Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:34][CH2:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:33])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[I:43][CH3:44]>>[I-:43].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:34][CH2:35][CH2:36][CH2:37][N+:38]4([CH3:44])[CH2:39][CH2:40][CH2:41][CH2:42]4)=[O:33])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CI
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCCN2CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCC[N+]2(C)CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Product: [I-]
Yield: 68 %

Procedure:
5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-N-(3-pyrrolidin-1-ylpropyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide was reacted with iodomethane using an analogous method to that described in Step 2 of Example 4 to afford the title compound (154 mg, 68%) as a white solid; 1H NMR (500 MHz, DMSO) δ 1.82 (3H, s), 1.93 (2H, td), 2.10-2.01 (4H, m), 2.94 (3H, s), 3.31-3.27 (4H, m), 3.49-3.34 (4H, m), 6.72 (1H, d), 7.67 (2H, d), 7.71 (1H, d), 7.88-7.83 (2H, m), 7.97-7.91 (4H, m), 8.03 (1H, s), 9.40 (1H, t); APCI-MSm/z: 589[M+]
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[N:7][CH:6]=[N:5]1.Cl[C:12]1[C:13]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:19][N:20]=2)[N:17]=1>CN(C=O)C>[CH3:3][N:4]1[C:8]([CH2:9][O:10][C:12]2[C:13]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[N:19][N:20]=3)[N:17]=2)=[N:7][CH:6]=[N:5]1
Reactant: Cn1ncnc1CO
Reactant: Clc1nn2c(-c3cccnc3)nnc2cc1N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3cccnc3)nnc2cc1N1CCCC1
Reaction time: 18 h
Yield: 60.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 16 mg, 0.41 mmol) was added to a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (EP-A-421210; 40 mg, 0.35 mmol) in dry DMF (2 ml) at room temperature. After 1 h at room temperature a solution of 6-chloro-3-(pyridin-3-yl)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.33 mmol) was added and the reaction stirred for 18 h. The residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (2×100 ml). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 0-10% ethyl acetate-methanol to afford the title pyridazine (75 mg, 60%). 1H NMR (250 MHz, CDCl3) 1.99-2.04 (4H, m), 3.52-3.57 (4H, m), 4.01 (3H, s), 5.65 (2H, s), 6.69 (1H, s), 7.57 (1H, q, J=7.7, 4.8 Hz), 7.97 (1H, s), 8.60-8.68 (2H, m), 9.51 (1H, d, J=1.6 Hz); MS (ES+) 378 [MH]+.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[C:11]([O:15][C:16]([NH:18][CH:19]([CH3:23])[C:20]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)c1cccn1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccn1NC(=O)C(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
Methyl 1-amino-1H-pyrrole-2-carboxylate (6 g, 48.1 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (8.10 g, 48.1 mmol) were dissolved in ethyl acetate (40 ml) and cooled in an ice-bath. Under an argon atmosphere, diisopropylethylamine (24.6 ml, 141.2 mmol) was added and, after stirring for 15 min, T3P solution (35.7 ml, 60 mmol, 50% in ethyl acetate) was dropwise added. After stirring for 20 min at 0° C., the reaction was left overnight at room temperature. The reaction mixture was poured onto water and extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate and the solvent evaporated under reduced pressure. 8.6 g (83% yield) of the final product was obtained and use in the next synthetic step without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([Sn](CCCC)(CCCC)CCCC)=[N:27][NH:28]2)=[C:24]([F:44])[CH:23]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.[Cu](I)I.C(OCC)(=O)C>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:2]3[N:3]=[C:4]4[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]4=[N:6][CH:7]=3)=[N:27][NH:28]2)=[C:24]([F:44])[CH:23]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)cc(F)c12
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(Cl)cc(F)c34)cnc21
Temperature: 90 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (7.6 g, 18.6 mmol) and 6-chloro-4-fluoro-3-tributylstannanyl-1H-indazole (crude from Step 3) were dissolved in DMF (180 ml) and purged with Ar gas. Tetrakis(triphenylphosphine)pallladium (1.07 g, 0.93 mmol) and then copper iodide (707 mg, 3.71 mmol) were added and the flask was stoppered and stirred in a 90° C. oil bath for 20 h. The reaction was cooled and water, ethyl acetate and sodium bicarbonate solution were added. The layers were separated, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water and sodium chloride solution, then dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) followed by trituration with diethyl ether/hexanes to give 3.9 g (47%) of 2-(6-chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde. (M+H)+=446.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]([N+:15]#[C-:16])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:8][CH3:9].Cl.[C:25](=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]([N:15]([CH3:25])[CH3:16])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:8][CH3:9]
Reactant: O=C([O-])[O-]
Reactant: [C-]#[N+]C(CC)(Cc1cc(OC)c(OC)c(OC)c1)c1cccs1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCC(Cc1cc(OC)c(OC)c(OC)c1)(c1cccs1)N(C)C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
3.7 g of 1-(3,4,5-trimethoxybenzyl)-1-(2-thienyl)propyl isocyanide are dissolved in 40 ml of methanol, and 5 ml of conc. hydrochloric acid are added to the solution. The mixture is stirred at 50°-60° C. for 2 hours. After the reaction, the mixture is evaporated to remove solvent and the residue (i.e., crude 1-(3,4,5-trimethoxybenzyl)-1-(2-thienyl)propylamine hydrochloride) is dissolved in a mixture of 30 ml of methanol and 2.5 g of 35% formalin. 1.84 g of sodium cyanoborohydride are added to the solution and the mixture is stirred at room temperature for 3 hours. After the reaction, the mixture is evaporated to remove solvent and 10% hydrochloric acid is added to the residue. The mixture is stirred for 15 minutes. After the reaction, the mixture is alkalized with potassium carbonate and extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=2:1) to give 1.8 g of 1-(3,4,5-trimethoxybenzyl)-1-(2-thienyl)-N,N-dimethylpropylamine as a colorless oil. yield; 46.2%
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:31]([OH:33])=[O:32])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:31]([O:33][CH2:2][C:1]#[N:4])=[O:32])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
N,N-Diisopropylethylamine (46 μL, 0.263 mmol) and subsequently bromoacetonitrile (83 μL, 1.197 mmol) were added to a solution of (S)-6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk35) (100.9 mg, 0.239 mmol) in acetonitrile (0.4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 2.5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk36) (108.5 mg, 98%).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C:13](O)=[O:14])[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.[ClH:41].[CH3:42][O:43][C:44](=[O:47])[CH2:45][NH2:46].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[ClH:41].[O:1]=[C:2]1[N:11]([CH2:12][C:13]([NH:46][CH2:45][C:44]([O:43][CH3:42])=[O:47])=[O:14])[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Reactant: COC(=O)CN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.3 %

Procedure:
To a solution of 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid (1.20 g, 2.22 mmol) obtained in Example 50 and glycine methyl ester hydrochloride (278 mg, 2.66 mmol) in N,N-dimethylformamide (20.0 ml), diethyl cyanophosphonate (425 ml, 2.66 mmol) and triethylamine (926 ml, 6.65 mmol) were added sequentially, and then the reaction mixture was stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure, and the residue was combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (5:1, v/v) to give the methyl ester of the title compound (883 mg, 65%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][C:41]2[C:50]3[C:45](=[CH:46][C:47]([O:58][CH2:59][CH2:60][N:61]4[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]4)=[C:48]([O:51][CH2:52][CH:53]4[CH2:57][CH2:56][CH2:55][CH2:54]4)[CH:49]=3)[N:44]=[CH:43][N:42]=2)[CH:36]=[CH:37][C:38]=1[F:39].C(N(CC)CC)C>CN(C)C=O.O>[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][C:41]2[C:50]3[C:45](=[CH:46][C:47]([O:58][CH2:59][CH2:60][N:61]4[CH2:62][CH2:63][N:64]([C:7]([C@H:5]5[O:6][C:2](=[O:1])[CH2:3][CH2:4]5)=[O:9])[CH2:65][CH2:66]4)=[C:48]([O:51][CH2:52][CH:53]4[CH2:54][CH2:55][CH2:56][CH2:57]4)[CH:49]=3)[N:44]=[CH:43][N:42]=2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: O=C1CC[C@@H](C(=O)O)O1
Reactant: Fc1ccc(Nc2ncnc3cc(OCCN4CCNCC4)c(OCC4CCCC4)cc23)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](C(=O)N2CCN(CCOc3cc4ncnc(Nc5ccc(F)c(Cl)c5)c4cc3OCC3CCCC3)CC2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
72 mg of (S)-(+)-5-oxo-tetrahydrofuran-2-carboxylic acid are dissolved in 2.5 ml of N,N-dimethylformamide, combined with 183 mg of (benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-tetrafluoroborate and stirred for 30 minutes at ambient temperature. This solution is then added to a mixture of 250 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentylmethoxy-7-[2-(piperazin-1-yl)-ethoxy]-quinazoline and 110 μl of triethylamine in 2.5 ml of N,N-dimethylformamide. The reaction mixture is stirred for five hours at ambient temperature. For working up the mixture is poured onto 50 ml of water. A white precipitate is formed, which is suction filtered and washed with water. The crude product is purified by chromatography over an Alox column (activity stage III) with methylene chloride/methanol (98:2) as eluant. The desired product is obtained as a light-coloured solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH3:18][C:19]1[N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]3[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]3)=[CH:5][CH:4]=2)[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: Cc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc2ccccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 60 °C
Yield: 35.4 %

Procedure:
To a solution of 4-bromomethylphenylboronic acid pinacol ester (564 mg, 1.90 mmol) in acetone (19 mL) was added 2-methylbenzimidazole (377 mg, 2.85 mmol), potassium iodide (16 mg, 0.095 mmol) and K2CO3 (394 mg, 2.85 mmol) and the reaction mixture heated at 60° C. for 3.25 h. The reaction mixture was diluted with H2O and extracted with EtOAc (×2). The organic layers were combined, dried (phase separation cartridge) and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC-MS to afford 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]1H-benzoimidazole as an off-white solid (234 mg, 35%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](SC)=[C:18]([C:21]#[N:22])[C:19]#[N:20])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[NH2:26][NH2:27]>CO>[NH2:20][C:19]1[NH:27][N:26]=[C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:11][CH:12]=2)[C:18]=1[C:21]#[N:22]
Reactant: NN
Reactant: CSC(Nc1ccc(CNC(=O)OC(C)(C)C)cc1)=C(C#N)C#N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2n[nH]c(N)c2C#N)cc1

Procedure:
A mixture of 117.8 g (342 mmol) of 3-[4-(N-Boc-aminomethyl)-phenylamino)2-cyano-3-methylmercaptoacrylonitrile, 20.54 ml (41.45 mmol) of hydrazine hydrate and 750 ml of methanol is heated under reflux for 3 hours and then concentrated by evaporation in vacuo at 50° C., yielding 5-amino-3-[4-(N-Boc-aminomethyl)-phenylamino]-4-cyano pyrazole in the form of an amorphous residue; TLC-Rf=0.28 (methylene chloride/methanol [9:1]).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](=[O:8])[CH3:7])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.[Cl-].[Na+].O>[C:17]1([C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:1]2[CH:5]=[C:4]([C:6](=[O:8])[CH3:7])[N:3]=[CH:2]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1c[nH]cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(1H-imidazol-4-yl)ethanone (200 mg, 1.82 mmol) in DMF (4 mL) was introduced triethylamine (0.38 mL, 2.72 mmol) and trityl chloride (506.34 mg, 1.82 mmol). The reaction mixture was stirred at room temperature for 2 h. Aqueous brine solution (5 mL) was added to the reaction mixture and the product extracted with EtOAc (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute, 1-10% methanol gradient in DCM) to give the title intermediate as a clear oil: 1H NMR (500 MHz, CDCl3) delta 2.55 (3H, s), 7.18-7.06 (6H, m), 7.40-7.29 (9H, m), 7.44 (1 H, d, J=1.3 Hz), 7.58 (1H, d, J=1.4 Hz); LC-MS: m/z=+375.10 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:12]=[C:11]([CH:28]=O)[C:10]=2[OH:30])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>>[ClH:1].[C:31]([NH:35][CH2:28][C:11]1[CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][CH:19]=2)[CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[OH:30])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(CCCc2ccc(C(F)(F)F)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: CC(C)(C)NCc1cc(CCCc2ccc(C(F)(F)F)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: Cl

Procedure:
3-((tert-Butylamino)methyl)-3′,4′-dichloro-5-(3-(4-(trifluoromethyl)phenyl)propyl)-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 3′,4′-dichloro-2-hydroxy-5-(3-(4-(trifluoromethyl)phenyl)propyl)-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:44])([F:32])[F:45])=[CH:39][CH:38]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C(F)(F)F)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79 μmol), (4-trifluoromethyl-phenyl)-acetic acid (21.8 mg, 106 μmol) and DIPEA (48.94 μL, 277 μmol) in THF (3 mL), T3P (166 μL, 277 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as a white solid. (91%, 45 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: Nc1cccc(C(=O)O)c1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2cccc(C(=O)O)c2)C1
Yield: 69 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and 3-aminobenzoic acid, the title compound was isolated in 69% yield (98% purity by HPLC). MS(ESI+): 332.4; MS(ESI−): 330.6.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9](Cl)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([C:10]([F:13])([F:12])[F:11])=[N:17][N:16]=[N:15]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(N=C(Cl)C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Five grams (22.6 mmol) of N-(4-methylphenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 3, 2.68 g (40.7 mmol) of sodium azide, 1.57 g (11.3 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 23 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×3). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 5.01 g of 1-(4-methylphenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 97.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[N:16]O)[C:7]2=1.[OH2:18]>O1CCOCC1.CO>[F:1][C:2]1[C:14]2[N:13]([CH3:15])[C:12]3[CH2:11][CH2:10][CH2:9][NH:16][C:8](=[O:18])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: Cn1c2c(c3cccc(F)c31)C(=NO)CCC2
Solvent: CO
Solvent: C1COCCO1
Product: Cn1c2c(c3cccc(F)c31)C(=O)NCCC2
Reaction time: 1 h

Procedure:
A mixture of 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one oxime (1.8 g) and polyphosphoric acid (ca. 20 ml) in dioxan (30 ml) was stirred under nitrogen at 100°-110° for 1 h. After cooling, the reaction mixture was poured into iced water (1 l) and the resulting suspension was extracted with dichloromethane. The organic extract was concentrated in vacuo to give a solid which was taken up in methanol and adsorbed onto silica. Purification by FCC eluting with System A (200:8:1) gave the title compound (850 mg), m.p. 233°-235°.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1Cl
Yield: 57.8 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (500 mg, 2.23 mmol), the [3-chloro-4-(methyloxy)phenyl]boronic acid (831 mg, 4.46 mmol), copper (II) acetate (608 mg, 3.345 mmol), powdered molecular sieves (400 mg) and pyridine (0.36 mL, 4.46 mmol) in DCM (75 mL) were stirred at room temperature in the presence of air. After 5 days the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (1.06 g) was purified by flash chromatography (Biotage SP4, 40+M silica column) with a gradient of EtOAc (0 to 20%) in hexane to afford 470 mg of title compound (D33) containing an impurity.