Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl.C(Cl)Cl.O>C(Cl)Cl>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 20 °C
Reaction time: 6 h
Yield: 19.6 %

Procedure:
A mixture of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (300 mg, 0.717 mmol, 1.0 eq), BCl3/CH2Cl2 (7.17 ml, 7.17 mmol, 10 eq. 1 M) in CH2Cl2 (20 ml) was stirred at 20° C. under a nitrogen atmosphere for 6 h. Water (50 ml) was added into the mixture. The mixture was extracted by EA (3×50 ml). The combined organic phases were washed (sat NaHCO3), brine, dried (Na2SO4), filtered and concentrated. The residue was purified by recrystallization (solvent: EA/PE and DIPE) to afford title compound 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 50) (50.9 mg, 19.6%) as a yellow solid. LC-MS (m/z)=363.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.72-0.74 (m, 2H), 0.94-0.99 (m, 2H), 1.89-1.94 (m, 1H), 6.41 (s, 1H), 6.84 (s, 1H), 7.58 (d, J=4 Hz, 1H), 7.49-7.81 (m, 3H), 8.29 (d, J=5.2 Hz, 1H), 10.08 (s, 1H), 12.14 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:11]([NH2:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=O)=[CH:21][CH:20]=1)[CH3:17]>ClCCl>[CH:1]1([CH2:4][N:5]2[C:6]3=[N:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=[C:11]3[N:12]=[C:26]2[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=2)[CH2:2][CH2:3]1
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Reactant: Nc1cc([N+](=O)[O-])cnc1NCC1CC1
Solvent: ClCCl
Product: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])cnc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 76 %

Procedure:
To a solution of N2-(cyclopropylmethyl)-5-nitro-2,3-pyridinediamine (792 mg, 3.80 mmol) in dichloromethane (50 mL) at room temperature was added 4-ethoxy-benzeneacetyl chloride (795 mg, 4.00 mmol). The mixture was stirred for 10 hours. The mixture was concentrated in vacuo and the residue dissolved in dichloroethane (25 mL) and acetic acid (25 mL). The mixture was stirred for 48 hours at 85° C. The reaction was then cooled to room temperature and brought to pH=10 by addition of 1 M NaOH aqueous solution. The mixture was extracted with EtOAc (50 mL). The aqueous phase was back-extracted with additional EtOAc (2×50 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([2.5%. MeOH+0.5% NH4OH aq] in CH2Cl2) to provide 1.02 g of the title compound 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-6-nitro-3H-imidazo[4,5-b]pyridine (76.0% yield from N2-(cyclopropylmethyl)-5-nitro-2,3-pyridinediamine). 1H-NMR (400 MHz, CDCl3): δ 0.44 (m, 2H), 0.52 (m, 2H), 1.10 (m, 1H), 1.40 (t, J=6.8 Hz, 3H), 4.01 (q, J=6.8 Hz, 2H), 4.10 (d, J=7.2 Hz, 2H), 4.35 (s, 2H), 6.86 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 8.80 (d, J=2.3 Hz, 1H) 9.26 (d, J=2.3 Hz, 1H). MS (ESI) (M+H)+: 353.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16]2)=[C:9]([CH:13]=1)[C:10](N)=[O:11].Cl.S(Cl)([Cl:24])=O.C(N(CC)CC)C>O>[Cl:24][CH2:18][CH2:19][CH:15]1[CH2:16][N:17]([CH3:20])[C:10](=[O:11])[C:9]2[CH:13]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=2[O:14]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(OC2CCN(C)C2)c(C(N)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(=O)N(C)CC(CCCl)O2
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of 19.2 g (0.48 mole) of sodium hydroxide in 500 ml of water was added 60 g (0.24 mole) of 5-methoxy-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide and the mixture was heated at reflux for 24 hr. The reaction mixture was cooled and the pH adjusted to 6.8 with concentrated hydrochloric acid. The mixture was concentrated under reduced pressure and the residue was boiled in isopropyl alcohol for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in 500 ml of chloroform and to this solution was added 114 g (0.96 mole) of thionyl chloride. The mixture was heated at reflux for 48 hr, then cooled with an ice/acetone bath. To the mixture was added dropwise 97 g (0.96 mole) of triethylamine at such a rate that the temperature did not exceed 25° C. The reaction solution was washed in sequence with water, 3N hydrochloric acid solution, water, 15% aqueous sodium hydroxide and water and finally dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a black solid. The solid was purified on a silica gel column using ethyl acetate as the eluting solvent to give on isolation 15 g (23%) of beige colored product, m.p. 98°-100° C.
Reaction SMILES: [CH3:1][C:2]1([OH:39])[CH:25]=[C:24]2[C@:19]([CH3:37])([CH2:20][CH2:21][C@H:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH2:23]2)[C@@H:18]2[C@@H:3]1[C@H:4]1[C@:15]([CH3:38])([CH2:16][CH2:17]2)[C@@H:7]([C@H:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1.[CH3:40][Si](C=[N+]=[N-])(C)C.N#N>C1(C)C=CC=CC=1.CO>[OH:39][C:2]1([CH3:1])[CH:25]=[C:24]2[C@:19]([CH3:37])([CH2:20][CH2:21][C@H:22]([O:26][Si:27]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:32])[CH3:33])[CH:34]([CH3:36])[CH3:35])[CH2:23]2)[C@@H:18]2[C@@H:3]1[C@H:4]1[C@:15]([CH3:38])([CH2:16][CH2:17]2)[C@@H:7]([C@H:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:40])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(C)[Si](O[C@H]1CC[C@@]2(C)C(=CC(C)(O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1)(C(C)C)C(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC1=CC3(C)O

Procedure:
To a solution of 7-hydroxy-7-methyl-3β-triisopropylsilyl-oxychol-5-en-24-oic acid (5) (5.38 g, 9.68 mmoles) in toluene (70 ml) and methanol (20 ml) was added dropwise at room temperature trimethylsilyldiazo-methane (2.0N in hexane, ~5 ml). After 30 minutes N2 evolution ceased, and the reaction mixture was a pale yellow. The solvent was removed in vacuo to give 4.67 g of crude 6 as a brown syrup. NMR (CDCl3) indicated a mixture of 7-isomers: δ 0.69 (two peaks, 18-Me); 3.63 (s, CO2Me); 5.12 & 5.18 (6-H). The mixture was used directly in the next reaction (Example 6).
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)([CH3:22])[CH3:21].C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].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>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1)([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CC(C)c1ccccc1B(O)O
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: CC#N
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3ccccc3C(C)C)nc1-2
Yield: 29.4 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 2-isopropylphenylboronic acid (65 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 298 (23 mg). ESI-MS: 363.1 (M)+.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[O:7]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-]c1ccccc1
Reactant: BrCCCCCCCCBr
Agent: [Na+]
Product: BrCCCCCCCCOc1ccccc1
Yield: 75 %

Procedure:
Preparation analogously to Example 38 by the reaction of sodium phenolate with 1,8-dibromooctane to give 8-phenoxy-1-bromooctane (b.p.11 =196°-202°; yield 75%) which is reacted with excess 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate. Isolation is hydrochloride. Yield, after recrystallisation from ethanol/isopropanol: 62%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](B(O)O)=[CH:7]2.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH3:29])[N:20]=[N:21][CH:22]=1>>[ClH:16].[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([C:17]1[CH:18]=[C:19]([CH2:23][N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[CH3:29])[N:20]=[N:21][CH:22]=1)=[CH:7]2
Reactant: Cc1ccc(C)c2c1C=C(B(O)O)CC2
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1ccc(C)c2c1C=C(c1cnnc(Cn3ccnc3C)c1)CC2
Product: Cl

Procedure:
The title compound, MS: m/e=331.3 (M+H+), was prepared from 5,8-dimethyl-3,4-dihydro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>C(Cl)Cl.ClC(OC(C)C)=O>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
A slurry of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (75.4 g, 0.3 mol) in CH2Cl2 (900 mL) at 1° C. was treated with triethylamine (60.7 g, 0.6 mol). Isopropyl chloroformate (300 mL, 0.3 mol, 1M in toluene) was added while maintaining the temperature less than 12° C. The resulting solution was stirred 16 h at ambient temperature. After 16 h, additional isopropyl chloroformate (15 mL, 0.015 mol, 1.0M in toluene) was added, and the reaction was stirred for 1 h. The reaction mixture was washed with 1N HCl (2×200 mL) and saturated NaHCO3 solution (2×200 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by filtration through Merck silica gel 62 (750 grams, CH2Cl2/MeOH 100/0 to 96/4) to give the title compound (95.48 g, 94.3%). 1H NMR (300 MHz, CDCl3): δ 1.20-1.24 (d, 6H), 1.40 (s, 9H), 2.46-2.52 (t, 2H), 2.81-2.86 (t, 2H), 4.294.32 (d, 2H), 4.86-4.97 (m, 1H), 5.19-5.28 (m, 1H), 6.67-6.72 (dd, 2H), 6.76 (s, 1H), 6.97-7.00 (d, 1H). MS (ES−) m/z 336.1 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[C:59]=2[F:65])=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[C:59]=2[F:65])[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2F)cc1
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(Cl)c2F)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.1 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5,6-difluoro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 96 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-chloro-2-fluoro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 23 h at rt, the reaction mixture was diluted with 50 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 78 mg white solid (46%). MS (ISP) 499.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:29]([NH:32][NH2:33])(=[O:31])[CH3:30]>>[C:29]([NH:32][NH:33][C:26]([CH:11]1[CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=2)[CH2:14][N:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:10]1)=[O:27])(=[O:31])[CH3:30]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(=O)NN
Product: CC(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
100 mg (0.25 mmol) of the compound from Example 44A and 37 mg (0.50 mmol) of acetohydrazide were reacted according to the General Method 11A. Yield: 106 mg (93% of theory)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1O[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[N:8][N:7]=1.[NH2:23][C:24]1[C:25]([CH3:33])=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[O:28].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(Cl)(Cl)Cl>CN1CCN(C)C1=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:23]([C:24]2[C:25]([CH3:33])=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:9]([C:11]2[CH:16]=[N:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:8][N:7]=1
Reactant: Cc1c(N)cccc1C(N)=O
Reactant: COCCCc1nnc(-c2ccc(-c3ccccc3)nc2)o1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CN1CCN(C)C1=O
Solvent: ClC(Cl)Cl
Product: COCCCc1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc(C(N)=O)c1C
Temperature: 200 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
5-[5-(3-Methoxypropyl)-1,3,4-oxadiazol-2-yl]-2-phenylpyridine (1.0 g) prepared in the Reference Example 7 was dissolved in 1,3-dimethyl-2-imidazolidinone (10 ml), followed by addition of 3-amino-2-methylbenzamide (1.53 g) prepared in the Reference Example 6 and D-10-camphorsulfonic acid (290 mg), and stirred at 200° C. for 16 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, which was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1), to afford the entitled compound (812 mg, 56%). The physico-chemical values are as follows.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=O.C=O.C1(C)C=C[C:27]([S:30](O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.C(N(CC)CC)C>[C:13]1([CH:18]2[S:30][CH2:27][N:2]([C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]2=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1
Reactant: O=C(O)Cc1ccccc1S
Reactant: CCOC(=O)C(C)(C)N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)N1CSC(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (3 g) was added to a suspension of ethyl 2-aminoisobutyrate hydrochloride (5 g) in toluene (60 mL) at room temperature. 2-Mercaptophenylacetic acid (6.44 g) was added to the mixture, which was then stirred at room temperature. After 10 minutes, a 35% formaldehyde aqueous solution (2.61 g) was added dropwise to the mixture. After the addition was completed, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was allowed to react under heating at reflux for 4 hours, while water generated was excluded by azeotropic distillation from the reaction system. The reaction mixture was cooled to room temperature, to which ethyl acetate was added, and was then washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure to give 5.49 g of the title compound as viscous oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:15]C)([O:13]C)[O:11]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:13][Si:18]([CH3:21])([CH3:20])[CH3:19])([O:11][Si:18]([CH3:21])([CH3:20])[CH3:19])[O:15][Si:10]([CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([O:11][Si:18]([CH3:21])([CH3:20])[CH3:19])[O:13][Si:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Reactant: C[Si](C)(C)Cl
Product: C=C(C)C(=O)OCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](CCCOC(=O)C(=C)C)(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
1.3-Bis(γ-methacryloxypropyl)-1,1,3,3-tetra(trimethylsiloxy)disiloxane (TETRA) was prepared following the same procedure as in Example (b) with 0.1 mole of γ-methacryloxypropyltrimethoxysilane (MEMO) and 0.2 mole of chlorotrimethylsilane.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:11][C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[C@@H:4]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C@@H:3]1[OH:18].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:19])[O:11][C:10]2[CH:9]=[CH:8][N+:7]([O-:28])=[CH:6][C:5]=2[C@@H:4]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C@@H:3]1[OH:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)Oc2ccncc2[C@@H](N2CCCC2=O)[C@@H]1O
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2cc[n+]([O-])cc2[C@@H](N2CCCC2=O)[C@@H]1O

Procedure:
The compound of example 1 (102mgm) and m-chloroperbenzoic acid (134mgm) were heated under reflux in chloroform (10 mL) for 2hr. The reaction mixture was cooled and evaporated and the resulting gum was chromatographed (chromatotron; chloroform ->10% methanol-chloroform in a gradient elution), and chromatographically homogenous fractions were combined and recrystallised from ethyl acetate-methanol to give the N-oxide of (E2) as a solid (54mgm) of m.p. 284°-285° C.
Reaction SMILES: [CH2:1]([C:3]1[C:22]([CH3:23])=[CH:21][C:6]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=4)[NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1)[CH3:2].C(=O)([O-])[O-:25].[Na+].[Na+].[ClH:30]>C(O)(=O)C>[ClH:30].[ClH:30].[CH2:1]([C:3]1[C:22]([CH3:23])=[CH:21][C:6]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH2:20])=[O:25])[CH:17]=4)[NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2nc(-c3n[nH]c4ccc(C#N)cc34)[nH]c2cc1C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc2nc(-c3n[nH]c4ccc(C(N)=O)cc34)[nH]c2cc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile [100 mg, Example 235(an)] in acetic acid (1 ml) and concentrated hydrochloric acid (1 ml) was heated at 80° C. for 30 minutes and then at 100° C. for 4 hours. The reaction was cooled to ambient temperature and stirred for 16 hours. The reaction was then heated at 80° C. for 2.5 hours and then at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and neutralized with aqueous sodium carbonate solution. The resulting white precipitate was collected by filtration and the aqueous layer was extracted with ethyl acetate, combined with the precipitate and concentrated in vacuo. The residue was taken up in methanol, transferred to a solid phase cartridge containing MP-carbonate resin (100 mg) and shaken for 16 hours. The reaction was then filtered, the resin washed with methanol and the combined organic layers concentrated in vacuo. The residue was triturated with diethyl ether, taken up in methanol and acidified with 4M hydrogen chloride in 1,4-dioxane. The solvent was removed in vacuo to give 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid amide dihydrochloride (58 mg) as a pale brown solid. LC-MS (METHOD M): RT=9.40 minutes, 320(M+H)+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:16]#[N:17].O(Cl)[Cl:19].[P+5].C([O-])(O)=O.[Na+]>>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:16]#[N:17]
Reactant: N#Cc1c(O)ccn2c(CC(F)(F)F)cnc12
Reactant: ClOCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P+5]
Product: N#Cc1c(Cl)ccn2c(CC(F)(F)F)cnc12
Temperature: 130 °C

Procedure:
A mixture of compound D9 (1 g, 4.148 mmol) and phosphorus(V) oxychloride (2 ml) was subjected to microwave heating at 130° C. for 15 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was then treated with NaHCO3 (aqueous sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4) and evaporated in vacuo. The crude product was purified by column chromatography (silica gel; Et2O as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D10 (0.6 g, 56%) as yellow solid.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([I:21])=[CH:23][CH:24]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: CC(=O)O
Product: Ic1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 81.4 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.04 g, 0.15 mmol) was reacted with 4-iodobenzaldehyde (0.045 g, 0.15 mmol) in the presence of glacial acetic acid (0.009 g, 0.15 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.012 g, 0.18 mmol) in methanol (5 ml) (Procedure D) to give compound 16m (0.059 g, 81%) as an oil.