.66 mmol), imidazole (170 mg, 2.5 mmol), copper (II) triflate benzene complex (83 mg, 0.16 mmole), 1–10 phenantroline ( 300 mg, 1.66 mmole), dibenzilideneacetone (37 mg, 0.16 mmole), and cesium carbonate (595 mg, 1.86 mmole) was suspended in xylenes (1 mL) in a sealed tube. The reaction mixture was heated at 110° C. for 18 h in an oil bath and then cooled down to room temperature. Ethyl acetate (20 mL) was added, the resulting solution was washed with water (2×20 mL), and the combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the crude product was dissolved in CH2Cl2 (8 mL) and trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by preparative HPLC ( NH4OAc) to give the title product (75 mg, 24% yield).
Reaction SMILES: [F:1]N(C(C)(C)C)S(C1C=CC(C)=CC=1)(=O)=O.[C:17]1([O-:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.[K+]>O1CCCC1.CCOCC>[F:1][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[OH:27]
Reactant: [O-]c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)N(F)C(C)(C)C)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1c(F)ccc2ccccc12
Yield: 60 %

Procedure:
Potassium hydride (93.6 mg as a 35% oil dispersion, 0.82 mmol) was suspended in anhydrous tetrahydrofuran (2.5 mL) under nitrogen. 1-Naphthol (72 mg, 0.5 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 5 minutes) to produce potassium naphtholate. N-Fluoro-N-t-butyl-p-toluenesulfonamide (122 mg, 0.5 mmole) was dissolved in anhydrous tetrahydrofuran (2.5 mL) and the solution was added dropwise to the potassium naphtholate. After 20 minutes the reaction mixture was diluted with ether (100 mL), washed with aqueous 1N oxalic acid solution (30 mL), water (30 mL), and saturated aqueous sodium chloride solution (30 mL), and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 25% methylene chloride in hexane) yielded 2-fluoro-1-naphthol (49 mg, 60% yield) as a white crystalline solid. This material, and an additional sample prepared by this procedure, were analyzed and provided the following results: 1H NMR (90 MHz, CDCl3) δ5.58 (b, 1H, OH), 7.00-8.30 (m, 6H, aromatic); 19F NMR (94.1 MHz, CDCl3) -146.78(m); HRMS calcd. for C10H7OF: 162.0480; found: 162.0439.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:31]([OH:32])=[CH:30][C:13]2[N:14]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:16][C:12]=2[CH:11]=1.[CH3:34]I>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:31]([O:32][CH3:34])=[CH:30][C:13]2[N:14]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:16][C:12]=2[CH:11]=1
Reactant: CI
Reactant: COC(=O)CCCCCOc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1O
Product: COC(=O)CCCCCOc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1OC

Procedure:
6-[[6-Hydroxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-5-yl]oxy]hexanoic acid methyl ester was methylated with methyl iodide according to general operating instructions 8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:13][CH2:14][S:15][CH3:16])[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.[Si:26](OS(C(F)(F)F)(=O)=O)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:13][CH2:14][S:15][CH3:16])[NH:5][C:6]([O:8][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:7]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.0 ml) of N-t-butoxycarbonyl-L-methionine methyl ester (131.5 mg, 0.5 mmol) and 2,6-lutidine (0.116 ml, 1.0 mmol), t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.172 ml, 0.75 mmol) was added dropwise at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 146 mg.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[NH2:26][OH:27].Cl.C([O-])([O-])=O.[K+].[K+].CCO>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:26][OH:27])=[NH:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=N)NO)cc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A 50-mL round bottomed flask was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile (120 mg, 0.325 mmol, 1 eq.), NH2OH/HCl (160 mg, 2.3 mmol, 7 eq), K2CO3 (320 mg, 2.3 mol, 7 eq.), EtOH (10 ml) and water (1 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure. The residue was purified by chromatography on silica gel using 1.5˜4% of methanol in dichloromethane as eluent to give the title compound (61 mg, 47% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].[Br:13]Br>C(Cl)Cl.CCOCC>[Br:13][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[C:7](=[O:12])[NH:6][CH:5]=1
Reactant: BrBr
Reactant: Cc1cccc2c(=O)[nH]ccc12
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc2c(=O)[nH]cc(Br)c12
Reaction time: 18 h
Yield: 29 %

Procedure:
To a suspension of 0.8 g (5.0 mmol) of 5-methyl-1-isoquinolinone in 30 ml of methylene chloride was added 0.85 (5.3 mmol) of bromine. The resulting orange mixture was stirred at 25° for 18 hours and diluted with 50 ml of ether. The solid was filtered and washed with methanol to give 0.35 g (29%) of product; mp 201°-210°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])=[O:7].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.C(N(CC)CC)C>ClCCl>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]2[S:6]([NH:5][CH2:4][CH2:3][NH:2][C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)(=[O:8])=[O:7]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCN)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)NCCNC(=O)c2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from Example 89, Step A was combined with 1.1 equivalents of 4-methoxybenzoyl chloride and 3.0 equivalents of triethylamine in dichloromethane. The reaction was stirred for 1.5 hours at room temperature and the solvent was removed under a stream of nitrogen to give the titled compound. ESI+ MS: 664 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:6]3=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[ClH:1].[CH2:27]([O:26][C:24]([N:15]1[CH2:14][CH2:13][CH2:12][C:7]2=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:6]2[CH2:16]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc2nc3c(c(-c4ccccc4)c2c1)CNCCC3
Product: CCOC(=O)N1CCCc2nc3ccc(Cl)cc3c(-c3ccccc3)c2C1
Product: Cl
Yield: 89 %

Procedure:
9-Chloro-2,3,4,5-tetrahydro-11-phenyl-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 9-chloro-2,3,4,5-tetrahydro-11-phenyl-1H-azepino[4,3-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[NH:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7].Cl>>[CH3:10][N:8]([CH3:9])[C:6]([NH:5][C@H:4]([C:3]([OH:20])=[O:2])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)N(C)C
Agent: Cl
Product: COc1ccc(C[C@H](NC(=O)N(C)C)C(=O)O)cc1

Procedure:
Prepared according to the procedure of Example 56 from the resultant compound of Example 57 with the modification that the product was isolated by pouring the reaction mixture into 2M HCl and extracting with ethyl acetate which was dried over Na2SO4 and evaporated. EI-MS: M+ =266.
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:21])[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[N:9](C=O)[C:8]([CH3:20])([CH3:19])[CH2:7]3)[CH2:4]1.Cl.C(=O)(O)[O-].[Na+]>CO.O.C(OCC)(=O)C>[I:1][CH2:2][C:3]1([CH3:21])[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[NH:9][C:8]([CH3:20])([CH3:19])[CH2:7]3)[CH2:4]1
Reactant: Cc1c(C)c2c(c3c1OC(C)(CI)C3)CC(C)(C)N2C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CI)O2
Yield: 87 %

Procedure:
To a solution of 1,6,7,8-tetrahydro-2-(iodomethyl)-2,4,5,7,7-pentamethyl-2H-furo[3,2-e]indole-6-carbaldehyde (1.93 g, 4.83 mmol) in methanol (10 mL) was added concentrated hydrochloric acid (3 mL), and the mixture was heated to reflux for 3 hours under the nitrogen atmosphere. The reaction mixture was added dropwise to a mixture of sodium bicarbonate (3.7 g, 44 mmol) in water-ethyl acetate to neutralize, which was extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10:1) to obtain 1.56 g of the title compound.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[CH2:40]([NH:43][C:44](=[O:51])[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1)[C:41]#[CH:42]>CN(C=O)C.[Cu]I>[Cl:29][C:27]1[CH:28]=[C:23]([C:17]2([C:19]([F:22])([F:20])[F:21])[O:16][N:15]=[C:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([N:1]4[CH:42]=[C:41]([CH2:40][NH:43][C:44](=[O:51])[C:45]5[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=5)[N:3]=[N:2]4)=[CH:5][CH:6]=3)[CH2:18]2)[CH:24]=[C:25]([Cl:30])[CH:26]=1
Reactant: [N-]=[N+]=Nc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: C#CCNC(=O)c1ccncc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)nn1)c1ccncc1
Reaction time: 5 h

Procedure:
CuI (211 mg) is added to a solution of 3-(4-azido-naphthalen-1-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (500 mg), DIPEA (3.3 ml) and N-prop-2-ynyl-isonicotinamide (180 mg) in DMF (2.0 ml). After 5 hours at room temperature, the reaction is quenched with a saturated solution of NaHCO3 and extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and concentrated in mow. The crude product is purified on a semi-preparative HPLC to yield N-(1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalen-1-yl}-1H-[1,2,3]triazol-4-ylmethyl)-isonicotinamide as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (728 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromo-2-(2-ethoxyethoxy)ethane (496 mg), and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column-chromatography (silica gel, eluent:hexane/ethyl acetate=9/1→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[C:4]([O:9][CH3:10])=[CH:5][C:6](=[O:8])[CH:7]=1.[Si](O[N:20]=[C:21]([CH3:24])[CH:22]=[CH2:23])(C(C)(C)C)(C)C>ClC1C=CC=CC=1>[CH3:10][O:9][C:4]1[C:3](=[O:11])[C:2]2[N:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:7]=2[C:6](=[O:8])[CH:5]=1
Reactant: COC1=CC(=O)C=C(Br)C1=O
Reactant: C=CC(C)=NO[Si](C)(C)C(C)(C)C
Solvent: Clc1ccccc1
Product: COC1=CC(=O)c2ccc(C)nc2C1=O
Yield: 56.8 %

Procedure:
In a 50 mL round bottom flask 2-bromo-6-methoxy-1,4-benzoquinone (282 mg, 1.3 mmol) was dissolved in dry chlorobenzene (28 mL) along with 1-(tert-butyldimethylsilyloxy)-2-methyl-1-aza-1,3-butadiene (130 mg, 0.65 mmol). The solution was stirred and heated to reflux for 22 h under N2. The dark reaction was allowed to cool and was added to a silica gel column (2.5×9 cm). The column was eluted with EtOAc/hexane (5:1) then EtOAc and finally ethanol. The solvent was removed, benzene was added, and the resulting mixture was heated and filtered to remove insoluble impurities. Evaporation of the filtrate gave 75 mg, 57% of the crude product. 1H NMR (CDCl3) δ2.81 (s, 3H), 3.92 (s, 3H), 6.18 (s, 1H), 7.44 (d, J=5 Hz, 1H) 8.80 (d, J=5 Hz, 1H).
Reaction SMILES: FC(OC(=O)C)(F)F.Cl[C:10]1[N:15]=[CH:14][C:13]([CH2:16][C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[N:20]=[C:19]([C:27]([NH:29][C@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]3[OH:36])=[O:28])[CH:18]=2)=[CH:12][CH:11]=1.[CH3:37][S-:38].[Na+]>CS(C)=O.C(OCC)(=O)C>[OH:36][C@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]1[NH:29][C:27]([C:19]1[CH:18]=[C:17]([CH2:16][C:13]2[CH:14]=[N:15][C:10]([S:38][CH3:37])=[CH:11][CH:12]=2)[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=1)=[O:28]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2c(n1)CCCC2
Reactant: C[S-]
Agent: CC(=O)OC(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSc1ccc(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)nc3c2CCCC3)cn1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-5,6,7,8-tetrahydroquinoline-2-carboxamide trifluoromethyl acetate (0.060 g, 0.18 mmol) in 1 mL of DMSO was added sodium thiomethoxide (9.8 mg, 0.14 mmol). The mixture was heated at 80° C. for 1 h, at 90° C. for 1 h, then cooled to rt. After 15 h, additional sodium thiomethoxide (9.3 mg, 0.14 mmol) was added and the mixture was heated at 100° C. for 1 h, then cooled to rt. The mixture was diluted with ethyl acetate, washed 2× with water and 1× with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 35-85% ethyl acetate in hexanes, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 412.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 8.32 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 5.43-7.40 (m, 1H), 7.25 (d, J=8.2 Hz, 1H), 4.67 (d, J=5.5 Hz, 1H), 4.02 (s, 2H), 3.54-3.48 (m, 1H), 3.43-3.37 (m, 1H), 3.00 (br s, 2H), 2.72 (br s, 2H), 1.91-1.87 (m, 2H), 1.79 (s, 3H), 1.65-1.59 (m, 2H), 1.24-1.17 (m, 3H).
Reaction SMILES: ClC[C:3]1[CH:12]=C[C:10]2[C:5](=CC=CC=2)[N:4]=1.[CH3:13][O:14][CH:15]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)[C:16]([NH:18][CH3:19])=[S:17].[C:30](N)(=S)C.C=O.C(NCC)C>>[CH2:5]([N:4]([CH2:3][CH3:12])[CH2:30][C:15]([O:14][CH3:13])([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)[C:16]([NH:18][CH3:19])=[S:17])[CH3:10]
Reactant: CC(N)=S
Reactant: ClCc1ccc2ccccc2n1
Reactant: CNC(=S)C(OC)c1ccc2ccccc2n1
Agent: C=O
Solvent: CCNCC
Product: CCN(CC)CC(OC)(C(=S)NC)c1ccc2ccccc2n1

Procedure:
By the procedure of Example 1, using 2-(chloromethyl)quinoline in place of 2-(chloromethyl)pyridine, 2-methoxy-N-methyl-2-(2-quinolyl)thioacetamide is prepared. Reacting this thioacetamide with formaldehyde and diethylamine gives 3-diethylamino-2-methoxy-N-methyl-2-(2-quinolyl)thiopropanamide.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:16][CH:17]([SH:21])[C:18](O)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH2:22]=O.[NH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:16][CH:17]2[S:21][CH2:22][N:24]([CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:18]2=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:3])[CH3:1]
Reactant: C=O
Reactant: CC(C)(C)c1cc(CC(S)C(=O)O)cc(C(C)(C)C)c1O
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CC2SCN(C(c3ccccc3)c3ccccc3)C2=O)cc(C(C)(C)C)c1O
Yield: 95.1 %

Procedure:
3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-mercaptopropanoic acid (2.0 g; 6.45 moles), prepared substantially in accordance with the method described in Example 1A, was suspended in 20 ml of toluene. Under a nitrogen atmosphere, 0.2 g (6.45 mmoles) of paraformaldehyde was added, followed by 1.18 g (6.45 moles) of aminodiphenylmethane. An additional 10 ml of toluene was added and the resulting solution was heated at reflux temperature for 70 minutes with removal of water by means of a Dean-Stark apparatus. The solution was allowed to cool, after which the toluene was distilled off until about 10 ml of a light, brown solution remained. Fifteen milliliters of hexanes were added and the resultant solution was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with a saturated sodium bicarbonate solution and a brine solution, dried with sodium sulfate, filtered, and evaporated to provide a foam. The crude product was purified by silica gel chromatography and evaporated under vacuum to provide 2.99 g of a yellow foam. mp 286°-287° C. (dec).
Reaction SMILES: [Li]C.CCOCC.O([NH2:10])C.[Li][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH2:20][CH:19]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2>CCCCCC>[NH2:10][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH2:20][CH:19]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2
Reactant: [Li]c1cccc2c1CC(N(CCC)CCC)CC2
Reactant: CON
Agent: [Li]C
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2cccc(N)c2C1
Temperature: -15 °C

Procedure:
A stirred solution (9.2 ml) of 0.92M MeLi in ether (8.5 mmol) of methoxylamine in hexane (9 ml) was added dropwise (1 drop/s) followed by 2.6 ml (4.3 mmol) of a 1.55M solution of 5, 6, 7 or 8-lithio-2-(di-n-propylamino)tetralin (prepared from 5, 6, 7 or 8-bromo-2-(di-n-propylamino)tetralin and n-BuLi). The mixture was warmed to -15° C. for 2 hr and quenched with water (0.5 ml). Workup of the resulting mixture afforded the desired 5, 6, 7 or 8-amino-2-(dinpropylamino)tetralin.