Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)=[N:9]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 3-[2-(2-phthalimidoethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2.2 g), hydrazine monohydrate (2 ml), and ethanol (100 ml) was stirred for 1 hour under reflux. After being cooled to room temperature, the reaction mixture was concentrated, and the residue was partitioned between chloroform and water. The organic layer was separated, and extracted with 10% hydrochloric acid. The aqueous layer was washed twice with chloroform, neutralized with sodium hydroxide, and extracted three times with chloroform. The combined organic layers were washed with water and sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated to give 3-[2-(2-aminoethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.5 g). An analytical sample was prepared by recrystallization from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.[CH3:14][NH:15][CH3:16].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([N:15]([CH3:16])[CH3:14])[CH2:8]2
Reactant: CNC
Reactant: COc1cccc2c1CCC(=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2c1CCC(N(C)C)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a solution of 5-methoxy-2-tetralone (10.33 g, 58.62 mmol) dissolved in CH2Cl2 (400 mL) were added dimethylamine (5.6 M in EtOH, 14 mL, 76.206 mmol) and AcOH (0.46 mL, 5.862 mmol), and the mixture was stirred for 4 h at room temperature. It was then cooled to 0° C. and NaB(OAc)3H (0.45 eq, 5.59 g, 26.379 mmol) was added over a period of 20 min. After 1 h stirring at 0° C., NaB(OAc)3H (1.0 eq, 12.42 g, 58.62 mmol) was added over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was cooled again to 0° C., and H2O (250 mL) was added slowly. The pH of the solution was adjusted to 8.0 by adding NaHCO3 saturated aqueous solution, and the mixture was stirred at 0° C. for 15 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (4×100 mL). All organic phases were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (12.51 g) was purified by flash chromatography on silica gel (1:100:1-100:0:1 AcOEt/Hexane/Et3N) affording 8.86 g of the title compound (Rf=0.5 (AcOEt/Hexane/Et3N 10:10:2), brown colored oil, 74% yield).
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H](O)C(C)C)cc1
Temperature: 0 °C

Procedure:
The title compound was prepared by reacting 14.652 g of (S)-2-hydroxy-3-methylbutyric acid with 21.21 g cesium carbonate and 20.396 of para-methoxybenzyl chloride in 300 mL of DMF at room temperature for 40 hours. The reaction mixture was poured into 400 mL of ice water, extracted with 5×150 mL ether, and the combined ether solution was washed with 5×100 mL water and 100 mL saturated brine. After drying over Na2SO4 and filtration, the filtrate was concentrated under reduced pressure to give 30.62 g of crude product, which was purified by flash chromatography on silica gel with 10˜30% ethyl acetate in hexanes to afford 29.12 g title compound as a colorless oil (99%). RF: 0.58 (30% EtOAc in hexane). 1H NMR (500 MHz, CDCl3): δ7.30˜7.33 (m, 2H), 6.90˜6.93 (m, 2H), 5.20 (AB d, 11.9 Hz, 1H), 5.15 (AB d, 11.9 Hz, 1H), 4.07 (d, 3.4 Hz, 1H), 3.83 (s, 3H), 2.68 (br s, 1H), 2.04˜2.13 (m, 1H), 1.01 (d, 7.0 Hz, 3H), 0.83 (d, 6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:12]1(O)[CH2:19][CH2:18]C[CH2:16][CH2:15][CH2:14][CH2:13]1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].C(OCC)(=O)C>[CH:1]1([O:2][C:3](=[O:11])[C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:19][CH2:18]1
Reactant: OC1CCCCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Product: O=C(OC1CCCCCCC1)c1ccc(O)cc1
Temperature: 180 °C
Yield: 12.6 %

Procedure:
22.82 g (0.15 mol) p-hydroxybenzoic acid methyl ester, 38.47 g (0.30 mol) cyclooctanol and 26 mg (0.1 mmol) tetraisopropyl orthotitanate are placed under argon in a round-bottom flask with distillation bridge. The mixture is stirred and heated to 180° C. within 45 minutes. The pressure is reduced to 800 mbar and over the further course of distillation to 650 mbar. After a further 15 minutes the pressure is increased to 900 mbar and the reaction mixture stirred for a further 2 hours, during which time methanol continues to be removed by distillation. A further 9.62 g (0.075 mol) cyclooctanol and 2 drops of tetraisopropyl orthotitanate are added to the reaction solution and stirred for a further 4 hours at 180° C. It is allowed to cool and the residue is dissolved in 100 ml ethyl acetate and washed repeatedly with distilled water. The organic phase is concentrated to small volume. The crude product is purified by column chromatography (silica gel 60, 0040-0.063 mm, Merck) with an n-hexane/acetone mixture (3:1). The product obtained is freed from adhering cyclooctanol under high vacuum. The white crystalline residue is recrystallised in acetone. 4.70 g (12%) of colourless crystals are obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH3:30])=[C:7]([C:21](=[O:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]([NH:10][C:11]1[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:19][CH3:20])=[O:9])[CH2:2][CH2:3][CH3:4].CO[C:33](OC)(N(C)C)[CH3:34].CN(C)C>C1C=CC=CC=1>[CH2:1]([N:5]1[C:33]([CH3:34])=[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:21](=[O:29])[C:7]([C:8]([NH:10][C:11]2[C:12]([CH2:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH3:18])=[O:9])=[C:6]1[CH3:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(C)=C(C(=O)Cc1ccccc1)C(=O)Nc1c(CC)cccc1CC
Reactant: COC(C)(OC)N(C)C
Agent: CN(C)C
Solvent: c1ccccc1
Product: CCCCn1c(C)c(C(=O)Nc2c(CC)cccc2CC)c(=O)c(-c2ccccc2)c1C
Yield: 43.4 %

Procedure:
A mixture of 4.07 g (10 mmol) of the resulted 3-butylamino-N-(2,6-diethylphenyl)-2-phenylacetyl-2-butenic acid amide, 4.00 g (30 mmol) of N,N-dimethylacetamide dimethyl ketal, 0.4 ml of trimethylamine and 20 ml of benzene was refluxed for 3 hours under nitrogen atmosphere. The residue, obtained by concentrating the reaction mixture under vacuo, was column-chromatographed on silica gel to afford 1.87 g of the title compound, as oil.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.[CH:21]([NH2:23])=[O:22]>O>[CH:21]([NH:23][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2)=[O:22]
Reactant: NC=O
Reactant: COC(=O)c1ccc2c(c1)C(Cl)c1ccccc1CO2
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(NC=O)c1ccccc1CO2
Temperature: 110 °C
Yield: 90 %

Procedure:
Add 2.35 gm. of methyl 6,11-dihydro-11-chlorodibenz[b,e]oxepin-2-carboxylate to 20 ml. of formamide. Stir and heat the mixture at 110° C. for 3 hours. Cool to room temperature, dilute with water and separate the solids by filtration to obtain the title product (Yield 2.18 gm., 90%).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20]([C:22]1([CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH2:34][CH2:35][C:36]([NH:38][C@H:39]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:37])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O.C(#N)C.CN1C(=O)CCC1>[C:15]([O:19][C:20]([C:22]1([CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([O:33][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:14][CH:13]=3)[CH:30]=[CH:29][C:28]=2[CH2:34][CH2:35][C:36]([NH:38][C@H:39]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:40][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[O:37])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)CCc1ccc(O)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)CCc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (53.3 mg) was added to a mixture of di-tert-butyl N-(3-(2-(5-(tert-butoxycarbonyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoyl)-L-aspartate (154 mg), pyridine (0.12 mL), and NMP (0.12 mL) at 50 C, and the obtained mixture was stirred at 50 C for 30 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (53.3 mg) was added thereto, and the obtained mixture was stirred overnight at 50 C. The reaction mixture was fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (44.6 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]3([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:17][O:16]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH3:26]>CO>[NH2:26][CH2:17][C:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([OH:16])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:25][CH2:24][C:5]1=2
Reactant: N
Reactant: Cc1ccc2c(c1)c1c(n2CC2(c3cccnc3)CO2)CCN(C)C1
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CC(O)(CN)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,8-Dimethyl-5-((2-(pyridin-3-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.3 mmol) was dissolved in MeOH (2 mL) and aq. ammonia (2 mL) and the reaction mixture was allowed to stir at RT for 24 h. The progress of reaction was monitored by LCMS. The volatiles were removed under reduced pressure to obtain a crude oily product that was purified by reverse phase HPLC to afford 7 mg of 1-amino-3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol as TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.65 (m, 2H), 8.43 (dd, 1H), 7.75 (m, 1H), 7.18 (d, 1H), 6.88 (m, 2H), 4.67 (d, 1H), 4.55 (m, 2H), 4.29 (t, 1H), 3.90 (m, 2H), 3.69 (m, 1H), 3.5 (m, 2H), 3.1 (m, 1H), 3.11 (s, 3H), 2.34 (s, 3H). Separation by chiral HPLC provides enantiomers II-264a-b.
Reaction SMILES: N#N.Cl[C:4]1[N:9]=[C:8]([NH:10][C@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)[C:7]([N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=1.[CH3:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1.C(N(C(C)C)CC)(C)C>CO.O.CS(C)=O>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][C@H:11]2[NH:10][C:8]2[C:7]([N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=[C:4]([NH:30][C:27]3[CH:26]=[C:25]([CH3:24])[NH:29][N:28]=3)[N:9]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1N[C@@H]1CCc2ccc(F)cc21
Reactant: Cc1cc(N)n[nH]1
Agent: N#N
Solvent: CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccc([N+](=O)[O-])c(N[C@@H]3CCc4ccc(F)cc43)n2)n[nH]1
Temperature: 70 °C
Reaction time: 20 h
Yield: 90.1 %

Procedure:
Equip a 3 neck flask (22 L) with a thermocouple, condenser, overhead stirrer, N2 inlet, and heating mantle. To the flask, charge 6-chloro-N-[(1R)-6-fluoro-2,3-dihydro-1H-inden-1-yl]-3-nitropyridin-2-amine (600 g, 1.95 mol), 5-methyl-1H-pyrazol-3-amine (208.31 g, 2.14 mol), dimethylsulfoxide (6.0 L), and diisopropylethylamine (680.11 mL, 3.90 moles). Stir the solution at 70° C. for 20 hours. Cool the mixture to ambient temperature and dilute it with MeOH (6.0 L). Add de-ionized water (2.1 L) to the solution over one hour to give in an orange suspension. Stir the suspension for one hour, and then filter through polypropylene. Wash the filter cake with de-ionized water (12 L), transfer the solid to a tared dish and vacuum-dry (50° C.) to constant weight to provide the title compound (647 g, 90%). MS (m/z): 369 (M+1).
Reaction SMILES: [I:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[I:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)[CH2:4]1
Reactant: OC1CCC(CI)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: ICC1CCC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.8 %

Procedure:
A solution of 3-iodomethyl-cyclopentanol (7.71 g, 34.10 mmol) in methylene chloride (171 mL) was treated with 3,4-dihydro-2H-pyran (4.7 ml, 51.16 mmol) and pyridiniump-toluenesulfonate (857.1 mg, 3.41 mmol). The resulting reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was then washed with a saturated aqueous sodium chloride solution (1×200 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 petroleum ether/diethyl ether) afforded 2-(3-iodomethyl-cyclopentyloxy)-tetrahydropyran (7.91 g, 75%) as a yellow oil: EI-HRMS m/e calcd for C11H19IO2 (M+) 310.0430. found 310.0433.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][CH2:31]2>>[C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6]([NH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][CH2:31]2)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Yield: 72.6 %

Procedure:
According to the Step 70-5 in the synthetic method for EXAMPLE 70, compound 70-4 (50 mg) was treated with tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (30 mg) to afford compound 72-1 (52 mg) as a light yellow solid after preparative LC purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Na+].[CH3:23][S:24]([O-:26])=[O:25].FC1C=C(C=CC=1S(C)(=O)=O)C=O>>[CH3:23][S:24]([C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9])(=[O:26])=[O:25]
Reactant: CS(=O)[O-]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Agent: CS(=O)(=O)c1ccc(C=O)cc1F
Agent: [Na+]
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(S(C)(=O)=O)c2)s1

Procedure:
This is isolated as a minor by product in the synthesis of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) when excess methane sulfinic acid sodium salt is added in the first step of the synthesis (64a). The resulting aldehyde is converted into the title compound by the procedure described in parts 64b-d.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[CH:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[C:24]([F:26])[CH:23]=3)[N:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(C2CCCCC2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(C2CCCCC2)c2ccccc2c1=O

Procedure:
The product of Example 74A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60-11.61 (bs, 1H), 8.34 (dd, J=7.9, 1.4 Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 8.00 (ddd, J=8.1, 7.2, 1.5 Hz, 1H), 7.90 (ddd, J=8.0, 7.1, 1.0 Hz, 1H), 7.07-7.22 (m, 3H), 3.75 (s, 2H), 3.26 (d, J=10.3 Hz, 1H), 1.89-1.93 (m, 2H), 1.79-1.83 (m, 2H), 1.70-1.76 (m, 1H), 1.39-1.58 (m, 4H), 1.19-1.32 (m, 1H); MS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][C:16]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(C(OCC)=O)[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COCCO>O>[CH2:3]([O:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][CH:16]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: O=C(O)C(CCCc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
2.00 g of potassium hydroxide was added to a mixture of 3.91 g of diethyl 2-(4-benzyloxybenzyl)-2-(3-phenylpropyl)malonate obtained in Reference example 12(a), 30 ml of 2-methoxyethanol and 3 ml of water, and the resulting mixture was stirred on an oil bath of 130° C. for 1.5 hours. After the reaction, the reaction mixture was concentrated, water and ethyl acetate were added to the concentrated mixture, and then 6N hydrochloric acid was added thereto to make it acidic. Then, the ethyl acetate layer was separated, washed with an aqueous NaCl solution and dried over anhydrous magnesium sulfate, followed by concentration. The residual syrup was dissolved in 20 ml of xylene, and the mixture was stirred for one hour and concentrated. The syrup-like 2-(4-benzyloxybenzyl)-5-phenylvaleric acid thus obtained was dissolved in 40 ml of ethanol, and 1 ml of conc. sulfuric acid was added thereto. The resulting mixture was stirred at 80° C. for 3 hours and allowed to stand at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and water, followed by separation of the ethyl acetate layer. The extract thus obtained was dried over anhydrous magnesium sulfate and concentrated to obtain 3.32 g of the desired compound as a syrup.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([S:11]([NH:22][C:20]3[N:19]([C:23]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:24]=4[CH:25]=[CH:26][CH:27]=[N:28]5)[N:18]=[C:17]([CH3:16])[CH:21]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc3c(c2)CCC3(C)C)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 30 %

Procedure:
A mixture of 1,1-dimethylindan-5-sulfonyl chloride (0.030 g, 0.13 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.028 g, 0.12 mmol) in pyridine (0.12 mL) was heated at 80° C. for 1 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting crude residue was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.036 mmol, 28%). 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.90 (d, J=3.2 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.57 (d, J=9.2 Hz, 1H), 7.46 (dd, J=4.0, 8.4 Hz, 1H), 7.30-7.26 (m, 2H), 7.18 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.05 (s, 1H), 2.71 (d, J=7.6 Hz, 2H), 2.20 (s, 3H), 1.84 (d, J=7.2 Hz, 2H), 1.18 (s, 6H); MS: (ES) m/z calculated for C24H25N4O2S [M+H]+ 433.2. found 433.1.
Reaction SMILES: [H-].[Na+].[Cl-].[C:4]([CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:5].[CH2:26]([C:28]1[CH:33]=[C:32]([CH:34]=O)[CH:31]=[CH:30][N:29]=1)[CH3:27].CO>O1CCCC1.CN(C)C=O>[CH2:26]([C:28]1[CH:33]=[C:32](/[CH:34]=[CH:6]/[C:4]#[N:5])[CH:31]=[CH:30][N:29]=1)[CH3:27]
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1cc(C=O)ccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1cc(/C=C/C#N)ccn1
Reaction time: 1 h
Yield: 25.1 %

Procedure:
To a suspension of 1.79 g (0.041 mol) sodiumhydride in 50 ml tetrahydrofurane and 50 ml dimethylformamide were added 13.9 g (0.041 mol) (cyanomethyl)triphenylphosphonium chloride. After sirring for 1 hour at room temperature a solution of 5.54 g (0.041 mol) 2-ethyl-4-pyridinecarboxaldehyde in 10 ml tetrahydrofuran were added and stirring was continued for 15 hours. Then 10 ml methanol were added, the solvents were evaporated and the residue chromatographed on aluminiumoxide with dichloromethane to yield 1.63 g (25%) (E)-3-(2-ethyl-pyridin-4-yl)-acrylonitrile as white waxy solid. MS m/e (%): 158 (M+, 100).