Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH2:15]([SH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[H-].[Na+]>O1CCCC1>[CH2:15]([S:23][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(Cl)CCn1ccnc1
Reactant: CCCCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCSC(CCCCC)CCn1ccnc1

Procedure:
500 Mg. of 1-(3-chlorooctyl)imidazole in 10 ml. tetrahydrofuran was added to a fully reacted mixture of 750 mg. of n-octylmercaptan and 200 mg. of 56% sodium hydride dispersion in mineral oil in 30 ml. of tetrahydrofuran. After stirring under reflux for 12 hours the solvent was evaporated under vacuum and 150 ml. of ether was added. The resulting mixture was washed twice with water and the ethereal solution dried and evaporated. The residue was chromatographed on silica gel, eluting with 20% acetone/dichloromethane to afford 1-(3-octylthiooctyl)imidazole, as an oil. This material was converted to the oxalate salt by treatment of an ethereal solution with oxalic acid in ether until precipitation was complete, which salt was recrystallized from ethyl acetate as snow-white microcrystals, m.p. 105°-108° C.
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[Br:17][C:18]1[CH:19]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[F:24]>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]([S:25]([N:5]2[CH2:6][C:3]([F:7])([F:2])[CH2:4]2)(=[O:26])=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: FC1(F)CNC1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a suspension of 3,3-difluoroazetidine hydrochloric acid (0.947 g, 7.31 mmol) in 20 mL dichloromethane at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (2.80 mL, 16.1 mmol) followed by the addition of a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (2.0 g, 7.3 mmol) in 4 mL dichloromethane. The mixture was stirred at room temperature overnight and then heated at 55° C. for 5 hours, diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 10-50% ethyl acetate/heptanes gradient) to give the title compound (1.5 g, 62.1% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:11]([CH3:17])=[C:12]([C:14](O)=[O:15])[N:13]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:59]1([NH2:65])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>C(#N)C>[CH:59]1([NH:65][C:14]([C:12]2[N:13]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:11]=2[CH3:17])=[O:15])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1
Reactant: NC1CCCCC1
Reactant: COc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)O)c2C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)NC3CCCCC3)c2C)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Part C: To 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid (1.00 gram, 2.65 mmol) in dry acetonitrile (25 mL) is successively added diisopropylethylamine (DIPEA) (1.02 mL, 2.2 molar equivalents), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (HBTU) (1.21 gram, 1.2 molar equivalents) and the resulting solution is stirred for 15 minutes. Cyclohexylamine (0.36 mL, 1.2 molar equivalents) is added. After stirring for 50 hours, the resulting mixture is concentrated in vacuo. The residue is dissolved in dichloromethane and an aqueous NaHCO3 solution is added. The dichloromethane layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue is further purified by column chromatography (gradient: dichloromethane=>dichloromethane/methanol=99/1 (v/v), silicagel) to give N-(1-cyclohexyl)-2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamide (1.03 gram, 85% yield). Melting point: 160–161° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
Thionyl chloride (5 ml) and dimethylformamide (1 drop) were added to a solution of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzoic acid (1 g) in dichloromethane (5 ml), and the mixture was refluxed for 3 hours. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzoyl chloride as crystals. Then, the crystals were dissolved in dichloromethane (14 ml). The solution was dropwise added to a solution of 4-aminopyridine (250 mg) and diisopropylethylamine (375 mg) in dichloromethane (6 ml) under ice-cooling, and the mixture was stirred at room temperatue for 4 hours. After the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=15:1) to give 940 mg of (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)Cl>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)CCC2
Reaction time: 0.5 h
Yield: 928.3 %

Procedure:
To a solution of 5-aminoindane (10.0 g, 7.5 mmol) in CH2Cl2 (100 mL) was added dropwise acetic anhydride (9.2 g, 9.0 mmol) over a period of 1.5 min. After further stirring for 30 min, the mixture was quenched with 1M aqueous NaOH (100 mL). The CH2Cd2 layer was separated, washed successively with 1M aqueous HCl, brine, and was then dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel, eluting with ethyl acetate:hexanes (1:1) afforded 12.2 g (85%) of the title compound as a light brown powder.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:30])(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][S:24]4(=[O:30])=[O:29])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nn3)CC2)c(C)c1
Yield: 37.2 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and isothiazolidine 1,1-dioxide (66 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (70 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=[O:17])[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CC(c2nc3ccc(Br)cc3s2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC(c2nc3ccc(Br)cc3s2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
The product of Example 1B (931 mg, 3.33 mmole) and osmium tetraoxide (28 mg, cat.) were dissolved in 30 ml THF and 15 ml water. The solution was cooled to 0° C. Sodium periodate (1.5 g, 7.0 mmole) was added in small portions. The mixture was stirred at room temperature overnight. The solution was quenched with water, and extracted three times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated to give the crude product, which was purified by chromatography (20% hexane in dichloromethane) to give the title compound (710 mg, 76%). 1H NMR (500 MHz, CDCl3) δ ppm 8.00 (d, J=1.87 Hz, 1H), 7.84 (d, J=8.74 Hz, 1H), 7.59 (dd, J=8.73, 1.87 Hz, 1H), 3.96-4.10 (m, 1H), 3.54-3.76 (m, 4H). MS: (M+H)+=281/283
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1.N12CCCN=C1CCCCC2>C(#N)C>[OH:18][CH:19]1[CH2:20][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[N:36]=[CH:35][NH:34][C:33]4=[N:37][CH:38]=[CH:39][C:32]=34)[CH:28]=[N:27]2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC1(n2cc(-c3nc[nH]c4nccc3-4)cn2)CC(O)C1
Temperature: 50 °C

Procedure:
(3-[tert-Butyl(diphenyl)silyl]oxycyclobutylidene)acetonitrile (0.15 g, 0.00043 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.14 g, 0.00043 mol) in acetonitrile (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.064 mL, 0.00043 mol) was added under nitrogen. The mixture was heated to 50° C. over night. LCMS showed a peak with m/z of 425.4, indicating a de-silyl reaction occurred simultaneously during the Micheal addition. The reaction was concentrated and purified on combiflash (silica gel, 0-100% EtOAc/Hex) to yield the desired produt. LCMS (M+H) 425.4.
Reaction SMILES: C(=O)(O[CH:5]1[CH:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6]1)OC.[C:28]1([S:34]([CH2:37][N+:38]([O-:40])=[O:39])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1COCC1.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>[N+:38]([CH:37]([CH:5]1[CH:9]([CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:8]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=[CH:6]1)[S:34]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:36])=[O:35])([O-:40])=[O:39]
Reactant: COC(=O)OC1C=CC(OCc2ccccc2)C1COCc1ccccc1
Reactant: O=[N+]([O-])CS(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])C(C1C=CC(OCc2ccccc2)C1COCc1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
To a round bottomed flask equipped with an argon inlet, a magnetic stirrer and a cooling bath was dissolved crude 10 (9.8 g, 26.5 mmol), phenylsulfonylnitromethane (5.4 g, 26.8 mmol) and tetrakis(triphenylphosphine)palladium (0.6 g, 0.52 mmol) in THF (80 mL) at 0° C. The reaction mixture was degassed using argon for a few minutes. Triethylamine (8.4 g, 11.1 mL, 79.5 mmol) was added to the reaction mixture over the course of 10 minutes at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then quenched with 2 N HCl at 0° C. (100 mL) and extracted with hexane/ethyl acetate (1:1; 2×30 mL). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated in vacuo to afford a red-colored oily residue. Silica pad filtration was conducted using ethyl acetate to remove the baseline materials and give the title compound (14.2 g crude, >100%) as a light brown oil which was used in the next step without any further purification.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]([CH:9]([CH3:26])[CH2:10][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:12]#[N:13])[CH3:8].[OH-:27].[Na+]>O>[CH3:6][N:7]([CH:9]([CH3:26])[CH2:10][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:12]([NH2:13])=[O:27])[CH3:8]
Reactant: [OH-]
Reactant: CC(CC(C#N)(c1ccccc1)c1ccccn1)N(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(CC(C(N)=O)(c1ccccc1)c1ccccn1)N(C)C
Temperature: 90 °C

Procedure:
Conc. sulfuric acid (11 ml) was added to 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)-valeronitrile (6.3 g) at 0° C. and then water (1 ml) was added thereto. After being heated at 90° C. for 3 hours, the mixture was poured into ice-water, adjusted to pH 10 with 10% aqueous sodium hydroxide and extracted with ethyl acetate (50 ml×3). The extracts were combined, and washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The obtained crude crystal was recrystallized from diethyl ether to give 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)-valeramide (1.89 g). mp 132°-134° C.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10].[CH3:22][O:23][CH:24]([C:26]([O:28][CH3:29])=[O:27])[NH2:25]>C(Cl)Cl>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:9]([NH:25][CH:24]([O:23][CH3:22])[C:26]([O:28][CH3:29])=[O:27])=[O:10])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)C(N)OC
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (5.06 g, 0.05 mole) and p-nitrobenzyl chloroformate (10.78 g, 0.05 mole) are added to an ice-cold solution of methyl α-methoxyglycinate (6.10 g, 0.05 mole) in dry CH2Cl2 (100 ml). The resulting mixture is stirred in the cold and under N2 for 2 hours, and then washed with 3 portions of water. The CH2Cl2 phase is dried over MgSO4, filtered, and evaporated in vacuo. Recrystallization of the residue affords pure methyl N-(p-nitrobenzyloxycarbonyl)-α-methoxyglycinate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[C:13]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccccc1

Procedure:
In 100 ml of ethyl acetate was dissolved 40 g (210×10-3 mole) of 2-amino-4-chloro-5-nitrophenol, and 33 g of benzoyl chloride was added at room temperature and then the mixture was refluxed under heating for 2 hours. After the reaction, a solvent was distilled off under reduced pressure and the residue was recrystallized from hexane to obtain products. Yield: 60 g.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:34]([NH:41][CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:34]([N:41]([CH3:42])[C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[N:33][C:25]=1[S:24][CH2:23][CH2:22][S:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:20])=[O:21])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Reactant: CNCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
132 mg (0.81 mmol) of CDI were added to a solution of 250 mg (0.77 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (6 ml), and the mixture was stirred for 1 hour at RT. A solution of 93 mg (0.77 mmol) of N-benzyl-N-methylamine in DCM (6 ml) was then added, and stirring was continued for a further 16 h at RT. The reaction solution was then washed in each case three times with sat. aq. ammonium chloride solution and saturated aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC with the residue (DCM→DCM/MeOH 99.5:0.5) yielded 152 mg (0.36 mmol, 46%) of N-benzyl-N-methyl-2-(2-(phenylsulfonyl)ethylthio)nicotinamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15])[CH2:8][NH:9][C:10]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2)=[O:11]
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1
Temperature: 25 °C

Procedure:
The product from Example 192A (4.4 mmol) in toluene (10 mL) was treated with 5-amino-3-methylisoquinoline (460 mg, 2.9 mmol) and DIEA (3 mL). The mixture was heated at 80° for 1.5 hours, cooled to room temperature, and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.77 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.70-7.81 (m, 3H), 7.38-7.53 (m, 3H), 7.19 (t, 1H, 6.1 Hz), 4.47 (d, 2H, J=5.8 Hz), 2.65 (s, 3H); MS (ESI+) m/z 378 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])[N:6]=[C:5]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21]3[C@H:29]([C:30]([F:33])([F:32])[F:31])[CH2:28][C:27](=[O:34])[NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[CH3:42][S:43]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][C:10]([F:12])([F:11])[F:13])[N:6]=[C:5]1[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[C:21]3[C@H:29]([C:30]([F:33])([F:32])[F:31])[CH2:28][C:27](=[O:34])[NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:18][CH2:19]1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C[C@@H](C(F)(F)F)c2c(ncnc2N2CCC(c3nc(CC(F)(F)F)cn3CCO)CC2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1cc(CC(F)(F)F)nc1C1CCN(c2ncnc3c2[C@H](C(F)(F)F)CC(=O)N3)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Combine (R)-4-(4-(1-(2-hydroxyethyl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.93 g, 1.88 mmol), dichloromethane (14 mL), and triethylamine (0.79 mL, 3.0 eq). Place under nitrogen and cool to 0° C. Add methanesulfonyl chloride (0.17 mL, 1.2 eq) dropwise. After 30 minutes, dilute with dichloromethane and quench with saturated aqueous sodium bicarbonate. Separate the layers. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give (R)-2-(2-(1-(7-oxo-5-trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-1-yl)ethyl methanesulfonate as a yellow solid (1.07 g, 96%). MS (ES) m/z=571 [M]+.
Reaction SMILES: ClC(Cl)C.[NH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C([C@@H]1COC(=O)N1[C:26](=[O:48])[C@H:27]([CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][C:33]=1[Cl:47])[CH2:28][CH:29]=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:40]([O:39][C:35]1[CH:34]=[C:33]([Cl:47])[C:32]([CH2:31][C@@H:27]2[CH2:28][CH2:29][N:5]([N:6]3[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]3)[C:26]2=[O:48])=[C:37]([Cl:38])[CH:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NN1CCC(O)CC1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1N1CCC(O)CC1
Yield: 87.2 %

Procedure:
Stir a mixture of dichloroethane (500 mL), N-amino-4-hydroxypiperidine (10.66 g, 91.88 mmol), (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (40.2 g, 76.57 mmol) and sodium triacetoxyborohydride (48.47 g, 229.71 mmol) at room temperature for 21 hours. Bring the reaction to 55° C. and is stir for 1 hour. Cool the reaction, dilute with dichloromethane, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica with a 100% ethyl acetate and 10% methanol in methylene chloride to afford 30 g (90%) of the titled product. MS (m/z): 449 (M+).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39]Cl)=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42]>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:39][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:37][CH:38]=2)=[CH:28][C:27]=1[C:41]([F:42])([F:43])[F:44]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 60 °C
Yield: 26.7 %

Procedure:
To a suspension of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (75 mg, 0.343 mmol) and DIPEA (0.163 ml, 0.934 mmol) in DCM (2 mL) was added 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (100 mg, 0.311 mmol). The solution was heated at 60° C. overnight. Purification via MDAP then afforded the title compound (42 mg, 26.7% yield). LCMS: rt=3.49 min, [M+H+]=505
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[S:9][C:8]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[S:9](=[O:27])[C:8]=2[C:17]#[N:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1=C(c2ccccc2)Nc2ccccc2S1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#CC1=C(c2ccccc2)Nc2ccccc2S1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-phenyl-4H-1,4-benzothiazine-2-carbonitrile (0.10 g) and 3-chloroperbenzoic acid (0.17 g, purity 80%) in dichloromethane (8 ml) was stirred at 0° C. for 30 min. The mixture was filtered and the filter cake was washed with dichloromethane and dried to give the title compound as pale crystals. Yield 66 mg; mp 182-184° C.; 1H-nmr(DMSO) δ (ppm): 12.31 (br, 1H), 8.09-7.99 (m, 1H), 7.83-7.60 (m, 7H), 7.60-7.48 (m, 1H); IR(KBr) ν (cm−1): 3211, 3161, 2985, 2935, 2850, 2193 (C≡N ), 1603, 1548, 1502, 1463, 1429, 1004, 771, 703; MS m/e (rel. intensity): 250 (86%; M+−16), 249 (87%), 218 (39%), 211 (100%), 190 (11%), 146 (23%), 108 (43%), 69 (43%).