Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:17]3[C:22]([NH2:23])=[N:21][CH:20]=[C:19]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=4)[N:18]=3)=[N:15][N:16]=2)=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+].Cl>CO>[NH2:23][C:22]1[N:21]=[CH:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:31]([CH3:33])[CH3:32])=[O:34])=[CH:26][CH:25]=2)=[N:18][C:17]=1[C:14]1[O:13][C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=2)=[N:16][N:15]=1
Reactant: CC(=O)OCc1ccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CO)cc4)o3)n2)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
[4-[5-[3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl acetate (118 mg, 0.2445 mmol) was suspended in methanol (2 mL) and treated with NaOH (489.0 μL of 1 M, 0.4890 mmol). The resulting mixture was stirred at 55° C. for 1 h. The reaction mixture was cooled to room temperature and then neutralised with HCl (978.0 μL of 1 M, 0.9780 mmol), filtered and washed with acetonitrile. The resulting yellow powder was heated in acetonitrile (5 mL), cooled and filtered to give a pale yellow powder. This was purified by column chromatography on silica gel eluting with 5% MeOH/CH2Cl2 to give the product as a pale yellow powder (73 mg, 70%); 1H NMR (400 MHz, DMSO) d 2.98-3.02 (m, 6H), 4.64 (d, 2H), 5.44 (t, 1H), 7.54-7.62 (dd, 4H), 7.78 (br s, 2H), 8.12-8.18 (dd, 4H) and 8.98 (s, 1H) ppm; MS (ES+) 417.23
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:3]=1.[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9](=[CH:20][O:21][CH2:22][CH3:23])[C:10]([CH:12]2[CH2:13][CH2:14]2)=[O:11])=[C:4]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Cl)ccc1C(=O)CC(=O)C1CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(Cl)cc1S(C)(=O)=O)C(=O)C1CC1
Yield: 99.7 %

Procedure:
A mixture of 1-[4-chloro-2-(methylsulphonyl)phenyl]-3-cyclopropylpropan-1,3-dione (7.1 g) and triethyl orthoformate (6.9 g) in acetic anhydride was stirred and heated at reflux for 2 hours. The mixture was evaporated to dryness, toluene was added and the solution was re-evaporated to give 1-[4-chloro-2-(methylsulphonyl)phenyl]-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (8.4 g) as a red gum which was not purified further.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]>C(Cl)Cl>[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C

Procedure:
Morpholine (2.2 ml, 25 mmol) was slowly added to 3-Nitro-benzenesulfonyl chloride (5.5 g, 25 mmol) in CH2Cl2 at 0° C. The reaction was warmed up to rt in 0.5 h. After CH2Cl2 was removed in vacuo, saturated NaHCO3 solution was added and the solid was filtered and dried to give 4-(3-Nitro-benzenesulfonyl)-morpholine as an off white solid (5.9 g, 87%). MS (ESI) m/z=273 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1.[C:16](Cl)(Cl)=[S:17]>C(Cl)Cl>[Cl:7][C:8]1[C:13]([N:14]=[C:16]=[S:17])=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1
Reactant: Nc1ccc(Cl)nc1Cl
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: S=C=Nc1ccc(Cl)nc1Cl
Reaction time: 48 h

Procedure:
A slurry of sodium carbonate (15.2 g, 144 mmol), 2,6-dichloropyridin-3-amine (9.00 g, 55.2 mmol), and thiophosgene (5.50 mL, 71.8 mmol) in 100 mL anhydrous DCM was allowed to stir in a sealed vessel for 2 days. The reaction mixture was filtered through a glass frit, rinsing with DCM. The filtrate was concentrated in vacuo to give 2,6-dichloro-3-isothiocyanatopyridine as a peach-colored solid.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[C:22]([C:32]([NH2:34])=[O:33])[CH:23]=[C:24]([C:27]4[CH:31]=[CH:30][S:29][CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].[NH2:35][CH:36]1[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[OH:42][CH:39]1[CH2:40][CH2:41][CH:36]([NH:35][CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[C:22]([C:32]([NH2:34])=[O:33])[CH:23]=[C:24]([C:27]5[CH:31]=[CH:30][S:29][CH:28]=5)[CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH2:37][CH2:38]1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12
Reactant: NC1CCC(O)CC1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCNC4CCC(O)CC4)CC3)c[nH]c12
Yield: 7.5 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (0.09 mmol) and 4-aminocyclohexanol (33.4 mg, 0.45 mmol) were allowed to react in the presence of K2CO3 (44 mg, 0.45 mmol) and NaI (Cat. 5 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (3.6 mg, 7.7%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.[CH3:17][N:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]2[CH:33]=[CH:34][N:35]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:20]=2[C:19]1=[O:46]>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:22]2[C:21]3[CH:33]=[CH:34][N:35]([S:36]([C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[C:20]=3[C:19](=[O:46])[N:18]([CH3:17])[CH:23]=2)=[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: Nc1ccc(Br)c(OCC2CC2)c1[N+](=O)[O-]
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c([N+](=O)[O-])c4OCC4CC4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 4-bromo-3-(cyclopropylmethoxy)-2-nitroaniline and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C25H25N4O6S (M+H)+: m/z=509.1. found: 509.1.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH2:12][NH:13][C:14]([C:16]3[S:17][C:18]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:23][CH:22]=[C:21]([O:31][CH3:32])[C:19]=4[N:20]=3)=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.[NH4+:41]>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:41]=[C:14]([C:16]4[S:17][C:18]5[C:24]([N:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:23][CH:22]=[C:21]([O:31][CH3:32])[C:19]=5[N:20]=4)[NH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3ccc4c(c3)OCCO4)nc12
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc(-c4ccc5c(c4)OCCO5)c[nH]3)nc12
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture of 0.19 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid [2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-ethyl]-amide and 0.54 g ammonium triflouroacetate was melted at 175° C. for 45 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 6:4 gave 0.13 g (71%) 2-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazol-2-yl]-4-methoxy-7-morpholin-4-yl-benzothiazole as yellow solid; M.p.: 235–237° C.; MS (ISP): m/e=451 (M+H+).
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.[Pt]=O>[NH2:3][CH2:2][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)CC1
Yield: 93.9 %

Procedure:
A solution of methylamine hydrochloride (1.01 g, Wako Pure Chemical Industries) and 1-(tert-butoxycarbonyl)-4-oxopiperidine (1.99 g, Aldrich) in methanol (13 ml) was stirred in the presence of platinum oxide (69 mg, Wako Pure Chemical Industries) at room temperature for 3 hours under hydrogen atmosphere of ordinary pressure. The hydrogen was purged with a nitrogen gas, and the platinum catalyst was removed by filtration. Then, the reaction mixture was adjusted to pH of from 10 to 11 with 1 N aqueous sodium hydroxide. The reaction mixture was added with water (10 ml), and the product was extracted three times with ethyl acetate (15 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (2.01 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)([C:14]([O:16]CC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14](=[O:16])[NH:41][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: NC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of solution of 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (9.35 mmol; 3.53 g) in DMF (40 mL) was added cyclohexylamine (11.22 mmol; 1.28 mL), N, N-diisopropyl-N-ethylamine (23.38 mmol; 4.14 mL) and HBTU (11.22 mmol; 4.26 g), and the resulting mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, and the resulting solution was washed with a 1N hydrochloric acid solution (2×25 mL), and brine (25 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 70% EtOAc in heptane) to yield 4-cyclohexylcarbamoyl-4-(4-methoxycarbonyl-benzyl)-piperidine-1-carboxylic acid tert-butyl ester after evaporation. The material thus obtained was dissolved in dichloromethane (25 mL) and trifluoroacetic acid (25 mL) was added. The resulting mixture was stirred for 2 hours at room temperature and evaporated. The residue was dissolved in dichloromethane (300 mL) and washed with a saturated sodium bicarbonate solution (50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated to yield 4-(4-cyclohexylcarbamoyl-piperidin-4-ylmethyl)-benzoic acid methyl ester. MS (ESI) m/z 459.30 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)([CH3:4])[CH3:3].[H-].[Na+].I[CH3:17]>C1COCC1.CN(C=O)C>[CH3:17][O:13][C:7]1([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: CI
Reactant: C[Si](C)(C)C#CC1(O)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1(C#C[Si](C)(C)C)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution (0° C.) of 4-{(trimethylsilyl)ethynyl}tetrahydropyran-4-ol prepared as described in the above example (2.5 g, 12.6 mmol) in a THF-DMF mixture (55 mL, 10:1), sodium hydride (60% suspension in oil, 0.504 g, 12.6 mmol) was added portionwise. After addition, the mixture was stirred 15 minutes before iodomethane (0.788 mL, 12.6 mmol) was added. The temperature was slowly raised to room temperature and the reaction was stirred for another 2 hours. The reaction mixture was then quenched with water and the product was extracted with ethyl acetate (2×). The combined organic layers were diluted with hexanes and washed with water and brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/dichloromethane, 2:98) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 3.82-3.74 (m, 2H), 3.61-3.54 (m, 2H), 3.34 (s, 3H), 1.90-1.82 (m, 2H), 1.71-1.63 (m, 2H), 0.21 (s, 9H).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50])#[N:42]>O1CCCC1.O>[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49]([N:22]1[C:23]([C:24]2[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:19]([F:18])[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21]1)(=[O:51])=[O:50])#[N:42]
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccccc2C#N)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.13 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and 2-cyanobenzenesulfonyl chloride (151 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:4) to give the title compound as a pale-yellow oil (yield 238 mg, 98%).
Reaction SMILES: [OH-].[Na+].[Cl:3][O-].[Na+].[OH:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].Cl>>[Cl:3][C:13]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:6])=[N:15][CH:14]=1
Reactant: O=C(O)c1cccnc1O
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Cl)cnc1O
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To an agitated solution of 216.0 g of sodium hydroxide pellets in 2.25 liters of 5% (1.51 moles) of sodium hypochlorite solution was added 150.4 g of 2-hydroxynicotinic acid. Temperature of the reaction mixture was 19° C. Three hours later 750 ml (0.50 mole) of sodium hypochlorite was added and stirring was continued overnight. The reaction mixture was mixed with 12N hydrochloric acid in an agitated vessel in such a manner that the receiving solution was always strongly acid and temperature was kept below 20° C. with an ice bath. The amount of 12N acid used was 600 ml. The mixture was readily filtered on a sintered glass suction funnel. The crystalline filter cake was washed with 600 ml of water followed by 800 ml of 1:1 isopropyl ether/isopropyl alcohol. Weight of the dry crystals was 143.5 g (76.6% yield). Analysis by 1HNMR analysis showed the dried product contained no starting material and about 5% 3,5 -dichloro-2-hydroxypyridine. See Example 3 for method of computing impurity.
Reaction SMILES: [CH2:1]([C:5]([CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:8][O:9][CH3:10])[CH2:6][OH:7])[CH:2]([CH3:4])[CH3:3].[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>>[CH2:1]([C:5]([CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:6][O:7][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:8][O:9][CH3:10])[CH:2]([CH3:4])[CH3:3]
Reactant: COCC(CO)(CC(C)C)CC(C)C
Reactant: C[Si](C)(C)Cl
Product: COCC(CO[Si](C)(C)C)(CC(C)C)CC(C)C

Procedure:
According to the procedure as described in Example 1,2,2-di-iso-butyl-1-methoxy-3-[(trimethylsilyl)oxy]propane was prepared from intermediate 2,2-di-iso-butyl-3-methoxy-1-propanol and reagent trimethylsilyl chloride.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[C@H:15]1[C@@H:19]2[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]2[C@@H:17]([C:25](O)=[O:26])[O:16]1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[C@H:15]1[C@@H:19]2[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]2[C@@H:17]([C:25]([NH:10][CH2:15][CH:19]([OH:20])[CH3:18])=[O:26])[O:16]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(O)CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 20 °C
Reaction time: 18 h
Yield: 113.6 %

Procedure:
Thionyl chloride (4.3 ml) was added to a stirred solution of (3aS,4S,6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (10.0 g), in chloroform (100 ml). The mixture was heated at reflux temperature under nitrogen for 60 min. After cooling to 20° C. the solvent was removed in vacuo and the residue azeotroped with toluene (2×50 ml). A suspension of the residue in chloroform (50 ml) was added dropwise at an equal rate with a solution of 1-amino-2-propanol (2.3 ml) and diisopropylethylamine (5.1 ml) in chloroform (50 ml) over 10 min to chloroform (50 ml) at 0° C. The mixture was stirred at 20° C. for 18 hours. Phosphate buffer (pH 6.5, 100 ml) was added and the phases separated. The aqueous phase was extracted with chloroform (50 ml). The combined chloroform layers were dried with sodium sulphate and the solvent removed in vacuo to give the title compound as a white foam (6.63 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH3:10].N1C[CH2:47][O:46][CH2:45]C1.CNC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:41]([S:38]([N:35]1[CH2:36][CH2:37][CH:32]([C:23]2[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=[C:20]([C:14]4[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([CH2:11][N:9]5[CH2:10][CH2:47][O:46][CH2:45][CH2:8]5)[CH:13]=4)[CH:21]=3)[NH:25][CH:24]=2)[CH2:33][CH2:34]1)(=[O:40])=[O:39])[CH3:42]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CN(C)C)c4)cc23)CC1
Agent: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CN5CCOCC5)c4)cc23)CC1
Yield: 17 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (20 μL, 0.214 mmol) for the dimethylamine to afford 12 mg of the title compound (17%).
Reaction SMILES: [N:1]([C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][C:6]1[O:10][C:9](C(O)=O)=[CH:8][CH:7]=1)=[N+:2]=[N-:3].C([O-])(O)=O.[Na+].[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>CCOC(C)=O.CCCCCC>[N:1]([C:4](=[CH:5][C:6]1[O:10][C:9]([F:25])=[CH:8][CH:7]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:2]=[N-:3]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)C(=Cc1ccc(C(=O)O)o1)N=[N+]=[N-]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(=Cc1ccc(F)o1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To 5-(2-azido-3-ethoxy-3-oxoprop-1-enyl)furan-2-carboxylic acid (0.50 g, 2.03 mmol) was added a mixture of NaHCO3 (0.34 g, 4.06 mmol) and Selectfluor® (1.08 g, 3.05 mmol), followed by water (4.0 mL), hexane (5.0 mL) and EtOAc (2.0 mL). The mixture was stirred at rt for 5 min. The organic layer was separated, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (0 to 30% EtOAc in heptane over 20 min) yielded pure ethyl 2-azido-3-(5-fluorofuran-2-yl)prop-2-enoate as a reddish oil (0.20 g, 45%). 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.15 Hz, 3H) 4.32 (q, J=7.16 Hz, 2H) 5.74 (dd, J=6.83, 3.66 Hz, 1H) 6.63 (s, 1H) 7.05 (t, J=3.59 Hz, 1H). 19F NMR (376 MHz, CD3OD) δ ppm −115.12 (dd, J=6.60, 3.30 Hz).
Reaction SMILES: C(O[CH:5]([O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1)[C:6](Cl)([Cl:8])[Cl:7])(=O)C.S(=O)(=O)(O)O.[OH-].[Na+]>CO>[Cl:7][C:6]([Cl:8])=[CH:5][O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OC(Oc1cccc(C)c1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(OC=C(Cl)Cl)c1
Temperature: 15 °C

Procedure:
By an electrochemical reductive dehydrohalogenation method 1(3-tolyloxy)-2,2,2-trichloroethyl acetate (15.8 g), concentrated sulphuric acid (98% w/v, 9.8 g) and methanol (220 ml) was charged into an electrolytic cell, which was surrounded by a cooling bath set to maintain the temperature at about 15° C, and fitted with a cylindrical diaphragm, stirrer, reference electrode (SCE) and a working electrode. The cathode was a lead plate (surface area about 40 cm2). Using a current density in the range 5 to 10 mA/cm2 the reaction was conducted in the potential range -1100 to 1700 mV (SCE). When reduction was completed the cathodic electrolyte was neutralised with caustic soda and extracted with methylene chloride, the extracts dried over anhydrous sodium sulphate and evaporated to yield a residue of crude 3-tolyl 2,2-dichlorovinyl ether.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14][CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1>CO.[Pd]>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]2=[O:28])[CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CCN([C@H]1CC[C@H](O)CC1)C2=O
Agent: [Pd]
Solvent: CO
Product: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCNCC2
Reaction time: 3 h

Procedure:
200 mg of Pd/C was added a solution of benzyl 2-(trans-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (2.13 g, 0.00551 mol) in methanol (50 mL) under nitrogen. The reaction mixture was stirred under an atmosphere of hydrogen for 3 hrs. The mixture was filtered, and the filtrate was concentrated to give 2-(trans-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (1.29 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH:13]([OH:16])[CH2:14][OH:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[C:24](OC)([CH3:26])[CH3:25].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH:13]2[CH2:14][O:15][C:24]([CH3:26])([CH3:25])[O:16]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)nc1)N(CC(O)CO)C1CCCC1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN(C2CCCC2)S(=O)(=O)c2ccc(Cl)nc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of 0.83 g (2.48 mmol) of 6-chloro-N-cyclopentyl-N-(2,3-dihydroxypropyl)pyridine-3-sulfonamide, 0.67 mL (5.45 mmol) of 2,2-dimethoxypropane and 47 mg of pTsOH in 5 mL of DMF is stirred for 3 hours at room temperature. The medium is taken up in 100 mL of EtOAc, washed with 50 mL of saturated NaHCO3 solution and 50 mL of water, and then dried over Na2SO4, filtered and concentrated under reduced pressure. 0.92 g 6-chloro-N-cyclopentyl-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]pyridine-3-sulfonamide is obtained in the form of a brown oil, which is used without further purification in the following step.