Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(CC)C2C=CC=CC=2)C=CC=CC=1.[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.[C:25]([NH:29][C:30]([C:32]([N:48]([CH3:52])[C:49](=[O:51])[CH3:50])([CH2:44][CH2:45][CH:46]=[CH2:47])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([NH:29][C:30]([C:32]([N:48]([CH3:52])[C:49](=[O:51])[CH3:50])([CH2:44][CH2:45][CH2:46][CH2:47][B:19]1[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]1)[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(CCCNC(=O)OC(C)(C)C)(C(=O)NC(C)(C)C)N(C)C(C)=O
Agent: CCP(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)N(C)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCCNC(=O)OC(C)(C)C)C(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
While under an atmosphere of argon, a solution of bis(1,5-dicyclooctadiene)diiridium(I)dichloride (6 mg; 0.009 mmol) and diphenylphosphinoethane (7 mg, 0.018 mmol) in dichloromethane (1 mL) was cooled to 0° C. and treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.174 mL, 1.2 mmol). After stirring for 30 min, a solution of tert-butyl 4-(tert-butylcarbamoyl)-4-(N-methylacetamido)oct-7-enylcarbamate (120 mg, 0.3 mmol) in dichloromethane (4 mL) was added and the solution was stirred an additional 16 h. Dichloromethane (10 mL) was added, and the solution was washed successively with water and sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated. Purification by column chromatography (3% methanol in dichloromethane) gave tert-butyl 4-(tert-butylcarbamoyl)-4-(N-methylacetamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)octylcarbamate (142 mg, 90%). ESI MS found for C27H52BN3O6 m/z [548.7 (M+Na+), 526.7 (M+1), 570.8 (M+HCOO−), 524.6 (M−1)].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(O)(=O)C>O>[CH2:18]([O:17][C:15]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)ccc1NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A mixture of 4-amino-3-methylbenzoic acid (35.1 g, 232 mmol) in water (400 mL) was treated with 2.5N NaOH (200 mL, 500 mmol) and benzyl chloroformate (37.0 mL, 259 mmol). After 1 h, 150 mL water was added, the resulting mixture was treated with glacial acetic acid (15 mL) and the solids collected by filtration. The filter cake was rinsed with water and the resulting solid taken up in ethyl acetate/2-methyl tetrahydrofuran. The organic was washed with brine, dried over MgSO4, filtered and concentrated. The resulting solid was dried under vacuum to give 45.1 g of the title compound. LCMS m/z=307.9 MH+, Rt=2.508 min.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:44]>C(OCC)(=O)C>[ClH:44].[NH2:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:30])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1)Cc1cc(F)c(F)cc1F

Procedure:
(R)-[3-[1-(Morpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 3a (0.07 g, 0.11 mmol) was dissolved in a little ethyl acetate. A solution of 3.1N hydrochloric acid in 6 mL of ethyl acetate was then added to the solution. The reaction mixture was reacted at room temperature for 4 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-(morpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 3 (70 mg) as a light yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7](=[S:9])=[S:8]>C(Cl)Cl.[O-]Cl.[Na+]>[CH2:6]1[N:1]([C:7]([S:9][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[S:8])[CH2:2][CH2:3][O:4][CH2:5]1
Reactant: S=C=S
Reactant: C1COCCN1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: S=C(SN1CCOCC1)N1CCOCC1
Reaction time: 1 h

Procedure:
In this example, a methylene chloride solution of N-oxydiethylenethiocarbamyl-N'-oxydiethylenesulfenamide was prepared by reacting morpholine, dissolved in methylene chloride, sequentially with a NaOCl bleach solution and carbon disulfide in the manner described in U.S. Pat. No. 3,985,743. At the end of the reaction the methylene chloride organic phase was separated from the water phase. The methylene chloride solution was diluted with methylene chloride to a total solids content of 12 percent. 100 volumes of this organic solution containing the N-oxydiethylenethiocarbamyl-N'-oxydiethylenesulfenamide was stirred with 100 volumes of hydrochloric acid having a normality of 0.06 N, the HCl being used in amount of 5.8 milliequivalents of acid based on 15.7 grams of solids. The aqueous acid and organic solutions were stirred together for about 15 minutes to a pH of the mixture of 2.7. The acid phase was separated from the organic solution by transferring the mixture to a separating vessel settling the layers, and decanting. The organic solution was then washed twice with 100 volumes of distilled water and separated from the water. The methylene chloride was then flashed off and the dried N-oxydiethylenecarbamyl-N'-oxydiethylenesulfenamide collected. The melting point of the N-oxydiethylenecarbamyl-N'-oxydiethylenesulfenamide was found to be 134.8° C. A sample of N-oxydiethylenecarbamyl-N'-oxydiethylenesulfenamide was aged in an air over at 100° C. for 60 minutes to test for stability. The melting point after aging was determined and found to be 133.0° C., for a ΔT of 1.8, this sample being very stable. When a control run was made without the acid wash, using only water washes, the unaged melting point was found to be 134.4° C. and the aged melting point was found to be 128.4° , for a ΔT of 6.0, which represents a very unstable product with unsatisfactory storage stability and product activity.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O1CCC[CH2:14]1.CO.C[Si](C=[N+]=[N-])(C)C>C(O)(=O)C>[CH3:14][O:8][C:7]([CH:4]1[CH2:3][CH2:2][CH:1]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)=[O:9]
Reactant: C1CCOC1
Reactant: O=C(O)C1CCC(C(=O)O)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold, stirred solution of cyclohexane-1,4-dicarboxylic acid (3.0 g, 17 mmol) in a mixture of 2:1 tetrahydrofuran/methanol (24 mL) was added trimethylsilyl diazomethane (9 mL of a 2.0 M in hexanes, 18 mmol). The reaction mixture was stirred at room temperature for 2 h. Acetic acid (5 mL) was added and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 10:1:0.01 hexanes/ethyl acetate/acetic acid) provided 4-(methoxycarbonyl)cyclohexanecarboxylic acid (1.00 g): 1H NMR (300 MHz, CDCl3) δ 3.68 (s, 3H), 2.53–2.47 (m, 2H), 1.97–1.89 (m, 4H), 1.74–1.66 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:10]1[CH:42]=[CH:41][C:13]([CH2:14][N:15]([C:30]2[N:31]=[CH:32][C:33]3[C:38]([C:39]=2[CH3:40])=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:16]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[C:5]([F:8])([F:7])[F:6])[CH3:2].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH2:1]([O:3][C:4]([C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]([C:30]2[N:31]=[CH:32][C:33]3[C:38]([C:39]=2[CH3:40])=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:16]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)(=[O:17])=[O:18])=[CH:41][CH:42]=1)([CH3:9])[C:5]([F:6])([F:7])[F:8])[CH3:2]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(C(C)(OCC)C(F)(F)F)cc2)c2ncc3ccccc3c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(C)(c1ccc(CN(c2ncc3ccccc3c2C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a mixed solution of ethyl 4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (102 mg, 0.17 mmol) prepared in Example 13 in ethanol (1 mL) and tetrahydrofuran (1 mL) was added 2 mol/L aqueous sodium hydroxide solution (340 μL, 0.68 mmol) at room temperature. The reaction solution was stirred at room temperature overnight, and then to the reaction solution was added 2 mol/L hydrochloric acid solution (1 ml). The mixture was extracted with chloroform three times. The organic layer was combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→10:1) to give 4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic acid (82 mg, 85%) as a colorless powder.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:25]2.C(OC=C)=C.C([O-])(=O)C>C1COCC1.Cl.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.CCOC(C)=O.C1(C)C=CC=CC=1>[C:6]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:25]2)(=[O:8])[CH3:7]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=COC=C
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2cccc(C(C)=O)c2n1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
A mixture of Pd(PPh3)4 (608 mg, 0.53 mmol), tributyl(1-ethoxyvinyl)tin (3.91 mL, 11.57 mmol), methyl 8-bromoquinoline-2-carboxylate (2.80 g, 10.52 mmol), and toluene (50 mL) was heated under argon at 100° C. for 18 h. The mixture was then concentrated under reduced pressure and adsorbed onto silica gel. Column chromatography (silica gel, 10-100% EtOAc in hexanes) afforded a mixture of vinyl ether (M+1=258.0) and the desired acetate. This mixture was dissolved in THF (40 mL), the solution was cooled to 0° C., 10 drops of 1N HCl were added, and the solution was stirred at 0° C. for 5 min. EtOAc (100 mL) was added and the resulting solution was washed successively with 1N NaOH (20 mL), water (40 mL) and brine (40 mL). Significant product remained in the aq. layer and was extracted with 25% IPA in CHCl3. The combined organic layers were dried over MgSO4, filtered, and concentrated to give methyl 8-acetylquinoline-2-carboxylate (1.98 g, 8.64 mmol, 82% yield) as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (d, J=8.4 Hz, 1H), 8.27 (dd, J=8.2, 1.4 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.00 (dd, J=7.2, 1.4 Hz, 1H), 7.79-7.86 (m, 1H), 3.98 (s, 3H), 2.92 (s, 3H). m/z (ESI, +ve ion) 230.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18](=[O:48])[C:19]2[C:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][C:22]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:21][C:20]=2[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:55](Br)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([C:18]([C:19]2[C:20]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:21][C:22]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:23][C:24]=2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:48])=[C:11]([C:12]([O:14][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:13])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)O)c(OCc2ccccc2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 73 %

Procedure:
To a solution of 5.98 g (9.28 mmol) of 3-benzyloxy-2-(2,6-dibenzyloxy-4-(1,1-dimethylethoxycarbonyl)benzoyl)benzoic acid in 75 mL of dry dimethylformamide was added 3.85 g (27.9 mmol) of potassium carbonate and 1.21 mL (1.74 g, 10.2 mmol) of benzyl bromide. The solution was stirred at room temperature under a nitrogen atmosphere for 13 h. The mixture was then poured onto 800 mL of water and extracted with three 400 mL portions of ether. The organic extracts were washed twice with water and then with brine, and dried over magnesium sulfate. Evaporation of the solvent afforded 6.76 g of the crude product, which was chromatographed on silica gel, eluting with 4/1 hexane-ethyl acetate to give 4.98 g (73%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1ccccc1Cl)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccccc1Cl
Yield: 67.1 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.31 g, 0.85 mmol) prepared in example 4b was reacted with 1-(2-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 8.27 mmol) prepared in example 16a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow gum (Yield 0.31 g, 67%).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH3:13])[C:11]=1[NH2:12].O=C1CCC(=O)N1[O:21][C:22](=O)[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1.[Cl-].[Na+].O>[NH2:12][C:11]1[N:10]([CH3:13])[N:9]=[CH:8][C:7]=1[NH:6][C:22](=[O:21])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: Cn1ncc(N)c1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(NC(=O)CNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a suspension of 4,5-diamino-1-methylpyrazole sulfuric acid salt (305 g) in tetrahydrofuran (3.05 L) was added tert-butyl 2-[(2,5-dioxo-1-pyrrolidinyl)oxyl]-2-oxoethylcarbamate (415 g) under ice-cooling. To the mixture was added diisopropylethylamine (556 ml) dropwise at a temperature below 10° C. The mixture was stirred at room temperature overnight. To the resulting solution were added brine and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate (3.0 L). The aqueous layer was extracted with tetrahydrofuran/ethyl acetate=1/1 (3.0 L) twice. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diisopropyl ether (1.0 L) and dried in vacuo to give tert-butyl 2-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-2-oxoethylcarbamate (307 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:40])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])=[N:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][C:10]1([CH3:40])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])=[N:33][CH:34]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CN(C)C(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)cn1
Yield: 64.7 %

Procedure:
A solution of the compound (120 mg, 0.21 mmol) obtained in Example 8-1) and 4 M hydrochloric acid (1,4-dioxane solution, 0.26 mL) in methanol (2 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (63 mg, 65%) as a colorless solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C>CS(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=[O:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
1-BOC-3-hydroxymethylpiperidine (2.15 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) were dissolved in 10 mL DMSO, 15 mL DMSO solution of SO3Py (4.77 g, 30 mmol) was added to the above mixture in dropwise and the result mixture was stirred at rt for 2 hrs. The mixture was poured into 100 mL ice-water, extracted with EtOAc (100 mL×3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo. The crude product was purified by chromatography on silica gel (PE/EtOAc 5:1) to give 1.46 g product as colorless oil (68.5%). 1H NMR (300 MHz, CDCl3) δ: 9.70 (1 H, s), 3.91-3.93 (1 H, m), 3.62-3.67 (1 H, m), 3.29-3.36 (1 H, m), 3.05-3.13 (1 H, m), 2.40-2.45 (1 H, m), 1.95-1.97 (1 H, m), 1.63-1.72 (1 H, m), 1.49-1.59 (1 H, m), 1.46 (9 H, s).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1OC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1OC1CCCCC1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
Fifty ml of a methanol solution containing 3.7 g of 2-cyclohexyloxynitrobenzene and 0.2 g of 5% palladium on carbon was stirred at room temperature under a hydrogen atmosphere for catalytic reduction. The catalyst was removed by filtration, and the filtrate was evaporated off to give 2.9 g of 2-cyclohexyloxyaniline as pale brown crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1>CO.[OH-].[Na+]>[CH2:2]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: c1c[nH]cn1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1ccnc1

Procedure:
Bromobutane (27.4 ml; 0.255 mole) was added dropwise to a stirred solution of imidazole (13.6 g; 0.2 mole) in a mixture of methanol (30 ml) and sodium hydroxide solution (30 ml; 10M) maintained at 30° to 40° C. When the addition was complete the reaction mixture was stirred and refluxed for 12 hours. The solvent was evaporated, the residue extracted with chloroform (2×50 ml) and the extracts dried over magnesium sulphate and concentrated under reduced pressure. The resulting yellow oil was purified to give 1-n-butylimidazole as a colourless oil, b.p. 122°-123° C./20 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:18]([S-:20])#[N:19].[K+].BrBr.O>CN(C=O)C>[NH2:19][C:18]1[S:20][C:3]2[CH:4]=[C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Agent: BrBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2nc(-c3ccc4nc(N)sc4c3)sc2c1
Reaction time: 20 h
Yield: 39.9 %

Procedure:
2-(4-aminophenyl)-6-methyl-benzothiazole 1 (4.0 g, 16.6 mmol) and KSCN (2.6 g, 26.7 mmol) were dissolved in DMF (20 ml) and cooled in an ice-bath. Br2 (0.9 ml, 17 mmol) in DMF (15 ml) was added dropwise under 3 h. The mixture was stirred for another 20 h. Water was added and the precipitate formed was collected by filtration and dried. The crude product was triturated on the sinter with several portions of boiling dichloromethane to afford 2 as a light green-yellow solid (1.97 g, 40%). Mp 250-251° C.; 1H NMR (DMSO): δ 2.45 (3H, s, Ar—CH3), 7.34 (1H, d, J=8.4, ArH), 7.50 (1H, d, J=8.4, ArH), 7.89 (1H, d, J=8.4, ArH), 7.91 (1H, s, ArH), 7.99 (1H, d, J=8.4, ArH), 8.51 (1H, s, ArH), 8.56 (2H, s, NH2); 13C NMR (DMSO): δ 21.10, 116.7, 120.7, 121.8, 122.1, 125.6, 126.9, 128.1, 129.7, 133.3, 134.5, 135.0, 151.7, 165.9, 169.3; HR-FAB-MS m/z Found: 298.0521 C15H12N3S2 (M+H+): requires M, 298.0473.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:17]3([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH2:16][N:15]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][CH2:36][C:32]=4[N:33]=[CH:34][N:35]=3)[C:12]2=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:17]3([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]3)[CH2:16][N:15]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][CH2:36][C:32]=4[N:33]=[CH:34][N:35]=3)[C:12]2=[CH:13][CH:14]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(OCc5ccccc5)ccc43)c21
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(O)ccc43)c21
Yield: 61.1 %

Procedure:
To a stirred solution of (R)-tert-butyl 5-(benzyloxy)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.80 g, 1.5 mmol) in MeOH (20 mL) under N2 was added 10% Pd/C (0.20 g). The reaction vessel was evacuated under vacuum and hydrogenated under H2 (50 psi) for 48 hours. The hydrogen gas was evacuated and the catalyst was removed by filtration. The filtrate was concentrated. The residue was purified by flash chromatography (DCM:MeOH, 30:1) to give (R)-tert-butyl 5-hydroxy-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.40 g, 60%) as an oil. LCMS (APCI+) m/z 437 [M+H]+; Rt=3.42 min.