Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:29][CH2:30][CH2:31][OH:32])[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[F:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]1([C:13]2[C:12]([N:24]([CH2:29][CH2:30][CH2:31][OH:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:36][C:35]5[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=5[F:33])=[CH:3][CH:4]=4)[N:9]=3)[CH:14]=2)[CH2:23][CH2:22]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Reactant: Nc1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccccc2F)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
A mixture of Compound (4) (16 mg, 31 μmol), 2-fluoroaniline (4.4 μL, 46 μmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (4 mg, 6 μmol) and cesium carbonate (30 mg, 92 μmol) in toluene (0.5 mL) and 1,2-dimethoethane (0.2 mL) was placed in a high pressure vial. Nitrogen was bubbled through the mixture for ˜20 min. Palladium acetate (0.7 mg, 3 μmol) was then added and the vial was sealed. The mixture was heated to 100° C. and stirred for 16 h. After cooling to RT, the mixture was diluted with EtOAc (10 mL) and filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give a crude mixture which was purified by flash column chromatography eluting with MeOH/DCM (0-20%). Further purification was done by preparative HPLC to give Compound (5) (3.68 mg, 22%) as a pale yellow solid. ESI-MS m/z calculated for [M+H]+: 552.21; found: 552.14. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.52 (s, 1H), 7.49-7.43 (m, 2H), 7.41 (dt, J=8.2, 1.5 Hz, 1H), 7.20-7.07 (m, 4H), 7.04-6.93 (m, 1H), 6.01 (brd, J=1.8 Hz, 1H), 5.71 (brd, J=4.6 Hz, 1H), 4.02-3.63 (m, 4H), 3.07 (s, 3H), 2.95 (d, J=4.9 Hz, 3H), 2.51-2.25 (m, 1H), 1.87-1.74 (m, 2H), 1.13-0.94 (m, 3H), 0.74-0.55 (m, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]12[N:14]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[F:23])[CH:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9][CH2:8]2>C1COCC1>[CH:11]12[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][C:16]=3[F:23])[CH:7]([CH2:13][CH2:12]1)[CH2:8][CH2:9][CH2:10]2
Reactant: N#Cc1ccc(N2C3CCCC2CC3)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(N2C3CCCC2CC3)c(F)c1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride (1.6 g; 43.2 mmol) in THF was treated with 4-(8-azabicyclo[3.2.1]oct-8-yl)-3-fluorobenzonitrile (2.48 g; 10.8 mmol) dropwise. After complete addition, the slurry was refluxed for 2 hours, allowed to cool to ambient temperature, and quenched with sodium sulfate decahydrate. The mixture was filtered and the filter cake was washed with THF (2×50 mL). The organics were combined and concentrated under reduced pressure. The residue was chromatographed (SiO2; 5% methanol in methylene chloride) to provide the title compound. 1H NMR (DMSO-d6) δ 7.03 (dd, 1H), 7.92 (dd, 1H), 7.85 (t, 1H), 4.21 (s, 2H), 3.60 (s, 2H), 1.93 (m, 2H), 1.77 (m, 5H), 1.42 (m, 1H), 1.32 (m, 2H); MS (ESI) m/z 235, (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C@:18]3([CH3:29])[C:23]([CH3:25])([CH3:24])[C:22](=[O:26])[N:21]([CH3:27])[C:20]([NH2:28])=[N:19]3)[CH:12]=2)[CH2:6]1.O.[Li+].[OH-]>C1COCC1.CO>[NH2:28][C:20]1[N:21]([CH3:27])[C:22](=[O:26])[C:23]([CH3:24])([CH3:25])[C@:18]([C:13]2[CH:12]=[C:11]([NH:10][CH:7]3[CH2:8][CH2:9][CH:5]([CH2:4][C:3]([OH:30])=[O:2])[CH2:6]3)[CH:16]=[CH:15][C:14]=2[F:17])([CH3:29])[N:19]=1
Reactant: COC(=O)CC1CCC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCC(CC(=O)O)C3)ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {3-[3-((S)-2-amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-4-yl)-4-fluoro-phenylamino]-cyclopentyl}-acetic acid methyl ester (example 95, 0.05 mmol) in THF (1 ml), MeOH (0.3 ml), and H2O (0.3 ml) was added LiOH (1N, 0.1 mmol) and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue diluted with aqueous HCl (0.5N) until pH=5 and EtOAc. The white solid which precipitate was filtered off, washed with H2O and dried. The organic phase was dried over Na2SO4 and evaporated to yield a white solid. The combined solid material was triturated with a mixture of dichloromethane and MeOH (10:1), filtered and the filtrate was concentrated in vacuo to yield a mixture of isomers of the title compound as a white solid. MS (ESI): m/z=405.5 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)cnn1C
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)cnn1C
Temperature: 78 °C
Yield: 74 %

Procedure:
1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.172 g, 0.4594 mmol) and ethyl formate (0.11 mL, 1.37 mmol) were dissolved in anhydrous ethanol (5 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.86 mL, 2.3 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a brown precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.136 g, 0.34 mmol, 74%).
Reaction SMILES: [Br-].[Li+].C[O:4][C:5](=[O:19])[CH:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][CH:6]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:5]([OH:19])=[O:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 95.4 %

Procedure:
Anhydrous lithium bromide (10.6 g, 121.8 mmol) was added to a stirring mixture of 2 (5.95 g, 24.4 mmol) in acetone (50 mL) under argon, and the mixture was refluxed for 2 hours. After cooling, the acetone was evaporated under reduced pressure, and the residue was taken up in ether (50 mL), washed with water (50 mL), brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the dibromide 3 (5.36 g, 86%) as an orange liquid; Rf(heptane-ethyl acetate, 8:2), 0.82. δH (400 MHz; CDCl3): 3.6 (2H, m), 3.45 (2H, m), 2.85 (2H, m), 2.1 (2H, m), 1.7 (2H, m; δc(400 MHz; CDCl3): 39.70, 33.79, 23.95.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([OH:31])[CH:23]=1>C1(C)C(C)=CC=CC=1.C(N(C(C)C)C(C)C)C.CCO>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:31][C:24]3[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A suspension of 7-(benzyloxy)-4-chloro-6-methoxyquinoline (20.00 g, 70.92 mmol) and p-nitrophenol (13.83 g, 100 mmol) in xylene (40 mL) and N-ethyldiisopropylamine (90 mL) was refluxed for 12 h. The mixture was cooled to rt and diluted with EtOH (200 mL). The solid was collected by filtration and dried in vacuo at 60° C. overnight to give the title compound as a pale yellow solid (22.6 g, 84.3%).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.N([O-])=O.[Na+].[F:15][B-](F)(F)F.[H+]>O>[Br:9][C:5]1[C:4]([CH3:10])=[N:3][C:2]([F:15])=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)nc(C)c1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-amino-5-bromo-4,6-dimethylpyridine (2 g) was suspended in fluoroboric acid (48% aqueous solution, 7.5 mL). Sodium nitrite (890 mg) dissolved in water (3 mL) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. The precipitated solid was collected by filtration and suspended in n-heptane (100 mL). The solution was stirred with heating under reflux for two hours. After cooling to room temperature, the precipitated solid was collected by filtration. The resulting solid was dried under reduced pressure to give the title compound (500 mg).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][O:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N)(=[S:16])C.O>FC(F)(F)C(O)=O>[NH2:2][C:1](=[S:16])[CH:3]1[CH2:8][O:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)N1CCC(C#N)CO1
Reactant: CC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)N1CCC(C(N)=S)CO1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of ethyl 5-cyanotetrahydro-2H-1,2-oxazine-2-carboxylate (i.e. the product of Step H) (0.63 g, 0.0034 mol) and thioacetamide (0.72 g, 0.0096 mol) in trifluoroacetic acid (about 2 mL) was stirred at 50° C. for 20 h. The reaction mixture was poured into water (10 mL) and extracted with diethyl ether (3×10 mL). The combined organic extracts were washed with water (10 mL), dried over magnesium sulfate, filtered and concentrated to provide an orange oil (about 0.76 g). The resulting oil was adsorbed onto Celite® (diatomaceous filter aid), and then purified by silica gel column chromatography (25% to 50% gradient of ethyl acetate in petroleum ether as eluant) to provide the title compound (0.19 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].S(Cl)([Cl:14])=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cccc(C(=O)O)c1
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)Cl)c1

Procedure:
A mixture of 50 g. of 3-cyanobenzoic acid and 100 ml. of thionyl chloride were stirred overnight in 500 ml. of methylene chloride. The solvent and excess thionyl chloride were removed in vacuo providing 55.3 g. of crude subtitle intermediate which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:17]([CH2:22][CH:23]=[CH2:24])[C:18]([O:20][CH3:21])=[O:19])[C:10](=[O:16])[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19])[C:10](=[O:16])[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](C(=O)OC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H](C(=O)OC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Step B (1.54 g) in ethyl acetate (30 mL) was added 5% palladium on carbon (298 mg). The reaction mixture was stirred under hydrogen (1 atm) at room temperature for 2 h, then filtered through a pad of Celite and concentrated to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2nccnc2Cl)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2nccnc2Cl)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
0.57 g of 5-(4-chlorophenyl)-4-(3-chloro-2-pyrazinyl)-6-methyl-2H-pyri dazin-3-one and 6 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.60 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.49 g of 3-chloro-5-(4-chlorophenyl)-4-(3-chloro-2-pyrazinyl)-6-methy lpyridazine (hereinafter, described as compound (12) of the present invention.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:15]([O:17]C)=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1(C(Cl)=O)[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C.[I-].[Na+]>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([C:15]([OH:17])=[O:16])=[N:11][C:12]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncccc1OCc1ccccc1
Reactant: O=C(Cl)N1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1nc(N2CCCC2)ccc1OCc1ccccc1
Yield: 83 %

Procedure:
6.48 g (25 mmol) of methyl 3-benzyloxypicolinate (N-oxide), 6.68 g (50 mmol) of 1-pyrrolidinylcarbonyl chloride, 6.46 g (50 mmol) of N,N-diisopropylethylamine and 7.49 g (50 mmol) of sodium iodide were refluxed under heating for two hours in 120 ml of acetonitrile. The solvent was distilled off, and water was added to the residue. The mixture was extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained mixture was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:30]=[O:31])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:13][CH:12]=1)=[O:10].[CH3:33][Mg]Br>O1CCCC1.C(OCC)C>[Cl:32][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:30]([OH:31])[CH3:33])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:13][CH:12]=1)=[O:10]
Reactant: C[Mg]Br
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(C(C)O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide (0.1 g, Example 17) in tetrahydofuran (3 ml), at 0° C., was treated with a solution of methylmagnesium bromide in diethyl ether (0.11 ml, 3M). The mixture was allowed to warm to room temperature then stirred for 2 hours. The reaction mixture was quenched with water (15 ml) and then extracted with ethyl acetate (15 ml). The organic extract was dried over sodium sulphate then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (2:1, v/v) to yield the title compound (68 mg) as a white solid, m.p. 206-211° C. [Elemental analysis:—C, 55.07; H, 4.00; N, 7.92%. Calculated for C23H19Cl2N3O4S:—C, 54.77; H, 3.80; N, 8.33%].
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([O:31][CH3:32])[CH:23]=2)[N:17]=1>[OH-].[K+]>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([O:31][CH3:32])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Yield: 100.4 %

Procedure:
The solution of N-(4-chloro-3-(1-(3-methoxy-4-nitrophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.500 g, 1.06 mmol) in 20% aq. KOH (20 mL) was stirred for 2-3 h at RT. Excess of solvent was removed under vacuum and filtered off remaining reaction mass to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.80 (br s, 2H), 3.72 (s, 2H), 3.91 (s, 3H), 7.27-7.39 (m, 2H), 7.78 (d, J=9.9 Hz, 2H), 8.98 (d, J=8.7 Hz, 1H), 8.25 (s, 1H); MS (m/z): 375.91 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[I-].[Na+].Br[CH2:17][CH2:18][CH2:19]Br.Cl>CS(C)=O.C1OCCOCCOCCOCCOC1>[C:10]([C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:19][CH2:18][CH2:17]1)#[N:11]
Reactant: COc1cccc(CC#N)c1
Reactant: BrCCCBr
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: CS(C)=O
Product: COc1cccc(C2(C#N)CCC2)c1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a solution of (3-methoxyphenyl)acetonitrile (3.0 g, 20.0 mmol) in DMSO (120 ml) was added 3 drops of 15-crown-5 and sodium hydride (60% w/w dispersion in mineral oil, 1.6 g) at room temperature and the reaction mixture was stirred for 30 min. Sodium iodide (3.6 g 24 mmol) and 1,3-dibromopropane (8.0 g 40 mmol) were added and the mixture stirred overnight. 2N HCl (50 ml) was added and the mixture extracted with ether (100 ml×2). The combined extracts were washed with water (100 ml×2) and brine (100 ml ), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 300 g; hexane/ethyl acetate (20/1)) to afford 2.10 g (56%) of titled compound as a colorless oil.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([C@H]1CC[C@H](O)CC1)(C)(C)C>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](O)CC1
Product: CC(C)(C)C1CCC(O)CC1

Procedure:
A commercially available mixture consisting of 28% cis-4-tert-butyl cyclohexanol and 72% trans-4-tert-butyl cyclohexanol was purified via preparative HPLC to obtain the essentially pure cis- and trans-isomers of 4-tert-butyl cyclohexanol.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][OH:23].[CH2:24](N(S(F)(F)F)CC)C.CO>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][O:23][CH3:24]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2CO
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2COC
Reaction time: 4 h

Procedure:
65 mg of the compound (177) obtained in Example 54 was suspended in 5 ml of tetrahydrofuran, and 270 μl of diethylaminosulfurtrifluoride was added to the solution. The solution was stirred for 4 hours, and 1 ml of methanol was added to the solution. The deposited solid matter was filtered off and washed with ether to obtain 34 mg of the subject compound (180).
Reaction SMILES: [N:1]([CH:4]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N+]=[N-]>C1COCC1.O=[Pt]=O>[NH2:1][CH:4]([C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N=[N+]=[N-])c1ccc(Cl)cc1)C(=O)OCc1ccccc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N)c1ccc(Cl)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl [2-azido-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (30 mg, 0.05 mmol) in THF (1 mL) was added PtO2 (8 mg) and the reaction was stirred at room temperature under hydrogen for 1 hour. The catalyst was removed by filtration through a plug of Celite with 100% EtOAc and the filtrate was concentrated to afford crude benzyl [2-amino-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.66 (25% EtOAc/hexanes). LCMS=611.3 (M+1)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])=[C:11]([CH2:26][N:27]([CH2:45][C:46]2[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[C:48]([C:56]([F:59])([F:58])[F:57])[CH:47]=2)[C:28]2[N:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:30][N:29]=2)[CH:10]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:59][C:56]([F:57])([F:58])[C:48]1[CH:47]=[C:46]([CH:51]=[C:50]([C:52]([F:53])([F:54])[F:55])[CH:49]=1)[CH2:45][N:27]([CH2:26][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[O:24][CH3:25])[C:28]1[N:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])=[CH:32][N:33]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(O)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
Tert-butyl 4-{2-[(4-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.0 g) is dissolved in ethanol (20 ml), and thereto is added 10% palladium-carbon (200 mg), and the mixture is stirred under hydrogen atmosphere at room temperature for 4 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure, and thereto is added hexane and the resulting crystal is filtered to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-hydroxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (835 mg). MS (m/z): 734 [M+H]+