Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:7][CH:8]=1)(=[O:40])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.35 g, 0.62 mmol) prepared in Example 7 in DMSO (7 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (1.05 g, 9.3 mmol), then aqueous solution (1N) of NaOH (3 mL, 3 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50% to 100% EtOAc in CH2Cl2) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 0.26 g, 72%)
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: CCOCC
Reactant: Fc1ccc(COc2ccc(Br)cn2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc(F)cc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a diethyl ether (150 mL) solution of 5-bromo-2-(4-fluoro-benzyloxy)-pyridine (3.75 g 13.3 mmol) described in Manufacturing Example 58-1-1 was added n-butyl lithium (2.55 M n-hexane solution, 6.26 mL, 16.0 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. N,N-dimethylformamide (1.54 mL, 20.0 mmol) was then added dropwise and stirred for 5 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (2.23 g, 72.5%).
Reaction SMILES: C([O:8][C:9](=[O:19])[CH2:10][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CO.[Rh]>[CH2:14]1[CH2:13][CH2:12][C:11]([CH2:17][NH2:18])([CH2:10][C:9]([OH:19])=[O:8])[CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: N#CC1(CC(=O)OCc2ccccc2)CCCCC1
Agent: [Rh]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Yield: 27.7 %

Procedure:
1.0 g (3.8 mmol) of (1-cyanocyclohexyl)acetic acid benzyl ester was distilled in 20 ml of methanol, mixed with 0.2 g of Rh/C 5 percent and hydrogenated at 10 bars of hydrogen pressure. After 23 hours at room temperature the suspension was filtered, the filtrate was concentrated to 3 ml, mixed with 25 ml of ethanol, concentrated to 4 ml and put on the cooling shelf. The precipitated product was filtered, washed with ethanol and dried. 0.18 g of Gabapentin was obtained, corresponding to a yield of 27 percent (relative to the (1-cyanocyclohexyl)acetic acid benzyl ester used). Data for the product was:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][C:14]=3[O:22][CH3:23])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28].O>C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:28]#[C:27][CH2:26][OH:29])=[CH:15][C:14]=3[O:22][CH3:23])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(I)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCNCC
Product: COc1cc(C#CCO)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide (469 mg) from Example No. 117, copper (I) iodide (57 mg), and bis(triphenylphosphine)-palladium (II) chloride (35 mg) are suspended in diethylamine (15 mL). Propargyl alcohol (70 μL) is added and the mixture is allowed to stir at rt for 16 h. The reaction mixture is poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer is washed with saturated aqueous ammonium chloride (3×10 mL) and brine (10 mL). The aqueous layer is back-extracted with ethyl acetate (20 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purified by column chromatography (dichloromethane/methanol, 50/1; 33/1; 25/1; 20/1) to afford 289 mg (73%) of the title compound as a white solid.
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:18]([OH:20])=O)[CH2:11][C@@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[CH2:21]([NH2:24])[CH2:22][CH3:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[NH2:8][C@@:9]1([C:18]([NH:24][CH2:21][CH2:22][CH3:23])=[O:20])[CH2:11][C@@H:10]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCN
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)C[C@@H]1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)[C@]1(N)C[C@@H]1c1ccccc1
Yield: 85 %

Procedure:
The title compound was prepared by coupling commercially available (1S,2R)-1-[(tert-butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid with n-propylamine in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and subsequent Boc detachment with trifluoroacetic acid (yield: 85% of theory over both stages).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].[Cl-].[NH4+]>C1COCC1>[CH3:9][C:4]1[CH:3]=[C:2]([Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:7]=[CH:6][C:5]=1[O:8][Si:16]([CH3:18])([CH3:17])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(Br)ccc1O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc([Si](C)(C)C)ccc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 4-bromo-2-methylphenol (1.5 g, 8.02 mmol) in THF (16 mL) at −78° C. was added n-butyl lithium (12.5 mL, 1.6 M solution in hexanes, 20.05 mmol) and the reaction was stirred at this temperature for 30 minutes. Trimethylsilyl chloride (2.5 mL, 20.05 mmol) was then added and the resulting mixture was stirred at −78° C. for a further 1.5 hours. The reaction was allowed to warm to room temperature and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with diethyl ether (2×20 mL) and the combined organic extracts were dried (magnesium sulphate) and concentrated under reduced pressure to give the intermediate 2-methyl-4-(trimethylsilyl)phenoxytrimethylsilane as a pale yellow oil (1.6 g). This intermediate was then diluted with THF (3 mL) and treated with TBAF (6.3 mL, 1.0 M solution in THF, 6.33 mmol) at room temperature. The reaction was stirred at this temperature for 5 minutes and poured into water (10 mL). The aqueous portion was then extracted with ether (3×5 mL) and the combined organic extracts were washed (saturated brine), dried (magnesium sulphate) and concentrated under reduced pressure. The resulting oily residue was pre-adsorbed onto silica and the 2-methyl-4-(trimethylsilyl)phenol isolated by column chromatography (SiO2; light petroleum to 7:3 light petroleum-diethyl ether) as a pale yellow oil (0.78 g, 68%). Rf=0.65 (7:3 light petroleum-diethyl ether, silica). 1H NMR (DMSO-d6): δH 0.17 (9 H, s), 2.1 (3 H, s), 6.77 (1 H, d, J=7.8 Hz), 7.12 (1 H, d, J=7.8 Hz), 7.17 (1 H, s), 9.36 (1 H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]([C:8]1[C:13]([B:14]2[O:18]C(C)(C)C(C)(C)[O:15]2)=[CH:12][C:11]([O:23]C2CCCCO2)=[CH:10][C:9]=1[CH3:30])=O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH:6]1[O:18][B:14]([OH:15])[C:13]2[CH:12]=[C:11]([OH:23])[CH:10]=[C:9]([CH3:30])[C:8]1=2
Reactant: COC(=O)CCC(=O)c1c(C)cc(OC2CCCCO2)cc1B1OC(C)(C)C(C)(C)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC1OB(O)c2cc(O)cc(C)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a solution of 4-[2-Methyl-4-(tetrahydro-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-oxo-butyric acid methyl ester (1.15 g, 2.57 mmol) in MeOH (50 mL) was added NaBH4 (0.244 g, 6.42 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, quenched with 6 N HCl and concentrated in vacuo. The residue was purified by silica gel flash column chromatography followed by lyophilization to give 3-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-propionic acid methyl ester (0.19 g, 30%). 1H NMR (400 MHz, Actone-d6) δ 8.20 (s, 1H), 7.96 (s, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 5.20 (m, 1H), 3.60 (s, 3H), 2.40 (m, 2H), 2.30 (m, 3H), 1.65 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3([O:14][C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[CH2:13][CH2:12]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2([O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)([OH:9])[CH2:10][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(OC2(C3(c4ccc(Cl)cc4)CO3)CC2)cc1
Reactant: c1c[nH]cn1
Product: OC(Cn1ccnc1)(c1ccc(Cl)cc1)C1(Oc2ccc(Cl)cc2)CC1

Procedure:
3.2 g=10 mmol of 2-(4-chlorophenyl)-2-[1-(4-chlorophenoxy)cyclopropan-1-yl]-oxirane (compound from Example 14) were reacted with 2.04 g=30 mmol of imidazol, as specified in Example 2a), in the absence of a solvent, and 2.9 g (75% of theory) of melting point: 172°-173° C. were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1.[C:19]([N:21]=[C:22](SC)[S:23][CH3:24])#[N:20]>C(#N)C>[C:19]([NH:21][C:22](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)[S:23][CH3:24])#[N:20]
Reactant: CN(C)Cc1ccc2cc(CSCCN)oc2c1
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Product: CSC(=NCCSCc1cc2ccc(CN(C)C)cc2o1)NC#N
Reaction time: 2 h

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran (12.0 g, 0.0454 mole) and dimethyl cyanodithioimidocarbonate (7.0 g., 0.048 mole) in acetonitrile (48 ml.) is allowed to stand 2 hours at room temperature. The solvent is evaporated at reduced pressure and the viscous oily residue is chromatographed on a column of 250 g. of silica gel. Elution with 8% methanol in chloroform removes the product. There is obtained 14.6 g. (89%) of N-cyano-N'-[2-(6-dimethylaminomethyl-2-(benzofuranylmethylthio)ethyl]-S-methylisothiourea as a yellow oil which gradually crystallizes, m.p. 98°-100° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C1COCC1>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][C:26]([OH:29])([CH:7]([C:8]([OH:10])=[O:9])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(O)Cc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of phenylacetic acid (13.7 g, 0.100 mol) in THF (90 mL) at 0° C. was slowly added iPrMgCl (2M in Et2O, 100 mL, 0.200 mol). The mixture was stirred at rt for 1 h and then N-Boc-4-piperidone (20.0 g, 0.100 mol) was added as a solid. Stirring was continued for 1 h and then the mixture was quenched with sat. NH4Cl and acidified to pH 2 using concentrated HCl. The mixture was extracted with EtOAc (×3) and the combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (33.3 g, 99%) as a colorless foam which was of sufficient purity to continue to the next step:
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[C:25]([C:24]1[C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:20][CH:21]=[CH:22][CH:23]=1)#[N:26]
Reactant: N#Cc1cccnc1Cl
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: N#Cc1cccnc1-n1c(/C=C/c2ccccc2)nc2ccccc21

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-chloro-3-cyanopyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate to give the titled compound.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH:16]=3)[CH:10]=2)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3]1.Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH:16]=4)[CH:10]=3)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3]2)=[N:27][CH:28]=1
Reactant: COCCn1cc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cn1
Reactant: Clc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccc(Cl)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 120 °C
Yield: 38 %

Procedure:
1-((2S,4R)-4-amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 11) (100 mg, 0.304 mmol), 2-bromo-5-chloropyridine (117 mg, 0.609 mmol), Davephos (23.97 mg, 0.061 mmol), Pd2(dba)3 (27.9 mg, 0.030 mmol) and sodium tert-butoxide (58.5 mg, 0.609 mmol) were combined in 1,4-dioxane (3 ml) and the mixture degassed over a period of 20 min before being heated at 120° C. for 25 min (microwave). The reaction mixture was partitioned between water (100 ml) and DCM (3×100 ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residual brown oil was dissolved in DMSO (2×1 ml) and purified by MDAP (HpH ×2). The solvent was evaporated under vacuum to give 1-((2S,4R)-4-((5-chloropyridin-2-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (51 mg, 0.116 mmol, 38% yield) as a yellow glass. LCMS (formate), Rt 0.87 min, MH+ 440.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[C:11]1([CH3:20])[C:12]([N:17]=[C:18]=[O:19])=[CH:13][CH:14]=[CH:15][CH:16]=1>CC(C)=O>[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:19])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1nc(CC(=O)O)cs1
Solvent: CC(C)=O
Product: Cc1ccccc1NC(=O)Nc1nc(CC(=O)O)cs1
Yield: 65.9 %

Procedure:
To a suspension of 2-amino-4-thiazoleacetic acid (4 g, 25 mmol) in 1:1 CH2Cl:acetone (100 mL) was added o-tolylisocyanate (3.5 g, 26 mmol). The mixture was heated to reflux for 8 hr at which time a yellow precipitate had formed the precipitate was filtered and the solid washed generously with 1:1 CH2Cl2:acetone. The solid was recrystallized with hot methanol and dried under vaccum to yield 4.8 g (66% yield) of the desired 2-(o-tolylureido)-4-thiazoleacetic acid 196.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:12]F>C(#N)C>[Cl:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([F:12])=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1Cl
Reactant: FF
Solvent: CC#N
Product: COC(=O)c1nc(F)cnc1Cl
Temperature: 25 °C

Procedure:
In 15 mL of acetonitrile was dissolved 0.3 g of methyl 3-chloro-2-pyrazinecarboxylate. At an ice-cooled temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced at a rate of 45 ml per minute for a period of 18 minutes. Then, while elevating the temperature from the ice-cooled temperature to room temperature, nitrogen gas was introduced for one hour, and the reaction product was concentrated under reduced pressure. The oily product thus obtained was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=10:1] to obtain 0.03 g of methyl 3-chloro-6-fluoro-2-pyrazinecarboxylate as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]([F:15])=[C:13]([CH2:16][CH3:17])[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)C>[Br:18][CH:16]([C:13]1[C:14]([F:15])=[C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:10]=[CH:11][N:12]=1)[CH3:17]
Reactant: CCc1ncnc(Sc2ccc(Cl)cc2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Product: CC(Br)c1ncnc(Sc2ccc(Cl)cc2)c1F
Temperature: 25 °C
Yield: 88.9 %

Procedure:
131 g of 4-(4-chloro-phenylsulfanyl)-6-ethyl-5-fluoropyrimidine, 103.8 g of N-bromosuccinimide and 7.98 g of azobisisobutyronitrile were dissolved in 850 ml of dichloroethane. The resulting mixture was refluxed for 2 hours, cooled to room temperature, and washed successively with 800 ml of water, 50 g of sodium metabisulfite in 950 ml of water and 500 ml of brine. The resulting solution was concentrated under a reduced pressure and crystallized at 5° C. in 391 ml of isopropanol to obtain the white compound, and the compound was washed with 50 ml of isopropanol at 5° C. to obtain the white title compound (150.7 g, yield: 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[CH3:25].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:9](=[O:11])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[S:32][CH:33]=1)[CH3:25]
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
A solution of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid (252 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.55 mL, 1.1 mmol), and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and then at 25° C. for 1.5 h. The reaction mixture was then treated with (2-amino-thiazol-4-yl)-acetic acid ethyl ester (409 mg, 2.2 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.4 mmol). This solution was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 85/15 hexanes/ethyl acetate) afforded {2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (183.3 mg, 43.5%) as a pale yellow oil: EI-HRMS m/e calcd for C21H25ClN2O3S (M+) 420.1274, found 420.1272.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1>[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:4][C@H:5]([C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[CH:17]=3)[S:13][CH:14]=2)[CH2:6][CH:7]([CH3:8])[CH3:9])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(Nc2nc([C@H](CC(C)C)NCc3ccc(F)cc3)cs2)ccc1-n1cnc(C)c1
Reaction time: 0.17 h

Procedure:
96 mg (0.2 mmol) [4-((S)-1-Amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride was suspended in tetrahydrofurane (3 ml). At room temperature under nitrogen 103 mg (0.8 mmol) N,N-diisopropyl ethyl amine was added and the reaction was stirred for 10 minutes. 28 mg (0.22 mmol) 4-fluorobenzaldehyde, 24 mg (0.4 mmol) acetic acid and 127 mg (0.6 mmol) sodium triacetoxyborohydride were added and the reaction was stirred at room temperature over night. 2N aqueous NaOH solution (6 ml) was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 48 mg (50%) of {4-[(S)-1-(4-fluoro-benzylamino)-3-methyl-butyl]-thiazol-2-yl}-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 480.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.37 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.34-7.31 (m, 3H), 7.24 (d, 1H), 7.13-7.02 (m, 4H), 6.67 (s, 1H), 3.77 (m, 4H), 3.69 (d, 1H), 3.53-3.49 (m, 3H), 2.14 (s, 3H), 1.59-1.51 (m, 3H), 0.85 (d, 3H), 0.78 (d, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>ClCCl.O>[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:25]([N:24]([CH3:28])[CH3:23])=[O:26])=[CH:15][CH:14]=1)#[N:13]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1ccc(OCCNCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)N(CCO)CCOc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
4-{2-[(2-Hydroxyethyl)amino]ethoxy}benzonitrile (5 g, 0.0242 mol; see Preparation C, step (ii) above) was taken in dry dichloromethane (50 mL) and cooled to 0° C. Triethylamine (4 mL, 0.03 mol), followed by N,N-dimethylcarbamoyl chloride (3.9 g, 0.03 mol), was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. Purification by column chromatography using dichloromethane in methanol yielded 6 g of the sub-title compound as pale yellow liquid.