Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2[C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:29]2[C:28]3[O:24][CH2:25][CH2:26][C:27]=3[CH:32]=[CH:31][CH:30]=2)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc2c1OCC2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCC3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-Dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=474.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]=2[CH:8]=[N:7]1)[CH3:2].[Cl-].[OH:18][NH3+:19].N.[Cl-].[NH4+]>C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[N:19][OH:18])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2=O
Reactant: [NH3+]O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cn1ncc2c1CCCC2=NO
Temperature: 25 °C

Procedure:
To a stirred solution of (4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (222 mg, 10 mmol) in ethanol (10 mL) was added hydroxylammonium chloride (74 mg, 10.5 mmol). The reaction mixture was heated at reflux for 1 hour. After cooling to room temperature, a solution of concentrated ammonia and saturated ammonium chloride (10 mL, 1:5, v/v) was added to the reaction mixture. The resulting solution was extracted with ethyl acetate (25 mL×3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo to give 4-hydroxyimino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (203 mg, 85%) as a white solid, which was used for the next step without further purification. The above white solid contained a pair of isomers in 10 to 1 ratio as determined by 1HNMR. for the major isomer, 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (s, 1 H), 4.89 (s, 2 H), 4.26 (m, 2 H), 2.73 (t, J=6.4 Hz, 2 H), 2.58 (t, J=6.4 Hz, 2 H), 2.10 (t, J=6.4 Hz, 2 H), 1.31 (t, J=7.2 Hz, 3 H). MS calcd. for C11H15N3O3 237, obsd. (ESI+) [(M+H)+] 238.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([CH3:24])[CH2:19][O:20]C(=O)C)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].ClCCl>C(O)C.O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C@@H:18]([CH3:24])[CH2:19][OH:20])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC[C@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: C[C@@H](CO)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 65 °C
Yield: 81.9 %

Procedure:
5.81 g of crude (R)-acetic acid 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-2-methyl-propyl ester (asserted 14.1 mmol)) were stirred in 26.6 ml of ethanol. A solution of 2.83 g of sodium hydroxide in 6 ml of water was added and the reaction mixture was heated at 60-70° C. for 5 h. After cooling to room temperature, 50 ml of water and 50 ml of dichloromethane were added. The dichloromethane layer was separated and the aqueous was extracted with a further portion of dichloromethane. The combined dichloromethane extracts were washed with water, dried over magnesium sulfate, filtered and evaporated under vacuum to give an orange oil (4.0 g).
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[F:33]C1C(N[C@H]2CCC[C@@H]2N)=NC=C(C(F)(F)F)C=1.N1N(C2C(C(O)=O)=NC=CC=2)N=CC=1>>[F:33][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ncccc1-n1nccn1
Agent: Cl
Agent: O=C(O)c1ncccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 122) from (1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 34; 100 mg, 0.33 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 66 mg, 0.35 mmol) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[CH2:14]([O:16]CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([C:5]([OH:9])=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1)[CH:14]=[O:16]
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Br
Reactant: CCOCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Br)cc(C(C)(C)C)c(O)c1C=O
Temperature: 25 °C
Yield: 61 %

Procedure:
A stirred, cooled (ice bath) solution of 4-bromo-2-tert-butyl-5-methyl-phenol (Intermediate 139, 0.85 g, 3.5 mmol) in anhydrous dichloromethane (7 mL) was treated with titanium tetrachloride (0.64 mL, 5.8 mmol) followed by α,α-dichloro methyl ether (0.3 g, 3.5 mmol). The reaction mixture was allowed to warm to ambient temperature for 4 h. The reaction mixture was diluted with diethyl ether, washed with brine (×1) and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230–400 mesh) using 1% ethyl acetate in hexane to afford the title compound as a yellow solid (0.58 g, 61%).
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>CC(O)C>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:13]=[CH:14][C:15]([NH:16][C@H:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:17][CH:18]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CC(C)O
Product: CC[C@H](CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 10.3 %

Procedure:
[RuCl(p-cymene)((R)-segphos)]Cl(17.6 mg, 0.0192 mmol), methyl 3-oxopentanoate (500 mg, 3.842 mmol), 4-trifluoromethylaniline (619 mg, 3.842 mmol) and 2-propanol (2.5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo, and the residue was purified by column chromatography on silica gel (eluent: hexane ethyl acetate=3/1) to give methyl (3R)-3-(4-trifluoromethylphenylamino)-pentanoate (109 mg) as a colorless oil in 10.3% yield. The enantiomeric excess of the product was found to be 92.7% ee determined by HPLC analysis using a SUMICHIRAL OA-2500 column (available from SUMIKA CHEMICAL ANALYSIS SERVICE LTD.).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=3)[N:7]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=2)[CH2:3][CH2:2]1.C([O:24][C:25](=O)[CH2:26][C:27]([CH3:29])=[O:28])(C)(C)C>C1(C)C(C)=CC=CC=1>[CH:1]1([C:4]2[N:8]([C:9]3[N:14]=[CH:13][C:12]([NH:15][C:25](=[O:24])[CH2:26][C:27](=[O:28])[CH3:29])=[CH:11][N:10]=3)[N:7]=[C:6]([C:16]([F:17])([F:18])[F:19])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Temperature: 145 °C
Yield: 30.9 %

Procedure:
Intermediate 38 (1.1 g, 4.08 mmol) and t-Butylacetoacetate (1.29 g, 8.17 mmol) were dissolved in xylene (2.9 ml) and heated to 145° C. for 90 mins Reaction mixture was cooled to rt to obtain a solid. Solid that formed was filtered, washed with petether and dried to obtain N-{2-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-5-yl}-3-oxobutanamide (445 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH3:35])[C:30]([S:36](Cl)(=[O:38])=[O:37])=[CH:29]2>ClCCCl.CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:36]([C:30]3[N:31]([CH3:35])[C:32]4[C:28]([CH:29]=3)=[CH:27][C:26]([F:25])=[CH:34][CH:33]=4)(=[O:38])=[O:37])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(S(C)(=O)=O)c2)CC1
Reactant: Cn1c(S(=O)(=O)Cl)cc2cc(F)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)cc2cc(F)ccc21
Temperature: 80 °C
Reaction time: 72 h
Yield: 24.8 %

Procedure:
To a solution of 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (cf. Example 24e, 0.048 g) in 1,2-dichloroethane (3.0 ml) was added 5-fluoro-1-methyl-1H-indole-2-sulfonyl chloride (0.035 g) and DMAP (0.025 g). The reaction mixture was stirred at 80° C. for 72 h, diluted with dichloromethane (2 ml) and chromatographed on silica gel using dichloromethane/ethyl acetate as eluent to obtain the title compound (0.019 g) as an off-white foam. MS (ISN): 564.3 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:10].[C:11]([S-:13])#[N:12].[K+].BrBr>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:10])=[CH:5][C:6]2[N:9]=[C:11]([NH2:12])[S:13][C:7]=2[CH:8]=1
Reactant: COc1ccc(N)cc1C
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1cc2sc(N)nc2cc1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-methoxy-3-methylbenzenamine (1.05 g, 7.66 mmol) in acetic acid (30 ml) at 0° C. as added KSCN with heavy stirring. The reaction mixture was then stirred at room temperature for 45 min. The reaction was cooled to 0° C. and bromine was added dropwise. The reaction was stirred at room temperature overnight. The precipitate was collected, washed by acetic acid, dichloromethane, minimal water and dried under high vacuum to give the product as brown yellow solid. LCMS-ESI+: calc'd for C9H10N2OS: 195.0 (M+H+). Found: 195.1 (M+H+).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17]O)=[CH:8][CH:7]=1.O.C(OCC)(=O)C>O1CCOCC1>[F:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][Br:2])=[CH:8][CH:7]=1
Reactant: OCc1ccccc1Cc1ccc(F)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccc(Cc2ccccc2CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
Phosphorus tribromide (6.4 ml, 67.3 mmol) was added dropwise to a solution of [2-(4-fluorobenzyl)phenyl]methanol (5.2 g, 24.05 mmol) in dioxane (125 ml). The reaction mixture was stirred for 1 hour at room temperature. Another portion of phosphorus tribromide (6.4 ml, 67.3 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. Water (60 ml) was added at 0° C. The reaction mixture was stirred for 30 min. Ethyl acetate (100 ml) was added. The phases were separated. The aqueous phase was washed with 1 N hydrochloric acid (100 ml). The combined aqueous phases were extracted with ethyl acetate (3×60 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane 1:3 as eluent, to give 5.96 g of 2-(4-fluorobenzyl)benzyl bromide.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:25]([C:23]3[CH:22]=[N:21][N:20]([CH2:19][C:18]4[CH:28]=[CH:29][C:15]([O:14][CH3:13])=[CH:16][CH:17]=4)[CH:24]=3)=[O:26])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2cc(C(=O)Nc3c[nH]c4ncc(Br)c(F)c34)cn2)cc1
Yield: 39.8 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (300 mg, 1.30 mmol, Example 1, Step H), 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (636 mg, 2.74 mmol), BOP—Cl (697 mg, 2.74 mmol), and triethylamine (0.909 mL, 6.52 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (230 mg, 39% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[BrH:12].BrBr>C(O)(=O)C>[Br:12][CH:9]([CH3:10])[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:11]
Reactant: CCC(=O)c1cnccc1C
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1ccncc1C(=O)C(C)Br
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-methylpyridin-3-yl)propan-1-one (4.72 g) in acetic acid (35 ml) was added hydrobromic acid (5.5 ml) and the mixture was cooled to 10° C. A solution of bromine (5.0 g) in acetic acid (15 ml) was gradually added to the reaction mixture and the mixture was stirred at 80° C. for one hr. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate to give the title compound (5.56 g) as a pale-yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:36]1[CH:40]=[CH:39][CH:38]=[N:37]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:36]2[CH:40]=[CH:39][CH:38]=[N:37]2)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](Cn2cccn2)CN1C(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.05 h
Yield: 21.6 %

Procedure:
To a stirred solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.96 g, 3 mmol) in DCM (10 mL) externally cooled in an ice-methanol bath was added triethylamine (0.91 g, 1.25 mL, 9 mmol) followed, dropwise over 0.05 h, methylsulfonyl chloride (0.38 g, 0.26 mL, 3.3 mmol). The mixture was stirred at 0-20° C. for 2 h, then pyrazole (0.27 g, 4 mmol) was added in one portion and stirring continued at 20° C. for 7 days. Mixture was poured into saturated aqueous NaHCO3 and extracted with DCM (3×20 mL). Combined organic extracts were dried (Na2SO4) then evaporated in vacuo to give an oil. Chromatography (SiO2, 0-100% Et2O in petrol) gave the title compound (0.24 g). MS: [M+H]+=371.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)([CH3:5])[CH2:3][OH:4].I[CH3:18].[H-].[Na+].O>CS(C)=O.CCOCC>[CH3:18][O:4][CH2:3][C:2]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)([CH3:1])[CH3:5]
Reactant: Cc1ccc2cccc(C(C)(C)CO)c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: COCC(C)(C)c1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution of 2-methyl-2-(2-methylquinolin-8-yl)propan-1-ol (0.43 g, 2.00 mmol) and iodomethane (0.37 mL, 5.99 mmol) in DMSO (10 mL) was added NaH (0.16 g, 3.99 mmol) at ambient temperature and stirred at ambient temperature for 30 minutes. Water (10 mL) and ether (40 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 8-(1-methoxy-2-methylpropan-2-yl)-2-methylquinoline (0.43 g, 93.0%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4cccc(C(F)(F)F)c4)C3)CC2)cc1
Yield: 87.8 %

Procedure:
The title compound (D195) (150 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinic acid (D137) (120 mg, 0.305 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (65.57 mg, 0.305 mmol).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][NH:36][CH3:37]>C1COCC1>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:20][N:36]([CH3:37])[CH3:35])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(OC[C@@H](O)CN(C)C)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (from intermediate A3) in 3 mL of dimethylamine in THF (2M) was stirred at 76° C. for 1 h in a microwave reactor. Upon completion (determined by LC/MS), the reaction was evaporated in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 96% EtOAc/(2M NH3/MeOH) as an eluent to afford (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:19]=[C:18]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:17]=2)=[CH:8][C:7]=1[CH3:43].[Li+].[OH-].O.Cl>C1COCC1.CO>[CH3:43][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:19]=[C:18]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:17]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:44])=[O:2]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of (2-methyl-4-{3-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(4-trifluoromethylphenylethynyl)-phenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester (0.26 g, 0.51 mmol) in THF (5.3 ml) and methanol (1 ml) was added a ice-cold solution of LiOH (1 M, 5.3 ml). The reaction mixture was stirred at 0° C. for 45 min., after which water (10 ml) and aqueous HCl (1M, 7.4 ml) were added. The mixture was extracted with ethyl acetate (2×80 ml), and the combined organic phases were dried and evaporated to give the title compound in 272 mg (94%) yield.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ncccc1C1CCOCC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (3.4590 g, 19.09 mmol), 4-aminophenol (3.12 g, 28.6 mmol), and cesium carbonate (18.66 g, 57.3 mmol) in DMSO (63.6 mL) at 110° C. to stir overnight. Reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed 50% sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in DCM, to provide 4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline. MS (ESI, pos. ion) m/z: 271.1 (M+1).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[CH2:23][CH2:22]1.[H][H].[Cl-].[NH4+]>C(OCC)(=O)C>[F:3][C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:28][CH2:29][CH:30]([OH:33])[CH2:31][CH2:32]2)[CH2:23][CH2:22]1
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(=O)CC4)CC3)c(F)c2)CC1
Reactant: [H][H]
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(O)CC4)CC3)c(F)c2)CC1
Temperature: 0 °C
Yield: 76.3 %

Procedure:
Sodium borohydride (0.99 g) and Solmix (40 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to 0° C. A Solmix solution in which 4′-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-bicyclohexyl-4-one (6) (10.7 g) synthesized according to the method described in Example 1 was dissolved in Solmix (40 ml) was added dropwise thereto, with caution in the evolution of hydrogen gas, and the mixture was stirred for 3 hours. A saturated aqueous solution of ammonium chloride (200 ml) and ethyl acetate (200 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed with brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=5:1 by volume) as an eluent and silica gel as a stationary phase powder. The product was further purified by means of recrystallization from a mixed solvent of heptane and Solmix (heptane: Solmix=1:1 by volume), and dried, giving 8.2 g of 4′-(2-fluoro-4-(4-pentylcyclohexyl)phenyl)bi(cyclohexane)-4-ol (15). The yield based on the compound (6) was 76.6%.