Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[N:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[N:23]=[CH:22][C:21]([C:20]([F:30])([F:19])[F:31])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncc(C(F)(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-trifluoromethyl-pyrimidine-2-carboxylic acid following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=434.2 [M+H]+.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:30][CH2:31]1)=[O:25])([CH3:3])[CH3:4]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and methanesulfonyl chloride. Light-yellow foam. MS (m/z): 491.2 (M+H)+.
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[CH:14]=[C:13]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[C:12]([Cl:34])=[CH:11][N:10]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH2:41].CCCCCC>C(OCC)(=O)C>[Cl:34][C:12]1[C:13]([CH:15]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:14][C:9]([NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:37]([O:36][CH3:35])[CH:38]=2)=[N:10][CH:11]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(Cl)ncc1Cl)c1c(F)cccc1F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2cc(C(c3c(F)cccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)cc1OC
Temperature: 150 °C
Yield: 30.3 %

Procedure:
To an N-methyl-2-pyrrolidone solution (20 ml) of the 2,5-dichloro-4-[(4-chlorophenylsulfonyl)(2,6-difluorophenyl)methyl]pyridine (755 mg, 1.68 mmol) obtained in Example 294 was added 3,4-dimethoxybenzylamine (0.745 ml, 5.04 mmol) under an argon atmosphere. The resulting mixture was heated at 150° C. for 5 hours. The reaction mixture was returned to room temperature and then, diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, water and brine, dried over magnesium sulfate, and concentrated. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated to give the title compound (295 mg, 0.509 mmol, 30%) as a white amorphous substance.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Cl:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Reactant: COC(=O)c1cc(F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3cc(F)ccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
Compound of example 6 (1.0 g, 3.2 mmol) in dry DMF (25 mL) was reacted with methyl 2-chloro-5-fluorobenzoate (1.22 g, 6.4 mmol) in the presence of NaH (50%, 0.776 g, 16 mmol) as described in example 16, to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][CH:19]([CH3:45])[CH:20]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:33]1[CH:32]=[CH:31][C:30]([CH:20]([CH:19]([CH3:45])[CH3:18])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:35][CH:34]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CNC(=O)OC(C)(C)C)C(C)C)cc1
Yield: 20 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-thieno[2,3-c]quinolin-4(5H)-one) (800 mg, 2.58 mmol) was reacted with tert-butyl 3-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (1.2 g, 3.09 mmol) to afford the desired product (250 mg, 20%) as a yellow solid: ESI MS m % z 493 [C28H32N2O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Br[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnn2)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccnn4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyridazin-3-yl)phenylboronic acid (80 mg, 0.37 mmol) was coupled to 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (94 mg, 0.37 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 2% methanol then trituration with diethyl ether gave 2-[3-(4-fluoro-3-(pyridazin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid: δH (400 MHz, CDCl3) 1.62 (6H, s), 4.46 (1H, s), 7.09 (1H, d, J 7), 7.41 (1H, dd, J 11 and 9), 7.61 (1H, dd, J 9 and 5), 7.64-7.68 (1H, m), 7.90 (1H, s), 8.07 (1H, dt, J 9 and 2), 8.43 (1H, dd, J 7 and 2), 8.72 (1H, d, J 7), 9.22 (1H, dd, J 5 and 2); m/z (ES+) 350 (M++H).
Reaction SMILES: Br.Br.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[S:29]>C1COCC1>[NH2:3][C:4]1[C:8]([NH:9][C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([F:19])([F:30])[F:31])=[S:29])=[CH:7][S:6][CH:5]=1
Reactant: Nc1cscc1N
Reactant: FC(F)(F)c1ccccc1N=C=S
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1cscc1NC(=S)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.8 g of 3,4-diaminothiophene dihydrobromide was added to a mixture of 0.74 g of N-ethyl-N,N-diisopropylamine in 40 ml of anhydrous THF, and the mixture was stirred at room temperature for 10 minutes, and then admixed with 0.58 g of 2-trifluoromethylphenyl isothiocyanate. The mixture was stirred at room temperature for 3 hours and at 40° C. for a further 10 minutes, and left to stand at room temperature overnight. After the solvent had been distilled off, the residue was admixed with water and extracted with ethyl acetate, and the insoluble fraction was filtered off. The organic phase was washed with water and dried over sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography on silica gel using a mixture of 1 part by volume of toluene and 1 part by volume of ethyl acetate.
Reaction SMILES: [Mg].BrCCBr.Cl[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.O>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)([OH:28])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: BrCCBr
Product: OC1(Cc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium metal (4.15 g, 170.5 mmol) in anhydrous THF (40 ml) is added 1,2-dibromoethane (1.53 g, 8.12 mmol) and the mixture warmed gently. To the reaction mixture is added a solution of 1-chloromethyl-4-fluoro-benzene (23.5 g, 162.4 mmol) in THF (20 ml) dropwise over 1.5 hours. The reaction mixture is cooled to RT and stirred for 0.5 hours followed by cooling to −10° C. and addition of a solution of 1-benzyl-piperidin-4-one (9.19 g, 48.6 mmol) in THF (20 ml) dropwise over 0.5 hours. During the addition the reaction temperature is maintained below 0° C. After addition is complete the reaction is allowed to reach RT and stirred for 4 days. The resultant suspension is cooled in ice, treated with saturated ammonium chloride, stirred for 0.3 hours, treated with water and the mixture extracted with ethyl acetate. The ethyl acetate is dried with magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (methanol:dichloromethane: anmuoniumhydroxide, 1:100:0.5 elution) to afford 1-benzyl-4-(4-fluoro-benzyl)-piperidin-4-ol [MH]+ 300.8
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(C)nn(C)c2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-chloro-1,3-dimethylpyrazole-4-sulfonyl chloride as described in the synthetic METHOD B to give a white solid (14.8 mg) with purity >90%. MS (pos) m/z 397.2, 381.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21](OCC)=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27].[CH2:28]([NH2:31])[CH2:29][CH3:30].[C-]#N.[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([NH:31][CH2:28][CH2:29][CH3:30])=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27]
Reactant: CCOC(=O)c1cc(NCc2c(C)cccc2CC)c2nc(C)c(C)n2c1
Reactant: CCCN
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CCCNC(=O)c1cc(NCc2c(C)cccc2CC)c2nc(C)c(C)n2c1
Yield: 42.4 %

Procedure:
Ethyl 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (0.12 g, 0.33 mmol), propylamine (1.0 g, 17 mmol) and a catalytic amount of sodium cyanide were refluxed in methanol (20 ml) for 24 h. An additional amount of propylamine (1.0 g, 17 mmol) was added and the reaction mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using diethyl ether as eluent. Crystallization from diethyl ether gave 0.053 g (42%) of the title compound. 1H-NMR (300 MHz, CDCl3): δ 1.0 (t, 3H), 1.2 (t, 3H), 1.65-1.75 (m, 2H), 2.3 (s, 3H), 2.35 (s, 3H), 2.38 (s, 3H), 2.7 (q, 2H), 3.4-3.5 (m, 2H), 4.35 (d, 2H), 4.9 (bs, 1H), 6.2 (bs, 1H), 6.35 (s, 1H), 7.0-7.2 (m, 4H), 7.85 (s, 1H).
Reaction SMILES: [C:1]([O:11]C)(=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][NH2:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][NH:25][C:1](=[O:11])[CH:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[OH:3])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COC(=O)C(O)c1ccccc1
Product: COc1ccc(CCNC(=O)C(O)c2ccccc2)cc1OC
Reaction time: 5 h

Procedure:
33.2 g (0.2 Mol) of methyl mandelate and 72 g (0.4 Mol) of 2-(3,4-dimethoxyphenyl)-ethylamine are heated to 160-165° C. under an N2 atmosphere with stirring, for 5 hours using a descending condenser (to remove the methanol released). The cooled residue is dissolved in 300 ml of ethyl acetate, washed twice with 100 ml of 2N HCl, once with saturated NaHCO3 solution and saturated NaCl solution, dried over MgSO4 and distilled off from the solvent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:17](=O)[CH3:18])[CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][N+:8]([O-])=O)[CH3:2].[F:21][C:22]1[CH:28]=[CH:27][C:25](N)=[CH:24][CH:23]=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][N:8]([C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=2)[C:17]=1[CH3:18])=[O:20])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(C[N+](=O)[O-])c1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)cn(-c2ccc(F)cc2)c1C
Yield: 52.4 %

Procedure:
A mixture of 2-acetyl-4-nitro-3-phenyl-butyric acid ethyl ester (4.26 g, 14.3 mmol), 4-fluoroaniline (1.75 g, 15.73 mmol), and TsOH monohydrate (136 mg, 0.72 mmol) in toluene (40 mL) was refluxed overnight, while the generated water was collected with a Dean-Stark distillation head; then the reaction was cooled, diluted with EtOAc, washed with diluted sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution respective, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified on column to give the desired title compound (2.422 g); ESI MS (m/z): 324 (M+H+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:6]2[CH2:12][CH2:13][OH:14].[CH2:22]1[NH:27][CH2:26][CH2:25][N:24]2[C:28](=[O:31])[CH2:29][CH2:30][CH:23]12.C(N(CC)CC)C>C(O)C>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:5]1[N:6]([CH2:12][CH2:13][OH:14])[C:7]2[C:3]([N:4]=1)=[C:2]([N:27]1[CH2:26][CH2:25][N:24]3[C:28](=[O:31])[CH2:29][CH2:30][CH:23]3[CH2:22]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: O=C1CCC2CNCCN12
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN3C(=O)CCC3C2)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Temperature: 82.5 °C
Yield: 75618.7 %

Procedure:
Charge a 500 mL three necked round bottomed flask with 2-[6-chloro-8-(2-chlorophenyl)-2-methyl-purin-9-yl]ethanol (13.3 g, 0.0412 mmol) and ethanol (200 mL), followed by 2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (6.365 g, 0.0453 mol) and triethylamine (14.8 mL, 3.5 eq). Heat the mixture to 80-85° C. for 24 h. Cool the reaction to room temperature and concentrate under vacuum to give a yellow solid as the crude product. Purify the crude material by column chromatography, using 400 g of silica gel and eluting with dichloromethane/methanol (50:1), to give the product as a yellow solid (13.3 g). 1H NMR (dmso-d6): δ 7.55-7.41 (m, 4H); 5.72 (bs, 2H); 4.16-3.92 (m, 3H); 3.71 (s, 2H); 3.71-3.68 (m, 1H); 3.02-2.93 (m, 2H); 2.74 (m, 1H); 2.70 (s, 3H); 2.44 (m, 2H); 2.32-2.29 (m, 1H); 1.76-1.69 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=1>>[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: ClCc1ccncc1
Reactant: O=C1CCNCC1
Agent: Cl
Product: O=C1CCN(Cc2ccncc2)CC1

Procedure:
1-(4-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidone and 4-picolyl chloride hydrochloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH:17]=[C:16]2[I:32])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>O1CCOCC1>[I:32][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:11]3[S:42][C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][N:10]=3)[CH:14]=2)[N:18]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NNC(=O)c4ccccc4)ccc32)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(-c5ccccc5)s4)ccc32)cc1
Temperature: 110 °C
Yield: 40.2 %

Procedure:
To a suspension of N′-benzoyl-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (1.29 g, 2.31 mmol) in dioxane (24 mL) at RT was added Lawesson's Reagent (1.40 g, 3.46 mmol) (Aldrich). The solution was heated to 110° C. for 3 h. The mixture was concentrated and the residue was purified with flash chromatography (eluting with 0-60% EtOAc in Hex) to give 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-phenyl-1,3,4-thiadiazole (518 mg, 40%) as a light yellow-orange crystalline solid after washing with Et2O. MS (ESI, pos. ion) m/z: 557.9 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 7.96-8.10 (5H, m), 7.81 (2H, d, J=8.4 Hz), 7.77 (1H, s), 7.48-7.55 (3H, m), 7.28 (2H, d, J=8.2 Hz), 2.37 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].CC(O)=O.[BH3-]C#N.[Na+]>CO>[C:13]([CH:17]1[CH2:18][CH2:19][CH:20]([NH:23][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=2)[CH2:21][CH2:22]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CNC2CCC(C(C)(C)C)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl-4-formylbenzoate (73 mmol, 12 g) in 200 mL of MeOH was added 4-tert-butylcyclohexylamine (74 mmol, 13.2 mL) via syringe. The reaction mixture was heated to reflux for 0.75 h, then was cooled in an ice bath. The resulting precipitate was filtered and the filter cake was washed with 2×20 mL of cold MeOH. The solid was dried under reduced pressure, then suspended in 224 mL of MeOH. HOAc (652 mmol, 37.4 mL) was added to the solution, followed by NaBH3CN (42.7 mmol, 2.68 g) in several portions. The reaction mixture was stirred at ambient temperature for 1.5 b, then concentrated under reduced pressure to ca. 25% of the initial volume. 400 mL of EtOAc was added to the solution and the mixture was washed with 3×200 mL of 5% NaHCO3 followed by brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 1:1 EtOAc/hexanes to afford the trans isomer as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.00 (d, 2H), 7.40 (d, 2H), 3.92 (s, 3H), 3.88 (s, 2H), 2.40 (m, 1H), 2.01 (m, 2H), 1.79 (m, 2H), 0.95-1.15 (overlapping m, 5H), 0.85 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Fc1cccc(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccc(F)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-3-fluorobenzene and isolated as light-yellow gum. MS (m/e): 425.3 (MH+).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:15](=O)[C@@H:14]([CH2:23][C:24](O)=[O:25])[O:13][C@H:12]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:11]=2[CH:34]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-]>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:15][C@@H:14]([CH2:23][CH2:24][OH:25])[O:13][C@H:12]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:11]=2[CH:34]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CN1C[C@@H](CCO)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 88.2 %

Procedure:
To tetrahydrofuran (20 ml) were added (3R,5S)-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (2 g) and aluminum lithium hydride (0.4 g). The mixture was heated for 6 hours under reflux, to which was added water. Insolubles were then filtered off. The filtrate was concentrated, which was purified by means of a silica gel column chromatography (hexane:acetic acid ethyl ester=2:1 v/v as an eluent) to give 1.65 g of non-crystalline solid matter.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[CH2:19][OH:20].[Br:30][C:31]1[CH:32]=[N:33][C:34](Cl)=[N:35][CH:36]=1.C(N(CC)C(C)C)(C)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][C:10]=1[CH2:19][OH:20])[C:34]1[N:35]=[CH:36][C:31]([Br:30])=[CH:32][N:33]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCc1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
{2-[(3,5-Bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-methanol (7.0 g) is dissolved in toluene (70 ml) and thereto are added 5-bromo-2-chloro-pyrimidine (4.7 g) and N,N-diisopropylethylamine (4.23 ml) and the mixture is heated under reflux for 3 days. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→13:2) to give (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-methanol (7.37 g). MS (m/z): 588/590 [M+H]+