Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>O1CCCC1.C(OCC)C>[Si:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.1 %

Procedure:
To a solution of sodium hydride (1.3 g, 55.48 mmol) in anhydrous tetrahydrofuran (150 mL) at 0° C. under argon, was added a solution of 1,4-butanediol (5 g, 55.48 mmol) in anhydrous tetrahydrofuran (50 mL). The resulting mixture was stirred at room temperature for 45 minutes over which time a large amount of a white precipitate formed. t-Butyldimethylsilyl chloride (8.3 g, 55.48 mmol) was then added and the resulting mixture was stirred vigorously for 45 minutes and then diluted with diethyl ether (200 mL) and filtered. The filtrate was washed with 10% aqueous potassium carbonate (25 mL) and brine (2×50 mL). Purification by silica gel chromatography using hexane/ethyl acetate as eluent (7:3) gave 1-t-butyldimethylsilyloxy-4-hydroxybutane as a colorless oil (9.2 g, 80%). 1-t-Butyldimethylsilyloxy-4-hydroxybutane (2.0 g, 9.85 mmol), triphenylphosphine (3.07 g, 11.74 mmol) and diethyl azodicarboxylate (1.8 mL, 11.74 mmol) were added successively to a solution of 1,8-naphthalimide (1.92 g, 9.785 mmol) in anhydrous tetrahydrofuran (50 mL) at 0° C. under an atmosphere of argon. The reaction was allowed to warm to room temperature and stirred overnight. After removing the solvent under reduced pressure, the product was purified by silica gel chromatography using hexane/ethyl acetate (9:1) as the eluent to provide 4-t-butyldimethylsilyloxybutyl-1,8 naphthalimide as a colorless oil (3.68 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]#[C:14][CH:15]([NH:17][OH:18])[CH3:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[O-:21][C:22]#[N:23]>>[OH:18][N:17]([CH:15]([C:14]#[C:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=2)[CH:8]=1)[CH3:16])[C:22]([NH2:23])=[O:21]
Reactant: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)NO
Reactant: N#C[O-]
Product: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)N(O)C(N)=O

Procedure:
reacting the product of step 3 with cyanate to produce N-hydroxy-N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]urea.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:17]=[C:16]([O:18][CH3:19])[C:12]([C:13]([O-])=[O:14])=[C:11]([CH:20]=[CH2:21])[N:10]=1.[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([CH3:32])=[C:29]([CH:31]=1)[NH2:30])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:17]=[C:16]([O:18][CH3:19])[C:12]2[C:13](=[O:14])[N:30]([C:29]3[CH:31]=[C:25]([CH:22]([CH3:23])[CH3:24])[CH:26]=[CH:27][C:28]=3[CH3:32])[CH2:21][CH2:20][C:11]=2[N:10]=1
Reactant: Cc1ccc(C(C)C)cc1N
Reactant: C=Cc1nc(-c2c(C)cccc2C)cc(OC)c1C(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(-c2c(C)cccc2C)nc2c1C(=O)N(c1cc(C(C)C)ccc1C)CC2
Reaction time: 12 h

Procedure:
A solution of 6-(2,6-dimethylphenyl)-4-methoxy-2-vinylnicotinate (1.77 g, 5.95 mmol) and 5-isopropyl-2-methylaniline (4.44 g, 29.8 mmol) in toluene (26.5 mL) and acetic acid (13.2 mL) was heated to 110° C. and stirred at that temperature. After 12 h, the reaction mixture was removed from the heat and concentrated on the rotovap to remove the bulk of the solvent. The residue was partitioned between EtOAc and aqueous 1 N sodium hydroxide solution with added brine. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (0-15% EtOAc/DCM) to provide 2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one. The product contained some 5-isopropyl-2-methylaniline and was used in the next step without further purification. MS (ESI+) m/z 415.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:38][C@@:39]1([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:44][C@@H:43]([S:45][C:46]2[NH:50][CH:49]=[N:48][N:47]=2)[C@@H:42]2[C@H:40]1[C@H:41]2[C:51]([O:53][CH2:54][CH3:55])=[O:52].C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:38][C@@:39]1([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:44][C@@H:43]([S:45][C:46]2[NH:50][CH:49]=[N:48][N:47]=2)[C@@H:42]2[C@H:40]1[C@H:41]2[C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@H]2Sc1nnc[nH]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)CNC(=O)OC(C)(C)C)(C(=O)OCC)C[C@H]2Sc1nnc[nH]1
Reaction time: 0.33 h

Procedure:
Add thionyl chloride (2.5 mL, 34.32 mmol) to a stirred solution of ditert-butyl (1R,2S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.1 g, 4.23 mmol) in ethanol (40 mL) at 0-5° C. dropwise over 5 minutes with caution (exothermic reaction). Remove the cooling bath and heat the reaction mixture at reflux temperature for 16 hours. Evaporate the volatiles and dry the residue under high vacuum for 7 hours to obtain a colorless foam of diethyl (1R,2S,4R,5R,6R)-2-amino-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate hydrochloride. Add then 2-(tert-butoxycarbonylamino)acetic acid (0.89 g, 5.07 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.93 g, 5.07 mmol) to a solution of diethyl (1R,2S,4R,5R,6R)-2-amino-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate hydrochloride in anhydrous N,N-dimethylformamide (20 mL) at room temperature then add diisopropylethylamine (2 mL, 11.47 mmol) and stir the resulting yellow solution under nitrogen for 18 hours. Concentrate the solvent and partition the residue between ethyl acetate (40 mL) and a saturated solution of sodium hydrogen carbonate in water (40 mL). Stir the mixture for 20 minutes, separate the layers and extract the aqueous layer with more ethyl acetate (40 mL). Combine the organics layers, dry on sodium sulfate and concentrate to dryness. Purify the residue by flash chromatography eluting with ethyl acetate: iso-hexane (80:20 to 100:0) to give the title compound as a colorless solid (2.42 g, 4.86 mmol). MS (m/z): 498 (M+1), 520 (M+23).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[H-].[Na+]>CN(C)C=O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc2cc(OCCCCn3ccnc3)ccc2c1-c1ccc(Br)cc1
Temperature: 0 °C
Yield: 86.7 %

Procedure:
A solution of 100 mg (0.220 mmol) 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene (example 27.5), 0.024 g (0.35 mmol) of imidazole and 0.0144 g (0.330 mmol) sodium hydride (55% suspension in oil) in 0.5 ml of N,N-dimethylformamide was stirred for 1 hour at room temperature. The reaction mixture was then poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 v/v mixture of dichloromethane and methanol as the eluent yielding 84.2 mg (86.7%) 1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-1H-imidazole as colorless oil, MS: 441 (MH+, 1Br).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[CH3:34][O:35][NH2:36].CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=1)([CH3:14])[CH2:6]/[C:5]/2=[N:36]\[O:35][CH3:34]
Reactant: CON
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CO/N=C1\CC(C)(COc2ccc(CC3SC(=O)NC3=O)cc2)Oc2c(C)c(C)c(O)c(C)c21
Reaction time: 240 h

Procedure:
A mixture of 1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996), 0.6 g of methoxyamine hydrochloride and 5 g of methanol was allowed to stand for 10 days at room temperature. At the end of this time, ethyl acetate and an aqueous solution of potassium carbonate were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to give the title compound softening at 72°-76° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=N[CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.BrC1C=CC=[C:27]([F:31])C=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:27]([F:31])[CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Fc1cccc(Br)c1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=343.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)[C:7]=1[CH3:26])=[O:5])[CH3:2].[BH4-].[Na+]>CO.Cl[Ni]Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)[C:7]=1[CH3:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc([N+](=O)[O-])c2)c1C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(N)c2)c1C

Procedure:
The compound of Example 22 (0.86 mmol, 0.3 g) was dissolved in methanol and treated with NiCl2 and NaBH4 (17.2 mmol) using the procedure set forth in Example 40. The named product was purified over silica (m.p. 142° C.-143° C.).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:4][NH:5][C:6]3[N:26]=[C:10]([NH:11][C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([CH:25]=4)[CH2:17][CH2:18][CH2:19][O:20][C:21]([CH:24]=2)=[CH:22][CH:23]=1)[N:9]=[CH:8][C:7]=3[Cl:27].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:7]1[CH:8]=[N:9][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH:25]=3)[CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:24]=[C:3]([CH2:4][NH:5][C:6]=1[N:26]=2)[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:23][CH:22]=3
Reactant: Clc1cnc2nc1NCc1cc(ccc1Br)OCCCc1cccc(c1)N2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1cnc2nc1NCc1cc(ccc1-c1ccccc1)OCCCc1cccc(c1)N2
Yield: 27 %

Procedure:
A mixture of 11-bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene (30.0 mg, 0.067 mmol) (prepared according to Example 14, Step E), phenylboronic acid (9.8 mg, 0.081 mmol), tetrakis(triphenylphosphine)palladium(0) (7.8 mg, 0.0067 mmol), 1,2-dimethoxyethane (0.50 mL), and a solution of sodium carbonate in water (0.17 mL, 2.0 M) was sealed into a microwave vial and the resultant suspension was de-gassed by bubbling with N2. After degassing, the vial was microwaved at 150° C. for 20 min. The reaction mixture was diluted with EtOAc, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography to provide the desired product (8 mg, 27%) as a white powder. LCMS for C26H23ClN4O (M+H)+: m/z=443.1. 1H NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.41 (dd, J=6.0, 1.2 Hz, 2H), 7.32 (m, 2H), 7.14 (m, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 6.87 (m, 2H), 6.75 (m, 1H), 5.70 (t, 2H), 4.62 (m, 2H), 4.16 (m, 1H), 4.04 (m, 1H), 2.68 (m, 2H), 1.84 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][NH:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20].Cl>O>[CH3:15][NH:16]/[C:17](/[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)=[CH:18]\[N+:19]([O-:21])=[O:20]
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: Cl
Solvent: O
Product: CN/C(=C\[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 90.3 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (50 g) and N-methyl-1-(methylthio)-2-nitroetheneamine (40 g) in water (235 ml) was stirred and heated at 45°-50° C. The solution was stirred further for 3-4 hrs. It was acidified with hydrochloric acid and extracted with chloroform. The solution was basified with potassium carbonate and ranitidine base was separated. The water, if any, was removed by azeotropic distillation under reduced pressure at 40°-45° C. using isopropanol. The resultant solution was cooled to 10° C. and n-hexane (500 ml) was added. Ranitidine base was filtered off and dried under vacuum to give the crude product (66.2 g), m.p. 68°-70° C.; purity=99.4% (HPLC); IR(KBr): 3280, 3200, 2820, 2774, 1620, 1580, 1440, 1370, 1258, 1130, 1020, 990, 820, 790, 760, 680 and 600 cm-1 ; δH (CDCl3):2.23 [6H,s, --N(CH3)2 ], 2.75(2H, t, --SCH2CH2), 2.85(3H,br d, CH3NH--), 3.3 (2H,2t, --CH2NH--), 3.4(2H,s, >NCH2), 3.7 (2H,s, CH2 bridge linking), 6.0-6.2 (2H,AB,furan) and 6.5 (,1H,s,=CHNO2).
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[CH2:18]([O:17][C:15]([CH:14]1[CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[O:12]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)CCl
Reactant: O=Cc1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1OC1c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. solution of 1-naphthaldehyde (13.0 mL, 96.1 mmol) and ethyl chloroacetate (10.3 mL, 96.1 mmol) in tetrahydrofuran (900 mL) was added (1.0 M in tetrahydrofuran) sodium bis(trimethylsilyl)amide (96.1 ml, 96.1 mmol) dropwise. The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to 0° C. The reaction was then quenched with water (200 mL). The reaction mixture was then diluted with ethyl acetate (800 mL). The organic reaction layer was then washed in succession with water and saturated sodium chloride, the organic layer was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a pale oil. The crude residue was chromatographed (silica gel with 5% ethyl acetate-95% hexane) to give 3-naphthalen-1-yl-oxirane-2-carboxylic acid ethyl ester as a clear oil. 1H NMR(300 MHz, DMSO) 8.12 (d, 1H), 7.95 (m, 2H), 7.51 (m, 4H), 4.77 (d, 1H), 4.24 (q, 2H), 3.72 (d, 1H), 1.27 (t, 3H). MS(APCI) m/z 241.1 (M−H). Anal. Calcd. for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.47; H, 5.87.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([NH2:10])=[N:6][O:7][C:8]=1[CH3:9].[S:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([S:20](Cl)(=[O:22])=[O:21])=[CH:12]1>C1COCC1>[Cl:3][C:4]1[C:5]([NH:10][S:20]([C:13]2[C:14]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:11][CH:12]=2)(=[O:22])=[O:21])=[N:6][O:7][C:8]=1[CH3:9]
Reactant: Cc1onc(N)c1Cl
Reactant: O=S(=O)(Cl)c1csc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(NS(=O)(=O)c2csc3ncccc23)c1Cl
Yield: 45.5 %

Procedure:
The title compound was prepared by the method of Example 1(C) using NaH (0.12 g, 4.9 mmoles), THF (6 ml), 4-chloro-5-methyl-3-aminoisoxazole (0.26 g, 2.0 mmoles) and thieno[2,3-b]pyridine-3-sulfonyl chloride (0.50 g, 2.1 mmoles), giving 0.30 g (47%) of the title compound as an orange-brown oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[CH:6][C:4]=1[NH2:5].[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=1[N:35]=[C:36]=[S:37]>C1COCC1>[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=1[NH:35][C:36]([NH:5][C:4]1[CH:6]=[C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([F:19])([F:17])[F:18])[CH2:14][CH2:15]2)[CH:8]=[CH:9][C:3]=1[NH:2][CH3:1])=[S:37]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CNc1ccc(N2CCC(C(F)(F)F)CC2)cc1N
Solvent: C1CCOC1
Product: CNc1ccc(N2CCC(C(F)(F)F)CC2)cc1NC(=S)Nc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-methylamino-5-(4-trifluoromethyl-piperidin-1-yl)aniline (90 mg, 0.3 mmol) and N-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (93 mg, 0.3 mmol) in THF (10 mL) was stirred at rt for 4 h. The reaction mixture was concentrated and directly used in the next step. Yield: 180 mg (98%). HPLC-method A: Rt=2.23 min. MS m/z: 556 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6]CN(C)C)(=O)[CH:2]=[CH2:3]>CC(C)=O>[CH3:6][O:5][C:1]1[CH:2]=[CH:3][C:1]([OH:5])=[CH:2][CH:3]=1
Reactant: C=CC(=O)OCCN(C)C
Solvent: CC(C)=O
Product: COc1ccc(O)cc1
Yield: 0.5 %

Procedure:
Into a 1 liter autoclave were charged 200 g (1.40 mol) of N,N-dimethylaminoethyl acrylate obtained by a conventional rectification under reduced pressure in an nitrogen atmosphere, 44.4 g of acetone and 0.4 g of hydroquinone monomethyl ether (polymerization inhibitor). After its internal temperature had been lowered to 20° C. or below, 22.2 g of distilled water was added thereto. The ratio of the charged materials was as follows: Dimethylaminoethyl acrylate : water : acetone =100 : 11.1 : 22.2. After adding water, the air in the reaction system was replaced with nitrogen gas until the concentration of dissolved oxygen had been lowered to 1.5 ppm, and then the reaction was allowed to start by introducing methyl chloride from a bomb at a pressure of 1.8 kg/cm2. The reaction was allowed to proceed for 22 hours, during which the reaction temperature was so controlled that it would not exceed 40° C. After the reaction, the remaining pressure was released. The mixture contained 0.03% of free amines and 4 ppm of dissolved oxygen. After 45.4 g of water had been added thereto, the acetone contained in the resulting solution was removed off at reduced pressure at a temperature of 20° to 30° C. There was obtained 330 g of aqueous solution of unsaturated quaternary ammonium salt which contained 0.8 ppm of dissolved oxygen. The concentration of the quaternary ammonium salt contained in the product, the concentration of acrylic acid contained therein and its hue (APHA) (according to JIS-K-4104) were 81.8%, 0.07% and 10, respectively.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.FC(F)(F)S(O[C:32]1[CH:33]=[N:34][CH:35]=[C:36]([CH3:38])[CH:37]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:38][C:36]1[CH:37]=[C:32]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:33]=[N:34][CH:35]=1
Reactant: Cc1cncc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(-c2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (250 mg, 0.68 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (70 mg, 0.11 mmol/g, 0.0068 mmol) was added along with 5-methyl-3-pyridinyl trifluoromethanesulfonate (241 mg, 1.026 mmol) and 680 μl of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 95 mg of title compound were recovered as whitish solid (42%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(5-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[CH:24]=[O:25])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[CH:24]=[O:25]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Yield: 96.7 %

Procedure:
A solution of (R/S) 5-(tert-butyldimethylsilyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (150 mg, 0.42 mmol, 1.00 equiv) and TBAF (800 mg, 800.00 mmol, 1922.79 equiv) in THF (5 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with 10 mL of H2O and then extracted with 3×20 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 10-20% of ethyl acetate in petroleum ether to give 0.1 g (98%) of (R/S) 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as an off-white solid. LCMS (method A, ESI): RT=1.33 min, m/z=246.0 [M+H]+.