Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[S:11]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:13])=[O:12].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][S:11]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:12])=[O:13]
Reactant: [H][H]
Reactant: COc1ccccc1/C=C/S(=O)(=O)Nc1ccccc1S(N)(=O)=O
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1CCS(=O)(=O)Nc1ccccc1S(N)(=O)=O
Yield: 71.6 %

Procedure:
(E)-2-(2-(2-Methoxyphenyl)vinylsulfonamido)benzenesulfonamide (94 mg, 0.26 mmol) was dissolved in methanol (5 mL) in a 5 mL syringe. The solution was injected to the H-cube (1 ml/min, full hydrogen; 10% Pd/C). The solvent was then removed under reduced pressure and the crude material was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (69 mg, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]=1[S:12]([OH:15])(=O)=[O:13])=[O:5])[CH3:2].S(Cl)([Cl:18])=O>>[Cl:18][S:12]([C:7]1[CH2:8][O:9][CH2:10][CH2:11][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:15])=[O:13]
Reactant: CCOC(=O)C1=C(S(=O)(=O)O)COCC1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C1=C(S(=O)(=O)Cl)COCC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
4-(Ethoxycarbonyl)-5,6-dihydro-2H-pyran-3-sulfonic acid (27.5 g) was dissolved in thionyl chloride (82.6 ml) and the mixture was stirred at room temperature →85° C. for 3 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). The obtained solution was partitioned by adding diluted brine (120 ml). The ethyl acetate layer was washed twice with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/7→1/5). The objective product was concentrated under reduced pressure and the crystals produced by freezing were washed with hexane to give ethyl 5-(chlorosulfonyl)-3,6-dihydro-2H-pyran-4-carboxylate (7.81 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][N+:5]([O-:7])=O.[O:10]1[CH2:14][CH:13]=[CH:12][CH2:11]1>>[CH3:9][O:8][CH:3]([O:2][CH3:1])[C:4]1[C@H:12]2[CH2:11][O:10][CH2:14][C@H:13]2[O:7][N:5]=1
Reactant: C1=CCOC1
Reactant: COC(C[N+](=O)[O-])OC
Product: COC(OC)C1=NO[C@@H]2COC[C@H]12

Procedure:
Starting from the commercially available 1,1-dimethoxy-2-nitroethane (CAS69425-53-2) and 2,5-dihydro-furan following general procedure A, the product (3aS,6aS)-rel-3-dimethoxymethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole was obtained as a light brown oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([O:13][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][O:16][CH2:14][CH3:15])=[CH:26][CH:25]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCOc1ccc(CCl)cc1
Reactant: Cc1c(O)cnn(C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2C)cc1
Yield: 57.9 %

Procedure:
By using 1.0 g of 2-t-butyl-5-hydroxy-4-methyl-3(2H)-pyridazinone, 1.1 g of 4-ethoxymethoxybenzyl chloride and 1.0 g of anhydrous potassium carbonate and similarly to the procedures in Preparation Example 2, 1.1 g of the aimed product was obtained as an oil.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].Cl.N>O.CO>[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: NNCCO
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Nc1c(N=O)cnn1CCO
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a flask having an inner volume of 50 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 4.59 g (30 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 94.3% by weight synthesized in the same manner as in Example 1, 2.98 g (31.5 mmol) of 2-hydroxyethylhydrazine with a purity of 80.5% by weight, 7.8 ml of methanol and 4.5 ml (54 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for 3 hours. After completion of the reaction, 7 ml of water was added to the mixture and the resulting mixture was cooled up to 10° C. Then, 3.5 ml (58 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. The precipitated crystals were collected by filtration, and then, the crystals were washed with 2.5 ml of cold water and 2.5 ml of cold methanol, and dried under reduced pressure to obtain 3.40 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole (Isolation yield: 69.7%) as reddish orange crystals with a purity of 96.0% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C:18]3[C:13](=[C:14]([OH:28])[C:15]([C:20]([NH:22][C@@H:23]([C:25]([OH:27])=[O:26])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH:17]=3)[C:12]3[C:29]([OH:46])=[C:30]4[C:41](=[O:42])[C:40]5[C:35](=[C:36]([OH:45])[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=5)[C:33](=[O:34])[C:31]4=[CH:32][C:11]=3[C@@H:10]2[OH:47])[C@H:5]([OH:48])[C@@H:4]([O:49][C@@H:50]2[O:55][CH2:54][C@@H:53]([OH:56])[C@H:52]([OH:57])[C@H:51]2[OH:58])[C@H:3]1[OH:59].[OH-].[Na+:61]>O.CO>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C:18]3[C:13](=[C:14]([OH:28])[C:15]([C:20]([NH:22][C@@H:23]([C:25]([OH:27])=[O:26])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH:17]=3)[C:12]3[C:29]([OH:46])=[C:30]4[C:41](=[O:42])[C:40]5[C:35](=[C:36]([O-:45])[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=5)[C:33](=[O:34])[C:31]4=[CH:32][C:11]=3[C@@H:10]2[OH:47])[C@H:5]([OH:48])[C@@H:4]([O:49][C@@H:50]2[O:55][CH2:54][C@@H:53]([OH:56])[C@H:52]([OH:57])[C@H:51]2[OH:58])[C@H:3]1[OH:59].[Na+:61]
Reactant: COc1cc(O)c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)N[C@H](C)C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](O)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc([O-])c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)N[C@H](C)C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](O)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O

Procedure:
A solution of benanomicin A (82.7 mg) in a mixture of 10 ml of water and 1.1 ml of 0.1M NaOH was lyophilized. The residue was dissolved in 3 ml of methanol and chromatographed on a Sephadex LH-20 column (300 ml) developed with methanol to obtain benanomicin A sodium salt (75.8 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[Cl:27])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.[Cl-].[Li+]>O1CCOCC1>[Cl:27][C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[N:34]=[CH:35][S:36][CH:37]=2)=[CH:3][CH:4]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(-c3cscn3)cc2)cn1
Yield: 84.2 %

Procedure:
A mixture of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (236 mg, 0.489 mmol), 4-(tributylstannyl)-1,3-thiazole 238 mg, 0.636 mmol), lithium chloride (27 mg, 0.636 mmol) and tetrakis(triphenyphosphine)palladium (57 mg, 0.0489 mmol) in 1,4-dioxane (10 ml) was refluxed for 5 hr under nitrogen atmosphere. After evaporation, the residue obtained was chromatographed on a column of silica gel (50 g) eluting with ethyl acetate/hexane (3:4) to afford 200 mg (84%) of the title compound as a pale brown gum.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:13][N:14]([CH3:18])[C:15]([S:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)=[O:16]
Reactant: CN(C)C(=O)Cl
Reactant: Sc1nc(-c2ccccc2)c[nH]1
Solvent: c1ccncc1
Product: CN(C)C(=O)Sc1nc(-c2ccccc2)c[nH]1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
In 50 ml of pyridine was dissolved 5.0 g (28.4 millimoles) of 2-mercapto-4-phenylimidazole, and 3.13 ml (34.1 millimoles) of N,N-dimethylcarbamoyl chloride was added to the solution and the mixture was heated at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and 200 ml of water and 200 ml of chloroform were added to the concentrate to effect extraction. The chloroform layer was concentrated and the concentrate was recrystallized from ethanol to obtain 2.4 g (yield=34%) of intended 2-(N,N-dimethylcarbamoylthio)-4-phenylimidazole (compound No. 21) in the form of a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[C:36]([F:38])([F:37])[F:39])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: FC(F)(F)c1cc(I)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(2.65 g, 11.9 mmol) in THF (20 ml) was added 1.0 lithium bis(trimethylsilyl)amide in THF (7.3 ml, 7.30 mmol, Aldrich) and stirred for 15 min. To the solution was added a solution of 1-(bromomethyl)-4-iodo-2-(trifluoromethyl)benzene (1.62 g, 4.44 mmol) in THF (10 ml). The resulting orange solution was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (150 ml). The phases were separated and the aqueous phase washed with ethyl acetate (50 ml). The combined organic phases were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was loaded in dichloromethane and purified on silica 100 g×2 using 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.3 g). LCMS: (System 4) MH+=508, tRET=3.22 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[C:19](Cl)(=[O:21])[CH3:20].O>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)(=[O:21])[CH3:20]
Reactant: COC(=O)c1nc(N)sc1-c1ccc(SC)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1nc(NC(C)=O)sc1-c1ccc(SC)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Methyl 2-amino-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (8.8 g) was dissolved in pyridine (88 ml), and then acetyl chloride (6.7 ml) was added dropwise to the solution at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes and at 50° C. for 2 hours. After cooled to 0° C., water was added to the solution. The precipitate was filtered in vacuo, and the solid was washed with ethyl ether to give methyl 2-(acetylamino)-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (9.3 g) as an off-white solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([C:17]1[C:18]([I:44])=[C:19]([CH2:39][O:40]C(=O)C)[C:20]([I:38])=[C:21]([C:36]=1[I:37])[C:22]([NH:24][CH2:25][CH:26]([O:32]C(=O)C)[CH2:27][O:28]C(=O)C)=[O:23])[C:8]([CH:10]1[CH2:14][O:13]C(C)(C)[O:11]1)=[O:9])(=O)C.[OH-].[Na+].O>CO>[OH:4][CH2:5][CH2:6][N:7]([C:8](=[O:9])[CH:10]([OH:11])[CH2:14][OH:13])[C:17]1[C:18]([I:44])=[C:19]([CH2:39][OH:40])[C:20]([I:38])=[C:21]([C:36]=1[I:37])[C:22]([NH:24][CH2:25][CH:26]([OH:32])[CH2:27][OH:28])=[O:23]
Reactant: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCC(O)CO)c1c(I)c(CO)c(I)c(N(CCO)C(=O)C(O)CO)c1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
5-[N′-(2-Acetoxyethyl)-2,2-dimethyl-1,3-dioxolane-4-carboxamido]-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (47 mg, 0.049 mmol) was dissolved in methanol (0.5 ml) and an aqueous solution of sodium hydroxide (2M, 0.25 ml) was added slowly followed by water (2 ml). After stirring at room temperature for 20 minutes, the reaction mixture was neutralized with a strongly acidic Son exchange resin. The resin was filtered off, and the filtrate acidified to pH=1 using hydrochloric acid (5M). After stirring at room temperature for 3.5 hours the reaction mixture was evaporated to dryness and the solid residue was purified by preparative HPLC giving 28 mg (76%) of product.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([C:7]2[N:8]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([CH3:20])=[CH:18][CH:17]=3)[C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1[nH]c(-c2ccccc2)nc1Cl
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CO)cc1

Procedure:
1 g of 2-phenyl-4-chloro-5-hydroxymethylimidazole, together with 0.7 ml of p-methylbenzyl bromide and 3 g of potassium carbonate, was stirred in 10 ml of dimethylformamide at 30° C. for 2 days. The reaction solution was poured into 100 ml of water, and the precipitate deposited was chromatographed on a column of 30 g of silica gel, followed by eluting with chloroform. The initially eluted fraction was collected, and recrystallization from aqueous methanol yielded 0.5 g of 2-phenyl-4-chloro-5-hydroxymethyl-1-(4-methylbenzyl)imidazole as colorless, needle-formed crystals, m.p. 173°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20]([CH2:22][C@@H:23]1[CH2:27][CH2:26][C@H:25]([O:28][C:29](=[O:31])[CH3:30])[CH2:24]1)=[O:21]>>[C:29]([O:28][C@@H:25]1[CH2:26][CH2:27][C@H:23]([CH2:22][C:20]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:21])[CH2:24]1)(=[O:31])[CH3:30]
Reactant: CC(=O)O[C@H]1CC[C@@H](CC(=O)Cl)C1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](OC(C)=O)C3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and (rac)-(cis)-acetic acid 3-chlorocarbonylmethyl-cyclopentyl ester, (rac)-(cis)-2-(3-acetoxy-cyclopentyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-acetamide was obtained. Separation by preparative chiral HPLC (Chiralpack AD, eluent heptane/isopropanol 85:15) afforded the tide compound as later eluting isomer. Light yellow crystals (4% yield). MS: m/e=434(M+H+), mp 172-173° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Cl[CH2:55][C:56]([NH2:58])=[O:57]>O>[C:56]([CH2:55][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)(=[O:57])[NH2:58]
Reactant: NC(=O)CCl
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OCC(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 56.8 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol) and cesium carbonate (63.4 mg, 195 μmol) were combined with dimethyl formamide (2 mL). 2-Chloroacetamide (15.2 mg, 162 μmol) was added to the mixture with stirring to give a white suspension. The tube was capped and heated at 50° C. overnight. The reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with ethyl acetate in hexanes) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid carbamoylmethyl ester as an off-white solid (62 mg, 58% yield). LCMS (ES+) m/z calcd. for C33H33Cl2F2N4O5 [(M+H)+]: 673. found: 673.
Reaction SMILES: [C:1]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C[Si]([N:16]=[N+:17]=[N-:18])(C)C>CCOCC>[C:1]([C:4]1[N:16]=[N:17][NH:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C#Cc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCOCC
Product: CC(=O)c1nn[nH]c1-c1ccccc1
Temperature: 140 °C
Yield: 28 %

Procedure:
A mixture of 30 g (0.21 mole) of acetylphenyl-acetylene and 24 g (0.21 mole) of trimethylsilyl azide was heated at 140°C for 24 hours. It was then cooled, dissolved in ether, and extracted with dilute sodium hydroxide. This aqueous layer was separated and made acidic with dilute HCl. The precipitate was recrystallized from benzene-petroleum ether to give 11 g (28%) of 4-acetyl-5-phenyltriazole, m.p. 117°-118°C.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1>[Ni]>[N:1]1([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(CN2CCC2)cc1
Agent: [Ni]
Product: Nc1ccc(CN2CCC2)cc1

Procedure:
Prepared analogously to Example 55 by catalytic hydrogenation of 4-(azetidin-1-yl-methyl)-nitrobenzene with Raney nickel as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14].[CH:16]([N:19]1[C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:23]2[N:19]([CH:16]([CH3:18])[CH3:17])[N:20]=[CH:21][CH:22]=2)[C:7]([CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(I)c(C(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C(C)C)c(C(F)F)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
To a solution of 2-amino-4-difluoromethyl-5-iodo-benzoic acid methyl ester (750 mg, 2.29 mmol) in dioxane (30 mL) were added 1-isopropyl-5-tributylstannanyl-1H-pyrazole (1.1 g, 1.2 equiv) and Pd(dppf)2Cl2 (187 mg, 0.1 equiv) and the resulting mixture was stirred at 90° C. for 18 h. Another portion of catalyst (0.1 equiv) was added and the mixture was stirred at 90° C. for an additional 6 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 30:70)) to provide the title compound as an off-white solid (380 mg, 54%). ES-MS: m/z 310.3 [M+H]+, rt 5.54 min.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]([CH3:37])([CH3:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C>[CH3:27][C:28]([CH3:37])([CH3:36])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:32][CH2:31]1
Reactant: CC(C)(C)CN1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)CN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
7.15 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 2.9 gm of potassium carbonate and 4.5 gm of 1-(2,2-dimethyl-propyl)-piperazine were refluxed for 5 hours in 100 ml of absolute ethanol. Then, the hot reaction mixture was suction filtered. The crystals which precipitated out of the filtrate were then recrystallized from isopropanol in the presence of activated charcoal.
Reaction SMILES: C([O:5][C:6](=[O:20])[NH:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)[CH:9](O)[CH3:10])(C)(C)C.[H-].[Na+].O>C1COCC1>[F:19][C:14]1[CH:13]=[C:12]([CH:8]2[CH:9]([CH3:10])[O:20][C:6](=[O:5])[NH:7]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CC(O)C(NC(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1OC(=O)NC1c1ccc(F)c(F)c1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
Into a well-stirred solution of [1-(3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) in THF (20 mL) was added 95% NaH (0.09 g, 3.8 mmol) at room temperature. When the reaction was carried out on a larger (>5 g) scale, 1.0 equivalent of KH and 1.5 eq. of NaH was used as the base. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel (First isomer: 0.16 g, Rf=0.6, 3:1 hexane-EtOAc; second isomer: 0.18 g, Rf=0.5, 3:1 hexane-EtOAc). NOE experiments suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups. The 1H NMR spectrum for the trans diastereomer is as follows. 1H NMR (CDCl3) δ 1.49 (d, J=6.0 Hz, 3H), 4.37 (dq, J=6.0 Hz, J=7.2 Hz, 1H), 4.45 (d, J=7.2 Hz, 1H), 6.63 (br s, 1H), 7.08–7.28 (m, 3H).