Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].Cl[C:20]1[CH:21]=[C:22]([N:30]=[C:31]=[O:32])[CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27].C(Cl)[Cl:34]>>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:31]([NH:30][C:22]2[CH:23]=[CH:24][C:25]([C:26]([F:29])([F:28])[F:27])=[CH:20][C:21]=2[Cl:34])=[O:32])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Reactant: ClCCl
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)cc1-c1c(Br)cnn1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 3-chloro-4-trifluoromethyl-phenyl isocyanate (0.059 g, 0.263 mmol) and stirred overnight at ambient temperature. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 53 as a colorless solid (0.1 g, 73%). LCMS m/z (%)=535 M+H+ (81Br 37 Cl, 39), 533 M+H+ (81Br 35Cl, 100), 531 M+H+ (79Br 35Cl, 63), 1H NMR (400 MHz, DMSO-d6) δ: 8.582 (bs, 1H), 8.456 (bs, 1H), 7.864 (s, 1H), 7.654 (d, J=8.28 Hz, 1H), 7.557 (d, J=2.76 Hz, 1H), 7.536 (d, J=2.76 Hz, 1H), 7.369 (d, J=9.13 Hz, 1H), 4.133 (m, 1H), 3.752 (s, 3H), 1.375 (d, J=6.61 Hz, 3H), 1.217 (d, J=6.61 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.C[Mg]Br.O1CC[CH2:25][CH2:24]1>CCOCC>[CH2:24]([C:2]1([OH:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1)[CH3:25]
Reactant: O=C1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a vigorous stirring solution of benzyl (4-oxocyclohexyl)methylcarbamate (1 g) in tetrahydrofuran (20 mL) at −78° C. was slowly added 1 Methylmagnesium bromide (11.48 ml, 11.48 mmol) in ether. After completion of the addition, the mixture was stirred at −78° C. for 2 hours and was warmed to 0° C., and stirred in an ice bath for 30 minutes. The reaction was quenched with a cold NH4Cl aqueous solution. The precipitates were filtered off and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane and loaded onto Analogix purification system, and was eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH2:13]C([O-])=O.[K+]>C1(C)C=CC=CC=1>[C:1]1([C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[CH:13]/[C:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[O:6]1)=[O:11]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: O=C1OC(=O)c2ccccc21
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)/C=C1\OC(=O)c2ccccc21
Yield: 52 %

Procedure:
14.8 g (0.1 mol) of phthalic anhydride and 9.9 g (0.05 mol) of potassium tert-butyl malonate are added to 200 ml of toluene, and the reaction mixture is heated under reflux for 6 hours. After terminating the reaction, 100 ml of water is added, and an organic layer is separated out. The organic layer is washed with 100 ml of 5%-aqueous ammonium bicarbonate solution, and toluene is distilled off under a reduced pressure. The residue thus obtained is purified by column chromatography, to give 6.4 g (0.026 mol) of tert-butyl (Z)-3-phthalidylideneacetate. The yield is 52.0%.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.[CH2:14](O)[CH3:15]>B(F)(F)F.CCOCC>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:13]([C:15]3[CH:14]=[CH:9][CH:7]=[CH:6][CH:5]=3)=[CH:12][CH:11]=[N:1][C:2]=12)=[O:8]
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Reactant: CCO
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(c1ccco1)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 0.86 g of (3-amino-1H-pyrazol-4-yl)-2-furanylmethanone and 0.63 g of 1-phenyl-1-propynone in 35 ml of ethanol with several drops of boron trifluoride etherate was refluxed for 18 hours. The solvent was removed and the residue chromatographed on silica gel with ethyl acetate:hexane (1:20) as eluent and a gradual change to ethyl acetate:hexane (2:5). Elution with ethyl acetate gave a solid which was recrystallized from dichloromethanehexane, giving the desired product, mp 185°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][NH:19]2.C(NCC)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][NH:19]2
Reactant: Clc1ccccc1CCC1CCCN1c1ncnc2[nH]cnc12
Solvent: CO
Solvent: CCNCC
Product: Clc1ccccc1CC[C@@H]1CCCN1c1ncnc2[nH]cnc12
Yield: 42.4 %

Procedure:
110 mg of the racemate 6-{-2-[2-(2-chlorophenyl)ethyl]pyrrolidin-1-yl}-9H-purine are dissolved in 7 ml of methanol and 2 ml of diethylamine and divided into 9 vials. The solutions are separated by means of supercritical CO2 (SFC) on Chiralcel OD-H using 5 ml/min of CO2+40% of MOH0, 5 DEA, giving 46.6 mg of 6-{(R)-2-[2-(2-chlorophenyl)ethyl]pyrrolidin-1-yl}-9H-purine (“A5b”) having an enantiomer ratio of 98.8%:1.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].CS(O[CH:27]([C:42]#[N:43])[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:29]=1)(=O)=O>C1COCC1.CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH:27]([C:42]#[N:43])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:29]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Reactant: CS(=O)(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Reaction time: 48 h

Procedure:
3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (0.82 g, 3.40 mmol) is stirred together with 0.34 g (3.40 mmol) potassium bicarbonate in 10 ml THF/DMF (1:1) for 15 minutes. Then 1.0 g (3.40 mmol) α-cyano-4-fluoro-3-phenoxybenzyl methanesulfonate in 5 ml THF/DMF (1:1) is added and the mixture stirred for approximately 48 hours. The reaction is diluted with ether, washed with water (3×) and sat. NaCl, dried and solvent is removed. The crude product is purified by prep. TLC developing with 10% ethyl acetate/hexane to yield α-cyano-4-fluoro-3-phenoxybenzyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]1[CH2:18][O:19][CH3:20])[CH3:2].[CH3:21]OC(C1OC=CC(=O)C=1OCC1C=CC=CC=1)C>>[CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]1[CH:18]([O:19][CH3:20])[CH3:21])[CH3:2]
Reactant: COC(C)c1occc(=O)c1OCc1ccccc1
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Product: CCn1ccc(=O)c(OCc2ccccc2)c1C(C)OC
Yield: 29.6 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one using 2-(1-methoxyethyl)-3-benzyloxy-pyran-4(1H)-one 3.12 g (12 mmol, 1 eq.) yielded the title compound (1.03 g, 29.6%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:31])[CH:28]([CH3:30])[CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36].CCN=C=NCCCN(C)C>N1C=CC=CC=1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][CH:27]([NH:31][C:35]([C:34]3[C:33]([CH3:32])=[N:41][CH:40]=[CH:39][CH:38]=3)=[O:36])[CH:28]([CH3:29])[CH3:30])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC(C)C(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ncccc1C(=O)NC(CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12)C(C)C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 76.7 %

Procedure:
To a solution of 4-(2-amino-3-methyl-butyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide (1.47 g, 3.31 mmol) in pyridine (35 mL) was added 2-methyl-nicotinic acid (544 mg, 3.97 mmol) and EDCI (1.02 g, 5.30 mmol). The solution was stirred 6.5 hours at room temperature, then diluted with water (100 mL). The mixture was poured into a separatory funnel and diluted further with water (50 mL) and EtOAc (150 mL). The layers were shaken and separated. The aqueous layer was extracted with EtOAc (3×50 mL), then the combined organic layers were washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield an orange semi-solid residue which was purified via column chromatography. The resulting yellow solid was placed on the high-vacuum pump overnight, after which 1.43 g of 6,6-dimethyl-4-{3-methyl-2-[(2-methyl-pyridine-3-carbonyl)-amino]-butyl}-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide was obtained (77% yield).
Reaction SMILES: ClC1C=CC=CC=1C(Cl)=O.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[CH:24]=[CH:23][C:22]=1[C:28]1[C:33]([C:34]2[NH:35][CH:36]=[CH:37][N:38]=2)=[CH:32][N:31]=[C:30]([NH:39][CH2:40][CH2:41][NH:42]C2C=CC([N+]([O-])=O)=CN=2)[N:29]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[C:33]([C:34]2[NH:38][CH:37]=[CH:36][N:35]=2)=[CH:32][N:31]=[C:30]([NH:39][CH2:40][CH2:41][NH:42][C:12]2[N:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)[N:29]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C(Cl)c1ccccc1Cl
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccccc3Cl)n2)nc1

Procedure:
6-[(2-{[4-(2-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]-pyridine-3-carbonitrile was prepared from 2-chlorobenzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:20]CC4C=CC(OC)=CC=4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][N:16]=1)[N:13]=[CH:12][C:11]([C:30]#[N:31])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(F)c(Cl)c4)c(C#N)cnc3cn2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc2cnc(N)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 63.1 %

Procedure:
A solution of 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-methoxybenzyl)amino]-1,7-naphthyridine-3-carbonitrile (0.623 g, 1.45 mmol) and trifluoroacetic acid (14.5 mL) in methylene chloride 14.5 mL was stirred at room temperature overnight. The reaction was diluted with toluene and the solvents were evaporated. The crude product was purified by flash column chromatography (3% MeOH in CHCl3) to give a yellow solid (0.287 g, 64%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 7.1 (s, 1 H) 7.3 (m, 1 H) 7.5 (t, J=9.0 Hz, 1 H) 7.6 (dd, J=6.2, 2.4 Hz, 1 H) 8.4 (s, 1 H) 8.8 (s, 1 H) 10.0 (s, 1 H)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1COCC1.CCCCCC>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: CC1CO1
Reactant: FC(F)(F)c1ccccc1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
General Procedure HH: To a solution of 1-iodo-2-(trifluoromethyl)benzene (1.5 g, 5.5 mmol) in THF (10.0 mL) was added 2.5 M of n-BuLi in hexane (2.2 mL) at −78° C. and stirred for 10 min. Propylene oxide (370 mg, 6.4 mmol) was added to the reaction mixture at −78° C. and slowly warmed to rt. The reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a yellow oil. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to yield the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.30 (d, J=6.1 Hz, 3H), 1.46 (d, J=4.3 Hz, 1H), 2.82-3.06 (m, 2H), 4.03-4.12 (m, 1H), 7.32-7.38 (m, 1H), 7.41-7.45 (m, 1H), 7.48-7.53 (m, 1H), 7.67 (d, J=8.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([N:14]([CH2:20][C:21]1[N:25]([CH3:26])[C:24]([CH3:27])=[CH:23][N:22]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1CCl.[CH3:38]N(C)C=O.[OH-].[K+]>O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([N:14]([CH2:20][C:21]1[N:25]([CH2:26][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[C:24]([CH3:27])=[C:23]([CH3:38])[N:22]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13]
Reactant: CN(C)C=O
Reactant: COc1ccc(C(=O)N(CCC(C)C)Cc2ncc(C)n2C)c(Cl)c1OC
Reactant: COc1ccccc1CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Cn1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc(C)c1C
Temperature: 40 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
A mixture of 0.74 g (1.9 mmol) of (2-chloro-3,4-dimethoxyphenyl)-N-(3,4-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide, 0.94 g (6.0 mmol) of 2-methoxybenzyl chloride, 10 mL of dimethylformamide and 0.63 mL (8.0 mmol) of 50% KOH is stirred vigorously under nitrogen at 40° C. for 20 h. The reaction mixture is poured into 100 mL of water and extracted with 50 mL of chloroform. The extract is washed with 100 mL of water, and the solvent is evaporated under reduced pressure. The residue is diluted with 50 mL of xylenes, and the volatiles are thoroughly evaporated under reduced pressure. Column chromatography of the residue on 30 g of silica gel using chloroform-diethyl ether (98:2, v/v) as an eluent afforded 646 mg (67%) of the title compound as a cream colored foam. Mass Spec m/z (M++1) 514.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[C:28]([NH2:31])(=[O:30])[CH3:29]>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([NH:31][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(N)=O
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CC(=O)Nc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 72.7 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 186 and acetamide (89 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (294 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O-:17])=[O:16])=[C:13]([CH2:18]Br)[NH:12][C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:10]1.[O:25]=[C:26]1[N:33](C(OC(C)(C)C)=O)[CH2:32][CH:31]2[NH:41][CH:27]1[CH2:28][O:29][CH2:30]2.[CH3:42]CN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:42])=[O:16])=[C:13]([CH2:18][N:41]2[CH:27]3[C:26](=[O:25])[NH:33][CH2:32][CH:31]2[CH2:30][O:29][CH2:28]3)[NH:12][C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:10]1
Reactant: CC(C)(C)OC(=O)N1CC2COCC(N2)C1=O
Reactant: O=C([O-])C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1=C(CN2C3CNC(=O)C2COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
The titled compound was prepared by following procedure. To a solution of methyl (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (compound C, 0.089 g, 0.20 mmol) and tert-butyl 6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate 133a (0.096 g) in CH2Cl2 (3 ml) was added DIPEA (0.2 ml, 1.14 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue (0.120 g, MS: calc'd (MH+) 606, measured (MH+) 606) was dissolved in dichloromethane (3 ml). To it was added trifluoroacetic acid (2 ml) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (10 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:25][CH2:26][CH2:27]Br)(=[O:24])[CH3:23]>CN(C)C=O.O>[C:22]([O:25][CH2:26][CH2:27][O:8][C:4]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)(=[O:24])[CH3:23]
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Reaction time: 16 h
Yield: 42.5 %

Procedure:
To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (250 mg) in dimethyl formamide (5 ml) at room temperature was added potassium carbonate (510 mg) and 2-bromoethyl acetate (205 mg), the mixture was stirred for 16 hrs. The reaction was diluted with water (60 ml) and extracted with ethyl acetate (3×30 ml). The organic fractions were combined, washed with water (2×30 ml) and brine (30 ml) and dried over magnesium sulfate, filtered concentrated under reduced pressure. The residue was purified by column chromatography (silica, 30 g) eluted with ethyl acetate:hexane (1:1) to yield the title compound as a white solid (151 mg).
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:15]=2)=[CH:10][C:9]=1[Cl:28].[C:29]([O-:32])(=[O:31])[CH3:30].[K+]>O>[C:29]([O:32][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:15]=2)=[CH:10][C:9]=1[Cl:28])(=[O:31])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Temperature: 130 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To N,N-dimethylformamide (200 ml) are added 5-(4-bromomethyl-3-chlorophenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (24.3 g) and potassium acetate (29.0 g), which are stirred at 130° C. for 3 hours. The reaction mixture is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 11.8 g of desired compound.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH3:1][N:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:7][CH2:8]1)[S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:26]([F:38])([F:37])[F:25])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CN([C@H]1CC[C@H](CCCCN2CCCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to examples 31.5 and 31.6, trans-Methanesulfonic acid 4-(4-methylamino-cyclohexyl)-butyl ester.trifluoro-acetic acid and 4-trifluoromethyl-phenyl-sulfonylchloride were reacted, followed by treatment with piperidine to give trans-N-Methyl-N-[4-(4-piperidin-1-yl-butyl)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide, MS: 461 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[N:15]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)NC(OC)=N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 12 h
Yield: 91.7 %

Procedure:
To a well stirred solution of (+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl) pyrimidine (4.1 g, 10.62 mmol) and 4-(N,N-dimethylamino)pyridine (1.69 g, 13.80 mmol) in CH2Cl2 (200 mL) was added solid 4-nitrophenyl chloroformate (2.78 g, 13.80 mmol) at room temperature. The reaction mixture was stirred for 12 h and washed with 0.5 N NaOH solution (2×50 mL). The organic layer was separated and dried (Na2SO4). The solvent was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane/hexane (20%-50%) as the eluent to give (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (5.37 g, 92%) as a viscous oil.
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:9]=1[CH2:10]Cl.[CH3:17][O:18][C:19]1[C:24](C)=[CH:23][C:22]([N:26]2[C:31](=[O:32])[N:30](CC3C(F)=CC(F)=CC=3F)[C:29]3[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=3[S:27]2(=[O:48])=[O:47])=[CH:21][C:20]=1C>CN(C=O)C>[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:9]=1[CH2:10][N:30]1[C:29]2[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=2[S:27](=[O:47])(=[O:48])[N:26]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[C:24]([O:2][CH3:1])[CH:23]=2)[C:31]1=[O:32]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3c(Cl)cccc3Cl)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (52 mg, 0.11 mmol) was prepared from (IntA1) (67 mg, 0.20 mmol), K2CO3 (83 mg, 0.60 mmol) and 2,6-dichlorobenzyl chloride (47 mg, 0.24 mmol) in DMF (2 mL) using the methods of (115).