Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)[C:7]2=[O:16].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.[H][H]>C1COCC1.[Pt].C(O)C>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[CH2:17][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([O:14][CH3:15])[C:10](=[O:13])[N:11]([CH3:12])[C:2]=2[CH2:26][CH3:27])[C:7]1=[O:16]
Reactant: [H][H]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1c2c(c(Br)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
A solution of 5-bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (0.40 g, 0.93 mmol), tri-n-butyl vinyl tin (0.38 g, 1.21 mmol), and bis(tri-phenylphosphine)palladium (II) chloride (65 mg, 0.093 mmol) in THF (30 mL) was heated under reflux for two hours. The product mixture concentrated under vacuum. The residue was subjected to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provide the intermediate vinyl intermediate. ES MS M+1=377. A mixture of this vinyl intermediate (60 mg, 0.16 mmol) and 5% platinum on charcoal (50 mg) in ethanol (20 mL) was stirred under a balloon of hydrogen at room temperature for 30 minutes. The resultant mixture was filtered, and concentrated under vacuum to provide the titled compound.
Reaction SMILES: [C:1]([CH:9]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C@H:10]1[CH2:11][CH2:12][C@@H:13]1[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:32])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH:20]=[O:21])[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>O1CCCC1.CCOCC>[C:1]([CH:9]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C@H:10]1[CH2:11][CH2:12][C@@H:13]1[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:32])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[C@@H:18]([CH3:19])[CH2:20][OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The (5α,20R)-4-benzoyl-3-oxopregnane-20-carboxaldehyde (436 mg, 1.0 mmole) in tetrahydrofuran:methanol (2.0 ml, 1:1) is mixed with sodium borohydride (9.5 mg, 0.25 mmole) at 0° C. for 1 hours. The mixture is then diluted with ether and washed with 0.5 N hydrochloric acid and brine and then dried and the solvent is evaporated to leave, as a resiue, (5α,20R)-4-benzoyl-21-hydroxy-20 -methylpregnan-3-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:24]([O:26]C)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1C(=O)O
Yield: 85.9 %

Procedure:
To a stirred solution of methyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl carboxylate (5.37 g) in THF (116 ml) was added 0.25 N NaOH (116 ml, 29.0 mmol) at room temperature. The resulting mixture was stirred over night. After removal of the solvent, the mixture was acidified by the addition of 1 N HCl and extracted with CHCl3. The combined extracts were washed with brine, dried over Na2SO4 and evaporate The residue was recrystallized with n-hexane-CHCl3, to give (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid [4.44 g, 85% (2 steps)] as a white powder. 1H-NMR (DMSO-d6) δ1.37 and 1.41 (s, 9H, amide isomers), 2.26 (d, J=13.9 Hz, 1H), 2.65 (m, 1H), 3.47 (d, J=11.5 Hz, 1H), 3.81 (m, 1H), 4.30 (m, 1H), 5.14 (m, 1H), 7.02-7.86 (m, 7H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)O1.I[C:20]1[CH:21]=[C:22]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH3:39][C:38]1[C:20]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[CH:21][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:24])=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc([N+](=O)[O-])cc1
Yield: 57.1 %

Procedure:
4,4,5,5-Tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (0.35 g, 0.0014 mol) was mixed with 3-iodo-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide (0.73 g, 0.0018 mol) and potassium carbonate (0.50 g, 0.0036 mol) in toluene (15.00 mL), ethanol (2.10 mL) and water (2.00 mL) and the mixture was degassed. To the reaction was added tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.000086 mol) and the mixture was heated to reflux for 8 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 30% EtOAc/hexanes to give the product (0.32 g, 57% yield). 1H NMR (CDCl3): δ□ 8.33 (dd, 2H), 7.76-7.93 (m, 5H), 7.43-7.54 (m, 5H), 2.35 (s, 3H). MS (EI) m/z=401 (M+H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=1[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:4]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(I)cc1C(=O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(I)cc1C(=O)c1ccccc1Cl
Temperature: 0 °C
Yield: 90 %

Procedure:
Bromoacetyl bromide, 15 ml, was added to a solution of 52 g (0.145 mol) of (2-amino-5-iodophenyl)(2-chlorophenyl) methanone in 300 ml of methylene chloride cooled to 0° C. A 10% aqueous solution of sodium carbonate, 150 ml, was added slowly with stirring and the two phase system was stirred in the cold for 30 minutes. The organic layer was separated, washed with water and dried over sodium sulfate. The solution was filtered and evaporated. Crystallization of the residue from methylene chloride/ether yielded 61 g (90%) of 2-bromo-N-[2-(2-chlorobenzoyl)-4-iodophenyl]acetamide with m.p. 150°-152° C. A solution of 50 g of this material in 1 liter of methylene chloride was added to 800 ml of liquid ammonia with dry-ice cooling. After refluxing for 16 hours, the cooling was discontinued and the ammonia was allowed to evaporate. The remaining solution was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 1 liter of ethanol and the solution was heated to reflux for 30 minutes after the addition of 15 ml of acetic acid. The crystals separated from the cooled reaction mixture were collected to leave 38 g (89%) of 5-(2-chlorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one which melted at 260°-262° C. after recrysyallization from tetrahydrofuran/ethanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[C:36]([O:39][CH:40](Br)[CH3:41])(=[O:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O:24][CH:40]([O:39][C:36](=[O:38])[CH3:37])[CH3:41])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (1.55 g, 3.54 mmoles) and K2CO3 (636 mg, 4.6 mmoles) in DMF (4 ml) was added at 5° C. 1-bromoethyl acetate (769 mg, 4.6 mmoles). The mixture was stirred at 5° C. for 1 hour, diluted with ethyl acetate (300 ml), washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column (50 g) with 1% methanol in CHCl3. The desired fractions were combined and concentrated to a small volume. The resdiue was triturated with isopropyl ether to give 1.29 g (70%) of the title compound as the isopropyl ether solvate. Estimated purity 90% (by HPLC). Mp. 103°-110° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:10]([NH2:11])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[CH3:1][N:2]1[C:10]([NH:11][C:21]([NH:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[S:22])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1
Reactant: Cn1nc2c(c1N)CCCC2
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: Cn1nc2c(c1NC(=S)NC(=O)c1ccccc1)CCCC2
Temperature: 60 °C

Procedure:
To a solution of compound 17 (5.0 g, 33.1 mmol) in 40 mL of acetone at 0° C. was added dropwise benzoyl isothiocynate (5.4 g, 33.1 mmol). The reaction mixture was gradually warmed up and stirred in an oil bath of 60° C. until TLC indicated there was no starting material remained. Concentration of the reaction mixture on rotavapor gave a yellow solid, which was further recrystallized in ethyl acetate to yield the desired product 18.
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1.[CH2:28]([N:30]([CH2:33]C)CC)C.CN.[O:37]1CCCC1>>[CH3:28][NH:30][C:33]([N:11]1[CH2:12][CH2:13][C:14]2[N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:3]=3[F:2])[N:7]=[C:8]([C:15]3[CH:22]=[CH:21][CH:20]=[C:17]([C:18]#[N:19])[CH:16]=3)[C:9]=2[CH2:10]1)=[O:37]
Reactant: C1CCOC1
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Product: CNC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 4.9 %

Procedure:
To a mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.060 g, 0.171 mmol) and triethylamine (60 mg, 0.60 mmol) in CH2C2 at 0° C. was added para-nitrophenylchloroformate (38 mg, 0.188 mmol) and the mixture was stirred at 0° C. for 45 min. 2 M methylamine in tetrahydrofuran (2 ml, 4 mmol) was added and the mixture was stirred for 3 days at room temperature. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic) to give 3.4 mg of 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methylamide (12a).
Reaction SMILES: B(F)(F)[F:2].[CH2:5]([O:7][P:8]([N:13]1[CH:19]2[CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:18]2)([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]>C(Cl)Cl>[CH2:5]([O:7][P:8]([NH:13][C@H:19]1[C@H:14]([F:2])[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:18]1)([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]
Reactant: FB(F)F
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Solvent: ClCCl
Product: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1F)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.8 %

Procedure:
BF3 etherate (3.10 mL, 24.4 mmol) was added to a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (3.00 g, 8.14 mmol; Example H, step D) in DCM (10 mL) at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 3 days. The solvent was removed in vacuo, ethyl acetate (30 mL) and saturated sodium bicarbonate (20 mL) were added. The organic layer was separated, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give trans-benzyl 3-(diethoxyphosphorylamino)-4-fluoropiperidine-1-carboxylate (0.53 g, 17%) as oil.
Reaction SMILES: Cl.N[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:46](O)=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].F[P-](F)(F)(F)(F)F.N1C2C=CC=C(O[P+](N3CCCC3)(N3CCCC3)N3CCCC3)C=2N=N1.CCN(C(C)C)C(C)C>O1CCCC1>[C:33]([O:37][C:38](=[O:39])[NH:40][CH:41]([C:46]([C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1)=[O:47])[CH2:42][CH:43]([CH3:44])[CH3:45])([CH3:34])([CH3:36])[CH3:35]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cc(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)c2nn[nH]c2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.9 %

Procedure:
In 15 ml of tetrahydrofuran, 300 mg (0.620 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride was dissolved, and 771 mg (3.10 mmol) of tert-butoxycarbonyl-L-leucine, 1.60 g (3.10 mmol) of (benzotriazolyloxy)tripyrrolidino-phosphonium hexa-fluorophosphate (PyBOP) and 0.54 mL (3.10 mmol) of Hunig's base were added thereto and the mixture solution was stirred at room temperature for three days. The reaction solution was concentrated under reduced pressure, and then the residue was partitioned between ethyl acetate and water. The organic phase was washed with a saturated sodium chloride solution, dried, and then concentrated under reduced pressure. The residue was purified by Megabond Elute Silica Gel (10 g, ethyl acetate), to obtain 320 mg (78%) of [1-(9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-ylcarbonyl)-3-methyl-butyl]carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[C:2]=[S:3].C(N(C(C)C)CC)(C)C.Cl.[NH:23]([CH2:25][C:26](OCC)=[O:27])[NH2:24]>ClCCl>[NH2:24][N:23]1[CH2:25][C:26](=[O:27])[N:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[C:2]1=[S:3]
Reactant: O=C(O)c1ccc(N=C=S)cc1
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NN1CC(=O)N(c2ccc(C(=O)O)cc2)C1=S
Yield: 52.5 %

Procedure:
179 mg (1 mmol) of 4-isothiocyanatobenzoic acid and 523 μl (3 mmol) of diisopropylethylamine were stirred in 8 ml of dichloromethane and then with 155 mg (1 mmol) of ethyl hydrazinoacetate hydrochloride at room temperature for 96 hours. After the solvent was concentrated, the mixture was partitioned between ethyl acetate and 30% acetic acid. The aqueous layer was extracted with ethyl acetate again, and the organic layers were combined, washed with water and then with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting solid was mixed with a 190:10:0.8 liquid mixture of ethyl acetate, methanol and acetic acid, and the insoluble was dried to obtain 132 mg of the desired product (yield 53%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])OC)[CH3:2].Cl.[F:13][CH:14]([F:20])[C:15](=[N:17]NC)[NH2:16].[C:21]([O-])(=O)C.[Na+]>CO>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[N:8]([CH3:21])[N:17]=[C:15]([CH:14]([F:20])[F:13])[N:16]=1)[CH3:11]
Reactant: CNN=C(N)C(F)F
Reactant: CC(=O)[O-]
Reactant: CCOC(OCC)C(=N)OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)c1nc(C(F)F)nn1C
Temperature: 30 °C
Reaction time: 72 h
Yield: 32.6 %

Procedure:
A solution of diethoxyacetonitrile (75 g, 0.579 mol) in methanol (210 mL) was added at room temperature to a solution of sodium methoxide (28.3 g, 0.522 mol) in methanol (450 mL). The mixture was stirred overnight, and then methanol was evaporated. The residue was diluted with dichloromethane (200 mL) and water (300 mL). The organic layer was separated, and the aqueous one was extracted with dichloromethane (2×150 mL). The combined organic layer was dried over Na2SO4 and evaporated to give 83 g of crude methyl 2,2-diethoxyacetimidate (−90% yield). A solution of methyl 2,2-diethoxyacetimidate prepared above (0.6208 mol, 125.1 g of 80% purity) in methanol (300 mL) was added to a solution of 2,2-difluoro-N′-methylethanehydrazonamide hydrochloride (0.6208 mol, obtained in Step 1) in methanol (700 mL). Anhydrous sodium acetate (61.1 g, 0.745 mol) was added, and the mixture was stirred at 30° C. for 3 days. The reaction mixture was then evaporated, and the residue subjected to chromatography (ethyl acetate/hexane 1:4→1:1) on a silica gel column, followed by vacuum distillation to give 47.6 g (32.6%) of 5-(diethoxymethyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:3][O:4][C:26](=[O:28])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(CO)CCNCc1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCN(Cc2ccccc2[N+](=O)[O-])C(=O)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
2-Methyl-4-(2-nitrobenzylamino)butanol (5.00 g, 21.0 mmol), triethylamine (8.49 g, 84.1 mmol) were dissolved in toluene (50 ml). Under ice cooled condition, a solution in which triphosgene (2.50 g, 8.42 mmol) was dissolved in toluene (10 ml) was slowly added dropwise thereto and heated to reflux for six hours after stirred at room temperature for one hour. The reaction mixture was poured into water and, after standing to cool, extracted with ethyl acetate. The organic layer was washed with 0.1 N hydrochloric acid water and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 6-methyl-3-(2-nitrobenzyl)-[1,3]-oxazepan-2-one (2.00 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:26]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[C:8]([O:20][C:21](=[O:25])[NH:22][CH2:23][CH3:24])[CH:7]=1.[ClH:35]>O1CCOCC1.CO.[H][H].[C].[Pd]>[Cl-:35].[CH2:23]([NH:22][C:21]([O:20][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH3+:26])[C:3]([O:2][CH3:1])=[O:34])[CH:11]=[CH:10][C:9]=1[OH:12])=[O:25])[CH3:24]
Reactant: [H][H]
Reactant: Cl
Reactant: CCNC(=O)Oc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CCNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)OC)ccc1O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-(4-Benzyloxy-3-ethylcarbamoyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (220 mg) was dissolved in 4M HCl in dioxane (3 ml) and the solution was left at room temperature for ca 2 hr. Evaporation of solvent gave a white solid which was redissolved in methanol (5 ml) and hydrogenated at 1 atmosphere of hydrogen gas over 5% palladium-carbon (44 mg). After stirring overnight at room temperature the catalyst was removed by filtration and washed with methanol. Evaporation of the filtrate gave a gum which was crystallised from methanol-ether. (S)-2-(3-Ethylcarbamoyloxy-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride was obtained as a white solid, 110 mg; NMR (500 MHz, d6 DMSO) 1.07 (3H, t J 7), 2.94-3.09 (4H, m), 3.67 (3H, s), 4.18 (1H, t J 6), 6.84 (3H, br s), 7.56 (1H, t J 5.5), 8.43 (ca 3H, br s), 9.55 (1H, s); HPLC/MS retention time 3.41 min, m/z 283 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.Cl.[NH2:22][OH:23].[OH-].[Na+].Cl>CCO.O>[CH3:1][CH:2]([CH3:20])[C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[N:22][OH:23]
Reactant: NO
Reactant: CC(C)C(=O)c1c(-c2ccccc2)nn2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=NO)c1c(-c2ccccc2)nn2ccccc12
Temperature: 0 °C
Yield: 28.3 %

Procedure:
To a solution of 5.32 g (20 mmol) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one in 32 ml of anhydrous EtOH was added 3 g of hydroxylamine hydrochloride, followed by dropwise addition of a solution of 4.0 g NaOH in 12 ml water. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 11 ml of 6N HCl and 200 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The organic phase was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure to obtain 4.6 g of crude compound, which was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to furnish 1.58 g (30.1%) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one oxime. Compound 1016.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])[CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 1-methylpiperidin-4-ol (0.542 g) in tetrahydrofuran (10 mL) at 0° C. was added NaH (60% in mineral oil) (0.753 g). After stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (1.036 g) was added as a solution in tetrahydrofuran (10 mL). The reaction was removed from the ice bath and allowed to warm to room temperature. After 1 hour, the reaction was poured into water and the pH adjusted to ˜7 with 1N aqueous HCl. The reaction was extracted with dichloromethane (3×100 mL), washed with brine, dried over magnesium sulfate, filtered, and concentrated. The product was suspended in dichloromethane (mL), sonicated and then filtered to give the title compound.