Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:19])[CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.N1C=N[C-]=N1.[Na+].O.C(OCC)C>CN(C)C=O>[Cl:19][C:2]([Cl:1])=[CH:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: OC(CC(Cl)Cl)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [c-]1nc[nH]n1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: OC(C=C(Cl)Cl)(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A solution of 5.0 g (0.014 mol) of 1,1-dichloro-3-(4-chlorophenyl)-3-hydroxy-4-(1,2,4-(1H)-triazolyl)butane and 3.85 g (0.043 mol) of sodium 1,2,4-triazolide in 75 mL of dimethylformamide was stirred at room temperature for 28 hours. To this solution was added 200 mL of water and 200 mL of diethyl ether. The organic phase was separated from the aqueous phase and then washed thrice with 100 mL portions of water and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a yellow oil which solidified on standing overnight. This material was recrystallized from benzene to give the above named product in a yield of 2.6 g (58 percent of theoretical), melting at 95°-99° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[C:25]([NH:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccccc1

Procedure:
1.3 Grams of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in reference example 1 was dissolved in 80 ml of dimethylformamide. To this solution was added 1.2 g of triethylamine, then under an ice-cooled condition, 0.8 g of benzoyl chloride was added dropwise thereto. The reaction mixture was stirred under an ice-cooled condition for 3 hours, then the reaction mixture was concentrated under a reduced pressure, to the residue thus obtained was added water, the crystals formed were collected by filtration. Recrystallized from ethanol-water to obtain 0.5 g of 2-benzamido-3-(oxindol-3-yl)propionic acid in the form of light brown powdery substance. Melting point: 140°-142° C. (decomp.) [α]D20 -66° (C=0.1, methanol)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CSc1ccc(CC(=O)Cl)cc1
Temperature: 90 °C
Yield: 68.7 %

Procedure:
A mixture of 158 g (0.87 mole) of 4-methylthiophenylacetic acid and 150 ml (2 moles) of thionyl chloride was heated at 90° C. for 2 hours. After completion of the reaction, an excess of thionyl chloride was distilled off under reduced pressure, giving about 120 g of 4-methylthiophenylacetyl chloride as a black oily product. The oily product thus obtained was subjected to the subsequent reaction without isolation and purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:18]([Cl:29])[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.O>CN(C)C=O>[Cl:29][C:18]1[CH:17]=[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:42]4[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]4)=[C:6]([O:30][CH3:31])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][C:19]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CN1CCNCC1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCN4CCN(C)CC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A starting compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 50 mg), potassium carbonate (138 mg), and 1-methylpiperazine (0.055 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 54 mg (yield 100%) of the title compound.
Reaction SMILES: [N:1]#[N:2].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:18]([NH:20][C@@H:21]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:22]([OH:36])[CH2:23][C@@:24]1([C:33]([NH2:35])=[O:34])[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:19])[CH2:15][S:16][CH3:17])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClC1C=CC=C(C(OO)=[O:52])C=1>CO>[N:1]#[N:2].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:18]([NH:20][C@@H:21]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C@H:22]([OH:36])[CH2:23][C@@:24]1([C:33]([NH2:35])=[O:34])[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:19])[CH2:15][S:16]([CH3:17])=[O:52])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CSC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@]1(C(N)=O)CCCN1C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N#N
Solvent: CO
Product: CS(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@]1(C(N)=O)CCCN1C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
A solution of 193 mg of N2 -[3(S)-[[N-(benzyloxycarbonyl)-S-methyl-L-cysteinyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide in 2 ml of methanol was cooled to -70° C. A solution of 62 mg of 3-chloroperbenzoic acid in5 ml of methanol was added and the mixture was stirred at -70° C. for 30 minutes. The solvent was then removed by evaporation and the residue was chromatographed on silica gel using System G for the elution to give 62 mg of N2 -[3(S)-[[N-(benzyloxycarbonyl)-3-(methylsulphinyl)-L-alanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a 1:1 mixture of diastereomers; MS: m/e 601 [M+H]+.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.[CH:25]12[CH2:31][CH:30]1[CH2:29][CH2:28][CH:27]([CH2:32][O:33][C:34]1[C:46](Cl)=[CH:45][C:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[C:36]([F:48])[CH:35]=1)[CH2:26]2>>[CH:25]12[CH2:31][CH:30]1[CH2:29][CH2:28][CH:27]([CH2:32][O:33][C:34]1[C:46]([CH:1]3[CH2:7][CH2:6]3)=[CH:45][C:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[C:36]([F:48])[CH:35]=1)[CH2:26]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3CC3C2)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-chloro-2-fluorobenzoate, the title compound was obtained as a brown oil (1.29 g, 99%, crude yield): MS (ES+) m/z 361.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.[I:10][C:11]1[N:12]=[C:13]([CH3:16])[NH:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I:10][C:11]1[N:12]=[C:13]([CH3:16])[N:14]([C:2]2[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=2)[CH:15]=1
Reactant: Cn1ncc(Cl)cc1=O
Reactant: Cc1nc(I)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(I)cn1-c1cnn(C)c(=O)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of 160 mg (1.11 mmol) of 5-chloro-2-methyl-2H-pyridazin-3-one (CAS: [14628-34-3]), 230 mg (1.11 mmol) of 4-iodo-2-methyl-1H-imidazole (CAS: [73746-45-9]), in 3.5 ml of dry DMF were added 721 mg (2.21 mmol) of cesium carbonate. The suspension was stirred for 30 min at 45° C., then for 3 h at 65° C. and allowed to cool. The cristallised product is filtered off, washed with ethyl acetate and dried in vaccuo to yield 250 mg (0.791 mmol, 71%) of the title compound as a crystalline light yellow solid, MS: m/e=316.9 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])(O)O>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])[CH:11]=[CH:10]2
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: COc1cc(C(=O)O)ccc1B(O)O
Product: COc1cc(C(=O)O)ccc1-c1ccc2cc(O)ccc2n1

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol and 4-borono-3-methoxybenzoic acid. 1H NMR (CD3OD, 400 MHz): δ 8.81 (d, J=8.4 Hz, 1H), 8.14 (d, J=9.2 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.89 (dd, J=6.8, 1.6 Hz, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.69 (dd, J=9.2, 2.8 Hz, 1H), 7.48 (d, J=2.8 Hz, 1H). MS (ESI): m/z 295.7 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][C:19](O)=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(OC(NCCCC(OC1C(C)=CC=CC=1C)=O)=O)(C)(C)C>>[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][C:19]([O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CN1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: Cc1cccc(C)c1OC(=O)CCCNC(=O)OC(C)(C)C
Product: CN1CCC(OC(=O)CCNC(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from 1-methylpiperidin-4-ol and N-(tert-butoxycarbonyl)-β-alanine in a similar manner as described for 2,6-dimethylphenyl 4-[(tert-butoxycarbonyl)amino]butanoate. 1H NMR (400 MHz, CDCl3): δ 4.99 (s, 1H), 4.74-4.79 (m, 1H), 3.32-3.6 (m, 2H), 2.58 (s, 2H), 2.45-2.49 (t, 2H), 2.23 (s, 3H), 2.16-2.19 (m, 2H), 1.83-1.88 (m, 2H), 1.62-1.71 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=C(C#N)[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.O.S(=O)(=O)(O)O.[C:24]([OH:27])(=[O:26])[CH3:25]>O>[O:1]=[C:2]1[C:15]2[CH:14]=[C:25]([C:24]([OH:27])=[O:26])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2
Reactant: N#Cc1ccc2oc3c(c(=O)c2c1)CCCC3
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2oc3c(c(=O)c2c1)CCCC3
Yield: 88.5 %

Procedure:
To 88.0 g of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carbonitrile obtained in Example 12 was added 1.5 l of a mixed solution of water-sulfuric acid-acetic acid (1:1:1), and the mixture was heated for 2 hours under refluxing and stirring conditions. After being cooled, the reaction mixture was combined with 1.5 l of water and then ice-cooled for 2 hours. The resulting crystal deposit was collected by filtration, washed with water and then air-dried. The deposit was recrystallized from acetic acid to obtain 84.9 g (yield: 88.5%) of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carboxylic acid as light yellowish prism-like crystals having a melting point of 253° to 255° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[H-].[Na+].I[CH3:16]>O1CCCC1>[CH3:16][O:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: OCc1cc(Br)c2occc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(Br)c2occc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.372 gm (0.40 mMol) 5-hydroxymethyl-7-bromobenzofuran in tetrahydrofuran was added to a mixture of 1.80 mmol sodium hydride (60% suspension in mineral oil) in 2 mL tetrahydrofuran. After stirring at room temperature for 1 hour, 204 μL iodomethane were added and stirring was continued for 2.5 hours. The reaction mixture was quenched by the addition of water and the resulting mixture was extracted well with ethyl acetate. The organic phase was concentrated under reduced pressure to provide a nearly quantitative yield of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1ccc(Cl)cc1C=O
Yield: 923.5 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (3.1 g, 2 mmol), 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (5.46 g, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.1 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 150° C. for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (Yield: 5 g, 92.5%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1>>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CC(=O)c1ccc(Br)cc1
Product: CC(=O)c1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 1-(4-bromophenyl)ethanone (398 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 300 mg (81% isolated yield) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>O.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([F:17])([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2
Reactant: F[B-](F)(F)F
Reactant: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1=O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)C1(F)Cc2cc(Cl)ccc2C1=O

Procedure:
0.734 g (3 mmol) of 5-chloro-2-methanesulfonylindan-1-one and 1.77 g (5 mmol) of N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) are suspended in a mixture of 2.5 ml of water and 7.5 ml of acetonitrile and stirred under reflux for 4 h. The reaction mixture is cooled, concentrated under reduced pressure and purified chromatographically on silica gel using the mobile phase dichloromethane. This gives 5-chloro-2-fluoro-2-methanesulfonylindan-1-one of melting point 150° C.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C@@H:21]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:69])(=[O:68])[NH:38][C:39](=[O:67])[C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([C@H:52]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[C:60]4[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=4)[OH:53])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)=[CH:33][C:32]=1[S:70]([C:73]([F:76])([F:75])[F:74])(=[O:72])=[O:71])[CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][CH3:18])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl>C(Cl)Cl.CO>[ClH:66].[P:1]([OH:8])([OH:3])([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C@@H:21]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:69])(=[O:68])[NH:38][C:39](=[O:67])[C:40]2[CH:41]=[CH:42][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([C@H:52]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[C:60]4[CH:61]=[CH:62][C:63]([Cl:66])=[CH:64][CH:65]=4)[OH:53])[CH2:48][CH2:47]3)=[CH:44][CH:45]=2)=[CH:33][C:32]=1[S:70]([C:73]([F:74])([F:76])[F:75])(=[O:71])=[O:72])[CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][CH3:18])=[O:2]
Reactant: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CCOP(=O)(O)O)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 143.4 %

Procedure:
A solution of di-tert-butyl 2-(((R)-3-(4-(N-(4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)(ethyl)amino)ethyl phosphate (INTERMEDIATE 55, 147 mg, 0.14 mmol) in DCM (3.17 ml) was treated with a solution of HCl (4M in dioxane, 0.60 ml). When the addition was completed, a white precipitate was observed. The mixture was diluted with MeOH after an hour and the volatiles were evaporated under reduced pressure to give a gummy residue. The material was dissolved in MeOH, and diluted with ˜20 ml DCM, resulting in a white precipitate. The mixture was concentrated under reduced pressure to provide a white solid. The material was triturated in 10-15 ml CH2Cl2, and dried under high vacuum to provide the title compound (108 mg, 95%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[N+:13]([CH3:16])([O-:15])=[O:14].C[O-].[Na+].C(O)CCC>CS(C)=O.CO>[C@@H:2]1([CH2:16][N+:13]([O-:15])=[O:14])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: CCCCO
Product: O=[N+]([O-])C[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
50 g of moisture-free D-glucose are dissolved in 200 ml dimethyl sulphoxide and 100 ml methanol. 100 ml nitromethane and a suspension of 30 g sodium methylate in 320 ml methanol are added to the latter and stirring takes place for 24 hours at room temperature. 250 ml n-butanol are added to the reaction mixture and stirred for 1 hour at 0° C. The latter is then filtered and the residue washed with 100 ml isopropanol and 100 ml diethyl ether. After drying, 71 g of a bright yellow powder are obtained. The latter is dissolved in 200 ml water and passed through a column with 100 g of cation exchanger (Aldrich, Amberlyst 15, strongly acid H+ form). The ion exchanger is washed with 500 ml water. The aqueous, red solution is concentrated to 100 ml and heated to 90 ° C. over 30 hours. 2 g of fine activated carbon are added to the hot solution, which is then stirred for 10 minutes, filtered through 5 g kieselguhr and rewashed with 200 ml water.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:8].[Na+].[I-:24]>CC#N>[I:24][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:8]
Reactant: [I-]
Reactant: C[C@H](CSC(=O)OCCCCCl)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](CSC(=O)OCCCCI)C(=O)N1CCC[C@H]1C(=O)O
Yield: 102 %

Procedure:
1-[(2S)-3-(4-chlorobutoxycarbonyl)mercapto-2-methyl-1-oxopropyl]-L-proline (5.80 g, 0.0157 Mol) was dissolved in CH3CN (100 ml) and NaI (23.9 g, 0.160 Mol) was added to the solution. The mixture was refluxed for 7 h, then concentrated and diluted with CH2Cl2. The solid formed was filtered off and the organic phase was washed with H2O (3×50 ml), dried over sodium sulphate and evaporated under reduced pressure affording 1-[(2S)-3-(4-iodobutoxycarbonyl) mercapto-2-methyl-1-oxopropyl]-L-proline (7.10 g) as an oil that was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:19]1([C:25]2[NH:26][C:27]([CH:30]=O)=[CH:28][N:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([C:25]2[NH:26][C:27]([CH2:30][N:1]3[CH2:2][CH2:3][CH:4]([C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=4)=[O:8])[CH2:5][CH2:6]3)=[CH:28][N:29]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cnc(-c2ccccc2)[nH]1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C1CCNCC1
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)C1CCN(Cc2cnc(-c3ccccc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To piperidin-4-yl(3-(trifluoromethyl)phenyl)methanone (1-1) (147 mg, 0.50 mmol) and 2-phenyl-1H-imidazole-5-carbaldehyde (1-2) (86 mg, 0.50 mmol) in 10 mL of CH2Cl2 was added MP-BH(OAc)3 (200 mg, 0.4 mmol), and the mixture was stirred at room temperature for 16 h. The reaction was filtered to remove the resin, and the filtrate was concentrated under a stream of N2 gas. The crude product was purified by reversed phase HPLC to give 111 mg (54%) of 1-3. HRMS (ES) 414.1786 (M+H) found, 414.1788 required.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:23]=[C:22]2[O:24][CH2:25][CH2:26][O:27][C:21]2=[CH:20][C:7]=1[CH2:8][N:9]1C(=O)C2=CC=CC=C2C1=O)[CH3:2].NN.C(OCC)C>C(O)C>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:23]=[C:22]2[O:24][CH2:25][CH2:26][O:27][C:21]2=[CH:20][C:7]=1[CH2:8][NH2:9])[CH3:2]
Reactant: CCOCOc1cc2c(cc1CN1C(=O)c3ccccc3C1=O)OCCO2
Agent: NN
Solvent: CCO
Solvent: CCOCC
Product: CCOCOc1cc2c(cc1CN)OCCO2

Procedure:
N-(2-ethoxymethoxy-4,5-ethylenedioxybenzyl)phthalimide (625 mg, 1.69 mmol) was mixed with 0.2 mL (6.4 mmol) hydrazine in 30 mL ethanol and refluxed for three hr. The reaction mixture was cooled, 30 mL ethyl ether was added to the mixture, and a white precipitate was removed by filtration. The filter cake was washed three times with diethyl ether and the combined organic solutions were evaporated to yield a residue that was partitioned between ethyl ether and 10% sodium hydroxide. The organic phase was washed three times with 10% sodium hydroxide, and the aqueous washes were combined and back-extracted twice with dichloromethane. The organic solutions were combined and washed with brine and dried over sodium sulfate/potassium carbonate. Subsequent evaporation of solvent gave 2-ethoxymethoxy-4,5-ethylenedioxybenzylamine as a light yellow oil (346 g, 86% crude), which solidified upon standing. IR: 3375 cm-1.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:33]([CH2:35][CH3:36])#[C-:34]>CO.O>[Cl:12][C:13]1[CH:14]=[C:15]([C:16]2[N:9]=[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]3[C:34]=2[NH:33][CH2:35][CH3:36])[CH:18]=[CH:19][CH:20]=1
Reactant: [C-]#[N+]CC
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCNc1c(-c2cccc(Cl)c2)nc2ccc(C(F)(F)F)cn12
Temperature: 25 °C
Yield: 53 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 μmol, Eq: 1.00), 3-chlorobenzaldehyde (91.0 mg, 73.7 μl, 648 μmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 μmol, Eq: 0.3) were dissolved in MeOH (2.00 mL). The resulting colorless solution was stirred at rt. To this solution was added dropwise isocyanoethane (34.0 mg, 45.9 μl, 617 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. To the yellow clear solution was added dropwise water until the mixture got turbid and the product precipitated from the MeOH/water mixture. The solid was filtered off, washed with MeOH/water (1:1) and hexane and dried under vacuum, to give a yellow solid (111 mg, 53.0%). MS: 339.0 [M]+; 1H-NMR (D6-DMSO): δ 8.90 (s, 1H), 8.23 (s, 1H), 8.15 (d, 1H), 7.71 (d, 1H), 7.52 (t, 1H), 7.47-7.36 (m, 2H), 5.17 (t, 1H), 3.02 (m, 2H), 1.12 (t, 3H).