Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)=[O:4].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C1COCC1>[CH3:35][O:34][C:32](=[O:33])[CH2:31][NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1
Reactant: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Product: COC(=O)CNCC(=O)NCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 36.1 %

Procedure:
{[({2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-carbamoyl)-methyl]-amino)-acetic acid methyl ester (44 mg, 88%) was prepared by treating 2-amino-N-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-acetamide (104 mg, 0.25 mmol) with methyl bromoacetate (0.023 mL, 0.25 mmol) in THF (5 mL) at 60° C. for 2 h followed by column purification [silica, DCM:ethyl acetate (80:20 to 20:80)].
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])([O-:9])=[O:8].[ClH:19].[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33][C:34](=[O:36])[NH2:35])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[ClH:19].[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=2)[C:29]=1[CH2:33][C:34](=[O:36])[NH2:35])=[O:13])([O-:9])=[O:8]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccccc3[N+](=O)[O-])ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
50 Milliliters of anhydrous pyridine and 20 ml of DMF were added to 5.0 g of 2-nitrobenzoic acid, 3.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 4.4 g of DCC and 218.2 mg of DMAP, followed by stirring for 2 hours under cooling with ice and 24 hours at room temperature. Then, the precipitate was filtered and washed with 100 ml of warm DMF. This wash liquid and the filtrate were combined, and the solvent was distilled off under reduced pressure. To the residue was added 20 ml of DMF, and the resulting solution was added dropwise to 600 ml of acetone, followed by stirring for 2 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using chloroformmethanol-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To 1/2 of the residue were added 20 ml of methanol and 1.4 ml of concentrated hydrochloric acid to suspend the residue. The suspension was added dropwise to a mixed liquid of 200 ml of ether and 200 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 2.42 g of 6-amidino-1-carbamoylmethyl-2-naphthyl 2-nitrobenzoate.hydrochloride.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25](=[O:27])[CH3:26])[C:5]1=[O:30])[CH:2]=[CH2:3].C[Si](C)(C)[C:34]([F:37])([F:36])[F:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25]([OH:27])([CH3:26])[C:34]([F:37])([F:36])[F:35])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)=O)C1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)(O)C(F)(F)F)C1=O
Reaction time: 2 h

Procedure:
A solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one (30 mg, 0.065 mmol; Example 149, Step B) and trimethyl(trifluoromethyl)silane (48.5 μL, 0.327 mmol) in THF (0.5 mL) was treated with 1 M tetrabutylammonium fluoride solution in THF (196 μL, 0.196 mmol) at 0° C. After being stirred for 2 h, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and saturated NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by the flash chromatography on silica gel (eluent: 10 to 20% EtOAc/Hexane, gradient elution) to provide the title compound as the major product.
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[C:29]([OH:35])(=[O:34])[CH2:30][CH2:31][C:32]#[CH:33].C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C>>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([C:33]#[C:32][CH2:31][CH2:30][C:29]([OH:35])=[O:34])[N:3]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:4]=[C:5]2[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:7]1=[O:13]
Reactant: C#CCCC(=O)O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCC(=O)O)n(Cc3cccc4ccccc34)cc21

Procedure:
The sub-title compound was prepared from 5-iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione, and 4-pentynoic acid in the presence of bistrimethylsilyltrifluoroacetamide in a manner analogous to the method of Example 13 above.
Reaction SMILES: [OH:1][C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[O:1]([C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred, room temperature solution of ethyl (R)-3-hydroxybutanoate (5.00 g, 37.8 mmol) and tert-butyldimethylsilyl chloride (6.85 g, 45.5 mmol) in DMF (90 mL) was added imidazole (3.87 g, 56.9 mmol). This reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between hexane (300 mL) and water (100 mL). The organic layer was washed with water (2×100 mL) then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1)[CH3:4]>O1CCCC1.CO>[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1)[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCOCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCOCC)c1
Yield: 62 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 14 eq) of sodium hydroxide and methyl 3-[2-(2-ethoxyethoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane and isopropyl ether, 245 mg of 3-[2-(2-ethoxyethoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=63° C.). Yield=62% over the two steps.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2.C([BH3-])#N.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:17])([F:18])[F:19])[CH2:14][NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(CC(O)(CNc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1cc(F)cc2c1OCC2

Procedure:
Analogously to Example 1, the corresponding imine is produced starting from 250 mg of 4-(2,3-dihydro-5-fluoro-7-benzofuranyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 124 mg of 5-aminoquinolin-2[1H]-one. After reaction with sodium cyanoborohydride, the title compound is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[CH:16]1([C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ccc(OC(=O)C2CCCCC2)cc1

Procedure:
The title compound was prepared from 6.0 g of 4-hydroxybenzophenone, 6.0 ml of cyclohexanecarbonyl chloride, pyridine (70 ml). Recrystallized from ethyl acetate-ethanol-water; M.P.~111°-112° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH2:15]([NH2:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:15]([NH:25][C:12]([CH:10]1[CH2:9][S:8][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:11]1)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCN
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Product: CCCCCCCCCCNC(=O)C1CSC(c2cccnc2)N1

Procedure:
2-(3-Pyridyl)thiazolidine-4-carboxylic acid and decylamine were used as the starting materials and treated the same manner as in Example 39 to give N-decyl-2-(3-pyridyl)thiazolidine-4-carboxamide. Yield, 80%. Melting point 88° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:6]([Cl:17])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[K].[C:25]1([CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O.O>[Cl:17][C:6]1[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=[C:2]([NH:36][S:33]([CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:34])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cccc(Oc2c(Cl)nc(N3CCOCC3)nc2Cl)c1
Reactant: NS(=O)(=O)CCc1ccccc1
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(Oc2c(Cl)nc(N3CCOCC3)nc2NS(=O)(=O)CCc2ccccc2)c1
Yield: 90.3 %

Procedure:
A solution of 4-[4,6-dichloro-5-(3-methoxy-phenoxy)-pyrimidin-2-yl]-morpholine (1.0 g) and 2-phenyl-ethanesulfonic acid amide potassium salt (1.57 g, Referential Example 1e) in DMSO (15 ml) was stirred at 60° C. for 24 h. The solution was diluted with water (75 ml) and extracted twice with diethyl ether (75 ml) before it was acidified with 10% aq. citric acid. The mixture was extracted twice with EA (150 ml). The organic phase was washed with water (50 ml). The product precipitated upon evaporation of the solvent. The solid was collected, washed with diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-chloro-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (1.28 g) as off-white powder. LC-MS: tR=5.34 min, [M+1]+=505.12, [M−1]−=502.97.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=[C:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13]>>[CH:1]1([NH:6][CH2:7][CH:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C1CCOC1=O
Reactant: NC1CCCC1
Product: O=C1OCCC1CNC1CCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.1 %

Procedure:
A mixture of 4.44 g (0.0521 mole) of cyclopentylamine and 5.12 g (0.0521 mole) of dihydro-3-methylene-(3H)-furanone was stirred at room temperature for 40 minutes and then distilled under vacuum to give 8.41 g of (rac)-3-[(cyclopentylamino)methyl]dihydro-2(3H)-furanone, b.p. 120-128 degrees, 0.3 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:10][Si:11]([CH3:14])([CH3:13])Cl>BrCCBr.C1COCC1>[CH3:10][Si:11]([CH3:14])([CH3:13])[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cccc(Cl)c1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1cccc([Si](C)(C)C)c1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A solution of m-chlorotoluene (25.3 g, 0.20 mol), 1,2-dibromoethane (2.18 g, 11.6 mmol) and THF (40 cm3) was added to magnesium turnings (5.35 g, 0.22 mol). The mixture was heated under reflux in an atmosphere of argon for 4 h, after which the heating bath was removed and trimethylchlorosilane (23.9 g, 0.22 mol) was added so that gently reflux was maintained. The mixture was stirred for another 30 min and then separated between 5% NaHCO3 (100 cm3) and dichloromethane (3×100 cm3). The organic extract was washed with brine and dried (MgSO4). The solvent was removed under reduced pressure affording the title compound (29.4 g, 89%) as a pale yellow liquid, which was used without purification in the next reaction. All spectroscopic data were identical to those reported in the literature (Eisenhut et al., ibid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:8]=1)[NH2:5].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:5][C:4]1[CH:6]=[C:7]([O:9][C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:21]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1cc(Cl)cc(Oc2cncnc2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)cc(Oc2cncnc2)c1)c1cccc(Cl)c1
Reaction time: 0.08 h
Yield: 6.2 %

Procedure:
Compound 9 (29 mg, 0.13 mmol, 1.0 eq) was dissolved in CH2Cl2 (1.2 mL) and DMAP (32 mg, 0.26 mmol, 2.0 eq) was added and the reaction stirred for 5 min. 3-Chlorobenzoyl chloride (23 mg, 0.13 mmol, 1.0 eq) was added and the reaction was stirred until determination of completion by LCMS. The reaction was diluted with CH2Cl2, washed with water (1×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 2.9 mg (6%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.07 (s, 1H), 8.75 (s, 2H), 7.96 (t, J=1.7 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.81 (t, J=1.7 Hz, 1H), 7.68-7.66 (m, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.46 (t, J=2.0 Hz, 1H), 7.05 (t, J=2.0 Hz, 1H); ES-MS [M+1]+: 360.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
20 g (143.66 mmol) of 4-methylthioaniline was placed in a flask and dissolved in 660 mL of CH2Cl2. The solution was cooled to 0° C. and 35.42 g (143.66 mmol) of m-chloroperbenzoic acid was added. The mixture was stirred for 3 h at room temperature and poured into CHCl3. It was then washed with saturated NaHCO3 solution, dried over MgSO4 and the solvent was removed, yielding a crude product that was purified by chromatography on silica gel, using MeOH/EtOAc/hexane mixtures of increasing polarity as eluent. The title compound of the example was obtained as a white solid (17.84 g, 80%).
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][C:10]=2[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1.C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O>ClCCl>[CH:1]1([C:5]2[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]([C:22]#[N:23])=[N:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1ccc(OCC(F)(F)F)c(C2CCC2)c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: N#Cc1cc(OCC(F)(F)F)c(C2CCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a solution of 3-cyclobutyl-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide (Example 108d, 3.5 g, 14.2 mmol) in dichloromethane (55 ml) under argon atmosphere was added trimethylsilylcyanide (1.83 g, 2.47 ml, 18.4 mmol) followed by addition of dimethylcarbamoyl chloride (CAN 79-44-7, 2.28 g, 1.95 ml, 21.2 mmol). The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (2.95 g, 77%) as light yellow solid. MS (ESI, m/z): 257.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH2:23]Br>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([N:14]3[CH2:15][CH2:16][N:17]([CH2:23][C:22]4[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:21]=4[F:20])[CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1
Reactant: Fc1ccc(F)c(CBr)c1
Product: Fc1ccc([C@H]2CC[C@H](N3CCN(Cc4cc(F)ccc4F)CC3)CC2)cc1

Procedure:
The title compound was prepared from trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine and 2,5-difluorobenzyl bromide by the method described in example 15 to give the product (69%, mp: 85°-86° C.). Calc'd for C23H27F3N2 : C, 71.12%; H, 7.01%; N, 7.22%. Found: C, 71.11%; H, 7.01%; N, 7.19%.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[CH:28]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:31][OH:32]>CO>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH2:25]2)[C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][C@H:9]1/[CH:28]=[N:31]/[OH:32])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: NO
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](C=O)N(C(=O)OC(C)(C)C)C2)CC1
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](/C=N/O)N(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of (2S,4S)-1-Boc-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-2-formylpyrrolidine (312 mg, 0.88 mmol) prepared in Step A in methanol (5 ml) and TEA (0.64 ml, 4.4 mmol) was added hydroxylamine hydrochloride (305 mg, 4.4 mmol), and stirred at rt for 2 h. After the reaction finished, the solution was concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (208 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:40](=[O:41])[N:39]([CH3:43])[CH3:38])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(OC(=O)N(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with N,N-dimethylcarbamoyl chloride
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]#[N:10].NC1C(C)=CC=CC=1.[ClH:19].[CH3:20][C:21]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>ClC1C=CC=CC=1>[ClH:19].[CH3:20][C:21]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=1[NH:23][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[NH:10]
Reactant: Cc1ccccc1NC#N
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Agent: Cl
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1N
Product: Cc1ccccc1NC(=N)Nc1ccc([N+](=O)[O-])cc1C
Yield: 91 %

Procedure:
A vigorously stirred mixture of 2-methylphenyl-cyanamide [1.107 g, 0.380 mmol, prepared from o-toluidine by the method of Safter et al. (1948)] and 2-methyl-4-nitroaniline hydrochloride in chlorobenzene (45 ml) was heated at 90° for 3 h and then allowed to cool to 25°. The resulting pale yellow precipitate was collected, washed with CH2Cl2, and dried, giving 2.284 g (91%) of the hydrochloride of the desired product (pure by NMR). A 681 mg sample was recrystallized twice from absolute EtOH to give 600 mg (88%) of the desired product as pale yellow microcrystals suitable for the next reaction: mp 196-200; (CD3OD, 300 MHz) 2.37 (s, 3), 2.47 (s, 3), 7.33-7.40 (m, 4), 7.59 (d, 1), 8.18 (dd, 1), 8.27 (d, 1). A 473 mg sample of the hydrochloride was dissolved in 50 ml of hot water, filtered, cooled to 25°, and treated with 5 ml of 5 N NaOH. The resulting bright yellow precipitate of the title compound (free base) was dried (403 mg, 92%) and then recrystallized twice from 95% EtOH to give the analytical sample as yellow platelets: mp 177-179; (DC3OD, 300 MHz) 2.31 (s, 6), 7.01-7.35 (m, 5), 7.98 (dd, 1), 8.06 (d, 1). Analysis calculated for C15H16N4O2 :C, 63.37; H, 5.67; N, 19.71. Found: C, 63.41; H, 5.42; N, 19.90.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:5]1)[CH3:2].[C:17]1([C:23]2[O:24][C:25]([C:31]([F:34])([F:33])[F:32])=[C:26]([C:28](O)=[O:29])[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:1]([O:3][CH:4]1[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([NH:14][C:28]([C:26]3[N:27]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:24][C:25]=3[C:31]([F:33])([F:34])[F:32])=[O:29])=[CH:12][CH:13]=2)[CH2:5]1)[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCOC1CN(c2ccc([N+](=O)[O-])cn2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC1CN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1
Yield: 69.2 %

Procedure:
2-(3-Ethoxy-azetidin-1-yl)-5-nitro-pyridine (59 mg, 0.264 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (74 mg, 0.29 mmol), Et3N (186 uL, 1.32 mmol) and BOP (122 mg. 0.277 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-ethoxy-azetidin-1-yl)-pyridin-3-yl]-amide as a solid (79 mg). ES-MS calcd for C21H19F3N4O3 (m/e) 432.41, obsd 433.1 (M+H).