Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])=[N:7][N:6]=[CH:5][C:4]=2[CH:3]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[CH:34]1([NH:37][C:38](=[O:55])[C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:40]=2)[CH2:36][CH2:35]1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:34]1([NH:37][C:38](=[O:55])[C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[C:41]([C:2]3[C:11](=[O:12])[N:10]([CH3:13])[C:9]4[C:8]([C:14]5[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=5[F:21])=[N:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[CH:40]=2)[CH2:35][CH2:36]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c(Br)cc2cnnc(-c3ccc(F)cc3F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(-c3ccc(F)cc3F)c2n(C)c1=O
Temperature: 100 °C

Procedure:
To a suspension of 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one (8) (80.0 mg, 0.227 mmol) in 3:1 1,4-dioxane: 1 M aq Na2CO3 (3.2 mL) was added N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (82.1 mg, 0.273 mmol) and tetrakis(triphenylphosphine)palladium (0) (21.0 mg, 0.0182 mmol). The reaction mixture was stirred and heated in a microwave at 100° C. for 55 min and then cooled to room temperature. The mixture was diluted with water and extracted with CHCl3/iPrOH (4:1). The combined organic extract was washed with 2 M Na2CO3, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography [eluting with a gradient of 40-50% B in A where the eluents were: A=CH2Cl2; B=4% MeOH in EtOAc] to give N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide as a white solid. MS (ESI, pos. ion) m/z: 447 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.52-0.60 (m, 2H), 0.64-0.73 (m, 2H), 2.21 (s, 3H), 2.85 (td, J=3.9, 7.3 Hz, 1H), 3.16 (s, 3H), 7.32-7.42 (m, 2H), 7.45-7.54 (m, 1H), 7.74 (d, J=1.4 Hz, 1H), 7.79-7.91 (m, 2H), 8.19 (s, 1H), 8.41 (d, J=3.9 Hz, 1H), 9.45 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH3:14].[CH3:15][Mg]Br>O1CCCC1.O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([CH3:15])([OH:13])[CH3:12])=[CH:4][C:3]=1[CH3:14]
Reactant: CC(=O)CCc1cc(C)c(Br)c(C)c1
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(CCC(C)(C)O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-bromo-3,5-dimethylphenyl)butan-2-one (100 mg) in tetrahydrofurane (2 mL) is added at 0° C. methylmagnesium bromide (840 μL of a 1.4 M solution in tetrahydrofurane/toluene 1:3). The mixture is stirred for 2 hours while warming to room temperature and then partitioned between saturated aqueous NH4Cl solution and diethylether. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 105 mg; LC (method 8): tR=0.47 min; Mass spectrum (ESI+): m/z=271 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:31])[C:16]1[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][N:22]([CH3:24])[C:20]1[CH:21]=[C:16]([N:15]([CH3:14])[CH3:31])[N:17]=[C:18]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)[N:19]=1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: CN(C)c1cc(N(C)C)nc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3nc(N(C)C)cc(N(C)C)n3)CC2)cc1
Yield: 109.8 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (0.7 g), 1-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine (0.9 g) and potassium carbonate (0.7 g) in dimethylformamide (10 ml) was stirred at 80° C. for 6 hr. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (1.6 g). The obtained brown solid was crystallized from ethyl acetate/ethanol (2:1, 30 ml) to give the title compound (0.9 g) as pale-yellow crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.[C:21](OC)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C1COCC1.CCCCCC>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccnc(F)c1
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)C(=O)Cc1ccnc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a solution of diisopropylamine (12.6 mL, 89.9 mmol) in anhydrous THF (50 mL) is added n-butyllithum (42.2 mL of an 1.6M in hexane) dropwise at 0° C. After 30 min at 0° C., 2-fluoro-4-methylpyridine (5 g, 45 mmol) is added. The resulting mixture is stirred at 0° C. for 30 min. After the addition of methyl isobutyrate (5.4 mL, 47.3 mmol) at 0° C., the reaction mixture is stirred overnight. The reaction mixture is quenched with acetic acid at 0° C., diluted with water, and extracted with ethyl ether. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, EtOAc/heptane 7:93 to 60:40) to give 4.8 g of 1-(2-fluoro-pyridin-4-yl)-3-methyl-butan-2-one as a light yellowish solid.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.Cl[C:7]1[CH:12]=C([N+]([O-])=O)C=[C:9]([Cl:16])[C:8]=1N1C=CC=C1.[Cl:22][C:23]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([Cl:33])[C:24]=1[NH2:25].COC1CCC(OC)O1.C(=O)(O)[O-].[Na+]>CCOCC>[Cl:16][C:9]1[N:25]([C:24]2[C:23]([Cl:22])=[CH:29][C:28]([N+:30]([O-:32])=[O:31])=[CH:27][C:26]=2[Cl:33])[C:12]([Cl:4])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(-n2cccc2)c(Cl)c1
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Cl)c(-n2c(Cl)ccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Sulfuryl chloride (4.68 g, 2.80 ml, 34.7 mmol) is added dropwise to 1-(2,6-dichloro-4-nitrophenyl)pyrrole (4.46 g, 17.4 mmol), prepared from 2,6-dichloro-4-nitroaniline and 2,5-dimethoxytetrahydrofuran following Example 12 procedures, in 20 ml of ether at 0°. After addition is completed, the mixture is stirred at RT for 60 hours. The reaction mixture is then poured into saturated aqueous sodium bicarbonate and extracted with ether. The combined organic layers are washed with brine, dried and stripped of solvent. The residue is purified by prep. TLC to give 2,5-dichloro-1-(2,6-dichloro-4-nitrophenyl)pyrrole, which is reduced with 16% aq. titanium(III) chloride to give 3,5-dichloro-4-(2,5-dichloro-1-pyrrolyl)aniline.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH3:16][C:17]([N:21]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:23]=[CH:22]1)([CH3:20])[CH:18]=O.O>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:18][C:17]([CH3:20])([N:21]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:23]=[CH:22]1)[CH3:16]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CC(C)(C=O)n1cnc(-c2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCC(C)(C)n1cnc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of sodium hydride (1.2 eq) in THF was added slowly methyl diethylphosphonoacetate (1.2 eq) at 0° C. under dry conditions and the mixture was stirred at room temperature for 30 minutes. A solution of 2-Methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionaldehyde (1 eq), in THF was added dropwise at room temperature and the mixture was stirred for 1 hour at the same temperature. The mixture was poured into H2O and the whole was extracted with ethyl acetate. The organic layer was washed with NaCl(sat), dried over sodium sulfate, filtered and concentrated. To a solution of the residue in ethyl acetate, was added Palladium, 10 wt. % on activated carbon and left stirring under 1 atm hydrogen overnight. After the catalyst was filtered off, the filtrate was purified by flash chromatography using a solvent gradient 97% DCM, 3% MeOH and 0.1% TEA to yield 4-Methyl-4-(4-pyridin-3-yl-imidazol-1-yl)pentanoic acid methyl ester (75%). MH+(274).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[C:21]([O:35][C:36]2[CH:37]=[CH:38][C:39]([C:42](OCC)=[O:43])=[N:40][CH:41]=2)=[CH:22][C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[NH:25][C:24]=2[CH:34]=1)(=[O:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[C:21]([O:35][C:36]2[CH:37]=[CH:38][C:39]([CH2:42][OH:43])=[N:40][CH:41]=2)=[CH:22][C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[NH:25][C:24]=2[CH:34]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(C)=O)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(CO)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
20 mg of lithiumaluminium hydride was added to a tetrahydrofuran (2 ml) solution of 90 mg of ethyl 5-((6-(1-acetylpyrrolidin-2-yl)-2-pyridin-2-yl-1H-benzimidazol-5-yl)oxy)pyridine-2-carboxylate obtained in Example 495 with cooling with ice, and the reaction liquid was stirred at 0° C. for 30 minutes. The reaction liquid was diluted with chloroform, washed with aqueous saturated ammonium chloride, aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13]Cl)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: O=C(CCl)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: Cl
Product: O=C(CN1CCCC1)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a solution of 7-chloro-4-(2-chloroacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (3.5 g, 10.4 millimoles) prepared as described in Example 4a, in 100 ml CH2Cl2, was added pyrrolidine (7.2 g, 104 millimoles). The resulting reaction solution was allowed to stir at room temperature for 18 hours, after which it was evaporated to dryness. The residue was dissolved in ether and the resulting ethereal solution was washed with two portions of H2O, with brine, and was dried over Na2SO4,filtered and evaporated to dryness. The residue so obtained was dissolved in CH3CH-diethyl ether and a hydrochloride salt was prepared. There was obtained a 81.8% yield of the title compound; mp 280°-282°.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].C=O.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].[CH2:22](NCCCC)CCC.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH2:22][O:21][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Reactant: CCCCNCCCC
Reactant: CCCCO
Agent: C=O
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCOCc1c(C)c(OC(C)=O)c(C)c(C)c1O
Reaction time: 6 h

Procedure:
4-Acetoxy-2,3,5-trimethylphenol (5.83 g; 30.0 mmol), 87.3% paraformaldehyde (1.24 g; 36.0 mmol), 1-butanol (14.46 g; 195.0 mmol), dibutylamine (0.39 g; 3.0 mmol) and benzoic acid (1.83 g; 15.0 mmol) were mixed together, then the mixture was reacted under reflux with stirring for 6 hours. After completion of the reaction, toluene was added into the resulting mixture for extraction of the resulting product in toluene, and then the toluene phase was separated. After the separated toluene phase was sequentially washed with water, an aqueous 1% dilute sulfuric acid solution, an aqueous 5% sodium hydrogen carbonate solution and water, the toluene phase was distilled under reduced pressure to distill off compounds with low boiling points, to give 4-acetoxy-2,3,5-trimethyl-6-butoxymethyl-1-hydroxybenzene.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(ON=O)CC(C)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](N)=[C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=2[Cl:35])[CH:18]=1>C(#N)C.O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][C:26]=2[Cl:35])[CH:18]=1
Reactant: CCOC(=O)CS
Reactant: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CSc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 60 °C

Procedure:
Ethyl mercaptoacetate (0.11 ml) followed by isoamylnitrite (0.16 ml) were added to a solution of the product from example 15 step (i) (0.5 g) in dry acetonitrile (20 ml) and heated at 60° C. for 10 h. The mixture was diluted with water, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with dichloromethane, yield 0.60 g.
Reaction SMILES: [C:1]([CH:9]1[O:14][CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22]COC(Cl)=O>ClCCCl>[ClH:22].[C:1]([CH:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCCl
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Solvent: ClCCCl
Product: Cl
Product: O=C(c1ccccc1)C1CNCCO1
Yield: 66.6 %

Procedure:
A solution of 2-benzoyl-4-benzylmorpholine (600 mg, 2.13 mmol) and chloroformic acid 1-chloromethyl ester (457 mg, 3.20 mmol) in 1,2-dichloroethane (8.0 ml) was refluxed for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml). The solution was refluxed for 1 h and concentrated under reduced pressure. The crude product was crystallized from ethyl acetate and filtrated to give 2-benzoylmorpholine hydrochloride (323 mg, 67%) as a colorless crystal.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[S:13])[CH3:2].[Cl-].[CH2:15]([S:22][CH2:23][C@H:24]([NH2+:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:25][Cl:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[ClH:26].[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]1[N:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[C@@H:24]([CH2:23][S:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:25][S:13]1)[CH3:2]
Reactant: CC(C)C[NH2+][C@H](CCl)CSCc1ccccc1
Reactant: CCc1cc(C#N)ccc1N=C=S
Agent: [Cl-]
Product: CCc1cc(C#N)ccc1N=C1SC[C@H](CSCc2ccccc2)N1CC(C)C
Product: Cl

Procedure:
(1S)-1-(Benzylthiomethyl)-2-hydroxyethylamine was made from (L)-S-benzylcysteine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4-(benzylthiomethyl)-1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((1S)-1-(benzylthiomethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((1S)-1-(benzylthiomethyl)-2-chloroethyl)-N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((1S)-1-(benzylthiomethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method C1b to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(benzylthiomethyl)-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].CC1(C)C(C)(C)OB([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2B2OC(C)(C)C(C)(C)O2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2F)C1

Procedure:
A solution of Pd(PPh3)4 (Strem Chemicals Inc., Newburyport, Mass., 0.643 g, 0.557 mmol), 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.353 g, 5.57 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (ASW Medchem, Brunswick, N.J., 2.000 g, 5.57 mmol), and potassium carbonate (3.08 g, 22.27 mmol) in 12 mL dioxane and 6 mL water was heated to 120° C. for 3 days. The reaction mixture was diluted with diethyl ether, washed with water, the organics dried over MgSO4 and concentrated to provide tert-butyl 5-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. The resulting residue was dissolved in 10 mL THF and was treated with HCl 4 N in dioxane (9.74 ml, 39.0 mmol), and allowed to stir at room temperature overnight. The reaction mixture was diluted with diethyl ether/heptane, and the resulting solid was filtered and dried yielding 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.930 g, 5.82 mmol). [M+H]+=296.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[CH:5]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:6]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[CH:5]2
Reactant: Clc1nc2ccc(Br)cc2cc1C1CCOCC1
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2C2CCOCC2)cc1
Temperature: 130 °C

Procedure:
A glass microwave reaction vessel was charged with 6-bromo-2-chloro-3-(tetrahydro-2H-pyran-4-yl)quinoline (1.46 g, 4.47 mmol) and (4-methoxyphenyl)methanamine (5.80 mL, 44.7 mmol) in N-methyl-2-pyrrolidinone (5.80 mL). The reaction mixture was stirred and heated in a microwave reactor at 130° C. for 180 min. The reaction mixture was poured into water and extracted with EtOAc and DCM. The combined organic extracts were washed with saturated ammonium chloride, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude material was purified by silica gel chromatography by eluting with 1:4 to 1:1 EtOAc in hexane, to provide 6-bromo-N-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine as yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: O=C=Nc1ccccc1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN
Product: CCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 18.7 %

Procedure:
Using the general method of Example 146 Part B, 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (2.50 g, 8.9 mmol) was reacted with phenyl isocyanate (1.78 mL, 16.4 mmol) to provide 0.67 g of N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28]>C(#N)C.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([C:27]([NH:26][CH2:29][CH3:30])=[O:28])[C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1
Reactant: Cc1cnc(-c2cc(F)ccc2F)cc1Nc1ccnc2cn[nH]c12
Reactant: CCN=C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCNC(=O)n1ncc2nccc(Nc3cc(-c4cc(F)ccc4F)ncc3C)c21
Temperature: 75 °C

Procedure:
N-(2-(2,5-Difluorophenyl)-5-methylpyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (106 mg, 0.314 mmol) was suspended in acetonitrile (3.1 mL). Isocyanatoethane (30.8 μl, 0.393 mmol) and 1 drop of pyridine were added and the mixture was heated at 75° C. for 2 hours. The mixture was cooled to give a solid which was collected by filtration to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (3H, t, J=7.07 Hz) 2.38 (3H, s) 3.34-3.45 (2H, m) 7.25-7.42 (3H, m) 7.76 (1H, ddd, J=9.47, 6.06, 3.16 Hz) 7.93 (1H, s) 8.41 (1H, d, J=5.30 Hz) 8.54 (1H, s) 8.60 (1H, s) 9.09 (1H, t, J=5.81 Hz) 11.05 (1H, s). MS [M+H] found 409.4.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:49])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH2:40][O:41]C3CCCCO3)[CH:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:41][CH2:40][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:49])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[CH:38][N:37]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(isobutyl-methyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M279) (5.82 g, 8.34 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (2.84 g, 69%).