Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:20])[CH3:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([NH:21][CH3:22])[S:14]2)[CH2:10]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>>[OH:20][C@H:18]([C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([NH:21][CH3:22])[S:14]2)[CH2:10][C@@H:9]1[OH:8])[CH3:19]
Reactant: CNC1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H](C(C)O)O[C@@H]2S1
Agent: ClB(Cl)Cl
Product: CNC1=N[C@@H]2C[C@H](O)[C@@H]([C@H](C)O)O[C@@H]2S1

Procedure:
The material described above, 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.180 g, 0.558 mmol), was deprotected with BCl3 using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:12), (3aR,5R,6S,7aR)-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3 aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.105 g, 81%) and as a mixture of diastereomers.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=O)[O:30]C3C=CC=CC=3)=[CH:24][CH:23]=2)[N:9]=1.[CH3:38][C@H:39]1COCC[N:40]1C1C=C(C(S(C(C)(C)C)(=O)=O)(C)C)N=C(C2C=CC(NC(=O)OC3C=CC=CC=3)=CC=2)N=1>>[CH2:39]([NH:40][C:29](=[O:30])[NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:10]2[N:9]=[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])[CH:13]=[C:12]([CH2:14][S:15]([C:18]([CH3:20])([CH3:19])[CH3:21])(=[O:17])=[O:16])[N:11]=2)=[CH:23][CH:24]=1)[CH3:38]
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C(C)(C)C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C(C)(C)C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nc(CS(=O)(=O)C(C)(C)C)cc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
The following compounds were made in an analogous fashion from either phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(tert-butylsulfonylmethyl)pyrimidin-2-yl]phenyl]carbamate or phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-tert-butylsulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[C:7]([C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:8]=[CH:9]2
Reactant: COc1cc2ccccc2cc1OC
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2ccc(C(=O)C(C)C)cc2cc1OC

Procedure:
The solution of 2,3-dimethoxynaphthalene (16.5 g ), isobutyroylchloride (12.5 g) and aluminum chloride (15.7 g) in methylene chloride (200 ml) was stirred at ambient temperature overnight. The solution was then washed with saturated sodium bicarbonate and water, dried with sodium sulfate and evaporated. Finally the crude product was triturated with ether. Yield: 13.5 g, melting point 103-105° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26](O)=[O:27])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1N=C[N:32](C(N2C=NC=C2)=O)C=1.C([O-])(=O)C.[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26](=[O:27])[NH2:32])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c(CCC(=O)O)ccc2-c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-n2c(CCC(N)=O)ccc2-c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-[2-(2-carboxy-ethyl)-5-phenyl-pyrrol-1yl]-benzoic acid tert-butyl ester (1.33 mmol, 1.0 eq.) in THF (10 ml) was added CDI (1,1′ carbonyldiimidazole, 1.60 mmol, 1.2 eq). The mixture was stirred at 45° C. for 2 h. To the reaction mixture was then added ammonium acetate (1.72 mmol, 1.3 eq.). The mixture was stirred at 45° C. for 16 hours.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:57][N:56]4[C:58]([CH3:62])([CH3:61])[CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CO.O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:57][N:56]4[C:58]([CH3:61])([CH3:62])[CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc([C@@H]3C[C@H]4CCC(C)(C)N4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCC(C)(C)N4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 86.1 %

Procedure:
A solution of 0.320 g of (Cis)-2-butyl-6-(hexahydro-6,6-dimethylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at reflux for 18 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 99:1 to 1 chloroform-methanol to give 0.194 g of the desired product as a solid. FAB mass spec 576 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C:5]1[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH:28]2[CH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:19])[CH3:1])[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]=4[N:9]=3)=[CH:41][CH:42]=1)=[O:36])[CH2:29]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C(C)(C)C
Yield: 61.4 %

Procedure:
Following general N—C coupling procedure 1, 7-tert-Butyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.534 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (178 mg, 0.534 mmol, 1.0 eq) which gave 3-[6-(7-tert-Butyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (189 mg) in 61% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 10H) 1.59 (br. s., 2H) 1.74-1.84 (m, 12H) 3.00 (d, J=2.53 Hz, 7H) 4.14 (br. s., 2H) 6.48 (s, 1H) 7.85 (dd, J=8.84, 2.27 Hz, 1H) 8.28-8.39 (m, 2H) 8.80 (s, 1H) 9.89 (s, 1H). MS m/z 577.6 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6](/[CH:11]=[CH:12]\[CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:7][C:8]([OH:10])=[O:9].[C:22](O)([CH3:25])([CH3:24])[CH3:23]>>[CH3:5][C:6](/[CH:11]=[CH:12]\[CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:7][C:8]([O:10][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:9]
Reactant: CC(=CC(=O)O)/C=C\CC(C)CCCC(C)C
Reactant: CC(C)(C)O
Solvent: O=S(Cl)Cl
Product: CC(=CC(=O)OC(C)(C)C)/C=C\CC(C)CCCC(C)C

Procedure:
One gram of thionyl chloride is added with stirring at room temperature to 0.5 g. of trans/cis 3,7,11-trimethyldodeca-2,4-dienoic acid and the mixture heated at about 50° for 10 minutes. Excess thionyl chloride is removed by evaporation and then t-butyl alcohol (about 2 equivalents) is added and the mixture heated at about 50° for about 5 minutes. Excess t-butyl alcohol is removed by evaporation to yield trans/cis t-butyl 3,7,11-trimethyldodeca-2,4-dienoate which is purified by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=O)=[CH:5][CH:4]=1.[BrH:12].[NH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:25])[C:20]=2[OH:24])[C:15]1=[O:26]>C(O)C.[Pd]>[BrH:12].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:13][CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:25])[C:20]=3[OH:24])[C:15]2=[O:26])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC=O)cc1
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: COc1ccc(CCNC2CCc3c(ccc(O)c3O)C2=O)cc1

Procedure:
In 1000 volume parts of ethanol is dissolved 10 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide, followed by the addition of 100 parts of 4-methoxyphenylacetaldehyde. Using palladium-on-carbon as a catalyst, catalytic reduction is carried out at ordinary temperature and pressure. When a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The procedure yields 8 parts of 2-(4-methoxyphenethyl)amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide as colorless crystals melting at 198°-203° C.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][C:17]([OH:38])([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:37])([O:28]COCC[Si](C)(C)C)[CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[C:10]([CH3:39])[C:9]=1[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:15][CH2:16][C:17]([OH:38])([C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])([CH3:37])[CH3:27])=[CH:22][N:21]=3)[CH2:18][CH2:19]2)=[C:10]([CH3:39])[C:9]=1[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(O)(c3ccc(C(C)(C)OCOCC[Si](C)(C)C)cn3)CC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(O)(c3ccc(C(C)(C)O)cn3)CC2)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To compound 35 (44 mg, 0.078 mol) in CH2Cl2 (1.5 mL) at 0° C. is added TFA (0.15 μL). The mixture is stirred at 0° C. for 2 h and is quenched with 25% ammonium acetate, extracted with ethyl acetate. The organic phase is washed with brine, dried and concentrated to give a yellow residue which is purified by silica gel chromatography (0-5% methanol in CH2Cl2) to give the desired product (17 mg, 50%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: FC(F)(F)c1cc(Nc2nc3ccccc3[nH]2)ccc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-chloro-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and recrystallisation to give the title compound as a hydrochloride salt (white solid, mp 255-260° C.). MS(ES+) m/z 312 ([M+1]+, 100).
Reaction SMILES: [C:1]1([P:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C(P(CCCC)CCCC)CCC>C(#N)C.C1COCC1>[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: II
Solvent: CC#N
Solvent: C1CCOC1
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
100 mg (0.359 mmol) of triphenylphosphine oxide were treated with 9 mg I2 (35 μmol) and tributylphosphine 180 μL (0.72 mmol) in acetonitrile/THF (1:1 v/v) 1 mL. The mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere before it was quenched with H2O (100 μL). The reaction mixture was diluted with ethyl acetate (10 mL) and was washed with portions of sat. NaHCO3 (3×5 mL). The organic fraction was dried with Na2SO4, filtered and the solvent evaporated under vacuum. The resulting residue was recrystallized from methanol, the resulting crystals were filtered, washed and dried in vacuum, giving 88 mg (0.334 mmol, 93%) of triphenylphosphine.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[CH3:22][O:23][C:24]1[CH:32]=[N:31][C:30]([O:33][CH3:34])=[C:29]2[C:25]=1[C:26]([C:35](=[O:39])C(O)=O)=[CH:27][NH:28]2.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>Cl.O1CCOCC1>[Br:21][C:14](=[C:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:35]([C:26]2[C:25]3[C:29](=[C:30]([O:33][CH3:34])[N:31]=[CH:32][C:24]=3[O:23][CH3:22])[NH:28][CH:27]=2)=[O:39])[CH2:13][CH2:12]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)O)c[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(Br)c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A solution of 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester in 4N HCl-dioxane (10 mL) was stirred at room temperature for 2 h. The volatiles were then removed in vacuo and the residue was dissolved in CHCl3 (15 mL). To this solution was added 4,7-dimethoxy-6-azaindol-3-yl-oxoacetic acid (0.906 g, 3.37 mmol) and Hünig's base (2.40 mL, 13.8 mmol). After 5 min, BOPCl (0.950 g, 3.73 mmol) was added as a solid and the mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was then adsorbed directly onto silica gel and purified by flash chromatography (SiO2/EtOAc) to give the title compound (1.101 g, 71%) as a yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>O>[CH:21]1([N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: CCCNCCc1cccc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCN(CCc1cccc(OC)c1)C1CCCC1

Procedure:
A stirred mixture of 3.4 g of 3-methoxy-N-propyl-benzeneethanamine, 4 g of potassium carbonate and 15 ml of cyclopentyl bromide was refluxed for one hour after which 5 g of potassium carbonate were added thereto and the mixture was refluxed for another 3 hours. The mixture was poured into 50 ml of water and the mixture was extracted 3 times with 50 ml of ether. The organic phase was dried and filtered and the filtrate was evaporated to dryness to obtain 4.5 g of N-cyclopentyl-3-methoxy-N-propylbenzeneethanamine in the form of a red oil which was used as is for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](/[C:5](=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)/[CH2:6][C:7]([OH:9])=O)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:33]1[C@@H:41]2[C@@H:36]([CH2:37][CH:38]=[CH:39][CH2:40]2)[CH2:35][NH:34]1>O1CCCC1>[CH3:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)/[CH:10]=[C:5](\[CH2:6][C:7]([N:34]1[CH2:35][C@H:36]2[C@H:41]([CH2:40][CH:39]=[CH:38][CH2:37]2)[CH2:33]1)=[O:9])/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C(=C/c1cccc(C)c1)CC(=O)O
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)/C(=C/c1cccc(C)c1)CC(=O)N1C[C@H]2CC=CC[C@H]2C1
Temperature: -20 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a solution of (E)-3-methoxycarbonyl-4-(3-methylphenyl)-3-butenoic acid (1.05 g) in anhydrous tetrahydrofuran (20 ml) were added N-methylmorpholine (0.74 ml) and isobutyl chloroformate (0.75 ml) with stirring at -20° C. and the mixture was stirred for 20 minutes. To the mixture was added a solution of cis-3a,4,7,7a-tetrahydroisoindoline (773 mg) in anhydrous tetrahydrofuran (2 ml) with stirring at -20° C. After 1 hour, the deposit was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to give 446 mg of methyl (E)-2-(3-methylbenzylidene)-3-(cis-3a,4,7,7a-tetrahydro-2-isoindolinylcarbonyl)propionate as a colorless viscous oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-:10].[Na+].Cl>C1COCC1>[Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(Cl)ncc1Br
Yield: 64 %

Procedure:
5-Bromo-2,4-dichloro-pyrimidine (5.0 g, 22 mmol) was stirred in THF (10 mL) with 1N NaOH (30 mL) at r.t. for 3 h. The solution was made slightly acidic with 1N HCl and was extracted with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo. Precipitation from 20% CHCl3/hexanes and collection by filtration gave 2.92 g (64%) of 5-bromo-2-chloro-3H-pyrimidin-4-one as a white solid. 1H NMR (400 MHz, DMSO-d6): δ13.33 (br s, 1H), 8.35 (s, 1H). MS (ES) [m+H] calc'd for C4H2N2OBrCl, 209, 211, 213; found 209, 211, 213.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccccc1F
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccccc2F)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-fluorophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-fluorophenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12](=[O:13])[S:14][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: Cc1ccc(C(N)=O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nsc(=O)o2)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a toluene (60 mL) suspension of 4-methylbenzamide (20 g), chlorocarbonylsulfenyl chloride (15 mL) was added, and the resultant was stirred at 120° C. for 3 hours. The reaction solution was concentrated under reduced pressure. The obtained solid was washed with hexane to obtain the title compound (24 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.[CH2:9]([O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])[CH3:10]>C1COCC1>[NH2:1][C:2]1[S:3][C:4](/[CH:7]=[CH:14]/[C:12]([O:11][CH2:9][CH3:10])=[O:13])=[CH:5][N:6]=1
Reactant: Nc1ncc(C=O)s1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc(N)s1
Temperature: 65 °C
Yield: 60.5 %

Procedure:
2-Aminothiazole-5-carbaldehyde (0.25 g, 2 mmol) was dissolved in anhydrous THF (20 mL). (Ethoxycarbonylmethylene)triphenylphosphorane (0.790 g, 2.2 mmol) was added at room temperature and the reaction mixture was heated overnight at 65° C. The reaction mixture was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 50-80% EtOAc in Hexanes to provide pure (E)-ethyl 3-(2-aminothiazol-5-yl)acrylate (0.24 g) as a white solid. ES+(M+H)+199.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][CH:6]([F:12])[C:7](OCC)=[O:8]>C(O)C.C(O)CO>[CH:1]([NH:4][C:7](=[O:8])[CH:6]([Br:5])[F:12])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)C(F)Br
Solvent: CCO
Solvent: OCCO
Product: CC(C)NC(=O)C(F)Br
Reaction time: 2 h

Procedure:
A solution of 14.8 grams (0.25 mole) isopropyl amine in 25 milliliters ethanol was added dropwise to a solution of ethyl bromofluoroacetate, 40 grams (0.22 mole), and 5 drops ethylene glycol in 100 milliliters ethyl alcohol at 10°-15° C. The solution was stirred at 10°-20° C. for 2 hours and was then stored at -15° C. for 3 days. At this time, the solution was evaporated to leave a liquid, 41.8 grams, nD30 1,4629, identified by infrared spectroscopy as the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Br:12][C:13]1[CH:14]=[C:15](/[CH:16]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Br)c1)c1ccc(Cl)cc1F
Yield: 62.1 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (1.9 g, 11 mmol) was reacted with 3-bromobenzaldehyde (Aldrich) (1.57 mL, 13.4 mmol), methanolic solution (25 wt %) of sodium methoxide (2.8 mL, 12 mmol) in methanol (50 mL) at 50° C. for 3 h to give (Z)-3-(3-bromo-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (2.3 g, 60%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([S:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13]C(=O)C(C)(C)C)=[S:5])[CH3:2]>CO.[OH-].[Na+]>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]([S:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH2:13])=[S:5])[CH3:21]
Reactant: CCN(CC)C(=S)Sc1cnccc1NC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)C(=S)Sc1cnccc1N
Yield: 62.1 %

Procedure:
An opaque solution of 4-pivalamidopyridin-3-yl diethylcarbamodithioate (21.9 g, 67 mmol) in methanol (220 mL) and 1 N sodium hydroxide (220 mL) was stirred at r.t. for 20 h. Tlc showed consumption of starting material. The clear yellow solution was diluted with water (500 mL). After letting the turbid solution stand for 5 min, crystals precipitated out. The solid was filtered off, washed with water (2×50 mL) and diethyl ether (3×50 mL), and air dried to afford 4-aminopyridin-3-yl diethylcarbamodithioate (10.05 g, 62%) as colorless plate like crystals. 1H NMR: δ (CDCl3, 400 MHz) 1.30 (t, J=7 Hz, 3 H), 1.44 (t, J=7 Hz, 3 H), 3.90 (q, J=7 Hz, 2 H), 4.03 (q, J=7 Hz, 2 H), 4.68 (br. s., 2 H), 6.65 (d, J=5.5 Hz, 1 H), 8.25-8.30 (m, 2 H).