Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[CH2:11]([O:13][CH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][CH2:37][NH:36][CH2:35]2)[CH2:28][CH2:27]1)[CH3:12].C([BH3-])#N.[Na+].Cl>CO.BrCOC1C(O)=CC=C(C)C=1.C(OCC)(=O)C>[CH3:2][CH:1]([N:36]1[CH2:37][CH2:38][C:34]([CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][CH:26]([NH:25][C:17]3[N:16]([CH2:15][CH2:14][O:13][CH2:11][CH3:12])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=3)[CH2:27][CH2:28]2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:35]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: CC(=O)c1ccccc1
Agent: Cc1ccc(O)c(OCBr)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(C)c4ccccc4)C3)CC2)nc2ccccc21

Procedure:
According to the method of J. Am. Chem. Soc., 93, 2897 (1971), combine acetophenone (10 mmol) and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (10 mmol) in methanol (100 mL). Add bromocreosol green (0.5% by weight in methanol, 1 drop). Add dropwise, a solution of sodium cyanoborohydride (10 mL, 1M in tetrahydrofuran, 10 mmol) and at the same time maintain the pH of the reaction mixture, as indicated by a yellow color for the indicator, by the addition of a 5 M solution of hydrochloric acid in methanol. When the reaction is complete, concentrate the reaction mixture in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.C(O)(=O)C.Cl>O1CCOCC1>[Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)CCn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1
Temperature: 90 °C

Procedure:
To a solution of ethyl 3-(3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)propanoate (75 mg, 0.148 mmol) in dioxane (492 μL) was added acetic acid (253 μL, 4.43 mmol) and conc. HCl (363 μL, 4.43 mmol). The mixture was heated at 90° C. for 1 h. The solvent was evaporated to one-third its volume, diluted with water (2 mL) and extracted with EtOAc (2×2 mL). The combined organic fractions were extracted with 1N NaOH (1 mL), the aqueous layer was acidified with 2N HCl (1 mL) and extracted with EtOAc (3×2 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated. The product was triturated with hexanes (2×2 mL) and dried under high vacuum to give the title compound.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[CH:10]([C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][CH:17]=1)=[CH2:11]>>[CH:2]([C:4]1[CH:9]=[C:8]([CH:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH:7]=[CH:6][CH:5]=1)=[CH2:3]
Reactant: C=Cc1cccc([Mg]Br)c1
Reactant: CC(Cl)c1ccccc1
Product: C=Cc1cccc(C(C)c2ccccc2)c1

Procedure:
(1-Chloroethyl)benzene (formula VI) is subjected to coupling reaction with a Grignard reagent of 3-vinylphenylmagnesium bromide (formula VII) in the presence of a catalyst of nickel chloride (II)-diphosphine complex, to obtain 1-(3-vinylphenyl)-1-phenylethane. The reaction is carried out in a nitrogen atmosphere under atmospheric pressure at a temperature of 0° to 80° C. The ratio of (VI)/(VII) may be in the range of about 1.0 to 1.5. ##STR9##
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:9]([S:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C.O.C(OCC)(=O)C>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][CH:9]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])[CH:4]([CH2:5][OH:6])[CH2:3][OH:2])=[CH:21][CH:22]=1
Reactant: COC(=O)C(C(=O)OC)C(Sc1ccc(Cl)cc1)c1c(F)ccc(F)c1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCC(CO)C(Sc1ccc(Cl)cc1)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-[(4-Chloro-phenylsulfanyl)-(2,3,6-trifluoro-phenyl)-methyl]-malonic acid dimethyl ester (Example 10, step 3, 11 g, 26.3 mmole) was dissolved in 200 mL THF and DIBAL-H (1M in hexane, 105 mL) was added. The reaction was stirred at room temperature for five hours. Additional DIBAL-H (M in hexane, 100 mL) was added and the reaction was stirred at 60° C. for three hours. 300 mL water and 300 mL EtOAc were added. The organic layer washed with 1N HCl solution (2×100 mL), brine (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/hexane from 0/100 to 50/50 in 45 minutes). Yield: 6.2 g, 65%. 1H NMR (CDCl3 400 MHz) δ 7.28 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H), 7.00 (m, 1H), 6.75 (m, 1H), 4.85 (d, J=11.0 Hz, 1H), 4.36 (dd, J=7.3 and 3.7 Hz, 1H), 4.21 (dd, J=8.1 and 2.9 Hz, 1H), 3.85 (dd, J=8.8 and 2.9 Hz, 1H), 3.49 (m, 1H), 2.46 (m, 1H), 2.22 (br, 1H), 2.10 (br, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1.O=[Si]=O>C1COCC1.[Pt]>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: [Pt]
Agent: O=[Si]=O
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: CCCNCc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1N

Procedure:
A mixture of [3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-carbamic acid benzyl ester (0.033 mol) in THF (200 mL) was hydrogenated with 10% Pt/C (2 g) as a catalyst in the presence of thiophene solution (2 mL). After uptake of H2 gas (3 equiv.), the reaction mixture was filtered through Dicalite, and the filtrate was evaporated. The residue was purified by column chromatography (eluent: 90:10 CH2Cl2:(CH3OH:NH3)). The product fractions were collected, and the solvent was evaporated to yield the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[S:22][CH3:23].[CH2:24]([Sn](CC)(CC)CC)[CH3:25].[Li+].[Cl-]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:9]1[N:8]=[C:7]([S:22][CH3:23])[C:6]2[C:11](=[C:2]([CH2:24][CH3:25])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC[Sn](CC)(CC)CC
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1cccc2c(SC)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 135 °C
Yield: 73.7 %

Procedure:
To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (300 mg, 0.75 mmol), bis(tri-tert-butylphosphine)palladium (38 mg, 0.075 mmol), tetraethyltin (0.295 mL, 1.5 mmol), and LiCl (95 mg, 2.25 mmol) was added DMF (15 mL). The reaction vessel was evacuated and flushed with argon (2×). The mixture was then heated in a microwave synthesizer at 135° C. for 30 min. The mixture was partitioned between EtOAc and saturated aq sodium bicarbonate and the organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure onto Celite. The mixture was purified by silica gel chromatography eluting with 0-10% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-ethyl-4-(methylthio)quinazoline (193 mg, 73%) as a white solid. LC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1.IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:31])=[C:28]([C:35]([F:36])([F:37])[F:38])[CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccc(F)cc3C(F)(F)F)cc2)c2ccc3ccccc3c2N1
Yield: 52 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 4-fluoro-2-(trifluoromethyl)benzoyl chloride, the title compound (yield 52%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[Cl:9][C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:20][NH:21][C:22](=[O:35])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:25]=2)[CH2:15]1.CO>CC(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:20][NH:21][C:22](=[O:35])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:1])[S:31]([CH3:34])(=[O:32])=[O:33])[CH:25]=2)[CH2:15]1
Reactant: CS(=O)(=O)Nc1cccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Solvent: CC(C)=O
Product: CN(c1cccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1)S(C)(=O)=O
Yield: 32.1 %

Procedure:
Potassium carbonate (0.035 g) and iodomethane (0.015 ml) were added to a stirred solution of Example 139 (0.115 g) in acetone (1 ml), and stirring was continued at 22° C. for 72 h before a further portion of iodomethane (0.003 ml) was added. After stirring for a further 24 h, more iodomethane (0.003 ml) and potassium carbonate (0.007 g) were added, and the mixture stirred for a further 48 h. The mixture was applied in two equal portions to two ion exchange cartridges (2 g Isolute SCX, pre-conditioned with methanol). Elution with methanol (3 column volumes) followed by 10% 0.880 ammonia in methanol (2 column volumes), and evaporation of the first basic fraction from each elution in vacuo gave the title compound as a pale yellow gum (0.038 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@H:30]([CH3:32])[N:29]([CH:33]([CH3:35])[CH3:34])[C@H:28]([CH3:36])[CH2:27]3)=[N:23][N:24]=2)[CH:3]=1.[CH3:37][O:38][C:39]1[C:44]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:36][C@H:28]1[N:29]([CH:33]([CH3:35])[CH3:34])[C@@H:30]([CH3:32])[CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:42]4[CH:43]=[C:44]([NH:45][S:46]([CH3:49])(=[O:47])=[O:48])[C:39]([O:38][CH3:37])=[N:40][CH:41]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][N:23]=2)[CH2:27]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: CC(C)N1[C@H](C)CN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)N(C(C)C)[C@@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 100 °C
Yield: 24 %

Procedure:
6-Bromo-4-(5-{[(3R,5S)-3,5-dimethyl-4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (172 mg, 0.300 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (108 mg, 0.330 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (43.9 mg, 0.060 mmol) and potassium phosphate tribasic (191 mg, 0.900 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (2.5 ml) and water (0.25 ml). The mixture was heated under microwave irradiation at 100° C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (1 ml) and purified by high pH MDAP (Method E). The appropriate fraction was blown to dryness to give the title compound as a white solid (40 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])[CH3:32].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:31]([C:34]1[CH:39]=[CH:38][C:37]([O:1][C:2]2[CH:3]=[C:4]([C:14]3[N:15]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:16]([C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:17][CH:18]=3)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=2)=[CH:36][CH:35]=1)(=[O:33])[CH3:32]
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (92 mg, 0.214 mmol) synthesized in Example (38d) was dissolved in dichloromethane (10 mL), and 4-acetylphenylboronic acid (70 mg, 0.427 mmol), copper (II) acetate (60 mg, 0.330 mmol), triethylamine (0.15 mL, 1.08 mmol) and molecular sieves 4A (90 mg) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. The deposit of this reaction solution was Celite filtered. This mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=15%-25%) to afford the desired compound (73 mg, yield 62%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+].O1CCCC1.O>Cl.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][N:15]=[N:16][N:17]=2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-c2nnn[nH]2)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Reaction time: 24 h

Procedure:
Combine methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (1 mmol) and lithium hydroxide (1.1 mmol) in 1/1 tetrahydrofuran/water (5 mL). After 24 hours, dilute the reaction mixture with a 0.5M aqueous hydrochloric acid solution and dichloromethane. Separate the layers and extract the aqueous layer three times with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:10]([S:11][CH3:12])=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:8]=[C:7](Cl)[N:6]=1.CC1(C)C(C)(C)OB([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:10]([S:11][CH3:12])=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:8]=[C:7]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[N:6]=1
Reactant: COC(=O)Cc1nc(Cl)nc(N2CCOCC2)c1SC
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)Cc1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1SC
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A mixture of (2-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl)-acetic acid methyl ester (420 mg, 1.47 mmol.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline) (357 mg, 1.62 mmol.), (PPh3)4Pd (170 mg, 0.07 mmol.), 2M Na2CO3 (2.2 ml, 4.14 mmol, 3.0 eq.) and dioxane (10 ml) was added a reaction vessel which was flushed with argon. The reaction mixture was stirred at 90° C. for 12 hr then dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and water, the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:2) to give a pale yellow solid of 424 mg (43.8%).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(O)cc2)CCN(C)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(4-methoxyphenyl)propan-2-ol (0.145 g, 0.39 mmol) in DCM (10 mL) at −78° C. was added borontribromide (0.293 g in 5 mL DCM). The reaction mixture was stirred at −78° C. for 30 min. and then at 25° C. for 1 h. The solution was poured into ice water, saturated NaHCO3 was added, and the mixture extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, 0-75% MeOH:DCM) to give the product as an off white solid, 20 mg. 1H NMR (CDCl3, freebase) δ (ppm): 7.25 (d, 1H), 7.10 (m, 3H), 6.98 (d, 1H), 6.70 (d, 2H), 4.109 (m, 2H), 3.82 (m, 2H), 2.80 (m, 2H), 2.60 (s, 3H), 2.42 (s, 3H), 2.38 (m, 2H), 1.60 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(P(=[CH:31][C:32]([O:34][CH3:35])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:31]/[C:32]([O:34][CH3:35])=[O:33])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2[nH]ccc2c1
Yield: 96.4 %

Procedure:
A solution of 1H-indole-5-carbaldehyde (0.217 g, 1.5 mmol) and methyl (triphenylphosphoranylidene)acetate (0.535 g. 1.6 mmol) in DCM (4 mL) was stirred in a flask under reflux overnight, then the solvent was removed under reduced pressure. Purification by silica gel column chromatography, with a mixture of DCM/Hexane 8:2 as eluent system, gave 0.291 g of methyl (2E)-3-(1H-indol-5-yl)acrylate (97% yield).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][OH:11].ON=C(N)C1C=CC=CC=1>CCO>[OH:11][N:10]=[C:8]([NH2:9])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: NO
Agent: NC(=NO)c1ccccc1
Solvent: CCO
Product: NC(Cc1ccccc1)=NO
Yield: 81.5 %

Procedure:
Benzyl cyanide (1 g, 8.5 mmol) and hydroxylamine (50% in water, 1.04 cm3, 17 mmol, 2 eq) in EtOH (8.5 cm3) were reacted in the same manner as in the preparation of N′-hydroxybenzimidamide (EtOAc used in extraction) to give the product N′-hydroxy-2-phenylacetimidamide (1.04 g, 81.9%) as a pale yellow solid, mp 63.5-64.5° C. (lit 57-59° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8].[CH2:9]([Mg]Br)[CH3:10].O>CCOCC.O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([NH2:8])[CH2:10][CH2:9]1
Reactant: N#Cc1ccccn1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NC1(c2ccccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyridinecarbonitrile (1.00 g, 9.60 mmol) in ether (30 mL) were added successively at RT titanium tetraisopropoxide (3.1 mL, 10.0 mmol) and 1.0 M of ethylmagnesium bromide in tetrahydrofuran (19 mL). After the mixture was stirred for 30 min, water (5.0 mL) was added. The mixture was extracted with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford the crude product which was directly used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[CH3:9][S:10][CH3:11].ClN1C(=O)CCC1=O.C(N(CC)CC)C>ClC(Cl)C.CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:9][S:10][CH3:11])[C:3]=1[NH2:8]
Reactant: CSC
Reactant: Nc1ccccc1Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CSCc1cccc(Cl)c1N
Yield: 82 %

Procedure:
2-Chloro-phenylamine (12.76 g, 0.1 mole) and dimethyl sulfide (10 ml) were dissolved in dichloroethane (200 ml) and cooled in an ice-acetone-salt bath under a nitrogen atmosphere. N-chlorosuccinimide (14.70 g, 0.11 mole) dissolved in dichloroethane (300 ml) was slowly added via addition funnel over about 20-30 minutes. After stirring an hour beyond addition while allowing the reaction to reach room temperature, triethyl amine (30 ml) was added and the mixture was brought to reflux for 1 h and 20 minutes. The reaction was monitored by tlc (15:85 EtOAc:hexane on silica gel) which showed a single less polar product. The mixture was cooled and evaporated to dryness. The residue was taken up in methylene chloride, dry packed on silica gel, and placed onto a column of flash silica gel. The product was eluted from the column with 1:9 ethyl acetate:hexane to give 15.4 g of a homogeneous oil (82%), 2-chloro-6-methylsulfanylmethyl-phenylamine.