Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](S(C)(=O)=O)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].[C:35](C1C=CC(B(O)O)=CC=1)(=[O:37])[CH3:36].BrC1C=CC([C@H](N[C@H](C(NC2(C#N)CC2)=O)CCC)C(F)(F)F)=CC=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:35](=[O:37])[CH3:36])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:32][CH3:33])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(C(C)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between 4-acetylphenylboronic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloromethane complex.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:30]([Cl:29])[CH:31]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 74.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (596 mg, 1.37 mmol, 74%) was obtained.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=4[F:47])[C:38]([CH3:48])=[C:37]([OH:49])[C:36]3=[O:50])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO.O>[NH:28]1[C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH:39]([C:40]4[C:41]([F:47])=[CH:42][CH:43]=[CH:44][C:45]=4[F:46])[C:38]([CH3:48])=[C:37]([O:49][CH3:3])[C:36]3=[O:50])=[CH:31][C:30]=2[N:26]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1c(F)cccc1F
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Solvent: O
Product: COC1=C(C)C(c2c(F)cccc2F)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (10 eq in water), diazald (5 eq), ethylene glycol/Et2O (3/1 v/v), 1-(1H-benzo[d]imidazol-6-yl)-5-(2,6-difluorophenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (0.189 g, 0.5 mmol, 1 eq) and MeOH/H2O (90/10 v/v); yield: 0.058 g (32.6%); MS m/z: 356.3 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.65-1.81 (s, 3H), 3.83-3.93 (s, 3H), 6.14 (s, 1H), 6.83-7.78 (m, 6H), 8.15 (s, 1H), 12.07-12.07 (bs, 1H); HPLC (METHOD [A]): rt 11.24 min (99%)
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]#[N:15].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[C:14]([C:3]1[S:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)=[CH:6][C:2]=1[NH:1][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[O:17][CH3:16])#[N:15]
Reactant: N#Cc1sc(-c2ccc(F)cc2)cc1N
Reactant: COc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)Nc1cc(-c2ccc(F)cc2)sc1C#N
Reaction time: 16 h
Yield: 74 %

Procedure:
A solution of 3-amino-5-(4-fluorophenyl)thiophene-2-carbonitrile (2.0 g, 9.2 mmol) in pyridine (40 mL) was cooled in an ice bath, and 2-methoxybenzoyl chloride (1.2 mL, 9.2 mmol) was added dropwise. The cooling bath was removed, and the reaction was stirred for 16 h. The reaction was poured into water, and the resulting suspension was acidified with 1 M hydrochloric acid. The solid was filtered, washed with water, and dried under vacuum to give N-(2-cyano-5-(4-fluorophenyl)thiophen-3-yl)-2-methoxybenzamide (2.4 g, 74% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]([OH:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH:20]([CH3:23])[C:21]#[CH:22])(=O)=O>O1CCCC1>[CH3:22][CH:21]([O:14][C@H:12]([CH3:13])[CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:20]#[CH:23]
Reactant: C#CC(C)OS(C)(=O)=O
Reactant: C[C@@H](O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(C)O[C@H](C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a suspension of sodium hydride (60 wt % dispersion in mineral oil) (1380 mg, 34.6 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was added (2R)-1-benzyloxypropan-2-ol (5.00 g, 30.1 mmol) dropwise. The solution was stirred at 0° C. for 1 h then 1-methylprop-2-ynyl methanesulfonate (4780 mg, 32.3 mmol) was added dropwise and the reaction mixture was allowed to warm to room temp and stirred overnight. The reaction mixture was quenched by the addition of sat. aq. ammonium chloride and extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was adsorbed onto silica and purified by column chromatography (0-20% EtOAc in Heptane) to afford the title compound as a yellow oil (2.36 g, 36%, mixture of diastereomers).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][CH:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=2)=[N:4][N:3]=1.CO.[OH-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][CH:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)=[N:4][N:3]=1
Reactant: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(OC2CCN(C)C2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nnc(-c2ccc(Oc3cc(OC4CCN(C)C4=O)cc(C(=O)O)c3)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
A solution of Methyl 3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-5-(1-methyl-2-oxopyrrolidin-3-yloxy)benzoate (7 g) (Intermediate 2) in a mixture of THF and to methanol (1:1 ratio) was treated with a solution of sodium hydroxide (2 g) in water and the reaction mixture was stirred for 1 h at room temperature. The resulting solution was concentrated under vacuum to remove THF and methanol, diluted with water, and washed with EtOAc. The aqueous phase was cooled and acidified with 0.1N HCl and extracted with DCM, combined organic extracts washed with brine, dried over Na2SO4 and concentrated in vacuo to give the product (3.5 g) as white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](N)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[I-:19].[K+].II>COCCOC.[Cu]I>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([I:19])[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [I-]
Reactant: Nc1ccnc(Nc2ccc3c(c2)OCCO3)c1
Agent: [Cu]I
Agent: II
Agent: [K+]
Solvent: COCCOC
Product: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Temperature: 62.5 °C

Procedure:
Isopentyl nitrile (Aldrich Chemical Company) (3.9 mL, 29 mmol) was added to a mixture of N2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-pyridine-2,4-diamine (Example 2(a), 2.4 g, 9.8 mmol), potassium iodide (Aldrich Chemical Company) (1.6 g, 9.8 mmol), iodine (Aldrich Chemical Company) (1.2 g, 4.9 mmol) and copper (I) iodide (Aldrich Chemical Company) (1.9 g, 9.8 mmol) in 1,2-dimethoxyethane (60 mL). The reaction mixture was heated at 60-65° C. for 1 hr.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:24])[CH:3]=2)[CH:30]=[CH:31][C:26]=1[F:25])=[O:36])[CH3:39]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 165, step 3) was reacted with 4-fluoro-3-ethoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=512.4 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH2:6][N:7]=1.[Br:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]=[C:14]([NH:16][C@H:17]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:18][NH:19][C:20](=[O:33])[C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](OC)=[O:30])=[CH:23][CH:22]=3)[S:15][C:11]=2[CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]=[C:14]([NH:16][C@H:17]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:18][NH:19][C:20](=[O:33])[C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29](=[O:30])[NH:1][C:2]4[NH:7][CH2:6][CH2:5][CH2:4][N:3]=4)=[CH:25][CH:26]=3)[S:15][C:11]=2[CH:10]=1
Reactant: NC1=NCCCN1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccc(Br)cc2s1
Reaction time: 3 h
Yield: 34.5 %

Procedure:
66 mg of 2-amino-1,4,5,6-tetrahydropyrimidine is added to a solution of 70 mg of 11-2 in 2 ml of THF, and agitation is carried out at ambient temperature for 3 hours. The reaction medium is then chromatographed eluting with a CH2Cl2/AcOEt mixture 80/20 then with MeOH/CH2Cl2 10/90. 27 mg of expected product 11-3 is obtained.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Br)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([N:26]([CH2:34][CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]#[CH:25]>C(#N)C.C(N(CC)CC)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:25]#[C:24][CH2:23][N:26]([CH2:34][CH2:35][CH2:36][O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C#CCN(CCCOC1CCCCO1)C(=O)OC(C)(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)CCCOC1CCCCO1
Reaction time: 2 h
Yield: 58 %

Procedure:
A suspension of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 2(i)) (0.43 g) and tert-butyl prop-2-ynyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate (Example 2(ii)) (0.60 g) in anhydrous acetonitrile (6 ml) and triethylamine (6 ml) was purged with nitrogen for 5 minutes and then copper (I) iodide (0.004 g) and bis-triphenyphosphine palladium dichloride (0.014 g) were added. The mixture was stirred under nitrogen for 2 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (19:1 to 7:3) to afford the sub-titled compound (0.39 g) as a yellow gum.
Reaction SMILES: [I:1][C:2]1[N:3](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1.CC(O)=O>CO.C1(C)C=CC=CC=1>[I:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1
Reactant: Cc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(I)n2)s1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(-c2c[nH]c(I)n2)s1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A mixture of 2-iodo-4-(5-methylthiophen-2-yl)-1-trityl-1H-imidazole 2 (2.57 g, 4.83 mmol) and AcOH (3 mL) in MeOH (120 mL) was heated under reflux (2 h). The mixture was allowed to cool to room temperature and then concentrated to give a residue. The residue was taken up in toluene and concentrated to five a residue. The residue was diluted with CH2Cl2, H2O, saturated aqueous NaHCO3 and the organic phase was separated. The aqueous phase was re-extracted (CH2Cl2) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 15:85 then 30:70 then 40:60) to give 2-iodo-4-(5-methylthiophen-2-yl)-1H-imidazole 3 (1.2 g, 86%) as a colourless solid. 1H NMR (CDCl3, 400 MHz) □ 2.48 (d, J=1.0 Hz, 3H), 6.65-6.68 (m, 1H), 7.03 (d, J=3.5 Hz 1H), 7.14 (s, 1H).
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O-])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3].N1CCCCC1.C=O>CCO>[CH2:1]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(C(=O)[O-])C(=O)OCC
Agent: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C(CCC)C(=O)OCC
Temperature: 23 °C
Yield: 48.5 %

Procedure:
To a solution of ethyl n-propylmalonate (41.3 g, 237 mmol, 1 equiv) in EtOH (500 mL) at 23° C. was added piperidine (28.1 mL, 284 mmol, 1.2 equiv) followed by aqueous formaldehyde (37%, 88 mL). Following the addition, the reaction was refluxed for 29 h. After cooling to 23° C., the mixture was partitioned between diethyl ether (500 mL) and 1.0 N HCl (800 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (500 mL). The combined organic layers were washed with H2O (500 mL), brine (300 mL), dried (MgSO4), filtered and carefully concentrated to avoid loss of the potentially volatile product. The product was vacuum distilled (bp 70° C. at 15 mmHg) to give 16.4 g 21c (R9=n-propyl) (115 mmol, 49%) of the desired product: 1H NMR shows contamination with unidentified material; the product was used in the subsequent step without further purification: 1H NMR (300 MHz, CDCl3) 6.12 (s, 1H), 5.50 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 2.23 (t, J=7.5 Hz, 2H), 1.55-1.42 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1.Cl.[CH3:17][O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=3)=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: COC1CCNCC1
Reactant: OCc1cccc(-c2cnc(Cl)nc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1CCN(c2ncc(-c3cccc(CO)c3)cn2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
[3-(2-Chloropyrimidin-5-yl)phenyl]methanol (200 mg) was mixed with DMF (4 ml), and 4-methoxypiperidine hydrochloride (180 mg) and potassium carbonate (500 mg) were added thereto, followed by stirring at 70° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {3-[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]phenyl}methanol (249 mg).
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.BrBr.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])[CH:20]=[CH:21][CH:22]=1.C(=O)(O)[O-].[Na+]>C(OCC)C>[OH:30][C:29]1([C:7]2[CH:8]=[CH:9][C:4]([C:3]([F:12])([F:11])[F:2])=[CH:5][CH:6]=2)[C:28]2[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26](=[O:35])[N:25]1[CH2:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Mg]
Solvent: CCOCC
Product: COc1cccc(CCN2C(=O)c3ccccc3C2(O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At room temperature, 172 mg (7.08 mmol) of magnesium turnings in 10 ml of absolute diethyl ether were admixed with 1.6 g (7.11 mmol) of 4-trifluoromethylbromobenzene. The reaction was started by addition of a drop of bromine. After about 2 h, the magnesium had completely dissolved. The mixture was cooled to 0° C. and 0.5 g (1.78 mmol) of N-(2-(3-methoxyphenyl)ethyl)phthalimide was added. The reaction mixture was allowed to warm to room temperature and, after 2 h, admixed with 5 ml of saturated sodium bicarbonate solution. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried and evaporated to dryness using a rotary evaporator. The red crystalline residue was recrystallized from toluene. This gave a colorless product. Yield: 0.49 g. M.p.: 167° C.
Reaction SMILES: C[Si](Cl)(C)C.C[O:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[I-].[Na+]>C(#N)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([CH2:8][OH:7])[CH2:10][CH2:11]2)=[CH:16][CH:17]=1)#[N:22]
Reactant: COC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc([C@H]2CC[C@H](CO)CC2)cc1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Trimethylsilyl chloride (305.6 g, 2.81 mol) was dropwise added to trans-4-methoxymethyl-1-(4-cyanophenyl)cyclohexane (322.5 g, 1.41 mol), sodium iodide (421.6 g, 2.81 mol) and acetonitrile (2.5 l), with stirring in nitrogen atmosphere at 35° C. over 30 minutes, followed by agitating the mixture for 20 minutes, cooling it down to 10° C., filtering the reaction mixture by suction, pouring the mother liquor in ice water (2 Kg), extracting with chloroform (1.5 l), twice washing the chloroform solution with a 10% by weight aqueous solution of sodium thiosulfate (0.5 l), further three times washing with water (1 l), distilling off chloroform, and three times recrystallizing the residue from toluene (300 ml) for purification to obtain trans-4-(4-cyanophenyl)cyclohexylcarbinol (182.5 g, 0.848 mol). M.P.: 108.5-110.8° C. A solution of this trans-4-(4-cyanophenyl)cyclohexylcarbinol (107.6 g, 0.500 mol) in dichloromethane (0.7 l) was instantaneously added to a solution of pyridinium chlorochromate (161.7 g, 0.750 mol) in dichloromethane (1 l), prepared in advance, with stirring, at room temperature, followed by agitating the mixture at room temperature for 1.5 hour, adding diethyl ether (1 l) to the resulting reaction solution, and subjecting the supernatant to column chromatography using Florisil® (made by Floridin Co., Ltd.) as a filler to obtain trans-4-(4-cyanophenyl)cyclohexylcarbaldehyde (101.2 g, 0.474 mol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][NH2:10])=[C:4]([F:11])[CH:3]=1.[C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)(=O)[CH3:13].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:12]([CH3:13])=[C:15]3[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)=[N:10]2)=[C:4]([F:11])[CH:3]=1
Reactant: NNc1cc(O)c(Cl)cc1F
Reactant: CC(=O)C1CCCCC1=O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: Cc1c2c(nn1-c1cc(O)c(Cl)cc1F)CCCC2
Yield: 88.1 %

Procedure:
4-Chloro-2-fluoro-5-hydroxyphenylhydrazine (0.5 g), 2-acetylcyclohexanone (0.4 g) and a catalytic amount of acetic acid were admixed with xylene (15 ml), and the resultant mixture was heated under reflux for 5 hours while removing water. After cooling, the mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain 0.7 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole. m.p., 188.5°-190° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.OC=[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:14]1[C:15](=[O:20])[CH2:16][CH2:17][CH2:18][C:19]2=1
Reactant: O=C1CCCCC1=CO
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: O=C1CCCc2c1[nH]c1ccc(C(F)(F)F)cc21

Procedure:
6-(Trifluoromethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared from 4-(trifluoromethyl)aniline (5.5 g, 34 mmol) and 2-(hydroxymethylene)cyclohexanone (3.9 g, 31 mmol) in a similar manner as described above to give 2.25 g (29%). of a dark brown solid. 1H-NMR (DMSO-d6): δ 12.05 (s, 1H), 8.11 (s, 1H), 7.56 (s, 2H), 3.00 (t, 2H), 2.58 (t, 2H), 2.19-2.13 (m, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:43]=[CH:42][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:34]3[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=3)([C:24]3[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[OH:23])=[CH:16][C:15]=4[CH3:40])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:44]1[CH2:47][CH2:46][CH2:45]1>CN(C=O)C>[N:44]1([C:12]2[C:11]([CH2:10][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:43][CH:42]=3)=[C:20]([Cl:21])[C:19]3[C:14](=[C:15]([CH3:40])[CH:16]=[C:17]([C:22]([C:34]4[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=4)([C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[OH:23])[CH:18]=3)[N:13]=2)[CH2:47][CH2:46][CH2:45]1
Reactant: Cc1cc(C(O)(c2ccc(C(F)(F)F)nc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Reactant: C1CNC1
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(c2ccc(C(F)(F)F)nc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(N3CCC3)nc12
Temperature: 100 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloro-8-methylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (200 mg, 0.321 mmol, Intermediate 68), azetidine (183 mg, 3.21 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The reaction vessel was then cooled to room temperature and the solvent and excess azetidine were removed by reduced pressure distillation. The crude residue was taken up into EtOAc, then extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C34H29ClF3N7O, 643.2. m/z found, 644.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.82 (d, J=2.2 Hz, 1H), 7.90-7.86 (m, 2H), 7.85 (d, J=2.5 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.61-7.58 (m, 1H), 7.58-7.54 (m, 2H), 7.36 (dd, J=2.3, 1.1 Hz, 1H), 7.19-7.15 (m, 2H), 7.14 (d, J=1.1 Hz, 1H), 6.73 (s, 1H), 6.45-6.40 (m, 1H), 6.24 (d, J=1.1 Hz, 1H), 4.29 (s, 2H), 4.13 (t, J=7.5 Hz, 4H), 3.33 (s, 3H), 2.58 (s, 3H), 2.28-2.19 (m, 2H).