Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@H:12]([O:14][CH2:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[CH2:11][C@@H:10]1[C@H:21]1[O:25]C(C)(C)[N:23]([C:28](=[O:30])[CH3:29])[C@H:22]1[CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:38][C:36]1[CH:37]=[C:32]([CH:33]=[C:34]([F:39])[CH:35]=1)[CH2:31][C@H:22]([NH:23][C:28](=[O:30])[CH3:29])[C@H:21]([OH:25])[C@H:10]1[CH2:11][C@@H:12]([O:14][CH2:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[CH2:13][NH:9]1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCCC(C)(C)O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](OCCC(C)(C)O)CN1
Reaction time: 4 h
Yield: 100 %

Procedure:
Add 4M hydrogen chloride in dioxane (5 mL) to (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-(3-hydroxy-3-methyl-butoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.11 g, 0.207 mmol). Stir 4 hours and evaporate to give the title compound as a foam (0.102 g, 100%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:28])=[C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:28])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:24])=[CH:26][CH:27]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(Br)nc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(Br)nc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 93.4 %

Procedure:
To a mixture of 4-{[(5-bromo-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}benzoic acid (300 mg) synthesized above, β-alanine ethyl ester hydrochloride (157 mg), 1-hydroxybenzotriazole monohydrate (156 mg), triethylamine (283 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (196 mg) and the mixture was stirred at room temperature for 1.5 days. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-60% ethyl acetate/hexane) to give the title object compound (343 mg, 93%) as a pale-yellow oil.
Reaction SMILES: O[NH:2][C:3](=N)[C:4]1[CH:9]=[C:8]([C:10]2[N:19]=[C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:11]=2)[CH:7]=[N:6][CH:5]=1>N.CO.[Ni]>[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[N:19]=[C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: N=C(NO)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Reaction time: 16 h
Yield: 49.8 %

Procedure:
To a solution of 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinonitrile (from example 183: 200 mg, 0.48 mmol) in 5% ammonia in methanol (5 mL) was added Ra—Ni (catalytic) and the resulting slurry was stirred under hydrogen atmosphere for 16 h. After this time, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield 2-(5-(aminomethyl)pyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.1 g, 50% yield), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1>>[NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: N#Cc1cnc(Nc2cc(NCC3CCNCC3)c(N)cn2)cn1
Yield: 6.2 %

Procedure:
Crude tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (50 mg) was loaded onto a MP-TsOH SPE cartridge, then eluted after 20 minutes with 2 M ammonia in methanol. The basic fractions were concentrated. Preparative HPLC gave 5-(5-amino-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (2.36 mg, 2.4% over 3 steps).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[N:3]=1.[C:16](#[N:19])[CH:17]=[CH2:18].C(Cl)(Cl)Cl>C(O)(C)(C)C>[C:16]([CH2:17][CH2:18][NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)#[N:19]
Reactant: Cc1cc(C)nc(NCCCCCN)n1
Reactant: C=CC#N
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)nc(NCCCCCNCCC#N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.8 %

Procedure:
To a stirred solution of (XII) (966 mg) in t-butanol was added 250 mg of acrylonitrile dissolved in 1 ml t-butanol over a period of 1 hour. Continued stirring for 3.5 hours at room temperature and finally refluxed for 1.5 hours. Chloroform was added and the product was extracted into 1N H2SO4. The aqueous phase was washed once with CHCl3, then basified to pH 10 with 2N NaOH and the free amine extracted into CHCl3. The product (XIII) 1.04 g was obtained by evaporation of the solvents under vacuum.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>CN(C=O)C>[I:24][C:22]1[C:17]2[S:16][CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A solution of Example 219B (5 g, 15.7 mmol) in DMF (100 mL) was treated with N-iodosuccinimide (4.23 g, 18.8 mmol), stirred at ambient temperature for 2 hours, concentrated to half the original volume, and poured into 5% sodium thiosulfate (400 mL). The mixture was filtered and the filter cake was washed with water and dried. The solids were dissolved in dichloromethane (300 mL), treated with silica gel (80 g), and concentrated. The residue was transferred to a silica gel column (600 g) and chromatographed with ethyl acetate/heptane (1:6) to provide 5.2 g (75%) of the desired product. 1H NMR (CD2Cl2, 400 MHz) δ 7.95 (s, 1H), 7.33-7.29 (m, 4H), 7.12 (s, 1H), 7.10 (t, 1H), 7.02-6.99 (m, 4H), 4.76 (br s, 1H); 13C NMR (CD2Cl2, 400 MHz) δ 158.4, 156.8, 154.7, 154.4, 148.6, 138.4, 131.3, 131.2, 130.4, 124.4, 122.9, 120.0, 119.9, 118.8, 72.0.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([O-:25])=[O:24])=[CH:8][CH:7]=1)=[O:3].[Na+].C(N(CC)C(C)C)(C)C.[C:36]([O:42][CH2:43]Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(OCC)(=O)C>CN(C)C=O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[NH2:1][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([O:25][CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:24])=[CH:8][CH:7]=1)=[O:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ccc(COC(N)=O)cc3)C[C@H]12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ccc(COC(N)=O)cc3)C[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A solution of sodium (5R,6S)-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (13 mg) in dry dimethylformamide (0.5 ml) was cooled with ice, and thereto were added N,N-diisopropylethylamine (5 mg), benzyltriethylammonium chloride (5 mg) and pivaloyloxymethyl chloride (11 mg). The mixture was gradually warmed to room temperature and stirred for overnight. To the reaction mixture were added ethyl acetate and ice water to separate by a separating funnel. The organic layer was washed with cold water (three times) and a cold saturated aqueous sodium chloride solution (twice), and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel thin-layer chromatography (ethyl acetate) to give [(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (9.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C1COCC1>[Br:24][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: Cc1c(Br)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (3.3 g, 10 mmol) in THF (80 ml) at -70° C., N-bromosuccinimide (1.78 g, 10 mmol) was added over 10 minutes. The reaction was warmed to 20° C. over 3 hours and stirred for 18 hours. After dilution with aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate. The organic fractions were washed with water, dried (MgSO4), filtered and concentrated. The crude yellowish liquid (4.52 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 3-bromo-1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (3.6 g, 88%): mp (DSC) 153° C. Anal Calc'd. for C18H15NSBrFO2 : C, 52.95; H, 3.70; N, 3.43; S, 19.53. Found: C, 53.01; H, 3.93; N, 3.39; S, 19.06.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([C:13]([OH:15])=O)=[N:9][CH:10]=[CH:11][CH:12]=1.CCN(C(C)C)C(C)C.Cl.[CH3:26][C:27]1[C:28]([NH:37][C@H:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[NH2:43])=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(#N)C>[CH3:26][C:27]1[C:28]([NH:37][C@H:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[NH:43][C:13]([C:8]2[C:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:15])=[N:29][CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-c1ncccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 155 mg, 0.77 mmol), DIPEA (0.27 ml, 1.54 mmol) and (1S,2S)-1-N-[3-methyl-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 35; 200 mg, 0.68 mmol) in DCM (3 ml) and acetonitrile (5 ml) was added HATU (293 mg, 0.77 mmol). The reaction was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by reverse phase column chromatography (C18 silica, 0-100% water (0.1% formic acid)/acetonitrile) and then by reverse phase column chromatography (C18 silica, 5-95% water (0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([Cl:18])=[O:14])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1)C(C(=O)O)CC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(C(=O)Cl)CC2
Reaction time: 2 h

Procedure:
6-Methoxy-indane-1-carboxylic acid, 6.0 g (31 mmol), a compound of Formula 3, was dissolved in 50 ml of methylene chloride and reacted at ambient temperature with 4.0 ml (46 mmol) of oxalyl chloride in the presence of one drop of DMF. After 2 hours, the reaction mixture was brought to reflux and maintained for 15 minutes. It was then concentrated under vacuum and stirred for about 30 minutes, yielding 6-methoxy-indane-1-carboxylic acid chloride, which was sufficiently pure to be used for the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.ClCCl.C(OCC)C>[ClH:27].[ClH:27].[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[N:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Reaction time: 24 h

Procedure:
4-[5-(4-Fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (0.99 g) was dissolved in a mixture of methanol (30 ml) and dichloromethane (10 ml) and treated dropwise with a 1.0 M solution of HCl in diethyl ether (60 ml). After stirring for 24 h, the resultant suspension was filtered and the precipitate was washed with 1:1 diethyl ether/methanol, followed by diethyl ether and dried under vacuum, to furnish the title compound as an off white solid (0.86 g, 94%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:15]=[N:14][C:13](O)=[CH:12][CH:11]=1.P(Cl)(Cl)([Cl:19])=O>C(Cl)CCl>[Cl:19][C:13]1[N:14]=[N:15][C:10]([C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)=[CH:11][CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(-c2nc3ccccc3[nH]2)nn1
Solvent: ClCCCl
Product: Clc1ccc(-c2nc3ccccc3[nH]2)nn1
Yield: 20 %

Procedure:
6-(1H-Benzoimidazol-2-yl)pyridazin-3-ol (0.322 g, 1.570 mmol) was suspended in ethylene dichloride (10 mL). Phosphorus oxychloride was added (15 mL) and the mixture was stirred at reflux for 48 hours. All solvents were removed and the residue was washed with saturated NaHCO3 and extracted with ethyl acetate. The organic solution was dried, concentrated and purified by column chromatography to yield 0.075 g of 2-(6-chloro-pyridazin-3-yl)-1H-benzoimidazole (0.32 mmol, 20% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([CH:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][CH:15]=[O:16])=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.C1(C2C(C(S(C)(=O)=O)CC(O)O)=CC3C(=C(C(NC)=O)N(C4C=CC(C)=CC=4)N=3)C=2)CC1.[BH4-].[Na+].S(=O)(=O)(O)O>O1CCOCC1.O>[CH:1]1([C:4]2[C:12]([CH:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][CH2:15][OH:16])=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(C(CC=O)S(C)(=O)=O)cc2nn1-c1ccc(C)cc1
Agent: CNC(=O)c1c2cc(C3CC3)c(C(CC(O)O)S(C)(=O)=O)cc2nn1-c1ccc(C)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c2cc(C3CC3)c(C(CCO)S(C)(=O)=O)cc2nn1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of an approximately 1:1 mixture of compound (v) and compound (vi) (14.2 mg, 0.032 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was added sodium borohydride (28 mg, 0.74 mmol) and the reaction was stirred at RT for 1 h. The reaction mixture was acidified with 2 N aqueous sulfuric acid, then diluted with water (15 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (7 mL), dried (MgSO4) and evaporated to dryness. The residue was purified by flash column chromatography eluting with EtOAc/heptane (50-100%) to give racemic 5-cyclopropyl-6-[3-hydroxy-1-(methylsulfonyl)propyl]-N-methyl-2-(4-methylphenyl)-2H-indazole-3-carboxamide (viii) as a white solid (11 mg, 79%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:21])([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:11][CH2:10]1.[OH:22][C:23]1[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29].OC1C=C(C=CC=1OC)C=CC(O)=O.[Cl-].[Na+]>CN(C=O)C>[CH2:18]([O:17][C:15]([C:12]1([CH3:21])[CH2:13][CH2:14][CH:9]([CH2:8][O:22][C:23]2[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:10][CH2:11]1)=[O:16])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)C1(C)CCC(CI)CC1
Reactant: C=CCOC(=O)C=Cc1ccc(OC)c(O)c1
Agent: COc1ccc(C=CC(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C=Cc1ccc(OC)c(OCC2CCC(C)(C(=O)OCC=C)CC2)c1
Yield: 47.8 %

Procedure:
5 g of potassium carbonate and 1.1 g of allyl 4-iodomethyl-methyl-1-cyclohexanecarboxylate (Example 46) were added to a solution of 0.8 g of allyl 3-hydroxy-4-methoxycinnamate, derived from 3-hydroxy-4-methoxycinnamic acid by the allyl-esterification thereof, in 50 ml of DMF. The solution was reacted for 18 hours at 100° C. After reaction, 100 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution and was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 5 g of silica gel. From the fraction eluted with hexane and ethyl acetate=2:1, the solvent was removed in vacuo, yielding 0.7 g of allyl 3-[1-(4-allyloxycarbonyl-4-methylcyclohexyl)methoxy]-4-methoxycinnamate (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:15]O.[OH-].[Na+]>CO>[Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[CH:11]2[O:15][CH:10]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)C2OC12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4(RS)-t-butyldimethylsilyloxy-2-cyclopentenone (2.12 g; 10 mmoles) was dissolved in 25 ml of methanol. The solution was cooled to 0° C., and 30% aqueous hydrogen peroxide (5 ml; 45 mmoles) was added. Several drops of a 2N aqueous solution of sodium hydroxide were added, and the mixture was stirred for 30 minutes. The methanol was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ether. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give 4(RS)-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone as a crude product. The crude product was dissolved in 20 ml of methanol, and a solution of 1.62 g (10 mmoles) of methyl 6-mercaptohexanoate in 10 ml of methanol was added. Furthermore 1 ml of triethylamine was added. The mixture was stirred at room temperature for 18 hours in an atmosphere of nitrogen. After the reaction, the reaction mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane/ethyl acetate (6/1) as an eluent to give 2.24 g (6.02 mmoles; 60.2%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-methoxycarbonylpentylthio)-2-cyclopentenone.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6](I)[CH:7]=1.C([Mg]Cl)(C)C.B(OC)(OC)[O:20]C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([OH:20])[CH:5]=[N:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1
Reactant: Brc1cc(I)cnc1OCC1CC1
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Oc1cnc(OCC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-bromo-2-(cyclopropylmethoxy)-5-iodopyridine (12.5 g) in dry THF (300 mL) was added i-PrMgCl*LiCl (30 mL, 38.3 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 20 min and then B(OMe)3 (5.5 g) was added at 0° C. The mixture was allowed to warm to r.t. and stirred for 3 h. The mixture was quenched by the addition of brine (50 mL). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×3). The organic phases were combined and the solvent was removed under reduced pressure. The residue was treated according Typical Procedure 5a to obtain the title compound. MS ESI+: m/z=244 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:14][CH2:15][CH2:16][Cl:17])[CH:3]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(N)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N)cc1OCCCCl
Temperature: 60 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
To a solution of methyl 4-amino-2-hydroxybenzoate (500 mg, 2.99 mmol) and 1-bromo-3-chloropropane (0.294 mL, 2.99 mmol) in DMF (3 mL) was added CESIUM CARBONATE (1462 mg, 4.49 mmol). The resulting mixture was stirred at 60° C. for 6 hrs. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine, dried over MgSO4, concentrated. The crude product was purified by silica gel chromatography using a gradient of 20-50% EtOAc/Hexanes to give 686 mg (94%) methyl 4-amino-2-(3-chloropropoxy)benzoate.
Reaction SMILES: Cl.[F:2][CH:3]([F:14])[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[OH:13].C(N(CC)CC)C.[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[NH:28][C:27](=O)/[C:26]/2=[CH:35]/OC>CN(C)C=O>[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[N:28][CH2:27]/[C:26]/2=[CH:35]\[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH:3]([F:14])[F:2])=[C:6]([OH:13])[CH:7]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1ccc(OC(F)F)c(O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cc(CN/C=C2\CN=Cc3ccc(Br)cc32)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
An amount of 90 mg (0.40 mmol) of 4-difluoromethoxy-3-hydroxy benzylamine hydrochloride, is dissolved in N,N-dimethylformamide (4 mL). 50 ul (0.75 mmol) of triethylamine is added followed by 112 mg (0.40 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, the solvent is removed in-vacuo and the residue dissolved in 7.5% methanol in chloroform and passed thru a short pad of Florisil eluting with 7.5% methanol in chloroform, the eluate is evaporated and the solid triturated with ether, filtered and washed several times with anhydrous ether to give 116 mg of a pink solid (67% yield); mp 256-8° C., MS data ES(−) 437.0, 439.0 (M−1).