Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[OH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:32]3[CH2:33][CH2:34][C@H:30]([OH:29])[CH2:31]3)[CH2:26][CH2:27]2)=[O:21])[CH2:2][CH2:3]1
Reactant: O[C@H]1CCNC1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CC[C@H](O)C2)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (S)-3-hydroxyl-pyrrolidine in direct analogy to the general procedure used in example 129. MS: 463.3 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=O.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([CH2:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[CH2:4]1
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3,3-difluoropyrrolidine hydrochloride (965 mg, 6.722 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (1.720 g, 8.066 mmol), DIPEA (955.6 mg, 1.288 mL, 7.394 mmol) and crushed 4A MS (965 mg) in DCE (30 mL) were stirred at ambient temperature for 3 hours. NaBH(OAc)3 (2.848 g, 13.44 mmol) was added and the reaction stirred at ambient temperature for a further 16 hours. The mixture was filter through Celite (washing with DCM) and the filtrate concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give the sub-title product as a colourless oil that was used directly into next step without further purification. LC-MS ES+: 305.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[H-].[Na+].I[CH3:14]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:14])[CH:8]=[CH:7]2
Reactant: Clc1cccc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloroindole (610 mg, 4 mmol) in anhydrous DMF (6 mL) was added NaH (170 mg, 60% dispersion in mineral oil, 4.3 mmol) at 0° C. under argon. The mixture was stirred at room temperature for 30 min before adding iodomethane (240 mg, 4 mmol). The resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc (200 mL), washed with saturated NaCl (10 mL×3), dried over anhydrous MgSO4, filtered, and concentrated to give 7-chloro-1-methylindole. The residue was used directly for the next step without further purification. 1H NMR (500 MHz, CDCl3): δ4.14 (s, 3H), 6.46 (d, 1H, J=2.5), 6.95-6.98 (m, 2H), 7.12-7.14 (m, 1H), 7.48 (1H, dd, J=1.5, 7.5).
Reaction SMILES: [N:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[C:2]=[O:3].C1CCN2C(=NCCC2)CC1.Cl[CH2:25][CH2:26][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:31])[CH2:28][CH:29]=[CH2:30]>C1COCC1.CCOC(C)=O>[CH2:28]([C:27]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:31][C:2](=[O:3])[N:1]([CH:4]2[CH2:6][CH:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:25][CH2:26]1)[CH:29]=[CH2:30]
Reactant: O=C=NC1CC1c1ccccc1
Reactant: C=CCC(O)(CCCl)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C=CCC1(c2ccccc2)CCN(C2CC2c2ccccc2)C(=O)O1
Yield: 7.2 %

Procedure:
To a solution of (2-isocyanatocyclopropyl)benzene (800 mg, 5.03 mmol) in THF (15 mL) was added DBU (1.61 g, 10.48 mmol) and 1-chloro-3-phenylhex-5-en-3-ol (880 mg, 4.19 mmol), and the mixture was refluxed overnight. The solution was diluted with EtOAc, and washed with 1 N HCl (2×15 mL). The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give crude product, which was purified by preparative TLC to afford 6-allyl-6-phenyl-3-(2-phenylcyclopropyl)-1,3-oxazinan-2-one (100 mg, 6%). 1H NMR (CDCl3): 1.05-1.21 (m, 3H), 1.36-1.42 (m, 1H), 2.13-2.34 (m, 1H), 2.39-2.61 (m, 2H), 2.92-3.15 (m, 1H), 3.76-4.01 (m, 1H), 4.95-5.10 (m, 2H), 5.42-5.73 (m, 1H), 6.95-6.99 (m, 1H), 7.10-7.24 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1C=O.C[Si]([O:17][P:18]([O:24][Si](C)(C)C)[O:19][Si](C)(C)C)(C)C.C1(N)CCCCC1.[O:36]1CCC[CH2:37]1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[O:17][P:18]([CH2:37][OH:36])(=[O:24])[OH:19]
Reactant: C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: C1CCOC1
Solvent: NC1CCCCC1
Product: O=[N+]([O-])c1ccc(F)c(OP(=O)(O)CO)c1
Reaction time: 2.5 h

Procedure:
2-Fluoro-5-nitrobenzaldehyde (1.75 g, 10.0 mmol) was dissolved in tetrahydrofuran(50 mL). Tris(trimethylsilyl)phosphite (3.45 mL, 10.0 mmol) was added. The reaction mixture was stirred for 2.5 hours. Evaporation gave an oil which was dissolved in ethanol-ether. Addition of cyclohexylamine (1.14 mL,10.0 mmol) gave a solid salt which was filtered. Recrystallization from water gave 1.88 g (53.0%) of analytically pure product, mp 226-231° C.1H NMR (DMSO): d, 8.47 (m,1H), 8.11 (m,1H), 7.34 (t,1H), 4.85 (d,1H). MS (neg FAB): 249.9 (M-H). C7H7FNO6P/C6H13N.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:53][CH2:52]OCC1.CCO[C:57]([CH3:59])=O>>[CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:16]3[CH:12]=[N:11][C:10]4[C:52]([CH:53]=3)=[CH:59][CH:57]=[CH:8][CH:9]=4)=[C:12]2[N:11]=[C:10]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH:9]=1
Reactant: C1COCCO1
Reactant: COC(=O)Cc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)cc1
Reactant: CCOC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)Cc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)cc1
Temperature: 90 °C

Procedure:
Under Ar, compound, methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate (180 mg, 0.26 mmol) was mixed with Pd(dppf) Cl2 (21 mg, 0.26 mmol, K3PO4 (106 mg, 0.5 mmol), 3-quinoline bornic acid (55 mg, 0.31 mmol) and dioxane (10 mL with 1 ml water). The resulting mixture was heated at 90° C. and stirred over night. After cooled to room temperature, the mixture was diluted with EtOAc (60 mL) and filtered through celite. After concentration, the crude was purified with column (silica gel, 0˜30% EtOAc/Hexane) gave the product, methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate (150 mg). HPLC-MS tR=2.60 min (UV254 nm); mass calculated for formula C36H47N5O5Si2 685.3, observed LCMS m/z 686.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([OH:30])[C:23](=[CH:28][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25]>>[OH:30][C:22]1[CH:21]=[C:20]([NH:19][C:14]([C:8]2[S:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:9]=2[O:10][CH:11]([CH3:12])[CH3:13])=[O:16])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Product: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)cc1O
Yield: 59.1 %

Procedure:
Following a procedure analogous to Example 12, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (200 mg, 0.75 mmol) and methyl 4-aminosalicylate (117 mg, 0.70 mmol) [obtained by esterification of 4-aminosalicylic acid, sodium salt (Sigma) with iodomethane] provides 172 mg (59%) of product; mp 158.5°-160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:13][CH:14]([CH2:19]O)[C:15]([F:18])([F:17])[F:16])(=[O:12])=[O:11].[H-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.O>[F:16][C:15]([F:18])([F:17])[CH:14]1[CH2:19][N:13]1[S:10]([C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])(=[O:12])=[O:11]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(CO)C(F)(F)F)c(C)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of 690 mg (2.22 mmol) of 2,4,6-trimethyl-N-(2,2,2-trifluoro-1-hydroxymethylethyl)benzenesulfonamide in 10 mL of THF was added 180 mg (4.5 mmol) of 60% sodium hydride in mineral oil in several portions followed by 475 mg (2.5 mmol) of p-toluenesulfonyl chloride. The mixture stirred at room temperature over night and was then diluted with water and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were washed with three 20 mL portions of saturated aqueous sodium bicarbonate solution, 20 mL of brine, and two 20 mL portions of saturated aqueous ammonium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 650 mg (99%) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine as an oil which solidified to a waxy solid upon standing.
Reaction SMILES: Br[C:2]1[C:3]([C:9](O)=O)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[N:18]1[NH:19][N:20]=[CH:21][CH:22]=1.C[N:24](C=O)C>>[CH3:8][C:6]1[CH:7]=[C:2]([N:19]2[N:20]=[CH:21][CH:22]=[N:18]2)[C:3]([C:9]#[N:24])=[N:4][CH:5]=1.[CH3:8][C:6]1[CH:7]=[C:2]([N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)[C:3]([C:9]#[N:24])=[N:4][CH:5]=1
Reactant: c1cn[nH]n1
Reactant: Cc1cnc(C(=O)O)c(Br)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cnc(C#N)c(-n2ccnn2)c1
Product: Cc1cnc(C#N)c(-n2nccn2)c1
Temperature: 100 °C
Yield: 27 %
Yield: 35 %

Procedure:
To 3-bromo-5-methylpicolinic acid (1.5 g, 7.6 mmol) in DMF (19 mL) was added K2CO3 (1.2 g, 8.4 mmol) and 2H-1,2,3-triazole (440 μL, 7.6 mmol). The mixture was heated to 100° C. for 16 h, cooled to room temperature and extracted with EtOAc (2×). The combined organics were dried (Na2SO4) and concentrated. Purification via silica gel chromatography (5-60% EtOAc in hexanes) gave the title compound (490 mg, 35%) 1H NMR (500 MHz, Chloroform-d) 8.58-8.53 (m, 1H), 8.29-8.24 (m, 1H), 7.98 (s, 2H), 2.54 (s, 3H) and 5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinonitrile (387 mg, 27%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:29][C:28]([CH2:32][NH2:33])([CH2:30][NH2:31])[CH2:27]1>>[NH2:31][CH2:30][C:28]1([CH2:32][NH:33][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:29][O:26][CH2:27]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1(CN)COC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J=1.8 Hz, 1 H), 7.90 (d, J=1.9 Hz, 1 H), 7.81 (s, 1 H), 7.67 (t, J=3.6 Hz, 1 H), 7.57 (d, J=2.1 Hz, 1 H), 7.52 (t, J=3.8 Hz, 1 H), 7.43 (d, J=2.1 Hz, 1 H), 6.21 (s, 1 H), 5.26 (s, 2 H), 4.63 (s, 4 H), 4.55 (brs, 2 H), 3.82 (s, 2 H), 3.67 (t, J=2.4 Hz, 2 H), 3.45 (brs, 2 H), 2.46 (s, 3 H).
Reaction SMILES: [CH2:1]([N:4]1[C:9]([CH3:10])=[C:8]([Cl:11])[N:7]=[C:6]([Cl:12])[C:5]1=[O:13])[CH:2]=C.I([O-])(=O)(=O)=[O:15].[Na+].[OH2:20]>C(#N)C.C(Cl)(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[Cl:12][C:6]1[C:5](=[O:13])[N:4]([CH2:1][C:2]([OH:15])=[O:20])[C:9]([CH3:10])=[C:8]([Cl:11])[N:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O
Reactant: C=CCn1c(C)c(Cl)nc(Cl)c1=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)O

Procedure:
Ruthenium trichloride hydrate (114 mg, 0.547 mmol) was added to a stirred mixture of 1-allyl-3,5-dichloro-6-methylpyrazinone (5.45 g, 24.98 mmol) and sodium periodate (21.82 g, 0.102 mol) in water (75 ml), acetonitrile (50 ml) and carbon tetrachloride (50 ml). After 3 h the reaction mixture was extracted with methylene chloride (4 times) and the combined extracts were dried (Na2SO4) and evaporated in vacuo to a syrup. The 1H NMR (CDCl3) of this material showed it to be a 1:1 mixture of the acid and the aldehyde. The crude mixture was dissolved in acetone (50 ml) and Jones Reagent (2.7M) was added until the reaction remained orange. The reaction was then extracted into ethyl acetate which was then washed with brine, dried (Na2SO4) and evaporated in vacuo to give the title compound as a tan solid:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:13]=1[CH:14]=O.[SH:21][CH2:22][C:23](O)=[O:24].N1CCCCC1>>[NH:8]1[C:4]2[CH:3]=[C:2]([N:1]3[C:23](=[O:24])[CH2:22][S:21][CH:14]3[C:13]3[C:12]([F:11])=[CH:19][CH:18]=[CH:17][C:16]=3[F:20])[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: O=Cc1c(F)cccc1F
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(O)CS
Solvent: C1CCNCC1
Product: O=C1CSC(c2c(F)cccc2F)N1c1ccc2nc[nH]c2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.133 g, 1.0 mmol), 2,6-difluoro-benzaldehyde (0.142 mg, 1.0 mmol), mercapto acetic acid (0.157 g, 1.5 mmol), piperidine, according to method 9 step A. yield: 208 mg (62.8%), MS m/z: 332.3 (M+H)+, HPLC [A]): rt 5.76 min (97%)
Reaction SMILES: C1([Mg]Cl)CCCCC1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[NH2:16][C:17]1[N:21]([C:22]2[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:25]([NH:27][CH:28]2[CH2:30][CH2:29]2)=[O:26])[N:20]=[CH:19][C:18]=1[C:35]#N.C1C[O:40]CC1>>[NH2:16][C:17]1[N:21]([C:22]2[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:25]([NH:27][CH:28]2[CH2:30][CH2:29]2)=[O:26])[N:20]=[CH:19][C:18]=1[C:35]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:40]
Reactant: C1CCOC1
Reactant: Ic1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C#N)c1N
Agent: Cl[Mg]C1CCCCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccn2)c1N
Temperature: 25 °C
Yield: 33 %

Procedure:
Cyclohexylmagnesium chloride (5 mL, 2.0 M in Et2O) was added dropwise to the solution of 2-iodopyridine (1.03 g, 5 mmol) in THF (15 mL) at −20° C. The mixture was stirred at this temperature for 20 min before 3-(5-Amino-4-cyano-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (140 mg, 0.5 mmol) was added, then stirred at room temperature over night. The reaction was quenched by the addition of K2CO3 aqueous solution, then the mixture was extracted with EtOAc and the organic layers washed with water and brine. Purification by column chromatography on silica gel eluted with EtOAc provided the product as a white solid (60 mg, 33%). HPLC (4 minute 10-90 gradient) tR 2.09 min; MS m/z 362.20 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Mn]([O-])(=O)(=O)=[O:12].[K+].[OH2:17]>N1C=CC=CC=1>[F:1][C:2]1[C:3]([C:10]([OH:12])=[O:17])=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(C)c1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc(F)c(C(=O)O)c1

Procedure:
4-Fluoro-3-methylanisol (1.0 g, 7.1 mmol) was dissolved in a mixture of pyridine (16 mL) and water (32 mL). Potassium permanganate (3.4 g, 21 mmol) was added and the reaction mixture was refluxed for 3 h and then left at room temperature over night. After filtration and extraction with CH2Cl2 the aqueous phase was acidified with HCl precipitating the product (440 mg).
Reaction SMILES: S(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(C)(=O)=O.[C:45]1([SH:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11][C@H:7]2[CH2:6][S:51][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:33])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CSc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of (2S,4S)-2-mesyloxymethyl-N-(p-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine (9.6 g, 15.2 mmol) in THF (190 ml), thiophenol (2.34 ml, 22.8 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (3.4 ml, 22.8 mmol) were successively added dropwise in a nitrogen stream under cooling with ice. The reaction solution was stirred at room temperature for 15 minutes and the solvent was distilled off. To the residue, ethyl acetate was added. The organic layer was washed with 1N aqueous potassium hydrogensulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (Wakogel™ C-300 heptane-ethyl acetate 3:1) to give (2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-phenylthiomethyl-4-tritylthiopyrrolidine (9.24 mg, yield: 94%) as a yellow oily substance.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[N:5]1([NH:10][CH:11]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19](C)C=3O2)[CH2:9][CH2:8][N:7]=[CH:6]1.N1(NC2CC3C=CC=C(C)C=3O2)CCN=C1.NCCNC(=S)NC1C=CC2CCOC=2C=1C>CO>[N:5]1([NH:10][C:11]2[CH:15]=[CH:14][C:16]3[CH2:2][CH2:1][O:4][C:17]=3[C:18]=2[CH3:19])[CH2:9][CH2:8][N:7]=[CH:6]1
Reactant: Cc1cccc2c1OC(NN1C=NCC1)C2
Reactant: CC(=O)O
Agent: Cc1c(NC(=S)NCCN)ccc2c1OCC2
Solvent: CO
Product: Cc1c(NN2C=NCC2)ccc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2-Imidazolinylamino-7-methyl-2,3-dihydrobenzofuran hemiacetate. The above crude 6-[N'-(2-aminoethyl)thioureido]-7-methyl-2,3-dihydrobenzofuran is dissolved in 3 mL of methanol and treated with 0.25 g of mercuric acetate, forming a black color. The reaction mixture is stirred overnight at room temperature. The reaction mixture is filtered through celite, concentrated, and purified by silica gel chromatography to provide 0.131 g of 6-(2-imida zolinylamino)-7-methyl-2,3-dihydrobenzofuran as the hemiacerate salt.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:11][C:10](=[O:12])[C@H:9]1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.CCOC(C)=O>[CH2:24]([NH:31][C:32]([N:11]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:9]([CH3:13])[C:10]1=[O:12])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NCc1ccccc1
Reactant: C[C@@H]1C(=O)N[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)N(C(=O)NCc2ccccc2)[C@H]1Cc1ccccc1
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
To a solution of 4(S)-benzyl-3(S)-methylazetidin-2-one (50 mg, 0.28 mmol) in THF (4 mL) at −78°, lithium bis(trimethylsilyl)amide (280 μL, 280 mmol, 1 M in THF) was added. After 10 min, benzyl isocyanate (37.2 mg, 34.6 μL, 0.28 mmol) was added. Stirring was continued at −78° for 45 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with aqueous NaHSO4 (1M) and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 14% EtOAc in hexane) to give the title compound 4(S)-benzyl-3(S)-methyl-2-oxoazetidine-1-carboxylic acid benzylamide (23 mg, 27% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ7.38-7.19 (m, 10H), 6.94 (t, J=5.1 Hz, 1H), 4.53 (dd, J=14.9, 6.0 Hz, 1 H), 4.48 (dd, J=14.9, 6.0 Hz, 1H), 3.90 (ddd, J=8.6, 3.2, 2.9 Hz, 1H), 3.53 (dd, J=13.7, 3.5 Hz, 1 H), 2.95 (qd, J=7.6, 2.5 Hz, 1H), 2.92 (dd, J=13.3, 8.9 Hz, 1H), 1.14 (d, J=7.6 Hz, 3H); FAB MS m/z 309.3 (MH+); HRMS calcd for C19H21N2O2: 309.1603 (MH+); found: 309.1614.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[O:22][CH3:23])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[O:22][CH3:23])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc([N+](=O)[O-])cc1C(NC(C)c1ccc(F)c(F)c1)c1ccc(F)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(N)cc1C(NC(C)c1ccc(F)c(F)c1)c1ccc(F)cc1

Procedure:
Following a similar procedure to that described in Example (1b), 660 mg of isomer B of N-[1-(3,4-difluorophenyl)ethyl]-N-[(4-fluorophenyl)-(2-methoxy-5-nitrophenyl)methyl]amine [prepared as described in step (a) above], 762 mg of nickel chloride hexahydrate and 243 mg of sodium borohydride were reacted, to obtain 332 mg of isomer B of the title compound as a pale yellow oil.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].Br[CH2:15][C:16](=[CH2:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(O)C>[CH2:6]([O:5][C:3]([CH2:2][S:1][CH2:24][C:16](=[CH2:15])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4])[CH3:7]
Reactant: CCOC(=O)CS
Reactant: C=C(CBr)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: C=C(CSCC(=O)OCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
To a stirred solution of ethyl α-mercaptoacetate (1.6 g) in ethanol (15 ml), potassium tert-butoxide (1.5 g) was added at -10°-0° C. under nitrogen atmosphere, and the mixture was stirred for 10 minutes at room temperature. Under ice-cooling, tert-butyl 2-bromomethylacrylate (2.9 g) dissolved in ethanol (5 ml) was added to the reaction mixture and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 2.1 g (60%) of tert-butyl 2-(ethoxycarbonylmethylthiomethyl)acrylate.