Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[N:22]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:33][CH:30]2[CH2:29][CH2:28][N:27]([C:23]3[N:22]=[C:21]([C:20]([F:35])([F:34])[F:19])[CH:26]=[CH:25][N:24]=3)[CH2:32][CH2:31]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2nccc(C(F)(F)F)n2)CC1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NC2CCN(c3nccc(C(F)(F)F)n3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 80.7 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.70 mmol), 1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-ylamine (0.190 g, 0.77 mmol) and TEA (0.078 g, 0.77 mmol) was dissolved in dry MeCN (3 ml) and heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was purified by silica gel column chromatography using a 65:35 mixture of heptane and EtOAc as eluant, to give the title compound (0.280 g, 81%). 1H NMR (500 MHz, CDCl3): δ 8.45-8.41 (m, 1H), 7.58-7.52 (m, 2H), 7.49-7.42 (m, 3H), 6.74-6.70 (m, 1H), 5.26-5.19 (m, 1H), 4.59-4.51 (m, 2H), 4.41 (hep, 1H), 3.26-3.16 (m, 1H), 2.58-2.49 (m, 2H), 1.78-1.71 (m, 2H), 1.57 (d, 6H), 1.35-1.24 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 161.2, 160.3, 158.7, 156.6, 156.3, 134.5, 131.9, 130.2, 129.0, 125.3, 121.8, 119.6, 107.2, 104.9, 50.7, 47.9, 42.4, 32.2, 20.4; Mass Spectrum: M−H+ 496.
Reaction SMILES: CN(C=O)C.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[N:24]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[N:22][N:21]=2)=[CH:10][CH:9]=1.[CH2:44]([C:48]1[NH:52][C:51]([CH:53]=[O:54])=[C:50]([Cl:55])[N:49]=1)[CH2:45][CH2:46][CH3:47].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH2:44]([C:48]1[N:52]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[N:24]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]=[N:22][N:21]=3)=[CH:10][CH:9]=2)[C:51]([CH:53]=[O:54])=[C:50]([Cl:55])[N:49]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF (150 mL) solution of 5-(4′-bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole (30 g, 53.8 mmol) was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (10 g, 53.8 mmol) and K2CO3 (7.4 g, 53.8 mmol). The mixture was stirred at room temperature overnight. EtOAc (500 mL) was added and the organic was washed three times with a NaHCO3 solution (200 mL) followed by saturated aqueous NaCl (200 mL). Solvent was removed and purification was achieved by silica gel chromatography (50:50 EtOAc:hexanes) using an isocratic gradient to provide intermediate (11a) a white solid (41 g). MS m/z: [M+H+] calcd for C41H35ClN6O, 663.26. found 663.4. 1H-NMR (d4-MeOH): 0.83 (m, 3H), 1.26 (m, 2H), 1.53 (m, 2H), 2.53 (m, 2H), 5.56 (s, 2H), 6.87-6.96 (m, 8H), 7.05 (m, 2H), 7.25-7.43 (m, 10H), 7.53-7.58 (m, 2H), 7.84 (d, 1H), 9.73 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][F:35]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:33][CH2:34][F:35])[CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Reactant: FCCBr
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCN(CCF)CC3)c2)c2ccc(F)cc21
Yield: 100.7 %

Procedure:
Following the general method as outlined in Example 81, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 111 mg; 0.25 mmol) and 1-bromo-2-fluoroethane (64 mg; 0.50 mmol), 122 mg (100%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[C:31](O)=[O:32])[CH:24]=[CH:23]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:16]=1)[C:31]([C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[NH:22][CH:23]=[CH:24]2)=[O:32])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCNCc1ccc(C(C)(C)C)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
4.37 g (15 mmol) of 3-(4-tert-butyl-benzylamino)-propionic acid tert-butyl ester, 2.42 g (15 mmol) of 1H-indole-7-carboxylic acid and 3.25 g (16.5 mmol) of EDC.HCl were dissolved in 50 ml DCM. The reaction mixture was stirred at rt over night, washed twice with 1N aqueous HCl solution, once with 2N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave 6.25 g (97%) product as a white solid. MS (ISP) 435.4 (M+H)+.
Reaction SMILES: [N:1]1([CH2:12][CH2:13][OH:14])[C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[CH2:8][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][N:1]1[C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[CH2:8][C:4]=2[CH:3]=[N:2]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCn1ncc2c1-c1ccsc1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1ncc2c1-c1ccsc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0.50 g of 2-(1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazol-1-yl)ethanol was dissolved in 15 ml of methylene chloride, 1.00 ml of triethylamine and 0.28 ml of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with chloroform. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the drying agent by filtration, the resulting filtrate was concentrated under a reduced pressure to give 0.75 g of 2-(1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazol-1-yl)ethyl methanesulfonate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[N:10]1[CH3:26])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[N:10]1[CH3:26]
Reactant: Cc1c(N2C(=O)C(CNC(=O)OC(C)(C)C)N(C)C2=O)ccc(C#N)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N2C(=O)C(CN)N(C)C2=O)ccc(C#N)c1Cl
Yield: 180.1 %

Procedure:
A solution of the N-Boc-protected amine 13B (260 mg, 0.662 mmol) in CH2Cl2 (3 mL) and TFA (3 mL) was stirred at rt for 1.5 h. The solution was then concentrated under reduced pressure to afford the title compound (349 mg) as a brown foam as the TFA salt. 1H NMR (CD3OD) δ 2.32, 2.33 (s, 3H), 3.07, 3.09 (s, 3H), 3.49-3.64 (m, 2H), 4.50-4.52 (m, 1H), 4.63-4.65 (m, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.79, 7.80 (d, J=8.23 Hz, 1H); HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 1.50, 1.65 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 0.90, 1.11 min retention time (90%); MS (ES) m/z 293 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1.[Na+]>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:3])(=[O:15])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
Thionyl chloride (44.3 mL, 604 mmol, and 6.91 Eq) and N,N-dimethylformamide (DMF) (1 mL) were added to sodium 4-hydroxybenzenesulfonate (20.3 g, 87.2 mmol, and 1.00 Eq) under an argon atmosphere, and the mixture was stirred under reflux at 60° C. for 4 hours. The resultant mixture was cooled to room temperature and ice (160 g) was added thereto. The mixture was stirred and the water layer was extracted with dichloromethane (1×60 mL, 2×40 mL). The obtained organic layer was washed with ice water (40 mL) and dried with sodium sulfate. The solvent was removed by an evaporator and 4-hydroxybenzene sulfonyl chloride (10.4 g, 53.8 mmol, 62%) was obtained as oil.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[N+:11]([C:8]1[CH:7]=[C:3]([C:4]([O:6][CH3:18])=[O:5])[C:2](=[O:1])[NH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c[nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 2-hydroxy-5-nitronicotinic acid (0.80 g, 4.35 mmol, Combi-Blocks) in methanol (10 mL) at 0° C. was added thionyl chloride (1 mL) dropwise. The mixture was stirred at 0° C. for 1 h, then at 60° C. for 2 h. The excess methanol was removed under reduced pressure and the residue was neutralized with aqueous sodium bicarbonate solution. The solid was collected, washed with water and dried to afford the title compound (0.85 g, 99%). 1H NMR (DMSO-d6) δ 8.44 (s, 1H), 8.34 (s, 1H), 3.67 (s, 3H); MS(ESI+) m/z 199 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31].C(N(CC)CC)C>O1CCOCC1>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:28][CH2:29][CH:30]([OH:32])[CH3:31])=[C:3]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: CC(O)CN
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(O)CNc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Yield: 90 %

Procedure:
To a solution of 5-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole (3.0 g, 5.8 mmol) in 1,4-dioxane was added 1-amino-2-propanol (0.52 g, 7.0 mmol) and triethylamine (0.76g, 7.5 mmol). The mixture was heated at 100° C. for 2 hours. After extractive workup and recrystallisation from heptane-ethyl acetate (1:1) there was obtained 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(2-hydroxypropylamino)-4-trifluoromethylsulfonylpyrazole (Compound number 1-5, 2.67 g), 19F: −64.2; −80.9.
Reaction SMILES: [CH:1]([P:3](=[O:6])([CH3:5])[CH3:4])=[CH2:2].C[O-].[Na+].[P:10]([O-:15])([O:13][CH3:14])[O:11][CH3:12]>O1CCOCC1>[CH3:12][O:11][P:10]([CH2:2][CH2:1][P:3]([CH3:5])([CH3:4])=[O:6])(=[O:15])[O:13][CH3:14]
Reactant: COP([O-])OC
Reactant: C=CP(C)(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COP(=O)(CCP(C)(C)=O)OC
Yield: 53.2 %

Procedure:
95 g of vinyldimethylphosphine oxide are dissolved in dioxane and rendered alkaline with sodium methoxide solution. 100 g of dimethyl phosphite are added dropwise, in an exothermic reaction. The mixture is then subjected to fractional distillation, which gives 104 g of product, boiling point at 0.4 mm Hg: 182° C. (yield: 53% of theoretical). The first runnings of the distillation contain unreacted dimethyl phosphite and vinyldimethylphosphine oxide, which can be used again in a further batch.
Reaction SMILES: C(OC([C:8]1([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:20]=[CH:19][C:11]([C:12](N2C=CN=C2)=[O:13])=[CH:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].[NH2:44][CH2:45][CH:46]([OH:49])[CH2:47][OH:48]>C(Cl)(Cl)Cl>[OH:49][CH:46]([CH2:47][OH:48])[CH2:45][NH:44][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)C1(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)C=CC(C(=O)n2ccnc2)=CC1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(NCC(O)CO)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-(tert-butyloxycarbonyl)-4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals of N-(2,3-dihydroxypropyl)-4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:18].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+].[CH3:30][C:31]([CH3:33])=O>>[CH3:30][C:31]1([CH3:33])[NH:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8]([C:7](=[O:17])[C:6]=3[CH:5]=[CH:4][C:3]=2[NH:18]1)=[CH:9][CH:10]=[CH:11][CH:12]=4
Reactant: CC(C)=O
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)Nc2ccc3c(c2N1)C(=O)c1ccccc1C3=O
Reaction time: 48 h

Procedure:
1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in dry acetone (100 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto. After mixing and reacting in room temperature for 48 hours, the reacted mixture is transferred into a potassium carbonate column. The product is collected and recrystallized by methanol, so as to obtain the purple compound 20, and the production rate is 31%. In the purification steps of the Embodiment 21, regular extraction method will reduce the production rate, and thus the basic column is used to remove the acid in the rough extract, so as to increase the production rate.
Reaction SMILES: [CH2:1]([C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)[CH2:2][CH3:3].[H-].[Na+].[C:15]1([C:21]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:22]2[C:26]([C:27]3[C:32]([C:33]4[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:24]=[N:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:1]([C:4]1[N:12]([CH2:39][C:36]2[CH:35]=[CH:34][C:33]([C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[N:22]([C:21]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:23]=[N:24][N:25]=3)=[CH:38][CH:37]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)[CH2:2][CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1cc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc2cccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
To a stirred mixture of 2-propyl-1H-pyrrolo-[2,3-b]pyridine (29 mg, 0.18 mmol) in DMF (1 mL) was added NaH (6.7 mg of an 80% dispersion in oil, 0.271 mmol). After 20 min, N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (111 mg, 0.19 mmol) was added and the mixture was stirred for 30 min. Water was added and the mixture was extracted with EtOAc. Purification by flash chromatography (SiO2, 25% EtOAc/hexanes) gave 2-propyl-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)[1,1']-biphenyl-4-yl]methyl]-1H-pyrrolo[2,3-b]pyridine as a foam.
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](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:45]=[CH:44][S:43][C:42]=2[CH:46]=[O:47])O1>>[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]([C:41]2[CH:45]=[CH:44][S:43][C:42]=2[CH:46]=[O:47])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC1(C)OB(c2ccsc2C=O)OC1(C)C
Product: COc1cc(-c2csc3c(-c4ccsc4C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde were reacted together according to general procedure A to furnish the title compound. LCMS (Conditions a): MH+=539.0, RT=4.10 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.77 (s, 1 H), 9.53 (s, 1 H), 8.29 (d, J=5.3 Hz, 1 H), 7.98 (m, 2 H), 7.63 (m, 6 H), 7.36 (m, 1 H), 7.24 (s, 1 H), 7.15 (m, 1 H), 5.85 (br, 2 H), 4.04 (s, 3 H), 3.92 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([F:17])[CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([F:17])[CH:3]=1
Reactant: CC(=N[S@@](=O)C(C)(C)C)c1ccc(Cl)cc1F
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a stirred solution of the crude (S)—N-(1-(4-chloro-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (6.8 g, 24.7 mmol) in THF (200 mL) at −45° C. was added a solution of lithium tri-sec-butylborohydride (L-Selectride, 1.0 M in THF, 62 mL, 61.8 mmol) dropwise. The reaction was slowly warmed to room temperature and stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, and the crude material was purified by flash chromatography (SiO2, 25-70% ethyl acetate in hexanes) to afford the desired product as a viscous oil (5.4 g, 19.5 mmol, 79%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.CC([O-])(C)C.[K+].[SiH:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]
Reactant: Cn1ccc2ccccc21
Reactant: CC[SiH](CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2ccccc2n1C
Yield: 71.7 %

Procedure:
The reaction was conducted according to the General Procedure by heating N-methylindole (66 mg, 0.5 mmol, 1 equiv.), KOt-Bu (8.4 mg, 0.08 mmol, 0.15 equiv.) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 48 hours at 23° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica eluting with hexanes (isochratic) to obtain 88 mg (72%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.50 (dt, J=7.9, 1.0 Hz, 1H), 7.32 (dq, J=8.3, 0.9 Hz, 1H), 7.11 (ddd, J=8.2, 6.9, 1.2 Hz, 1H), 6.97 (ddd, J=7.9, 7.0, 0.9 Hz, 1H), 6.68 (d, J=0.9 Hz, 1H), 3.84 (s, 3H), 1.06-0.98 (m, 9H), 0.98-0.92 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 140.48, 136.86, 128.70, 121.44, 120.05, 118.51, 112.96, 108.71, 32.18, 6.83, 3.63. The HSQC spectrum of this reaction product as provided in FIG. 8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34].O>CN(C)C=O>[Cl:1][C:2]1[C:3](/[C:9](=[N:24]/[O:25][CH:33]([CH3:35])[CH3:34])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:22])[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)O/N=C(\CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.7 %

Procedure:
To a suspension of 300 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 315 mg of potassium carbonate in 3 ml of N,N-dimethylformamide, 195 mg of 2-iodopropane was added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was mixed with 20 ml of water and extracted with ethyl acetate (10 ml×2), the resulting organic layers were combined, washed with water (10 ml×2), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 258 mg of the desired product as white crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[O:7][C@@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:3])[CH3:2].[CH3:38]I>>[C:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[O:7][C@@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([N:23]([CH3:38])[C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1cccc(O[C@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Product: CC(=O)c1cccc(O[C@H](CCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure T and Scheme AD using N-(3-{1-[(3R)-3-(3-acetylphenoxy)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl iodide: ESMS m/e: 513.2 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([NH:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])[CH:12]([CH3:14])[CH3:13].[N:26]#[C:27]Br>O1CCCC1>[C:27]([N:15]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])#[N:26]
Reactant: CC(C)CNc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: N#CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CN(C#N)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Add lithium bis(trimethylsilyl)amide (45 mL, 1M in tetrahydrofuran) to a solution of N-[isobutyl]2-nitro-5-chloroaniline (5.2 g, 0.0226 mol) in tetrahydrofuran (50 mL) cooled in an ice bathe Stir for 30 minutes and add cyanogen bromide (5.3 g, 0.050 mol). Stir at room temperature for 3 hours. Concentrate under reduced pressure. Dissolve residue in dichloromethane, wash saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with hexane/ethyl acetate mixtures to provide 5.26 g (0.021 mol) of desired compound.