Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.C([Si](C)(C)[O:32][C@@H:33]1[CH2:38][CH2:37][C@H:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=2[CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH2:35][CH2:34]1)(C)(C)C>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:26])[C:10]3([CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[CH2:51][C:49](=[O:50])[NH:48][CH:47]3[C:41]3[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=3[O:39][C@H:36]3[CH2:35][CH2:34][C@@H:33]([OH:32])[CH2:38][CH2:37]3)[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(Cl)ccc1O[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2O[C@H]2CC[C@@H](O)CC2)N1

Procedure:
In a manner similar to the method described in example 1e, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 1b (1.52 g, 3.8 mmol) was reacted 1-[2-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (9.8 mmol) in toluene to give racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-(cis-4-hydroxy-cyclohexyloxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.4 g, 18%)
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[C:12]([CH3:30])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][C:12]1[CH:11]=[C:10]([S:7]([NH:6][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)(=[O:8])=[O:9])[CH:15]=[CH:14][C:13]=1[O:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCCC[C@@H]3c3ccnn3C)c(C)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)ccc1O[C@H]1CCCCC[C@@H]1c1ccnn1C
Yield: 73.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (182 mg, 0.31 mmol) prepared in Example 57a, triethylsilane (0.15 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (100 mg, 74%) as a colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCCCO1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: OC[C:3]1[CH:39]=[CH:38][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12](C(OC(C)(C)C)=O)[CH2:13][C@H:14]([O:23][Si](CC)(CC)CC)[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.Cl.[C:41]([O:44][CH2:45]C)(=[O:43])[CH3:42]>>[OH:23][C@H:14]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][NH:12][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:38]=[CH:39][C:3]([CH2:45][O:44][C:41](=[O:43])[CH3:42])=[CH:4][C:5]=2[CH2:11]1
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(CO)cc2C1
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)OCc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2

Procedure:
A solution of N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyl-oxy)propyl]-tert-butoxycarbonylamine (188 mg) in ethyl acetate (2 ml) was treated with 4N hydrogen chloride in ethyl acetate (2 ml) for 3 hours. The mixture was evaporated in vacuo and washed with diethyl ether three times. The residue was triturated in diisopropyl ether, and precipitated powder was collected by filtration to afford 6-[(2S)-2-hydroxy-3-phenoxypropyl]amino-3-acetyloxymethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene (113 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.N1C=CC=CC=1>O1CCCC1>[CH:17]([O:16][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:1][C:29]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:27][CH:26]=2)=[O:30])[CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:18])[CH3:19]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(Cc1cccc(COC(=O)Nc2ccc(C(F)(F)F)cc2)c1)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.5 %

Procedure:
A suspension in tetrahydrofuran (2.0 ml) containing 100 mg of ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate, 150 mg of α,α,α-trifluoro-p-tolylisocyanate and 35 μl of pyridine was stirred at room temperature for 14 hours. The solvent was removed, and the residue was treated with dichloromethane. After filtering off insoluble substances, the residue was purified by silica gel column chromatography, to give 149 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17]
Reactant: C1COCCN1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Solvent: CS(C)=O
Product: Cn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCOCC3)cc21

Procedure:
2.18 g of 6,7-dichloro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 3 cm3 of morpholine and 30 cm3 of DMSO were heated for 5 hours at 125°-130° C. About 3 hours were required for total dissolution of the dihalogeno-acid, and the reaction product then precipitated from the mixture. After returning to room temperature, the mixture was diluted with 30 cm3 of water. The precipitate was filtered off, washed with water and recrystallised from a mixture of DMF (1 volume) and methylcellosolve (1 volume). 1.68 g of 6-chloro-1-methyl-7-morpholino-4-oxo-1,4-dihydro quinoline-3-carboxylic acid were obtained; m.p. 334° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Sn](Cl)(Cl)(Cl)Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][C:23]=1[C:30]#[N:31]>C(O)(=O)C>[C:30]([C:23]1[CH:24]=[C:25]([N:28]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:29]2)[CH:26]=[CH:27][C:22]=1[F:21])#[N:31]
Reactant: N#Cc1cc(NN)ccc1F
Reactant: CCOC(=O)C(=O)CC(=O)c1ccco1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccco2)n(-c2ccc(F)c(C#N)c2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To ethyl 4-(2-furyl)-2,4-dioxobutyrate (3.5 g, 16.7 mmol) in 50 mL of glacial acetic acid was added 4-fluoro-3-cyanophenylhydrazine tin chloride (6.3 g, 16.7 mmol). The reaction was stirred at 100° C. for 4 h. The reaction was allowed to cool to room temperature and the acetic acid was removed in vacuo. The residue was diluted with ethyl acetate and the organics were washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by recrystallization from hexane/ethyl acetate to afford 2.5 g (46%) of the title compound. LRMS (ES+): 326.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(CCNC(C)=O)cc1

Procedure:
In close analogy to the procedure described above, 2-(4-methoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)C=Cc1c(F)cccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
A solution of 3-(2-chloro-6-fluoro-phenyl)-acrylic acid ethyl ester in dried tetrahydrofuran (300 mL) was added to a suspension of lithium aluminum hydride (30 g, 0.78 mol) in anhydrous tetrahydrofuran (200 mL) at 0° C. The reaction mixture was stirred for 3 hours, and then cooled to 0° C. and quenched by the addition of water (30 g) and a 10% aqueous solution of sodium hydroxide (30 mL). The resulting solid was filtered, washed with tetrahydrofuran, and then purified by silica gel column chromatography to afford 3-(2-chloro-6-fluoro-phenyl)-propan-1-ol (21 g, 0.11 mol, 43% from 2-chloro-6-fluoro-benzaldehyde).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]1[O:39][C@@H:32]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[CH2:1]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCNCc3ccccc3)cc2)cc1NC(C)C
Reactant: c1ccc([C@@H]2CO2)cc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3ccccc3)cc2)cc1NC(C)C

Procedure:
To a solution of methyl 4′-[2-(benzylamino)ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (250 mg) in ethanol (15 ml) was added (R)-(+)-styreneoxide (142 μl) at room temperature, and the mixture was stirred under reflux for 48 hours. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[benzyl[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (251 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17](CC[Si](C)(C)C)[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:27])=[O:28])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-cyclopropanecarboxylic acid ethyl ester (75 mg, 0.14 mmol) in THF (3 mL) is added 1M TBAF in THF (0.21 mL) and the solution is stirred at 60° C. for 2 h. The reaction is cooled to RT and diluted with EtOAc and washed with 1N HCl and brine. The organic layer is dried over MgSO4 and concentrated under reduced pressure to afford the title compound as a yellow oil, which is used in the next step without further purification: (M+H)+=448.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=2[S:20][CH3:21])=[O:12])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:32][S:33]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=2[S:20][CH3:21])=[O:12])[CH2:6][CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCOS(C)(=O)=O)CC1
Reaction time: 0.75 h

Procedure:
To a solution of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (93 mg, 0.251 mmol) in THF (2 ml) were added triethylamine (51 mg, 0.502 mmol) and 4-(dimethylamino)pyridine (3 mg, 0.025 mmol), and then dropped methanesulfonyl chloride (43 mg, 0.377 mmol) with ice-cooling. The mixture was stirred for 45 minutes. The reaction solution was concentrated in vacuo to provide crude 2-[4-(2-methanesulfonyloxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C1C(=O)N([Br:22])C(=O)C1.C([O-])(=O)C.[NH4+]>CCOCC>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([Br:22])[C:3](=[O:4])[CH3:5])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)C(Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring dispersion of benzyl acetoacetate (20 ml, 116 mmol) and NBS (21.64 g, 122 mmol) in Et2O (1000 ml) was added ammonium acetate (0.893 g, 11.58 mmol). The reaction was stirred at RT for 4 hours and then filtered, washed with water (400 ml), brine, dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.37-7.42 (5H, m, 5×ArH), 5.27 (2H, s, ArCH2OR), 4.82 (1H, s, CHBr), 2.42 (3H, s, RCOCH3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:4]([CH:16]=O)[CH2:3]1.Cl.[O:19]([NH2:21])[CH3:20]>C(O)(C)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:4]([CH:16]=[N:21][O:19][CH3:20])[CH2:3]1
Reactant: CON
Reactant: CN1CCC(c2ccc(Cl)c(Cl)c2)C(C=O)C1
Agent: Cl
Solvent: CC(C)O
Product: CON=CC1CN(C)CCC1c1ccc(Cl)c(Cl)c1
Yield: 40.2 %

Procedure:
To a solution of 1-methyl-3-formyl-4-(3,4-dichlorophenyl)piperidine (10 g, 33 mmol) in warm isopropanol (100 mL) was added methoxylamine hydrochloride (3 g, 36 mmol). The reaction was heated at reflux for 30 min. The solvent was evaporated off and the residue made basic (pH=9) using concentrated ammonia. Extraction with ether afforded 8.5 g of crude product. Purification by repeated column chromatography on silica using EtOAc/Et3N (95:5) as eleuent afforded 4 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH3:13]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH2:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: N
Reactant: Cc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1S(N)(=O)=O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of 3810.5 g of 5-chloro-2-methylbenzenesulfonyl chloride in 10.8 L of tetrahydrofuran was cooled to 0°-5° C. and 720 g of anhydrous ammonia was added while maintaining the temperature at 0°-5° C. When addition was complete, the suspension was stirred several hours at 0°-5° C., then allowed to warm to ambient temperature overnight. The precipitated ammonium chloride was filtered and washed with tetrahydrofuran. The filtrate was concentrated in vacuo until solids were formed. The solids were collected, washed with 1-chlorobutane and dried to give 2449 g of the title compound, m.p. 142°-145° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH:38]([NH:42]C(=O)OC(C)(C)C)[CH2:37]1.Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH2:42])[CH2:37]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(-c2csc3c(/C=C/CN4CCCC(N)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 19.6 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (100 mg, 0.207 mmol) and tert-butyl piperidin-3-ylcarbamate (124 mg, 0.621 mmol), were reacted according to General Procedure B. The crude product (137 mg, 0.206 mmol) was dissolved in methanol (1 mL) and treated with 6.0 M hydrochloric acid in 1,4 dioxane (0.514 mL, 2.06 mmol) and heated to 55 degrees Celsius for 20 hours. The mixture was cooled to room temperature then 1M sodium carbonate solution (5 mL) was added and product was extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified via HPLC preparation to furnish the title compound as an ivory powder (23.0 mg, 0.0406 mmol): LCMS (Conditions a): MH−=565 RT=3.35 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.45 (1H), 7.91 (2H), 7.65 (1H), 7.28 (3H), 7.10 (3H), 7.01 (1H), 6.64 (1H), 6.15 (1H), 5.59 (1H), 3.71 (3H), 3.85 (3H), 3.52 (1H), 3.14 (2H), 2.89 (1H), 2.78 (1H), 2.62 (1H), 2.16 (1H), 2.03 (1H), 1.66 (1H), 1.42 (1H), 1.15 (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:10]([NH2:13])[NH:11][N:12]=1.C([O:23][C:24](=O)[CH:25]([CH3:29])[C:26](=O)[CH3:27])C.C(OCC)C>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:12][N:11]3[C:24]([OH:23])=[C:25]([CH3:29])[C:26]([CH3:27])=[N:13][C:10]=23)=[CH:19][CH:18]=1
Reactant: Nc1[nH]nc(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(O)c1C
Temperature: 100 °C

Procedure:
To a mixture of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-1b; 0.642 g, 2.11 mmol) in acetic acid (2.6 ml) was added 2-methyl-3-oxobutyric acid ethyl ester (366 mg, 2.53 mmol). The reaction was heated at 100° C. for 5 hours. After cooling to room temperature, the precipitated solid was isolated by vacuum filtration and then repulped from diethyl ether to afford I-4A-1a (292 mg, 36%) as a colorless solid: +ESI MS (M+1) 384.1; 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.45–7.33 (m, 6H), 7.11 (d, J=8.7 Hz, 2H), 2.33 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: [C:1](SSC(C)(C)C)(C)(C)C.II.[S:13]([CH:37]([CH2:55]N=[N+]=[N-])[CH2:38][C@H](NC(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[S:14][CH:15]([CH2:33][N:34]=[N+:35]=[N-:36])[CH2:16][C@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:21]([O:20][C:18](=[O:19])[C@@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:16][CH:15]([S:14][S:13][C:37]([CH3:1])([CH3:55])[CH3:38])[CH2:33][N:34]=[N+:35]=[N-:36])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)SSC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: II
Product: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
Di-tert-butyl disulfide (5.67 ml, 29.4 mmol) and iodine (57 mg, 0.226 mmol) were added to (2S,2'S)-di-tert-butyl 4,4′-disulfanediylbis(5-azido-2-((tert-butoxycarbonyl)amino)pentanoate) (Compound 38) (312 mg, 0.452 mmol), and the mixture was stirred at 60° C. for 18 hours. The reaction solution was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid tert-butyl ester (Compound 39) (161 mg, 81%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[CH:13]=[C:14]([Br:18])[CH:15]=[C:16](Br)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(#N)C.[C:26](O)(=[O:28])C>CO>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[CH:13]=[C:14]([Br:18])[CH:15]=[C:16]([O:28][CH3:26])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cc(Br)n2nc(SCc3ccccc3)nc2c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1cc(Br)cc2nc(SCc3ccccc3)nn12

Procedure:
2-Benzylthio-5,7-dibromo[1,2,4]triazolo[1,5-a]pyridine (11.6 g, 0.029 mol) and 25 percent sodium methoxide in methanol (13.0 mL, 3.1 g, 0.057 mol) were combined with 300 mL of acetonitrile and the mixture was heated to reflux with stirring for an hour. An additional 26 mL of 25 percent sodium methoxide in methanol was then added. After a 15-min reaction period, the mixture was acidified with acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with 20 percent ethyl acetate in hexane to obtain 4.97 g (49 percent of theory) of the title compound as a tan powder melting at 80°-82° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:12][CH:13]([F:16])[CH2:14][NH2:15]>C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH2:14][CH:13]([F:16])[F:12])[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: NCC(F)F
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)CNc1nc(Cl)nc2ccoc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a flask was added 2,4-dichlorofuro[3,2-d]pyrimidine (2 g, 10.58 mmol, Arkpharm), DCM (20 mL) and TEA (2.95 mL, 21.16 mmol). A solution of 2,2-difluoroethanamine (0.858 g, 10.6 mmol, Matrix) in DCM (5 mL) was added drop-wise and the mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure. To the residue was added 1,4-dioxane (20 mL), TEA (2.95 mL, 21.2 mmol) and a solution of 2,2-difluoroethanamine (0.858 g, 10.58 mmol, Matrix) in 1,4-dioxane (5 mL). The mixture was stirred at rt for about 4 h, and then at about 55° C. overnight. The mixture was concentrated under reduced pressure, and the residue was taken up in EtOAc (120 mL) and water (25 mL). The organic layer was isolated and washed with water (2×25 mL). The combined aqueous layers were washed with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL), dried with MgSO4, filtered, concentrated under reduced pressure, and dried in a vacuum oven at about 70° C. over 2 days to give 2-chloro-N-(2,2-difluoroethyl)furo[3,2-d]pyrimidin-4-amine (2.20 g, 89%): LC/MS (Table 2, Method c) Rt=1.69 min.; MS m/z: 234 (M+H)+.