Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[C:7](=[O:8])[O:6]1)[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]2[C:14]([CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[O:6][C:7]2=[O:8])=[CH:13][CH:12]=1
Reactant: CCCCC1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(N)ccc21

Procedure:
To a suspension of 141 g (0.6 mol) of compound obtained in Example 1 in 250 ml of ethanol there are added 14 g of 5% Pd—C catalyst. The mixture is hydrogenated at a pressure of 34 kg/cm2. After the absorption of hydrogen has ceased, the hot mixture is filtered to remove the catalyst. The filter cake is washed with hot ethanol. On cooling, the crystals are separated and additional product is obtained from the condensed filtrate and washed to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[C:10][CH:11]([OH:20])[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]#[C:10][C:11](=[O:20])[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(C)c1C#CC(O)C#Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cccc(C)c1C#CC(=O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 93 %

Procedure:
C19H14O, FW=258.31 g/mol. 1-(2,6-Dimethylphenyl)-5-phenyl-1,4-pentadiyn-3-ol (1.57 g, 6.03 mmol) and manganese dioxide (3.15 g, 36.2 mmol) were combined in dichloromethane (35 mL) and stirred at room temperature for 40 minutes. Following completion of the reaction, the reaction mixture is filtered through celite, concentrated and the orange liquid product is isolated in 93% yield. Rf 0.90 (DCM) 1H NMR (500 MHz, CDCl3, ppm) d 7.61 (d, 2H, J=7.3 Hz), 7.48 (t, 1H, J=7.6 Hz), 7.40 (Ar, m, 3H), 7.08 (d, 2H, J=7.6 Hz), 2.52 (s, 6H); 13C NMR (125 MHz, CDCl3, ppm) d 160.7, 143.2, 133.3, 131.2, 131.0, 128.8, 127.2, 119.6, 119.3, 97.8, 91.5, 90.6, 89.6, 20.9; HR MS (EI) m/z calculated. 258.104465, found 258.104127.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C1COCC1>[CH2:26]([NH:28][C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:30])[CH3:27]
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 140 h

Procedure:
196 mg (0.6 mmol) of (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone are suspended in 10 ml of THF and after the addition of 70 mg (0.1 mmol) of ethyl isocyanate stirred for 140 hours at ambient temperature. The product precipitated is suction filtered, washed with ether and dried.
Reaction SMILES: IC.[F:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:5]=1[O:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[N:10]=[CH:9][C:8]=1[OH:20].[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:5]=1[O:6][C:7]1[C:8]([O:20][CH3:26])=[CH:9][N:10]=[C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[CH:12]=1
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(O)cn2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cnc(Nc2nc(C)cs2)cc1Oc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (0.0362 g, 0.255 mmol) is added to a mixture of 4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ol (0.255 mmol and potassium carbonate (0.0794 g, 0.574 mmol) in DMF (3 mL) and stirred overnight at room temperature. The reaction mixture is partitioned between water and ether. The organic layer is washed with water, dried, and concentrated. The residue is purified by silica gel chromatography, eluting with 15-20% EtOAc in hexanes, to afford N-(4-(2,6-difluorophenoxy)-5-methoxypyridin-2-yl)-4-methylthiazol-2-amine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4]>C(#N)C.[Cl-].[Na+].O.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[CH2:8][CH2:7][C@@H:2]([C:3]([O:5][CH3:6])=[O:4])[N:1]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H](N)CC#Cc1ccc(Br)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@H]1CCC(c2ccc(Br)cc2)=N1
Yield: 103 %

Procedure:
A solution of methyl (2S)-2-amino-5-(4-bromophenyl)-4-pentynoate (D75, 849 mg, 3.009 mmol) and silver-(I)-triflate in acetonitrile (30 ml) was stirred overnight at room temperature. Then brine was added and the product was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered and evaporated to afford the title compound (874 mg, 96%). UPLC: Rt 0.70 min; MS: (ES/+) m/z: 282, 284 [MH+], C12H12BrNO2 requires 282.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]([OH:24])=[O:23].I[CH2:26][CH:27]([CH3:29])[CH3:28].Cl>C1COCC1.[Cl-].[Na+].O>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:22]([OH:24])=[O:23]
Reactant: CC(C)CI
Reactant: O=C(O)CCc1ccccc1Br
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)CC(Cc1ccccc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To N,N-diisopropylamine (2.6 mL, 18.4 mmol) in dry THF (40 mL) under dry nitrogen and at 0° C. was added n-BuLi (2.5 M, 7.35 mL, 18.3 mmol) dropwise and the reaction was stirred at rt for 20 min. The reaction mixture was again cooled to 0° C. and 3-(2-bromophenyl)-propionic acid (1.9 g, 8.29 mmol, dissolved in dry THF, 40 mL) was added dropwise via cannula and then warmed to rt and stirred for 15 min. The reaction mixture was again cooled to 0° C. and 1-iodo-2-methyl propane (1.5 mL, 13.26 mmol) was added dropwise. The reaction was then warmed to rt and stirred overnight. Aqueous 10% HCl was added carefully followed by brine and the product was extracted with EtOAc (3×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex/AcOH, 4/6/0.5%) to afford 2-(2-bromobenzyl)-4-methylpentanoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[NH:21][CH2:20][CH2:19]2>>[CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[N:4]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[NH:21][CH2:20][CH2:19]3)[C@H:3]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Reactant: O=C1NCCc2cc(Br)ccc21
Product: CC1(C)OC(=O)N(c2ccc3c(c2)CCNC3=O)[C@H]1c1ccccc1
Yield: 53.6 %

Procedure:
The title compound was prepared as described in General Scheme A substituting (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) and 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (commercially available from Astatech Inc., Bristol, Pa.). The final reaction mixture was filtered through Celite® brand filter aid with MeOH and DCM, concentrated, and purified (ISCO: 5 g cartridge, 12 g column, 0 to 35 to 100%, 90/10 DCM-MeOH in DCM). Fractions with product were repurified (ISCO: 5 g cartridge, 12 g column, 0 to 100% EtOAc-heptanes) giving (S)-5,5-dimethyl-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-phenyloxazolidin-2-one (79.7 mg, 0.237 mmol, 53.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.80 (m, 1H), 7.70 (d, J=8.51 Hz, 1H), 7.53-7.56 (m, 1H), 7.36 (m, 6H), 5.49 (s, 1H), 3.30 (s, 2H), 2.73-2.88 (m, 2H), 1.62 (s, 3H), 0.90 (s, 3H). m/z (ESI) 337.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[C:26]([NH:30][S:31](Cl)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>N1C=CC=CC=1>[C:26]([NH:30][S:31]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Solvent: c1ccncc1
Product: CC(C)(C)NS(=O)(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 10 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (200 mg, 0.57 mmol) and N-tert-butylsulfamoyl chloride (J. Org. Chem.; 1976, 41, 4028) (108 mg, 0.63 mmol) as starting materials and pyridine as base.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]=[CH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2].CC(C)(O)[C:18]#[N:19]>>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]([C:18]#[N:19])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(O)C#N
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Product: N#CC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1

Procedure:
The novel process of the invention for the preparation of a compound of formula I wherein X is nitro comprises reacting 3-nitro-8,9-dihydro [5H] benzocycloheptene-5-one of the formula ##STR3## with acetone cyanhydrin of the formula to obtain 3-nitro-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile of the formula ##STR4## reducing the latter with diborane in an organic solvent to obtain 3-nitro-7-aminomethyl-6,7,8,9-tetrahydro [5H] benzocycloheptene-5-ol of the formula ##STR5## deshydrating the latter to form 2-nitro-6,7-dihydro [5H] benzocycloheptene-7-methanamine of the formula ##STR6## and either reacting the latter with formic aldehyde and sodium cyanoborohydride to obtain N,N-dimethyl-2-nitro-6,7-dihydro [5H] benzocycloheptene 7-methanamine of the formula ##STR7## which may be reacted with an alkyl chloroformate of the formula
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:15]([OH:17])=O)[CH2:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:18][C:19]1(C)OC(=O)CC(=O)[O:20]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19](=[O:20])[CH:18]=[C:15]([OH:17])[CH:11]2[CH2:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCC[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1C(O)=CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)norvaline (4.0 g), Meldrum's acid (2.40 g) and 4-(N,N-dimethyl)aminopyridine. (2.90 g) in tetrahydrofuran (60 mL) was added N,N′-carbonyldiimidazole (3.08 g) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (60 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate to give the title compound as colorless crystals (yield: 1.89 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.Cl.[N:12]([O-])=O.[Na+].[Sn](Cl)Cl>O.S(=O)(=O)(O)O>[ClH:9].[F:10][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([OH:8])=[CH:7][C:2]=1[NH:1][NH2:12]
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: NNc1cc(O)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 352.2 %

Procedure:
First, 32.3 g of 5-amino-2-chloro-4-fluorophenol was mixed with 150 ml of concentrated hydrochloric acid, and the mixture was stirred at 50° C. for 30 minutes, to which a solution of 15 g of sodium nitrite dissolved in 40 ml of water was added dropwise at 0° C. over 10 minutes. After stirring at 0° C. for 1 hour, the mixture was cooled to -50° C. Then, a solution of 132 g of tin (II) chloride dissolved in 132 g of concentrated sulfuric acid was rapidly added dropwise at -50° C., and the mixture was gradually warmed to room temperature and stirred for 1 hour. The solids formed were collected by filtration and dried at 80° C. under reduced pressure to give 75 g of the crude 2-fluoro-4-chloro-5-hydroxyphenylhydrazine hydrochloride crystals.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]3([CH3:25])[CH3:24])=[C:8]([C:26](=[O:28])[NH2:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH2:30]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:26]([C:8]1[CH:7]=[N:6][N:5]2[CH:29]=[C:2]([C:35]3[CH:34]=[N:33][N:32]([CH2:30][CH3:31])[CH:36]=3)[N:3]=[C:4]2[C:9]=1[NH:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][C:12]1([CH3:24])[CH3:25])(=[O:28])[NH2:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)nc23)C(C)(C)C1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CCN(C(=O)OC(C)(C)C)CC4(C)C)c3n2)cn1
Temperature: 100 °C
Yield: 87.2 %

Procedure:
To a reaction vial charged with (R)-tert-butyl 4-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (69.1 mg, 0.148 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (65.7 mg, 0.296 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (12.07 mg, 0.015 mmol) in dioxane (986 μl) was added potassium phosphate, dibasic (222 μl, 0.444 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 2 hrs. The reaction was diluted methanol (10 ml), filtered, and concentrated. The resulting brown oil was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated to give an oil. The oil was purified via flash chromatography (ISCO silica gel column, 0-100% EtOAc/hexanes) to afford (R)-tert-butyl 4-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (62.2 mg, 0.129 mmol, 87% yield) as a white solid. ESI-MS (analytical LCMS Method B): m/z 483.1 ([M+H]+). HPLC (analytical HPLC Method B) Rt: 3.345 min
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].C(O[CH:9]=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C>C(O)C>[NH2:17][C:16]1[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNCCO
Solvent: CCO
Product: CCOC(=O)c1cnn(CCO)c1N
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Ethanol (100 mL) and 2-hydroxyethylhydrazine (75% in water) (125 g) were combined, stirred, and heated to about 70° C. Ethyl (ethoxymethylene)cyanoacetate (200 g, 1.18 mol) and ethanol (100 g) were mixed and added over about 1 hour with stirring at about 80° C. After about 2 hours the reaction was completed to give 5-amino-4-ethoxycarbonyl-1-(2′-hydroxyethyl)-pyrazole (I) as evidenced by thin-layer chromatography (ethyl acetate:methanol 7:2, silica gel). The 4-ethoxycarbonyl group was hydrolyzed to the 4-carboxylic acid group by the addition of a solution of sodium hydroxide (60 g) dissolved in water (120 g), followed by refluxing for 3 hours while ethanol was removed by distillation. The pH of the resulting solution then was adjusted at about 0-25° C. to about 4 by the addition of 32% hydrochloric acid, whereupon the tan/yellow product, 5-amino-4-carboxy-1-(2′-hydroxyethyl)pyrazole (II) began to crystallize. After being cooled and stirred at about 0-50° C. for two hours, the reaction mixture was filtered and the solid was collected for use in the next step without drying. On a dry basis, the weight yield was 145 g, 72% of the theoretical yield based on ethyl (ethoxymethylene)cyanoacetate.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][CH:6]=1.[CH3:17][O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:17][O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[NH:7][CH:6]=2)[CH2:29][CH2:30]1
Reactant: COc1cnccc1N1CCNCC1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCI)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cnccc1N1CCN(CCCc2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 12 h
Yield: 36.1 %

Procedure:
A mixture of 3-[3-iodopropyl]-5-nitro-1H-indole (1.4 g, 4.2 mmol), 1-(3-methoxy-4-pyridinyl)-piperazine (0.98 g, 5.09 mmol) and K2CO3 (1.4 g, 10.2 mmol) in 30 mL of acetonitrile was heated to reflux for 4 h. The reaction mixture was cooled and stirred for 12 h. The solvent was removed and the residue dissolved in ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and concentrated, and the gummy residue was purified by flash silica gel chromatography (5% methanol in dichloromethane as eluant) to give 3-[3-[4-(3-methoxy-4-pyridinyl)-1-piperazinyl]propyl]-5-nitro-1H-indole, (0.6 g, 36%) as a yellow solid: IR (KBr) 3600, 2400, 1600, 1520, 1330, 1250, 815 cm-1 ; 1H NMR (DMSO-d6, 300 MHz) δ8.52 (d, J=2.2 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J=5.3 Hz, 1H), 7.96 (dd, J=2.3, 9.0 Hz, 1H), 7.48. (d, J=9.0 Hz, 1H), 7.42 (s, 1H), 6.81 (d, J=5.4 Hz, 1H), 3.84 (s, 3H), 3.21 (br s, 4H), 3.07 (dd, J=6.4, 14.7 Hz, 2H), 2.79 (t, J=14.7 Hz, 2H), 2.66 (br s, 4H), 1.97 (m, 2H); MS (m/e) 395 (M+).
Reaction SMILES: [Mg].II.Br[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[C:10]1([S:16]([N:19]2[C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=[C:20]2[C:29]([C:31]2[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=2)=[O:30])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:10]1([S:16]([N:19]2[C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=[C:20]2[C:29]([C:31]2[CH:32]=[CH:33][C:34]([S:37][CH3:38])=[CH:35][CH:36]=2)([OH:30])[CH2:5][CH:6]2[CH2:9][CH2:8][CH2:7]2)(=[O:17])=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CSc1ccc(C(=O)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: BrCC1CCC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CSc1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a stirred suspension of magnesium powder (1.6 g, 67.5 mmol) and iodine (3 pieces) in dry tetrahydrofuran (8 mL) was added (bromomethyl)cyclobutane (1.1 mL, 7.5 mmol) dropwise at room temperature. After the reaction initiated, a solution of (bromomethyl)cyclobutane (5.5 mL, 37.5 mmol) in dry tetrahydrofuran (30 mL) was added dropwise and then heated at reflux for 30 min. The resulting Grignard reagent was added to a solution of (1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanone (1.9 g, 4.5 mmol) at 0° C. and stirred for 1 h. The reaction was quenched with water, extracted with ethyl acetate (300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 15% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfanyl-phenyl)-ethanol (600 mg, 26.9%) as a light yellow solid; LC/MS m/e calcd for C26H25FN2O3S2 [M+H]+ 497.63, observed 496.8.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.[Cl:19][C:20]1[CH:49]=[CH:48][C:23]([C:24]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:31](=[O:40])[CH:30]=[C:29]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[O:25])=[CH:22][CH:21]=1>C1COCC1>[C:1]([Si:5]([CH3:13])([CH3:12])[C:6]1[N:7]([CH3:11])[C:8]([C:24]([C:23]2[CH:48]=[CH:49][C:20]([Cl:19])=[CH:21][CH:22]=2)([OH:25])[C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH:37]2[CH2:38][CH2:39]2)[C:31](=[O:40])[CH:30]=[C:29]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccnc1[Si](C)(C)C(C)(C)C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)cnc1[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
A solution of 2-(tert-Butyl-dimethyl-silanyl)-1-methyl-1H-imidazole (1.61 g, 8.2 mmol) in THF (40 mL) at −78° C. was treated with sec-butyllithium (1.3 M in cyclohexane, 7.9 mL, 10.3 mmol). The reaction mixture was warmed to 0° C., stirred for 3 hours, and cooled to −78° C. A solution of 6-(4-Chloro-benzoyl)-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one (2.87 g, 6.4 mmol) in THF (20 mL) was cannulated into the reaction mixture, slowly warmed to room temperature, and stirred overnight. The reaction mixture was quenched with ammonium chloride (12 mL), diluted with ether (200 mL), and washed with H2O (200 mL) and brine (200 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to give 6-[[2-(tert-butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-hydroxy-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one (4.35 g) as a yellow foam. The crude material was used in the next step without any further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:15][CH:16]([F:18])[F:17])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH2:15][CH:16]([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(CC(F)F)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC(F)F)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown oil (0.726 g; 89%). MS (ESI): m/z=369.12 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-])=O.[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH:15]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: C1CSCCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Product: N#Cc1cc(N)ccc1N1CCC(N2CCSCC2)CC1

Procedure:
Reductive amination was conducted according to J. Org. Chem., vol. 55, p. 2552 (1990) using 5-nitro-2-(4-oxopiperidin-1-yl) benzonitrile and thiomorpholine. Then, the nitro group was reduced in the same manner as in Starting Material Synthesis Example 40 to give the title compound, melting point: 138° C.