Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH2:18][CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[Li+].[BH4-]>>[OH:15][C@@H:9]1[CH2:8][N:7]([CH2:6][CH2:5][C@H:4]([N:16]2[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)[CH2:18][CH2:17]2)[CH2:3][OH:2])[CH2:14][CH2:13][C:10]21[CH2:12][CH2:11]2
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccc(C(F)(F)F)cc2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: O=C1CCN(c2ccc(C(F)(F)F)cc2)CCN1[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Yield: 75 %

Procedure:
In analogy to the procedure described in example 2, (S)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(4-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4 gave the title compound in 75% yield as a white foam. MS: 456.3 (MH+).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[Cl:44][C:45]1[C:50]([CH3:51])=[CH:49][C:48]([NH2:52])=[C:47]([O:53][CH3:54])[CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:52][C:48]3[CH:49]=[C:50]([CH3:51])[C:45]([Cl:44])=[CH:46][C:47]=3[O:53][CH3:54])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1cc(Cl)c(C)cc1N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1cc(Cl)c(C)cc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The coupling (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-chloro-2-methoxy-5-methyl-phenylamine according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=433.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:16][CH2:17][CH2:18][OH:19])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:16][CH2:17][CH:18]=[O:19])(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCO)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCC=O)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A solution of 2-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]-ethanol (322 mg, 0.95 mmol, as prepared in the preceding step), N,N-diisopropylethylamine (0.35 mL, 2.0 mmol), anhydrous dimethyl sulfoxide (0.20 mL, 2.9 mmol) and anhydrous dichloromethane (2.5 mL) was cooled to 0° C. under nitrogen. Sulfur trioxide pyridine complex (308 mg, 1.9 mmol) was added in portions over 10 minutes. The solution was stirred at 0° C. for 5 hours, then the reaction was quenched with 5% aqueous citric acid (25 mL). Diethyl ether (25 mL) was added, and the mixture was extracted. The aqueous layer was extracted with diethyl ether (25 mL), and the combined organic layers were washed with 5% aqueous citric acid (25 mL). The aqueous layer was extracted with diethyl ether (25 mL), and the combined organic layers were washed with pH 7 buffer (0.5M, 2×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to an oil. Crude product was purified by flash column chromatography through silica gel (0% to 5% acetone in dichloromethane) to give the title compound as a colorless oil (195 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 9.76 (t, 1H, J=1 Hz), 7.81 (dd, 1H, J=1.7, 7.9 Hz), 7.60-7.65 (m, 1H), 7.09 (d, 1H, J=8 Hz), 7.00-7.05 (m, 1H), 6.63 (br s, 1H), 6.59 (br s, 1H), 6.41 (t, 1H, J=2.2 Hz), 4.45 (d, 2H, J=1 Hz), 4.03 (s, 3H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H16O6S: 359.1 (M+Na). Found: 358.8.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:30]1[N:31]=[C:32]([CH3:42])[N:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:34]=1)#[CH:29]>C1COCC1.N1CCCCC1.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.[Cu]I>[F:41][C:38]1[CH:37]=[CH:36][C:35]([N:33]2[CH:34]=[C:30]([C:28]#[C:29][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=3)[N:31]=[C:32]2[CH3:42])=[CH:40][CH:39]=1
Reactant: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Reactant: Cc1cc(I)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-2-methyl-pyridine (656 mg, 3.0 mmol) was dissolved in 10 mL dry THF and 10 mL piperidine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (20 mg, 0.07 mmol) and bis(triphenylphosphin)palladium(II)chloride (175 mg, 0.10 mmol) were added and the reaction mixture was stirred at RT for 1 h. Copper(I)iodide (14 mg, 0.07 mmol) and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (IV-1) (500 mg, 2.5 mmol) were added. The reaction mixture was then refluxed for 3 h. The solvent was evaporated. The residue was taken up in 30 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient) and recrystallization from diethylether and the desired product was obtained as a light yellow solid (250 mg, 34%), mp=151° C., MS: m/e=292.1 (M+H+).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]([CH3:27])[CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:16]=[CH:15][C:14]=1[O:28][CH3:29])=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:29][O:28][C:14]1[CH:15]=[CH:16][C:17]([N:19]([CH3:27])[CH2:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: COc1ccc(N(C)CC2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N(C)CC2CCOCC2)cc1NC(N)=S
Reaction time: 18 h
Yield: 101 %

Procedure:
To a stirred suspension of 2.0 g (4.8 mmol) 1-benzoyl-3-{2-methoxy-5-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-phenyl}-thiourea in 15 ml methanol was added dropwise 0.4 ml (7.25 mmol) 5.4 M sodium methylate solution and stirring continued for 18 hrs at room temperature. The mixture was then concentrated in vactio and the residue subjected to column chromatography (1/1 hexane/ethyl acetate) to afford 1.5 g (100%) {2-methoxy-5-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-phenyl}-thiourea as a beige oil. ES-MS m/e (%): 310 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH3:11][C:12]1[N:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[N:28][OH:29])=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]1[N:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=4)[O:29][N:28]=3)=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(OCc2ccc(CC(Cl)=NO)cc2)n1
Reactant: C#Cc1ccc(N)nc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(OCc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a solution of 3-ethynyl-pyridin-2,6-diamine (300 mg, 2.25 mmol) described in Manufacturing Example 13-1-3 in anhydrous tetrahydrofuran (30 mL) was added (4-(6-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (1.50 g, 5.16 mmol) described in Manufacturing Example 3-1-5 under nitrogen atmosphere at room temperature. Triethylamine (1.25 mL, 9.00 mmol) was then added dropwise at room temperature, and stirred for 1.5 hours at room temperature. Water and ethyl acetate were added to the reaction mixture at room temperature, and the organic layer was separated. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (637 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1Cl.O.[NH2:12][NH2:13]>O1CCOCC1.C(O)C>[Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)nc1Cl
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: NNc1nc(Cl)c(Cl)nc1Cl
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
A solution was prepared by dissolving 21.8 grams of tetrachloropyrazine in 100 milliliters of dioxane. The solution was diluted with 250 milliliters of ethanol and 15 milliliters of hydrazine hydrate was slowly added thereto. The temperature rose from 23°C to 37°C. The solution was held, with stirring, at 23°C for 20 minutes and the 3,5,6-trichloro-2-hydrazinopyrazine product was isolated by pouring the reaction mixture in water and filtering off the solid product. The product melted at 167°-168°C and was recovered in a yield of 20.2 grams (94 percent of theoretical).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[Na+].C(OCC)(=O)C>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:17][CH2:16][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Brc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCC4(CC3)OCCO4)cc2)c2ccccc21
Temperature: 150 °C
Yield: 58.4 %

Procedure:
0.31 g of 8-(4-bromophenyl)-1,4-dioxa-8-azaspiro[4.5]decane is placed in 5 ml of anhydrous o-xylene. 0.24 g of 3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is added, then 0.15 g of sodium tert-butoxide is added, followed by 0.009 g of palladium acetate, and then the addition is completed with 0.0084 g of tri(tert-butyl)phosphine. The reaction mixture is heated at 150° C. for 4 h, then the heating is halted and the mixture is brought back to ambient temperature. Ethyl acetate is added and the mixture is washed twice with water and then twice with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a heptane/ethyl acetate (4/1) solvent mixture. 0.27 g of 4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#C.BrCC[F:21].CN(C=O)C>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][CH2:16][F:21])=[CH:11][N:12]=1
Reactant: C#CCN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: FCCBr
Solvent: CN(C)C=O
Product: CN1C(=O)CCN(CCF)c2nc(Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 154, on a 0.31 mmol scale, utilising 1-bromo-2-fluoroethane (Apollo Scientific; 235 mg, 1.44 mmol), as a white crystalline solid containing 0.6 equivalents of DMF (86 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:24]C2CCCCO2)[CH:18]([F:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:31]C2CCCCO2)[CH2:12][C@@H:11]1O.[N+](=C)=[N-].C1(C)C=CC(S([Cl:52])(=O)=O)=CC=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:24])[CH:18]([F:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:31])[CH2:12][C@H:11]1[Cl:52]
Reactant: CCCCC(F)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C=[N+]=[N-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(F)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 1.2 g of (5Z,13E)-(9S,11R,15R,16RS)-9-hydroxy-16-fluoro-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadienoic acid methyl ester (prepared from the corresponding acid in methylene chloride with 0.5-molar diazomethane solution at 0° C.), 800 mg of p-toluenesulfonic acid chloride, and 4 ml of pyridine is agitated for 16 hours at 0° C., then for 48 hours at 25° C. The mixture is worked up according to Example 1. Yield: 1.45 g of the 9-tosylate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[O:23][C:22]([C:24](OC)=[O:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[NH3:38]>CO>[NH2:38][C:24]([C:22]1[O:23][C:19]([S:16]([N:14]2[C:13]([C:28]3[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=3)=[C:12]([F:35])[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:15]2)(=[O:17])=[O:18])=[CH:20][CH:21]=1)=[O:25]
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Reactant: N
Solvent: CO
Product: CN(Cc1cn(S(=O)(=O)c2ccc(C(N)=O)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of methyl 5-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}-2-furoate (443 mg) in methanol (5 mL) was added 8 mol/L ammonia methanol solution (1 mL) at room temperature and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to give the title compound as a pale-yellow oil (yield 330 mg, 77%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C@H:30]([C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1)[CH3:31]>>[CH3:28][O:29][C@H:30]([C:32]1[N:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CO[C@@H](C)c1nc2ccccc2[nH]1
Product: CO[C@@H](C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(C)=O)CC3)ccc2n1

Procedure:
1-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone from Example 148 (0.125 g) was reacted with (S)-2-(1-methoxyethyl)-1H-benzo[d]imidazole via General Procedure D to produce 22.1 mg of 164 following reverse phase HPLC purification. MS (Q1) 530.3 (M)+
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[F:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][NH2:17])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1nc2cc(F)ccc2nc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1nc2cc(F)ccc2nc1NN
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution consisting of 47 g. (0.22 mole) of 2-chloro-6-fluoro-3-methoxyquinoxaline dissolved in 1000 ml. of ethanol, there were added 27.6 g. (0.55 mole) of hydrazine hydrate (26.8 ml.). The resulting mixture was stirred at room temperature overnight (i.e., at ca. 20° C. for approximately 16 hours). An additional amount of hydrazine hydrate (9.0 ml.) was then added and the final reaction mixture was allowed to stir at room temperature for a period of four hours. At this point, the precipitate was filtered and washed with ethanol to ultimately afford 43.3 g. (94%) of pure 6-fluoro-2-hydrazino-3-methoxyquinoxaline, m.p. 170°-174° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:5][C:6]=1[CH3:7].[Cu](C#N)[C:15]#[N:16].[C-]#N.[Na+]>CN(C)C=O>[C:15]([C:2]1[CH:3]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:5][C:6]=1[CH3:7])#[N:16]
Reactant: Cc1sc(C(=O)OC(C)C)cc1Br
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc(C(=O)OC(C)C)cc1C#N
Yield: 62.8 %

Procedure:
Isopropyl 4-cyano-5-methylthiiophene-2-carboxylate: A stirred solution of 1.9 g (7.3 mmol) of isopropyl 4-bromo-5-methylthiophene-2-carboxylate was dissolved in dry dimethylformamide (30 mL) and refluxed with copper cyanide (785 mg, 8.8 mmol) for 16 hours. The cooled solution was poured into 0.1 M aqueous sodium cyanide solution (300 mL) and extracted with diethyl ether (4×40 mL). The organic layers were washed with brine (2×40 mL), dried over anhydrous sodium sulfate, and the solvents removed in vacuo. Column chromatography on silica gel eluting with hexanes:ethyl acetate 9/1 (v:v), gave isopropyl 4-cyano-5-methylthiophene-2-carboxylate (960 mg, 63%) as a yellow crystalline solid 1H-NMR (DMSO-d6; 300 MHz) δ 8.01 (s, 1H), 5.09 (septet, 1H, J=6.2 Hz), 2.67 (s, 31H), 1.29 (d, 6H, J=6.2 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21].N1C=CC=CC=1.O>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: COc1cc(C=O)ccc1F
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=C2C(=O)OC(C)(C)OC2=O)ccc1F
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of titanium (IV) chloride (11.1 g) in THF (50 mL) was added dropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.26 g) and 4-fluoro-3-methoxybenzaldehyde (3.08 g) in THF (50 mL) at 0° C., and then a solution of pyridine (4.00 g) in THF (20 mL) was added dropwise. The reaction mixture was stirred for 1 hr, and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.20 g) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[S:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:11]2[CH:12]([S:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]([C:10]3[S:9][CH:13]=[CH:12][CH:11]=3)[S:9][CH:10]2[C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: C1CCSC1
Product: Clc1ccc(SC2C(c3cccs3)SC(c3cccs3)C2Sc2ccc(Cl)cc2)cc1

Procedure:
Starting from 4-chlorothiophenol, the synthesis of this compound is analogous to that of the tetrahydrothiophene synthesized in Example 2.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH3:47])[C@@H:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:38])[CH2:23][NH:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[CH2:18][C@H:17]2[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>Cl.CC(O)C>[ClH:45].[ClH:45].[Cl:46][C:41]1[CH:40]=[C:39]([C@H:17]2[C@H:16]([N:15]([CH3:47])[C:13](=[O:14])[C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:49])([F:48])[F:1])[CH:4]=3)[CH2:21][CH2:20][N:19]([C:22](=[O:38])[CH2:23][NH:24][CH:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)[CH2:18]2)[CH:44]=[CH:43][C:42]=1[Cl:45]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)CNC2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)CNC2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 189.6 %

Procedure:
A solution of the compound (0.23 g) obtained in step 1 in 2N hydrogen chloride/2-propanol (5 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to give N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-(N-piperidin-4-ylglycyl)piperidin-4-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide dihydrochloride (0.14 g, 63%) as a white powder.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[C:20]2[CH:19]=[C:18]([C:21](=[O:23])[CH3:22])[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.[Cl:24][C:25]1[CH:26]=[C:27]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1>C1COCC1>[Cl:11][C:12]1[C:20]2[CH:19]=[C:18]([C:21](=[O:23])[CH2:22][C:32]([C:27]3[CH:28]=[C:29]([Cl:31])[CH:30]=[C:25]([Cl:24])[CH:26]=3)([OH:37])[C:33]([F:36])([F:35])[F:34])[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1cc2c(Cl)cccc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1cc2c(Cl)cccc2s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
Add a solution of LiHMDS (1 M in THF, 4.3 ml, 4.31 mmol) to a mixture of 1-(4-chlorobenzo[b]thiophen-2-yl)ethanone (0.6 g, 2.87 mmol) in dry THF (10 mL) at −78° C. under N2. After stirring 1.5 hour at −78° C., add 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (836 mg, 3.44 mmol) to the reaction mixture and stir the resultant mixture for additional 2 hours. Quench the reaction with saturated NH4Cl solution and extract the aqueous mixture with EtOAc (10 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum afford crude 1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as brown solid (1.1 g, 84.6%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.07 (s, 1H), 7.75 (d, J=5.2, 1H), 7.47-7.36 (m, 2H), 2.72-2.68 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(Sc2ncc(Cl)cn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Sc2ncc(Cl)cn2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
5-Chloro-2-(4-methoxyphenylthio)pyrimidine (7.5 g) was dissolved in methylene chloride (60 ml) and the solution was cooled to -78° C. Boron tribromide (18 g) was added dropwise to the stirred solution, the temperature of the solution being maintained at -65° to -75° C. On completion of the addition the reaction mixture was stirred for a further one hour at -78° C. and then the temperature of the reaction mixture was allowed to rise slowly to 20° C. The reaction was quenched with water (50 ml), the resultant suspension cooled and filtered to give 4-(5-chloro-2-pyrimidylthio)phenol (5 g) as an almost colourless solid.