Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][C:18]3[CH:23]=[C:22]([S:24](Cl)(=[O:26])=[O:25])[C:21]([CH3:28])=[CH:20][C:19]=3[CH3:29])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH2:38])[CH:32]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][C:18]3[CH:23]=[C:22]([S:24]([NH:38][CH2:37][C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)(=[O:26])=[O:25])[C:21]([CH3:28])=[CH:20][C:19]=3[CH3:29])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)NCc2cccnc2)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 9H-fluoren-9-ylmethyl[5-(chlorosulfonyl)-2,4-dimethylphenyl]carbamate (1.0 g, 2.3 mmol) in CH2Cl2 (23 mL) was added 1-pyridin-3-ylmethanamine (0.46 mL, 4.5 mmol) and pyridine (0.55 mL, 6.8 mmol). The bright yellow solution was then stirred at room temperature overnight and then quenched by the addition of sat. aq. NaHCO3 solution. The reaction was extracted with EtOAc and the organic extracted were dried over Na2SO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-5% MeOH/DCM) afforded the title compound.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5](Br)[C:4]=1[OH:14].CN(C)[CH:17]=[O:18].[CH3:20][OH:21]>>[CH3:20][O:21][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([O:18][CH3:17])[C:4]=1[OH:14]
Reactant: CC(C)(C)c1cc(Br)c(O)c(Br)c1
Reactant: CN(C)C=O
Reactant: CO
Agent: [Na]
Product: COc1cc(C(C)(C)C)cc(OC)c1O
Reaction time: 2 h
Yield: 89 %

Procedure:
Sodium (18.2 g, 0.79 g atom) was dissolved in methanol (152 ml). 2,6-Dibromo-4-t-butylphenol (30 g), cuprous bromide (4 g, 0.028 mole) and dimethylformamide (152 ml) were added and the mixture boiled under reflux (88°-84° C.) with stirring for 2 hours. Work up as given in Example 1 gave 2,6-dimethoxy-4-t-butylphenol as a pale yellow oil, 19.9 g of 90% purity (89% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]([NH:21][N:22]1[C:27](=[O:28])[NH:26][C:25](=O)N[C:23]1=[O:30])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)CN[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:41]([N:26]1[CH2:25][C:23](=[O:30])[N:22]([NH:21][C:19](=[O:20])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:31][CH:32]([CH3:34])[CH3:33])[C:27]1=[O:28])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]c(=O)[nH]c1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(Cc2ccccc2)C1=O)[C@H](CC=Cc1ccccc1)C(=O)OC(C)(C)C
Yield: 105.7 %

Procedure:
A solution of 0.772 g of (E)-2(S)-(tert-butoxycarbonyl)-1(R)-isobutyl-5-phenylpent-4-enyl-1,3,4-oxadiazol-2(3H)-one (prepared as described in Example 34, part (i)) in 10 ml of toluene was treated with 0.387 g of N-benzyl glycine ethyl ester and 0.278 ml of triethylamine and heated overnight at reflux temperature. The mixture was cooled then diluted with ethyl acetate and washed in sequence with 5% aqueous citric acid, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulphate. Evaporation gave 0.918 g of N-(3-Benzyl-2,5-dioxo-1-imidazolidinyl)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleramide in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1O)[C:32]#[N:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][C:36]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=3[F:28])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: N#Cc1ccc(O)c(F)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: N#Cc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1
Yield: 89 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 3-fluoro-4-hydroxybenzonitrile (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane and ethyl acetate (100:0 to 50:50) to give the desired compound as a colorless foam (89%). MS (Turbo Spray): m/z=510.3 [M+H].
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([OH:29])=[O:28].[O:31]([C:38]1[S:39][CH:40]=[C:41]([CH2:43]O)[N:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([O:29][CH2:43][C:41]1[N:42]=[C:38]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:39][CH:40]=1)=[O:28]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCSC1=O
Reactant: OCc1csc(Oc2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)OCc2csc(Oc3ccccc3)n2)[C@@H]1C=C1CCSC1=O
Temperature: 20 °C
Reaction time: 17 h
Yield: 71.6 %

Procedure:
0.11 g of 4-dimethylamino-pyridine and 2 g of dicyclohexylcarbodiimide were added to a solution of 2.04 g of (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid [described in French Pat. No. 70-21682] in 20 ml of methylene chloride and the mixture was stirred at 20° C. for 15 minutes. A solution of 1.7 g of (2-phenoxy-4-thiazolyl)-methanol in 10 ml of methylene chloride was added dropwise to the mixture which was stirred at 20° C. for 17 hours and was filtered. The organic phase of the filtrate was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel, and was eluted with an 8-2 cyclohexaneethyl acetate mixture to obtain 2.44 g of (2-phenoxy-4-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate melting at 78° C.
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][O:14][C:9]=3[CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:24][S:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2>ClCCl>[CH:1]1([C:4]([C:32]2[C:31]3[C:35](=[C:27]([CH2:26][S:25][CH3:24])[CH:28]=[CH:29][CH:30]=3)[NH:34][CH:33]=2)([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][O:14][C:9]=3[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc2c(c1)OCCO2)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCCO4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
400 mg (1.82 mmol) of the compound from Example 142A and 0.17 ml (2.18 mmol) of trifluoroacetic acid were added to 322 mg (1.82 mmol) of the compound from Example 8A in 3 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and by recrystallization from acetonitrile. 184 mg (27% of theory) of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[OH:12].[OH-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16]>O>[C:15]([O:12][C:3]1[C:4]([CH3:11])=[C:5]([CH:9]=[CH:10][C:2]=1[Br:1])[C:6]([OH:8])=[O:7])(=[O:17])[CH3:16]
Reactant: Cc1c(C(=O)O)ccc(Br)c1O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1c(Br)ccc(C(=O)O)c1C

Procedure:
Water (12 mL) was added to 4-bromo-3-hydroxy-2-methylbenzoic acid (5 g, 21.6 mmol) in an Erlenmeyer flask and cooled in an ice bath. 50% Aqueous NaOH solution (8.06 g mixed with 12 mL water, 108 mmol) was added and the mixture stirred for few minutes until the solution was clear. Acetic anhydride (2.04 mL, 21.6 mmol) was added drop wise until pH 5 was reached; by that time the reaction mixture became a thick slurry having an off white color. The mixture was stirred overnight at room temperature. LCMS showed a major peak with the expected product mass and a minor polar peak of the starting material. The pH was adjusted to 2 and the precipitate was filtered. LCMS of the precipitate showed it as a 3:1 mixture of the expected acetate and the starting phenol. The filtrate also contained some product, so combined everything, dried and adsorbed on silica and subjected to silica gel column chromatography using ISCO. The main peak was collected, the solvent was removed and the product dried under vacuum. 1H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 7.81-7.33 (m, 2H), 2.37 (s, 6H), 2.34 (s, 3H).
Reaction SMILES: [C:1]([CH:8]([NH2:12])[CH2:9][CH2:10]Br)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1>C(Cl)Cl>[C:1]([CH:8]([NH2:12])[CH2:9][CH2:10][SH:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C1CSCCN1
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(N)CC[SH]1CCNCC1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A solution of 3-BOC-aminopropyl bromide (3.07 g; 12.9 mmol) and thiamorpholine (2.6 mL; 25.8 mmol) in CH2Cl2 (25 mL) is heated at the reflux temperature for 24 h. The mixture is cooled at r.t., filtered, washed with water (2×50 mL), dried over Na2SO4 and evaporated to dryness in vacuum. Purification by flash chromatography on silica gel (eluent CHCl3/CH3OH 9:1) yields 1-(3-BOC-aminopropyl)-thiamorpholine (3.1 g; 11.96 mmol), as a transparent oil.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[CH2:10]([OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-:23].[Na+].C(Cl)(Cl)Cl>O1CCOCC1>[CH2:10]([O:22][C:2]1[N:4]=[C:5]([O:23][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[N:7]=[C:8]([Cl:9])[N:1]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: [OH-]
Reactant: CCCCCCCCCCCCO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCOc1nc(Cl)nc(OCCCCCCCCCCCC)n1
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of 18.4 g (0.1 mole) of cyanuric chloride and 38.0 g (0.2 moles) of lauryl alcohol in 200 ml of dioxane there were added 9.9 g (0.25 moles) of powdered sodium hydroxide over a period of 10 minutes at a reaction temperature in the range of 25° to 45° C. After 3 hours the reaction mixture was found to be converted. The reaction mixture was poured into chloroform and further treated as indicated in Example I. After evaporation there were obtained 30.4 g of a white, solid substance which upon recrystallization from ethanol yielded 29.1 g of a pure 2,4-dilauroxy-6-chloro-s-triazine having a melting point in the range of 43.5°-44.9° C.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH2:32]([O:34][CH2:35][CH2:36][NH2:37])[CH3:33]>CN(C=O)C.O>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:37][CH2:36][CH2:35][O:34][CH2:32][CH3:33])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: CCOCCN
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
A solution of ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (44 mg, 0.103 mmol) and 2-ethoxyethylamine (15 μL, 0.135 mmol) in DMF (0.9 mL) was heated at 100° C. for 1.5 h. The reaction mixture was diluted with water and the resulting precipitate was collected by filtration. The filter cake was washed water and MeOH and dried under vacuum to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, br m), 8.51 (1H, s), 7.74 (1H, s), 7.31 (2H, dd, J=8.4, 5.7 Hz), 7.12 (2H, t, J˜9 Hz), 5.12 (2H, s), 4.11 (2H, s), 3.51 (4H, s), 3.46 (2H, q, J=7 Hz), 3.12 (3H, s), 2.81 (3H, s), 1.10 (3H, t, J=7 Hz); HRMS calcd for C24H27FN4O5+H+: 471.2044. Found: 471.2050.
Reaction SMILES: OC[CH2:3][C@@:4]12[C@@H:15]3[CH2:16][C@@:11]([CH:23]=[O:24])([C@:12]1([C:20]([OH:22])=[O:21])[C:13]([CH:17]([CH3:19])[CH3:18])=[CH:14]3)[CH:10]1[CH:6]([CH:7]([CH3:26])[CH:8]([Cl:25])[CH2:9]1)[CH2:5]2.C([O-])(O)=[O:28].[Na+].Cl[CH2:33][O:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36]>CN(C=O)C>[Cl:25][CH:8]1[CH:7]([CH3:26])[CH:6]2[CH:5]([C@@:4]3([CH:3]=[O:28])[CH2:15][C@H:16]4[C@@:11]([CH2:23][OH:24])([CH2:10]2)[C@:12]3([C:20]([O:22][CH2:33][O:34][C:35](=[O:36])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:21])[C:13]([CH:17]([CH3:19])[CH3:18])=[CH:14]4)[CH2:9]1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)C1=C[C@H]2C[C@]3(C=O)C4CC(Cl)C(C)C4C[C@@]2(CCO)[C@@]13C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C1=C[C@H]2C[C@]3(C=O)C4CC(Cl)C(C)C4C[C@@]2(CO)[C@]13C(=O)OCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 41 (23.7 mg) in DMF (5 mL) was added NaHCO3 (109 mg, 1.30 mmol), followed by ClCH2OC(O)CMe3 (0.093 mL, 0.65 mmol). The mixture was stirred at room temperature overnight. After aqueous work-up (ether) and purification by a PTLC, about 26.2 mg of 42 was obtained.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=O)[CH3:20])[C:14]=2[OH:22])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:23]([C:25]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)=[S:26])[NH2:24].CN(C)C=O>Cl.O>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=[N:24][NH:23][C:25]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[S:26])[CH3:20])[C:14]=2[OH:22])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CCCCCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 80.2 %

Procedure:
1-[5-(4-n-Hexylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.117 mmol, 35.1 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.117 mmol, 24.7 mg) were stirred with dimethylformamide (2.3 mL) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (46.3 mg, yield 80%).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].Cl.[O:14]1[CH2:18][CH2:17][CH2:16][NH:15]1>C(Cl)Cl.CCOC(C)=O>[O:14]1[CH2:18][CH2:17][CH2:16][N:15]1[S:2]([NH:5][C:6](=[O:7])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C1CNOC1
Reactant: CC(C)(C)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a cold (0° C.) solution of chlorosulfonyl isocyanate (0.437 mL, 5.02 mmol) in CH2Cl2 (10 mL) was added tert-BuOH (0.480 mL, 5.02 mmol) and the mixture was stirred for 1 h at 0° C. Then HCl salt of isoxazolidine (0.5 g, 4.56 mmol) and TEA (1.399 mL, 10.04 mmol) were added consecutively and the mixture was stirred overnight. Rxn was diluted with EtOAc and washed with ice cold 1N HCl, brine and then dried (MgSO4). Isolated crude product was purified by Biotage 25M column to afford tert-butyl isoxazolidin-2-ylsulfonylcarbamate as a beige solid (0.82 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (9 H, s), 2.38 (2 H, quin, J=7.37 Hz), 3.81 (2 H, m), 4.19 (2 H, t, J=7.30 Hz). To a cold (0-5° C.) solution of tert-butyl isoxazolidin-2-ylsulfonylcarbamate (0.82 g, 3.25 mmol) in DCM (2 mL) was added TFA (2 mL, 35.1 mmol) and the reaction mixture was stirred for 2 h at r.t and removed the solvent to afford isoxazolidine-2-sulfonamide (0.229 g, 46%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.40 (2 H, quin, J=7.32 Hz), 3.65 (2 H, m), 4.20 (2 H, t, J=7.32 Hz), 4.83 (2 H, brs).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]O>C(O)(=O)C>[CH2:1]([S:8]([C:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:16])([CH3:17])[CH2:11][C:10]=1[OH:18])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC1(C)CC(=O)C(SCc2ccccc2)=C(O)C1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(S(=O)Cc2ccccc2)=C(O)C1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
A solution of 10.3 g. (0.0391 mole) of 2-benzylthio-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one and 4.43 g. (0.0391 mole) of 30 percent hydrogen peroxide in 50 ml. of glacial acetic acid was allowed to stand at room temperature for 22 hours and was then poured into ice water and the mixture extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, filtered and the solvent removed by evaporation in vacuo, leaving 9.2 g. of amber viscous oil. After some difficulty in inducing crystallization, seed crystals were obtained by an ether solution of a small portion of the oil in a Dry Ice methylene chloride bath. The seed crystals, thus obtained, were used to induce crystallization of the main portion of the oil from ether-hexane to give 7.8 g. of light-pink crystals, m.p. 82°-83°C. A second recrystallization from ether-hexane gave the pure substance as light pink crystals, m.p. 82.5°-83.5°C.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O-])=[O:11])=O)(C)(C)C.[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.[ClH:41].C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[ClH:41].[NH2:8][C:9]([CH3:14])([CH3:13])[C:10]([N:28]1[CH2:29][CH2:30][N:25]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:26][CH2:27]1)=[O:11]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionate (4.06 g) in N,N-dimethylformamide (40 mL) were added 1-(benzyloxycarbonyl)piperazine (6.6 g), 1-hydroxybenzotriazole (3.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.67 g) and triethylamine (11.2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added 4 mol/L hydrochloric acid (1,4-dioxane solution, 25 mL), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added diethyl ether (50 mL), and the insoluble material was collected by filtration. The collected solid was washed with diethyl ether and dried under reduced pressure to give the title compound (4.65 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].[NH:7]([C:9]1[CH:14]=[C:13]([S:15]([OH:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[S:19]([OH:22])(=[O:21])=[O:20])N.C([O-])(=O)C.[K+:27]>C(O)(=O)C>[CH3:4][C:3]1[C:2]([CH3:6])([CH3:1])[C:14]2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][CH:11]=[C:10]([S:19]([O-:22])(=[O:21])=[O:20])[C:9]=2[N:7]=1.[K+:27].[K+:27]
Reactant: NNc1cc(S(=O)(=O)O)ccc1S(=O)(=O)O
Reactant: CC(=O)C(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1=Nc2c(S(=O)(=O)[O-])ccc(S(=O)(=O)[O-])c2C1(C)C
Temperature: 25 °C

Procedure:
To a three-necked flask equipped with mechanical stirrer and a reflux condenser were added 50 ml of acetic acid, 15 ml (140 mmol) of 3-methyl-2-butanone, 16.2 g (60 mmol) of 2-hydrazino-1,4-benzenedisulfonic acid and 13 g (133 mmol) of potassium acetate. The mixture was heated to reflux for 8 h and then cooled to room temperature. The brownish precipitate was filtered off and washed with acetic acid and acetonitrile. Yield: 13.8 g (58%) of the raw product (1k). 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.67 (1H, arom., d, 8.1 Hz), 7.59 (1H, arom., d, 8.2 Hz), 2.44 (3H, CH3, s), 1.57 (6H, (CH3)2, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1.C(N(CC)CC)C.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38]>C(Cl)Cl>[CH2:37]([NH:39][C:40]([N:17]1[CH2:18][CH2:19][C:20]2[N:12]([C@@H:6]3[C:7]4[C:3](=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=4)[CH2:4][C@H:5]3[OH:29])[N:13]=[C:14]([C:21]3[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=3)[C:15]=2[CH2:16]1)=[O:41])[CH3:38]
Reactant: CCN=C=O
Reactant: N#Cc1cccc(-c2nn([C@@H]3c4cc(Cl)cc(Cl)c4C[C@H]3O)c3c2CNCC3)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(Cl)cc(Cl)c3C[C@H]2O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
According to Scheme 17: To a solution of 3-[1-((1R,2R)-4,6-dichloro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (13e) (0.03 g, 0.071 mmol) in dry CH2Cl2 at 0° C. triethylamine (57 mg, 0.564 mmol) and ethylisocyanate (5.5 mg, 0.077 mmol) was added. The mixture was stirred for 1 h at room temperature and purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 31 mg of 3-(3-cyano-phenyl)-1-((1R,2R)-4,6-dichloro-2-hydroxy-indan-1-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid ethylamide (22a)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:15][NH:16][CH2:17]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=C(c2cc(F)cc(F)c2)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=C1CNC1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 210 mg (0.623 mmol) of tert-butyl 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine-1-carboxylate in 1 mL of CH2Cl2, was added 1.5 mL of TFA followed by stirring for 1 h at rt. The reaction mixture was concentrated and washed with ether to afford the title compound as white solid; Mass Spectrum: m/e=238 (M+1).