Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)(=[O:4])=[O:3].N.C1COCC1>CO.[Ni]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][NH2:18])=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1-c1ccc(CN)cc1

Procedure:
A solution of 1.0 g (3.9 mmol) of 2′-methanesulfonylbiphenyl-4-carbonitrile in a mixture of 10 ml of methanol saturated with ammonia and 3 ml of THF is treated with 400 mg of Raney nickel and hydrogenated at room temperature and normal pressure. The catalyst is filtered off and the filtrate is evaporated. A colourless solid is obtained; FAB 262
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH2:14])=[CH:11]2)=[N:6]1.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)=[O:31])=[CH:11]2)=[N:6]1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CCn1cc2cc(N)ccc2n1
Solvent: C1CCOC1
Product: CN(C)CCn1cc2cc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)ccc2n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(2-dimethylamino-ethyl)-2H-indazol-5-ylamine (42.0 mg, 0.206 mmol), 4-phenoxyphenyl isocyanate (43.4 mg, 0.206 mmol) and 2 mL of THF, was stirred at 50° C. for 6 hours. The solvents were removed under vacuo, the residue was dissolved in 1.5 mL of a 1:1 mixture of dimethylsulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 2.56 (s, 8H), 4.66 (m, 2H), 6.95–7.38 (m, 10H), 7.56 (m, 1H), 7.93 (m, 1H), 8.3 (s, 1H), 8.75 (m, 2H); MS (DCI/NH3) m/z 416 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:33])=[C:17]([C@:19]23[CH2:27][O:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[C@H:24]2[CH2:23][S:22][C:21]([NH2:32])=[N:20]3)[CH:18]=1.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:32][C:21]1[S:22][CH2:23][C@@H:24]2[C@@H:25]([C:28]([F:31])([F:29])[F:30])[O:26][CH2:27][C@:19]2([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:2][F:1])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:33])[N:20]=1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=C(O)c1cnc(CF)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(CF)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 42.5 °C
Yield: 70.8 %

Procedure:
5-(Fluoromethyl)pyrazine-2-carboxylic acid (32.6 g, 1.05 equiv) and (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (70.0 g, 1.0 equiv)1 were charged to a reactor and ethyl acetate (EtOAc, 630 mL) was added to the mixture to give a suspension. A solution of n-propane phosphonic acid anhydride (T3P, 146 g, 1.10 equiv, 50 wt % in EtOAc) was added at ambient temperature while controlling the internal temperature below 30° C. The reaction mixture was stirred at 40−45° C. >3 hours and monitored by HPLC. The reaction mixture was cooled to 15−20° C. and water (140 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (175 mL) while controlling the temperature below 30° C. EtOAc (245 mL0 was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (490 mL). The organic phases were combined and washed with 15% aq. NaCl (140 mL) and water (140 mL). The organic layer was filtered over Celite (1.0 Wt) and rinsed with EtOAc (140 mL). The solution was concentrated under vacuum to obtain a beige solid (quantitative crude yield) which was recrystallized from 1-propanol to afford N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide as a white solid (70.0 g). 1 A preparation of (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine is described herein above in step 1-(25) in the alternative preparation of N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide (Example 1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccc(Cl)cc2)n1
Yield: 54 %

Procedure:
In substantially the same manner as in Reference Example 31, 4-chlorobenzamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(4-chlorophenyl)oxazole. The yield was 54%. Recrystallization from isopropyl ether gave colorless needles, mp 97-98° C.
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:4]1)=O.Cl.Cl.[CH2:34]([N:37]([CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[CH:35]=[CH2:36].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[CH2:34]([N:37]([CH:44]1[CH2:49][CH2:48][N:47]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[CH2:6][N:5]([C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH2:21][C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:4]2)[CH2:46][CH2:45]1)[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[CH:35]=[CH2:36]
Reactant: O=C[C@@H]1CN([C@@H]2CCCCC2CC(=O)OCc2ccccc2)C[C@@H]1c1cccc(F)c1
Reactant: C=CCN(c1ncccn1)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccccc3)C[C@@H]2c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
The title compound was prepared from 2-(R)-(3-(S)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-cyclohexaneacetic acid, benzyl ester 83 mg, 0.195 mmol; prepared above as Aldehyde 6), 4-(N-allyl-N-(pyrimid-2-yl)-amino)piperidine dihydrochloride (64 mg, 0.219mmol, from Step A), 104 mg (0.49 mmol) NaHB(OAc)3, and 0.035 ml (0.25 mmol) triethylamine in 3 ml dichloromethane. The mixture was stirred overnight at room temperature. The reaction was diluted with 100 ml EtOAc and washed with 1M NaOH and saturated NaCl. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The material was purified using flash chromatography (5% EtOAc in hexane) to provide 83 mg of the title compound. RF: 0.3 (5% EtOAc/hexane). HPLC (Zorbax SB-C8 column, 4.6 mm×7.5 cm, Gradient: 90 H2O:10 CH3CN to 0 H2O:100 CH3CN over 7.5 minutes then hold at 100 CH3CN:0 H2O for 45 seconds, 2.25 mL/min, 220 nm): Retention Time: 4.6 minutes.
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[CH:12]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])([CH3:14])[CH3:13].C(N(CC)CC)C>>[CH:12]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][S:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)(=[O:10])=[O:2])([CH3:14])[CH3:13]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: CC(C)NCCCN
Solvent: CCN(CC)CC
Product: CC(C)NCCCNS(=O)(=O)c1ccc(N)cc1

Procedure:
Sulphanilyl fluoride (6.5 g, 37.1 mmol), N-isopropyl-1,3-propanediamine (5.71 ml, 40.8 mmol) and triethylamine (5.69 ml, 40.8 mmol) in N-butanol (15 ml) was heated at reflux for 10 hours. The mixture was allowed to cool, silica was added and the volatiles were evaporated. The residue was purified by chromatography eluting with DCM/methanolic ammonia (100:0) increasing in polarity to (90:10) to give the title compound as a clear oil which crystallized on standing (8.81 g, 88%). NMR: 0.89 (d, 6H), 1.43 (m, 2H), 2.41 (t, 2H), 2.58 (m, 1H), 2.68 (t, 2H), 3.16 (s, 2H), 5.85 (s, 2H), 6.58 (d, 2H), 7.38 (d, 2H); m/z: 272.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].S(Cl)(Cl)=O.[CH3:14]O>>[NH2:1][C@@H:2]([C:3]([SH:6])([CH3:5])[CH3:4])[C:7]([O:9][CH3:14])=[O:8]
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)C(C)(C)S
Yield: 100 %

Procedure:
To a methanol (18 mL, 1.14 M) solution containing L-penicillamine (3.0 g, 20.11 mmol, 1.0 eq) was added thionyl chloride (1.5 mL, 20.7 mmol, 1.03 eq). The resulting mixture was heated to reflux for 18 hr and the solvent removed in vacuo. The resulting clear semi-solid was used in the next step without further purification. Isolated 3.28 g (20.1 mmol, 100% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][O:13]CC[Si](C)(C)C)=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:7]=1)=[O:5])[CH3:2].F>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH:12]=[O:13])=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C=COCC[Si](C)(C)C
Agent: F
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CC=O

Procedure:
A solution of 5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-[2-(2-trimethylsilanyl-ethoxy)-vinyl]-1H-pyrazole-3-carboxylic acid ethyl ester I-3a (210 mg) in 95:5 acetonitrile:conc. hydrofluoric acid (3 ml) was stirred for 2 hours. The reaction was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (I-3b), which was taken directly on to the next reaction.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>CN(C)C=O.C(OCC)(=O)C>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(CCCCCBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(CCCCCC(=O)OCc1ccccc1)CN2c1ccccc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.4 g, 1.2 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in N,N-dimethylformamide (5 mL), was added benzyl 6-bromohexanoate (0.34 g, 1.2 mmol). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain the title compound (0.08 g, 12%); MS for C31H41N3O5 m/z 536.16 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:14][C:5]2[CH:6]=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[O:3]1.S(=O)(=O)(O)O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([N:14]1[C:5]2[CH:6]=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[O:3][C:2]1=[O:1])(=[O:22])[CH3:21]
Reactant: O=c1[nH]c2ccc3cccnc3c2o1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)n1c(=O)oc2c3ncccc3ccc21
Yield: 80 %

Procedure:
A suspension of 2-oxo-3H-oxazolo[4,5-h]quinoline (1.86 g, 10.0 mmol), acetic anhydride (50 ml) and sulfuric acid (0.5 ml) was refluxed overnight. The reaction was filtered and the filtrate concentrated. Methylene chloride was added and the resulting solution was washed (3×) with water, brine; dried over MgSO4 and concentrated to a solid. The solid was crystallized from ethanol to give 1.82 g (80% yield) of product. M.P. 192°-193° C.
Reaction SMILES: [CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[CH2:10]([O:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[CH2:10]([O:17][NH:18][CH2:9][CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([OH:8])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(CC(C)C)C(=O)O
Reactant: NOCc1ccccc1
Solvent: CO
Product: CC(C)CC(CNOCc1ccccc1)C(=O)O
Yield: 34.4 %

Procedure:
2.85 g of isobutylacrylic acid and 10.9 g of O-benzylhydroxylamine were heated under reflux in 30 ml of methanol for 8 days. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate and water. The organic layer was washed with 2N hydrochloric acid and water and then extracted six times with 30 ml of 5% sodium hydrogen carbonate solution each time. The aqueous solutions were combined, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give an oil which soon crystallized. Trituration with petroleum yielded 1.92 g (35%) of N-benzyloxy 2(RS)-isobutyl-3-aminopropionic acid of melting point 73°-75° C. Rf (toluene/acetic acid 4:1) 0.52.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=2[O:25]C)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[OH:25])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc(-c2ccc(O)cc2O)c2cccc(C(F)(F)F)c21
Temperature: 25 °C
Yield: 109.7 %

Procedure:
1-Allyl-3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.065 g, 0.18 mmol) was treated with boron tribromide (0.136 mL, 1.4 mmol) and 1.0 mL of cyclohexene at −78° C. and then slowly allowed to warm to ambient temperature. The reaction was quenched by dropwise addition of methanol to the cooled reaction. The solvent was removed and the residue portioned with EtOAc and 1N HCl. The organic phase was washed with brine and dried with Na2SO4). Removal of the solvent in vacuo afforded the crude product. Pure product was obtained by crystallization to give the product (0.066 g) as a white solid, mp 114-115° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](SC)=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[C:11]#[N:12])=[CH:4][CH:3]=1.[CH3:19][CH:20]([NH2:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:25][CH:20]([CH3:19])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(Nc1ccc(Cl)cc1)=C(C#N)S(C)(=O)=O
Product: CC(NC(Nc1ccc(Cl)cc1)=C(C#N)S(C)(=O)=O)C(C)(C)C
Yield: 85 %

Procedure:
3-(4-Chlorophenylamino)-2-methylsulfonyl-3-methylsulfanyl-propenenitrile (0.242 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in EXAMPLE 17, 2) without chromatography gave 0.240 g (85%) of the title compound. Mp 160.5-161.5° C. 1H NMR (200 MHz, CDCl3): δ=0.87 (s, 9H), 0.97 (d, 3H), 3.1 (m, 4H), 7.07 (d, 1H), 7.49 (d, 2H); Analysis: calc. for C16H22ClN3O2S: C, 54.00%; H, 6.23%; N, 11.81%; Found: C, 54.26%; H, 6.33%; N, 11.76%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21]I.[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c([N+](=O)[O-])n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester (11) (800 mg, 2.52 mmol) in dry DMF (15 mL), NaH (60% dispersion in mineral oil, 191 mg, 4.53 mmol) was added at 0° C. The resulting mixture was stirred for 30 minutes at 0° C. and methyl iodide (0.23 mL, 3.68 mmol) was then added. After stirring the reaction mixture for 30 minutes at 10° C., saturated aqueous NH4Cl (15 mL) was added. The reaction mixture was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with water, brine, dried over MgSO4 (anhydrous) and concentrated under reduced pressure. The crude product was purified by Biotage using 10% ethyl acetate in hexane to afford (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester 12 (789 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[C:28]([O:32][C:33](=[O:41])[NH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29].C([BH3-])#N.[Na+]>ClCCl>[C:28]([O:32][C:33](=[O:41])[NH:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:23][C:21]2[CH:20]=[CH:19][C:18]([N+:25]([O-:27])=[O:26])=[C:17]([NH:16][C:10]3[S:11][C:12]([C:13](=[O:14])[NH2:15])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[CH:22]=2)[CH2:37][CH2:36]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a mixture of 0.6 g (1.5 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b) and 0.328 g (1.6 mmole) of piperidin-4-yl-carbamic acid tert-butyl ester in 15 mL of dichloromethane was added 0.477 g (2.3 mmole) of sodium cyanoborohydride. The mixture was stirred for 3 hours, then quenched by the addition of 25 ml, of water. The mixture was extracted three times with 50 mL of ethyl acetate. The combined ethyl acetate layers were washed once with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient 100:0-80:20) to give 0.7 g of (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-ylamino]-4-nitro-benzyl}-piperidin-4-yl)-carbamic acid tert-butyl ester (VI.12a).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[C:5]2=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[F:17][C:13]1[CH:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cccc(-c2n[nH]c3nc(Cl)ncc23)c1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc3c(-c4cccc(F)c4)n[nH]c3n2)CC1
Yield: 6 %

Procedure:
The compound was prepared from 6-chloro-3-(3-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 9) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid in an analogous manner as described in Example 4 and was purified by HPLC (Gilson) to give a free base (6% yield). MS (M+H)+, 391.25.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@@H:10]([O:11]P(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@@H:6]1[OH:39])=[O:3].C1C(=O)NC(=O)N(C2OC(COP(OP(OC3OC(C(O)=O)C(O)C(O)C3O)(O)=O)(O)=O)C(O)C2O)C=1.C(O)C(N)(CO)CO.Cl.[Na+].[Cl-].CC(N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O)=O>O.C(O)C.C(O)CO>[OH:11][CH:10]1[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@H:6]([OH:39])[C@H:5]1[NH:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: CC(=O)N[C@@H]1[C@@H](O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H](OS(=O)(=O)O)O[C@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: O
Solvent: OCCO
Solvent: CCO
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
The enzyme of the present invention (2 μg), hexasaccharide of shark cartilage chondroitin sulfate C, purified by degrading with testicular hyaluronidase, as the acceptor (70 pmol) and UDP-GalNAc (3 nmol), UDP-GlcUA (3 nmol) and UDP-[3H]GalNAc (0.1 nmol, 0.1 μCi) as the donors were added to 50 mM Tris-HCl (pH 7.2) containing 20 mM MnCl2, 0.1 M (NH4)2 SO4 and 1 M ethylene glycol, and the total volume was adjusted to 50 μl, and then the reaction was carried out at 30° C. for 30 minutes and the enzyme was heat-inactivated. To the reaction solution, 3 volumes of 95% ethanol containing 1.3% potassium acetate was added, and the sample was centrifuged at 10,000×g for 20 minutes. The precipitate was dissolved in 50 μl of distilled water and applied to a Superdex Peptide column (300×φ10 mm: Amersham Biosciences, chromatography conditions; buffer: 0.2 M NaCl, flow rate: 0.5 ml/rain), and the eluate was fractionated at 0.5 ml and the radioactivity (count of [3H]) of each fraction was measured using a scintillation counter. Chondroitin synthesizing activity was determined by calculating the amount of radioactivity incorporated into fractions of higher molecular weight than the acceptor substrate. The results are shown in FIG. 3. In FIG. 3, the closed squares indicate radioactivity when hexasaccharide of chondroitin sulfate C was used as the acceptor, open triangles indicate radioactivity when the enzyme reaction product was treated with chondroitinase ABC and closed circles indicates control (wherein heat-inactivated enzyme of the present invention was used).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[CH:5]=[C:4]([OH:11])[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[CH:5]=[C:4]([O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:3]=1
Reactant: C1=COCCC1
Reactant: O=Cc1c(O)cc(O)cc1Cl
Solvent: ClCCl
Product: O=Cc1c(O)cc(OC2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
To a solution of 6-chloro-2,4-dihydroxybenzaldehyde (9.0 g, 52.2 mmol) in DCM (150 mL) was added 3,4-dihydro-2H-pyran (9 mL, 98.4 mmol), followed by PPTs (1.31 g, 5.2 mmol). The reaction mixture was stirred at room temperature for 1.5 h and quenched by saturated aqueous NaHCO3 (50 mL) at 0° C. The organic layer was separated, washed with brine (40 mL) and dried over anhydrous Na2SO4. Concentration in vacuo followed by purification with column chromatography on silica gel (EtOAc/PE=1:100) gave the title compound as a colorless oil (10.5 g, Yield: 87.3%). 1H NMR (400 MHz, DMSO-d6) δ12.00 (s, 1H), 10.17 (s, 1H), 6.72-6.78 (m, 1H), 6.57-6.64 (m, 1H), 5.50-5.70 (t, 1H), 3.60-3.73 (m, 2H), 1.55-1.87 (m, 6H) MS (ESI) m/z=257 [M+H]+.