Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=2[CH2:20][N:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])[CH:11]=1)[CH3:2].C([Sn](=O)CCCC)CCC.[N:45]([Si](C)(C)C)=[N+:46]=[N-:47]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:45]=[N:46][NH:47][N:19]=3)=[CH:14][C:13]=2[CH2:20][N:21]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])[CH:11]=1)[CH3:2].[CH2:27]([N:21]([CH2:20][C:13]1[CH:14]=[C:15]([C:18]2[N:45]=[N:46][NH:47][N:19]=2)[CH:16]=[CH:17][C:12]=1[C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:34])[CH:7]=[N:8][CH:9]=1)[C:22]([CH:24]1[CH2:25][CH2:26]1)=[O:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C#N)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cncc(-c2ccc(-c3nn[nH]n3)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Product: O=C(O)Cc1cncc(-c2ccc(-c3nn[nH]n3)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
(5-{2-[(N-Benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-cyano-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.253 g, 0.56 mmol) was dissolved in toluene (10 mL). Dibutyltin oxide (0.014 g, 0.06 mmol) was added, followed by azidotrimethylsilane (0.09 mL, 0.67 mmol), and the reaction was stirred at 80° C. for 5 hours, and at 100° C. overnight. The mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were concentrated and purified by preparative HPLC to give {5-[2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-(2H-tetrazol-5-yl)-phenyl]-pyridin-3-yl}-acetic acid ethyl ester the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:18][C:19]1[CH:28]=[C:27]([CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[C:8]([NH:18][C:19]1[CH:28]=[C:27]([CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CSc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.52 mL of triethylamine and 0.16 mL of benzoyl chloride were added to 3.8 mL of methylene chloride suspension containing 0.39 g of methyl 2-amino-4-((phenylthio)methyl)benzoate hydrochloride while ice-cooled and stirred at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent vas evaporated under reduced pressure, Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.29 g of methyl 2-(benzamido)-4-((phenylthio)methyl)benzoate as white solid.
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:17][CH2:16][C:15]2([CH2:26][C:25]3[C:20](=[N:21][CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](=[O:42])[N:30]4[CH2:35][CH2:34][C:33]([CH2:36][C:37]5[S:38][CH:39]=[CH:40][N:41]=5)=[CH:32][CH2:31]4)[CH:24]=3)[NH:19][C:18]2=[O:43])[CH2:14][CH2:13]1)[CH2:3][NH:4]C(=O)OC(C)(C)C.[ClH:44]>O1CCOCC1.CCOCC>[ClH:44].[NH2:4][CH2:3][C:2]([N:12]1[CH2:13][CH2:14][C:15]2([CH2:26][C:25]3[C:20](=[N:21][CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](=[O:42])[N:30]4[CH2:35][CH2:34][C:33]([CH2:36][C:37]5[S:38][CH:39]=[CH:40][N:41]=5)=[CH:32][CH2:31]4)[CH:24]=3)[NH:19][C:18]2=[O:43])[CH2:16][CH2:17]1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCC(=O)N1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (E)-tert-butyl (2-oxo-2-(2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1Hspiro[[1,8]naphthyridine-3,4′-piperidin]-1′-yl)ethyl)carbamate (41.1) (20 mg, 0.03 mmol) in 1,4-dioxane (1 mL) was added 2M HCl in ether (0.24 mL) drop wise at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 3 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was triturated with diethyl ether to get the desired compound as a brown solid (20 mg); 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 8.08-8.00 (m, 3H), 7.71 (d, J=3.4 Hz, 1H), 7.61 (d, J=3.4 Hz, 1H), 7.46 (d, J=15.2 Hz, 1H), 7.28-7.14 (m, 1H), 5.68-5.65 (m, 1H), 4.26-4.18 (m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 4H), 3.80-3.72 (m, 3H), 3.68-3.60 (m, 1H), 3.54-3.40 (m, 2H), 2.98 (s, 2H), 2.20-2.04 (m, 2H), 1.92-1.83 (m, 1H), 1.82-1.68 (m, 1H), 1.48-1.32 (m, 2H); ES-MS: 507.3 (M+1)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=2[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1.Br.Br.[C:23]12[CH2:30][NH:29][CH2:28][C:27]=1[CH2:26][NH:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[F:16][C:10]1[CH:9]=[C:8]2[C:13](=[C:12]([F:14])[C:11]=1[N:25]1[CH2:26][C:27]3[CH2:28][NH:29][CH2:30][C:23]=3[CH2:24]1)[N:4]([CH2:3][CH2:2][F:1])[CH:5]=[C:6]([C:18]([OH:20])=[O:19])[C:7]2=[O:17]
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(CCF)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 76.2 %

Procedure:
1-(2-Fluoroethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.29 g), 3,7-diazabicyclo [3.3.0]oct-1(5)-ene dihydrobromide (0.33 g) and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU, 0.46 g) were dissolved in acetonitrile (15 ml) and refluxed for 3 hours. The reaction mixture was kept at room temperature overnight and the precipitate was collected by filtration, washed with acetonitrile and methanol to give the title compound (0.29 g, yield 76%).
Reaction SMILES: [I-].[CH2:2]([C:4]1[C:17]2[C:8](=[S+:9][C:10]3[C:15]([N:16]=2)=[C:14]([CH3:18])[CH:13]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=3)[CH:7]=[C:6]([N:25]2[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)[CH:5]=1)[CH3:3].[Cl:39]CCl>Cl>[Cl-:39].[CH2:2]([C:4]1[C:17]2[C:8](=[S+:9][C:10]3[C:15]([N:16]=2)=[C:14]([CH3:18])[CH:13]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=3)[CH:7]=[C:6]([N:25]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:5]=1)[CH3:3]
Reactant: ClCCl
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cc(N4CCOCC4)cc(C)c3nc12
Agent: Cl
Agent: [I-]
Product: CCc1cc(N2CCCNCC2)cc2[s+]c3cc(N4CCOCC4)cc(C)c3nc12
Product: [Cl-]

Procedure:
A solution of 1-ethyl-9-methyl-7-morpholino-3-(4-Boc-1,4-diazepane-1-yl)phenothiazin-5-ium iodide (65 mg, 0.1 mmol) in dichloromethane (10 mL) and HCl (1.0 mL, 4 M solution in 1,4-dioxane) was stirred for 2 h at 50° C. Product was precipitated, liquid was decanted. Solid material was dissolved in methanol and concentrated to dryness.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]2[CH2:12][O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)[CH:2]=[CH2:3].[H-].[Na+].I[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]2[CH2:12][O:11][C:10](=[O:13])[N:9]([CH3:20])[C:8]=2[CH:14]=1)[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCc1cc2c(cc1OC)COC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc2c(cc1OC)COC(=O)N2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
210 mg of 7-allyl-6-methoxy-1,4-dihydrobenz[d][1,3]oxazin-2-one was dissolved in 6 ml of N,N-dimethylformamide. Thereafter, 46 mg of 60% sodium hydride was added to the reaction solution while cooling on ice. The obtained mixture was then stirred at room temperature for 20 minutes. Thereafter, while cooling on ice, 0.20 g of iodomethane was added to the reaction solution. The obtained mixture was then stirred at room temperature for 2 hours. Thereafter, the reaction solution was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 207 mg of the subject compound.
Reaction SMILES: C(OC(CCCCC)CCCC(CCCCCCC(OCC)=O)(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(=O)C.[C:40]([O:43][CH:44]([CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:45][CH2:46][CH2:47][C:48]([CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])(C(OC(C)(C)C)=O)[C:49]([O:51]C(C)(C)C)=[O:50])(=[O:42])[CH3:41]>>[C:49]([CH:48]([CH2:47][CH2:46][CH2:45][CH:44]([O:43][C:40](=[O:42])[CH3:41])[CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])([OH:51])=[O:50]
Reactant: CCCCCC(CCCC(CCCCOCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Product: CCCCCC(CCCC(CCCCOCC(=O)OCC)C(=O)O)OC(C)=O

Procedure:
This compound is prepared essentially by the method described in Example 1, Step D except that the di-tert.-butyl 2-(4-acetoxynonyl)-2-(6-ethoxycarbonylhexyl)-malonate of the example is replaced by di-tert.-butyl 2-(4-acetoxynonyl)-2-[4-(ethoxycarbonylmethoxy)-butyl]malonate. The title compound is purified by column chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1
Reactant: Cc1cc(N)cnc1CCCC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(N)cnc1CCCCN
Yield: 88.4 %

Procedure:
5-Amino-2-(3-cyanopropyl)-3-methylpyridine (23.0 g) was reduced with lithium aluminium hydride (12.47 g) in a mixture of tetrahydrofuran (750 ml) and diethylether (750 ml) over 3 hours, to give 5-amino-2-(4-aminobutyl)-3-methylpyridine (20.8 g) as an amber oil. N.M.R. (CDCl3): assignment, δ (p.p.m.) multiplicity; --CH2CH2CH2NH2, 1.3-1.9, m; 3--CH3, 2.22, s; CH2 (CH2)2CH2NH2, 2.6-2.8, m; 5--NH2, ca 3.5, broad resonance; 4-pyridyl proton, 6.77, d; 6-pyridyl proton, 7.88, d.
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][C@@H:16]2[C@:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=3)([CH2:12][CH2:13][N:14]([CH3:18])[CH2:15]2)[CH2:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)(Cl)[Cl:33]>>[ClH:33].[CH:1](=[C:8]1[CH2:17][C@@H:16]2[C@:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)([CH2:12][CH2:13][N:14]([CH3:18])[CH2:15]2)[CH2:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc([C@]23CCN(C)C[C@@H]2CC(=Cc2ccccc2)C(=O)C3)c1
Reactant: ClC(Cl)Cl
Agent: BrB(Br)Br
Product: CN1CC[C@]2(c3cccc(O)c3)CC(=O)C(=Cc3ccccc3)C[C@H]2C1
Product: Cl

Procedure:
The reaction was conducted as described in Example 3, using 0.1 g (0.28 mmol) di (±)-trans-7-benzylidene-1,2,3,4,4a,5,6,7,8,8a-decahydro-2-methyl-4a-(3-methoxyphenyl)-6-isoquinolinone, 0.16 ml (1.7 mmol) of boron tribromide and 6 ml of dry CHCl3. The crude reaction mixture was purified by flash chromatography, eluting with a mixture CH2Cl2 /MeOH/conc. NH4OH 86:10:0.6 respectively. The resulting solid was dissolved in MeOH and the solution brought to acidic pH with Et2O/HCl. The solvent was removed in vacuo, the resulting solid was triturated with acetone, yielding 0.07 g of the title compound. M.p.=256-260° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)#[N:2].C(=O)([O-])[O-:20].[K+].[K+].OO>CS(C)=O.C(OCC)(=O)C>[CH3:18][C:15]([S:13]([NH:12][C@H:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:20])[CH:8]=1)[CH2:10][CH3:11])=[O:14])([CH3:17])[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C#N)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C(N)=O)c1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 116.9 %

Procedure:
To a rapidly stirred solution of 2-Methyl-propane-2-sulfinic acid [(S)-1-(2-cyano-pyridin-4-yl)-propyl]-amide (4.40 g, 16.6 mmol) in DMSO (70 mL) at 10° C. was added potassium carbonate (3.00 g, 21.7 mmol) portionwise and hydrogen peroxide (30 wt. % in water, 6.16 mL, 54.4 mmol) dropwise. The reaction was stirred at room temp. for 3.5 h. The reaction was cooled to 5° C., diluted with ethyl acetate (100 mL) and quenched with sodium thiosulfate solution (10% in water, 25 mL), stirred at 5° C. for 1 h. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (4×100 mL), the combined organic extracts were washed with water (3×50 mL), brine, dried over sodium sulfate, filtered and concentrated to give 4-[(S)-1-(2-Methyl-propane-2-sulfinylamino)-propyl]-pyridine-2-carboxylic acid amide (5.50 g, 99%) as a thick oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Yield: 48.8 %

Procedure:
2,6-di-t-butyl-4-nitrophenol (6.3 g, 25 mmoles) is dissolved in methanol (100 ml), 0.6 g of palladium on carbon (10%) is added and the reaction medium is placed under a hydrogen atmosphere under 2 bars of pressure. The catalyst is filtered out and the solvent is evaporated off under reduced pressure. The residue is taken up in heptane and filtered. In this way 2,6-di-t-butyl-4-aminophenol (2.7 g, 48%) is obtained which will be used without further purification in the following stages. Pink powder. Melting point: 123-124° C.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O.[CH3:18]O>>[ClH:16].[CH3:18][O:12][C:11](=[O:13])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[NH2:1]
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CO
Product: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: Cl
Reaction time: 2 h
Yield: 90.1 %

Procedure:
L-tyrosine 1 (181.2 g, 1.0 mol) was suspended in methanol (1268 g), and thionyl chloride (428.3 g, 3.6 mol) was added dropwise thereto at 40° C. over 2 hrs. After further keeping at 40° C. for 3 hrs, the reaction mass was concentrated to about one third of the volume under reduced pressure. To the concentrate mass was added dropwise toluene (1268 g) at 40° C. over 1.5 hrs. After keeping at 0° C. for 1 hr, precipitates were filtered and dried under reduced pressure to give L-tyrosine methyl ester hydrochloride 2 (208.7 g, yield 90.1%) as white crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([N+:12]([O-])=O)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1>C(O)C.O.C(O)(=O)C.[Zn]>[CH3:1][S:2][C:3]1[C:11]([NH2:12])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CSc1nn2ccccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CSc1nn2ccccc2c1N
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methylthio-3-nitropyrazolo[1,5-a]pyridine (Reference; Heterocycles, 1977, 6, 379) (400 mg) in ethanol (20 mL), water (10 mL), acetic acid (2 mL) was added zinc powder (800 mg) and the reaction mixture was heated and stirred for 30 minutes at 80° C. The insoluble residue was filtered out, water was added to the filtrate and extraction was performed with ethyl acetate, and then the organic extract was washed with saturated aqueous sodium bicarbonate and brine. The organic extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to afford (2-methylthiopyrazolo[1,5-a]pyridin-3-yl)amine as a crude product.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-:29].[K+].OO>CO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]([NH2:15])=[O:29])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Agent: OO
Agent: [K+]
Solvent: CO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C(N)=O)c1ccc(F)cc1
Temperature: 65 °C
Yield: 60 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile (Method 42; 0.5 g, 1.3 mmol) in MeOH (50 ml) was added KOH solution (25%, 2 ml), followed by addition of H2O2 (30%, 0.1 ml). The resulting dark red solution was heated to 65° C. for 1 hour, cooled, and concentrated. The resulting residue was dissolved in EtOAc (50 ml), washed with water (30 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=30:1) to give the title compound (0.30 g, 60%). MS: Calcd.: 398. Found: [M+H]+ 399.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19])[CH2:2][CH3:3].[O:20]=[S:21]1(=[O:37])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35]Br.C(N(CC)CC)C.O>CN(C)C=O>[O:37]=[S:21]1(=[O:20])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35][N:16]1[CH2:17][CH2:18][CH:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH2:1][CH2:2][CH3:3])[C:5]2=[O:19])[CH2:14][CH2:15]1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Reactant: CCCn1c(=O)n(C2CCNCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(C2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccccc21
Temperature: 50 °C

Procedure:
To a solution of 4-(3-propyl-2-oxo-1-benzimidazolinyl)piperidine (440 mg, 1.7 mmol) in dry dimethylformamide (6 mL), under an argon atmosphere was added 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (615 mg, 1.74 mmol, prepared as shown in Example 22) followed by triethylamine (0.25 mL, 1.8 mmol). This solution was heated at 50° C. for four hours and then cooled to room temperature as water was added. The product was extracted, dried (Na2SO4) and evaporated. The residue was chromatographed on a column of silica gel eluting with a gradient of 0.5-2% methanol/chloroform containing 0.2% NH4OH to give 1,1-dioxido-2-(4-(4-(3-propyl-2-oxo-1-benzimidazolinyl)piperidin-1-yl)butyl)-5-chloro-1,2-benzisothiazol-3(2H)-one as a viscous oil. 1H NMR (400 MHz, CDCl3): d 8.02 (s, 1H), 7.84 (quartet, J=8 Hz, 2H), 7.30 (broad d, 1H), 7.05 (broad quintet, 2H), 6.98 (broad d, J=8 Hz, 1H), 4.40 (multiplet, 1H), 3.84 (t, J=7.1 Hz, 4H), 3.07 (broad d, J=11.1 Hz, 2H),2.43-2.47 (m, 4H),2.14 (broad t, J=11 Hz, 2H), 1.88-1.93 (quintet, 2H), 1.75-1.81 (multiplet, 4H), 1.62-1.66 (multiplet, 2H), 0.97 (t, J=7.3 Hz, 3H). This oil was converted to its hydrochloride salt and crystallized from methanol upon addition of diethyl ether to give a crystalline white solid, melting point 225-227° C.: Analysis calculated for C26H31ClN4O4S.HCl: C, 55.02; H, 5.68; N, 9.87; found: C, 54.76; H, 5.66; N, 9.80.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:51]4[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-methylpiperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H53Cl2N6O3 [(M+H)+] 747.3551, observed 747.3554.
Reaction SMILES: Br.C(O)(=O)C.[N:6]1[NH:7][C:8](=[O:32])[CH2:9][CH2:10][C:11]=1[C:12]1[S:16][C:15]2[CH2:17][CH2:18][CH:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])(=[O:24])=[O:23])[CH2:20][C:14]=2[CH:13]=1.C(OC(C)C)(C)C>CS(C)=O>[N:6]1[NH:7][C:8](=[O:32])[CH:9]=[CH:10][C:11]=1[C:12]1[S:16][C:15]2[CH2:17][CH2:18][CH:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])(=[O:24])=[O:23])[CH2:20][C:14]=2[CH:13]=1
Reactant: Cc1ccccc1S(=O)(=O)NC1CCc2sc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CC(C)OC(C)C
Product: Cc1ccccc1S(=O)(=O)NC1CCc2sc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
In 8 ml of a 25% hydrogen bromide-acetic acid solution was suspended 1.41 g of 2-[4,5-dihydropyridazin-3(2H)-on-6-yl]-5-[(2-methylphenyl)sulfonylamino]-4,5,6,7-tetrahydrobenzo-[b]thiophene, and 0.25 ml of dimethylsulfoxide was added thereto. The mixture was stirred at room temperature for 2 hours. Then, diisopropyl ether was added to the reaction mixture, and crystals precipitated were collected by filtration to obtain 1.00 g of 2-[pyridazin-3(2H)-on-6-yl]-5-[(2-methylphenyl)sulfonylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene.