Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1.[O:26]1[CH2:29][C:28](=O)[CH2:27]1>ClCCCl>[O:26]1[CH2:29][CH:28]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:27]1
Reactant: OC1CCNCC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OC1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
Sodium triacetoxyborohydride (3.18 g, 15.00 mmol) and acetic acid (0.859 mL, 15.00 mmol) were added to a solution of piperidin-4-ol (1.011 g, 10 mmol) and oxetan-3-one (0.721 g, 10.00 mmol) in DCE (35 mL) and the reaction mixture was stirred at room temperature overnight. Celite was added to the sticky reaction mixture and the reaction mixture was filtered, the filtrate was concentrated in vacuo to give brown oil. The solid was purified by flash chromatography on silica gel using an automated ISCO system (120 g column, eluting with 0-8% 2 N ammonia in methanol/dichloromethane). 1-(oxetan-3-yl)piperidin-4-ol (0.80 g) was obtained as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=1.S(Cl)([Cl:37])=O>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4ccccc4CO)cc3)CCCCN12
Solvent: ClCCl
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4ccccc4CCl)cc3)CCCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-[4-[2-(hydroxymethyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.318 g) in CH2Cl2 (5 mL) was added thionyl chloride (0.2 mL) and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and the residue was redissolved in CH2Cl2 (5 mL) and evaporated again. The residue was dried under vacuum to give 6-[4-[2-(chloromethyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][C:15]1([CH2:18][OH:19])[CH2:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:19][CH2:18][C:15]1([CH2:14][O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:16][CH2:17]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(COCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
Methane sulfonyl chloride (5.2 mL, 68.7 mmol) was added drop wise to an ice cooled solution of {1-[(benzyloxy)methyl]cyclopropyl}methanol (Compound 63E, 11 g, 57.2 mmol) and triethylamine (15.5 mL, 114 mmol) in dichloromethane (50 mL). The reaction mixture warmed to RT and allowed to stir overnight. The reaction mixture was filtered to remove solids. The filtrate was washed with saturated sodium bicarbonate solution followed by brine, dried over magnesium sulfate, filtered and concentrated to give 12 g (77%) of the desired product as light yellow oil which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.25-7.41 (m, 5H), 4.58 (s, 2H), 4.21 (s, 2H), 3.42 (s, 2H), 2.96 (s, 3H), 0.61-0.75 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[O:12]=[C:13]1[CH2:17][S:16][CH2:15][NH:14]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:14]2[C:13](=[O:12])[CH2:17][S:16][CH2:15]2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1CSCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CSCC2=O)cc1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 4-methoxybenzoyl chloride (20.7 g) in tetrahydrofuran (50 ml) was added dropwise to a mixture of 4-oxo-thiazolidine (12.5 g) and triethylamine (16.9 ml) in tetrahydrofuran (200 ml) at -5° C. with stirring. The mixture was stirred at that temperature for 3 hours and at room temperature for 4 hours, and allowed to stand overnight. After the solvent was evaporated in vacuo, the residue was mixed with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(4-methoxybenzoyl)-4-oxothiazolidine (18.1 g) as slightly brown prisms.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([C:10]([CH3:14])([CH3:13])[CH2:11]Cl)[CH:3]=1.Cl.N1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:14][C:10]([CH3:11])([CH3:13])[C:4]=2[CH:3]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CCl
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: CC1(C)COc2ccc(Br)cc21
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of 4-bromo-2-(2-chloro-1,1-dimethyl-ethyl)-1-methoxy-benzene (65 g, 0.234 mol), pyridine hydrochloride (121.8 g, 1.054 mol) and quinoline (110.67 mL, 0.936 mol) was refluxed at 164° C.–167° C. under argon for 5 hrs. After cooling to room temperature the reaction mixture was treated with ice-cold 6N HCl and extracted twice with ether. The organic layers were combined, dried (Mg2SO4), filtered and evaporated. The residue was purified on silica gel (10% ethyl acetate in hexane) to give 52 g of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (98%). 1H NMR (300 MHz; CDCl3): δ 1.32 (s, 6 H), 4.23 (s, 2 H), 6.67 (d, J=8.1 Hz, 1 H), 7.19 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8][OH:9])([O-:3])=[O:2].C(Cl)(Cl)[Cl:14]>>[Cl:14][C:7](=[N:8][OH:9])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Product: O=[N+]([O-])c1cccc(C(Cl)=NO)c1
Yield: 93.7 %

Procedure:
32.9 g (0.2 mol) of 3-nitrobenzaldoxime was suspended in 150 g of chloroform and chlorine gas was bubbled into the suspension while maintaining the reaction mixture at a temperature of from 5° to 10°C. 3-Nitrobenzaldoxime went into solution showing a green color upon reaction with chlorine to give a reaction mixture having a deep green color. The reaction mixture turned a pale yellowish-brown upon standing; chloroform was then removed from the reaction mixture under reduced pressure to give 37.6 g of pale yellow crystals having a melting point of 98°-101°C. Yield, 94%.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH2:16]([O:18][C:19](=[O:32])[CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=O)[NH:26][CH:25]=1)=[O:23])[CH3:17]>N1CCCCC1.C(O)C>[CH2:16]([O:18][C:19](=[O:32])[CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:7]=3)[NH:11][C:10]2=[O:15])[NH:26][CH:25]=1)=[O:23])[CH3:17]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)CNC(=O)c1c[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)CNC(=O)c1c[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)c1C
Temperature: 90 °C

Procedure:
A mixture of 5-methylaminosulfonyl-2-oxindole (0.06 g, 0.22 mmol), [(5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino]-acetic acid ethyl ester (0.075 g, 0.27 mmol) and piperidine (2 drops) in ethanol (5 mL) was heated in a sealed tube at 90° C. for 12 hrs. After cooling, the precipitate was collected by vacuum filtration, washed with ethanol, triturated with dichloromethane/ether and dried to give 0.035 g (36%), of the title compound as a yellowish brown solid.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([NH:28][CH:29]=[O:30])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22]CC[CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(C[CH2:47][C:48](=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH:29]([NH:28][C@@H:16]1[CH2:17][CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:47][C:48](=[O:51])[CH2:19]2)[C@@H:25]2[C@@H:15]1[C@H:6]1[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]1)=[O:30]
Reactant: C[C@]12CCCCC1C[C@@H](NC=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1C[C@@H](NC=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 97 %

Procedure:
The title compound II-bu was prepared in 97% yield from 3,3:17,17-bis(ethylendioxy)-7α-formamidoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The crude product was purified by flash chromatography (SiO2, n-hexane/acetone 70/30). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 8.18 (dd, 1H), 7.97 (d, 1H), 4.13 (m, 1H), 2.90-0.95 (m, 20H), 1.00 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[C:5]([OH:8])[C:4]([OH:9])=[CH:3][C:2]=1[C:10]([O:12][C@@H:13]1[O:18][C@@H:17]2[CH2:19][O:20][C:21]([C:23]3[CH:24]=[C:25]([OH:43])[C:26]([OH:42])=[C:27]([OH:41])[C:28]=3[C:29]3[C:34]([OH:35])=[C:33]([OH:36])[C:32]([OH:37])=[CH:31][C:30]=3[C:38]([O:40][C@H:15]3[C@@H:16]2[O:44]C(C2[C@H]4C5C(C([O:65][C@@H:14]13)=O)=CC(O)=C(O)C=5O[C@](O)(C4(O)O)C(=O)C=2)=O)=[O:39])=[O:22])=[O:11]>O>[CH:1]1[C:2]([C:10]([O:12][C@@H:13]2[O:18][C@@H:17]3[CH2:19][O:20][C:21]([C:23]4[CH:24]=[C:25]([OH:43])[C:26]([OH:42])=[C:27]([OH:41])[C:28]=4[C:29]4[C:34]([OH:35])=[C:33]([OH:36])[C:32]([OH:37])=[CH:31][C:30]=4[C:38]([O:40][C@@H:15]([C@@H:16]3[OH:44])[C@H:14]2[OH:65])=[O:39])=[O:22])=[O:11])=[CH:3][C:4]([OH:9])=[C:5]([OH:8])[C:6]=1[OH:7]
Reactant: O=C1O[C@H]2[C@@H]3OC(=O)c4cc(O)c(O)c(O)c4-c4c(cc(O)c(O)c4O)C(=O)OC[C@H]2O[C@@H](OC(=O)c2cc(O)c(O)c(O)c2)[C@@H]3OC(=O)c2cc(O)c(O)c3c2[C@@H]2C1=CC(=O)[C@](O)(O3)C2(O)O
Solvent: O
Product: O=C(O[C@@H]1O[C@@H]2COC(=O)c3cc(O)c(O)c(O)c3-c3c(cc(O)c(O)c3O)C(=O)O[C@H]([C@H]1O)[C@@H]2O)c1cc(O)c(O)c(O)c1

Procedure:
Hydrolysis of geraniin in boiling water, gallic acid ellagic acid and corilagin were produced, which were identified by thin-layer co-chromatography with authentic samples.
Reaction SMILES: [CH:1]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1.[Br:12]Br.S([O-])(O)=O.[Na+]>>[Br:12][C:1]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1
Reactant: BrBr
Reactant: C1CC2CC(C1)C1CCC2C1
Agent: O=S([O-])O
Agent: [Na+]
Product: BrC12CCCC(C1)C1CCC2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1.0 Gram (4.8 millimoles) of tricyclo [4.3.1.12,5 ] undecane is added to 2 ml (38.7 millimoles) of liquid bromine and the entirety is stirred at room temperature for 17 hours. The reaction mixture is added slowly to a cooled, saturated solution of sodium hydrogensulfite under stirring to decompose excess bromine. The aqueous solution is subjected to two extractions each with 20 ml of carbon tetrachloride and the combined extracts are dried with magnesium sulfate. Carbon tetrachloride is distilled out and the residue (1.9 g) is distilled under reduced pressure to collect a fraction boiling at 96°-8° C./2mmHg. Colorless crystals having a melting point of 57.5°-58.5° C. are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:11][C:12]1[C:13]([CH2:19]Cl)=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1>CS(C)=O>[Cl:11][C:12]1[C:13]([CH2:19][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: ClCc1nc(Cl)ccc1Cl
Reactant: Nc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1ccc(SCc2nc(Cl)ccc2Cl)cc1
Reaction time: 15 h

Procedure:
p-Aminothiophenol (6.25 grams; 0.05 mole) was dissolved in 40 ml. of dimethylsulfoxide and powdered dry sodium hydroxide (2.0 grams; 0.05 mole) added thereto. The resulting mixture was warmed slightly, stirred and an additional 20 ml. of dimethylsulfoxide added thereto to clear the solution. A solution of 3,6-dichloro-2-chloromethylpyridine (8.6 grams; 0.05 mole) in 20 ml. of dimethylsulfoxide was added thereto slowly, with stirring, over a period of about one hour. The temperature of the reaction mixture increased to about 30°-45° C. during the addition. Following the completion of the addition, the reaction mixture was cooled and poured over ice and allowed to stand for about 15 hours. The aqueous layer was then decanted and the residue extracted with 5-500 ml. portions of hexane and the product precipitate recovered therefrom. Recrystallization of the precipitate from benzene gave the desired N-(4-((3,6-dichloro-2-pyridinyl)methylio)benzenamine compound as a crystalline solid having a melting point of 110°-111° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][N:28]=3)[CH2:23]2)=O)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH:3][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][N:28]=3)[CH2:25]2)=[O:19])[N:5]=1
Reactant: Nc1cccnn1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(I)cn2)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To an ice-bath cooled solution of sodium hydride (60 wt % in mineral oil, (2.1 g, 52.4 mmol) in DMF (50 mL) under nitrogen atmosphere was added (dropwise) a solution of 3-aminopyridazine (2.74 g, 28.79 mmol) in DMF (50 mL). After several minute a solution of 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitro-phenyl ester (Example 5, step 3); 11.54 g, 26.18 mmol) in DMF (40 mL) was added. After 5 min the cooling bath was removed and reaction allowed to warm to ambient temperature and stir for 1.5 hr. Saturated sodium bicarbonate solution (500 mL) was added and the mixture was extracted with EtOAc (4×400 mL). Combined organic phases were washed with sat sodium chloride solution (500 mL), dried over sodium sulphate and filtered. The filtrate solvents were removed in vacuo to afford a crude product that was triturated with diethyl ether to afford the title compound (7.52 g, 72%) as a colourless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[C:13]([C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][CH2:23][CH2:24][N:25]([CH2:33][CH3:34])[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:13]([C:17]1[CH:36]=[CH:35][C:20]([CH2:21][N:22]([CH2:23][CH2:24][N:25]([CH2:33][CH3:34])[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CCN(CCNCc1ccc(C(C)(C)C)cc1)c1cccc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCN(CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12)c1cccc(C)c1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
81 mg (0.50 mol) of 1H-indole-7-carboxylic acid, 162 mg (0.5 mmol) of N′-(4-tert-butyl-benzyl)-N-ethyl-N-m-tolyl-ethane-1,2-diamine and 108 mg (0.55 mmol) of EDC.HCl were dissolved in 5 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed with 1N aqueous HCl solution, once with 1N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave 140 mg (55%) product as a colorless oil. MS (ISP) 468.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([O:13][C@H:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:17])=[O:16]
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To (S)(−)-1-benzyl-3-pyrrolidinol (5 g, 28.2 mmol) in pyridine (40 mL) was added methane sulphonyl chloride (2.03 mL, 26.2 mmol, 0.93 equiv.) dropwise. The reaction mixture stirred 3 h, was poured into ice water (100 mL) and extracted with DCM (3×50 mL). The combined organic extracts were washed with saturated aq NaHCO3, brine and dried (MgSO4) to give 3 g of the titled compound: low resolution MS (ES) m/e 256.0 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:14][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:17][N:18]([CH3:20])[CH3:19])=[CH:9][C:8]=1[S:10]([N:13]=[CH:17][N:18]([CH3:20])[CH3:19])(=[O:12])=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Product: CN(C)C=CC(=O)c1ccc(Cl)c(S(=O)(=O)N=CN(C)C)c1
Temperature: -10 °C

Procedure:
A mixture of 7.8 g (0.033 moles) of 5-acetyl 2-chlorobenzenesulfonamide [Chem. Abst., 63, 5563a (1965)] and 50 ml of N,N-dimethylformamide dimethyl acetal was refluxed for 5 hours, then cooled at -10° C. The precipitate formed was collected, washed with 50 ml of ether and air dried. The solid was boiled up in 400 ml of ethanol, treated with activated charcoal and filtered. The filtrate was cooled at -10° C. and filtered to collect an orange-red precipitate. The solid was washed with 50 ml of ethanol and dried in vacuo at 60° C. and gave 5.2 g of N'-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]sulfonyl]-N,N-dimethylmethanimidamide, mp 204°-206° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[O:13][CH2:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)[C:4]=2[O:3]1.[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]=O>>[CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[O:13][CH2:14][C:15]4[CH:21]=[C:20]([NH:22][CH2:29][C:25]5[NH:24][CH:28]=[CH:27][N:26]=5)[CH:19]=[CH:18][C:16]=4[N:17]=3)[C:4]=2[O:3]1
Reactant: O=Cc1ncc[nH]1
Reactant: CC1(C)Cc2cccc(NC3=Nc4ccc(N)cc4CO3)c2O1
Product: CC1(C)Cc2cccc(NC3=Nc4ccc(NCc5ncc[nH]5)cc4CO3)c2O1

Procedure:
Prepared from N2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (example 139, step B) and 2-imidazolecarboxaldehyde according to the procedure described for example 88. The title compound was obtained as a brown solid, MS (ISP) m/e=390.3 [(M+H)+].
Reaction SMILES: [CH2:1]([OH:10])[C:2]([CH2:4][O:5]P(O)(O)=O)=[O:3].[N:11]([CH2:14][C@@H:15]([OH:18])[CH:16]=[O:17])=[N+:12]=[N-:13].[OH-].[Na+]>C(O)C(N)(CO)CO>[N:11]([CH2:14][C@@H:15]([OH:18])[C@H:16]([OH:17])[C@@H:1]([OH:10])[C:2](=[O:3])[CH2:4][OH:5])=[N+:12]=[N-:13]
Reactant: O=C(CO)COP(=O)(O)O
Reactant: [N-]=[N+]=NC[C@@H](O)C=O
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Product: [N-]=[N+]=NC[C@@H](O)[C@H](O)[C@@H](O)C(=O)CO
Reaction time: 48 h
Yield: 30 %

Procedure:
DHAP (0.5 mmole) was added to an aqueous solution of (R)-3-azido-2-hydroxypropanal (1 mmole in 40 ml) and the pH value adjusted to 7.0 with 10N NaOH. To this solution was added fuculose-1-phosphate aldolase from E. coli (4 g), which had been treated with egg white lysozyme (40 mg) in Tris buffer (pH 7.5, 25 ml) for 1 hour at 35° C., to form a mixture and the mixture stirred slowly for 2 days. The stirred mixture was adjusted to a pH value of 4.7, and acid phosphatase (400 units) added. The resulting mixture was incubated at 37° C. for 48 hours, neutralized to a pH value of 7.0 and lyophilized. The residue was treated with MEOH and filtered to remove the insoluble material. The MEOH was removed under reduced pressure and the crude product purified with silica gel column chromatography (CHCl3 :MeOH=6:1) to give 6-azido-6-deoxy-D-xylo-hexulose in 30% yield.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]1([F:34])[O:26][C:25]2[CH:27]=[CH:28][C:29]([C:31](Cl)=[O:32])=[CH:30][C:24]=2[O:23]1>N1C=CC=CC=1.CO>[F:34][C:22]1([F:21])[O:26][C:25]2[CH:27]=[CH:28][C:29]([C:31]([NH:20][C:18]3[O:19][C:15]([C:12]4[CH:11]=[CH:10][C:9]([O:8][C:4]5[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=5)=[CH:14][CH:13]=4)=[N:16][N:17]=3)=[O:32])=[CH:30][C:24]=2[O:23]1
Reactant: O=C(Cl)c1ccc2c(c1)OC(F)(F)O2
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1ccc2c(c1)OC(F)(F)O2
Reaction time: 3 h
Yield: 12.3 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 2,2-difluoro-1,3-benzodioxole-5-carbonyl chloride (165.4 mg, 0.75 mmol) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (27.0 mg). Yield 12.3%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COc1ccc(B(O)O)cc1
Product: COC(=O)C(CC(C)C)c1cc(Oc2ccc(OC)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester prepared in Example 15, step (f)) and 4-methoxybenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH: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])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:40](N2C=CN=C2)=[O:41])=[CH:34][C:33]=1[F:47]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:40]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[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:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])=[CH:34][C:33]=1[F:47]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CNC(=O)n2ccnc2)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (48.8 mg, 0.115 mmol) and 2-Fluoro-4-{[(imidazole-1-carbonyl)-amino]-methyl}-benzoic acid methyl ester (183.3 mg, 0.764 mmol) in CH2Cl2 (8 mL) was stirred rt for 16 hrs. The reaction mixture was then purified by flash column to give 4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-methyl)-2-fluoro-benzoic acid methyl ester (64.5 mg, 88%).