Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([NH:19][C:20](=[O:22])C)[CH:18]=1)[CH2:4][CH2:5][CH3:6].[C:38]([N:42]=C=O)([CH3:41])([CH3:40])[CH3:39].Cl>C1COCC1.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[C:38]([NH:42][C:20]([NH:19][C:17]1[CH:18]=[C:13]([C:12]2[CH:11]=[C:10]([O:30][CH:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)[N:9]=[N:8][C:7]=2[CH2:3][CH2:4][CH2:5][CH3:6])[CH:14]=[CH:15][C:16]=1[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(C)=O)c1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 126.4 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine (Example 62, 0.5 mmol, 219 mg) in dry THF (1.0 mL) was added tert-butyl isocyanate (1.5 mmol, 149 mg), and the mixture was stirred at room temperature over night. It was then condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (5.0 mL), 2N HCl in ether (5.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (193 mg). LCMS: m/z 539 [M+1]. 1H NMR (400 MHz, CD3OD): δ 8.09-8.12 (1H, m), 7.55 and 7.65 (1H, s), 7.12-7.18 (1H, m), 7.00-7.08 (1H, m), 5.36-5.56 (1H, m), 4.41-4.48 (1H, m), 3.25-3.67 (4H, m), 3.08-3.15 (2H, m), 2.93 (3H, s), 2.02-2.58 (6H, m), 1.83-1.89 (2H, m), 1.40-1.70 (8H, m), 1.38 (9H, s), 1.26-1.36 (2H, m), 0.83 (3H, t).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][O:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][O:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCOC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCOC4)c23)C1
Temperature: 160 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide (205 mg, 0.625 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (626 mg, 3.12 mmol) and stirred at 160° C. for 18 hours in a sealed tube. The solvent was then removed in vacuo, and the residue was dissolved in EtOAc (50 mL) and washed with water (1×10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by C-18 flash chromatography (25M+) on Biotage SP4 unit eluting with a gradient of 7-80% CH3CN/water (25 CV) to provide tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (65 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 8.78 (br s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 4.54-4.47 (m, 1H), 4.05-3.98 (m, 2H), 3.96-3.90 (m, 1H), 3.83-3.72 (m, 1H), 3.70-3.60 (m, 1H), 3.47-3.39 (m, 2H), 3.18-3.09 (m, 2H), 3.07-3.00 (m, 1H), 2.41-2.33 (m, 1H), 2.28-2.16 (m, 1H), 2.03-1.95 (m, 1H), 1.85-1.74 (m, 2H), 1.42 (s, 9H); LCMS (APCI+) m/z 508.1, 510 (M+H)+, Retention time=3.42 minutes (Method 2).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2C=C(N2CCN(C)CC2)[C:9]2[CH:25]=[CH:26][CH:27]=[CH:28][C:8]1=2>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCOCC.CCCCCC.C1COCC1>[CH:3](=[C:2]1[C:1]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:13][C:7](=[O:6])[C:8]2[CH:28]=[CH:27][CH:26]=[CH:25][C:9]1=2)[CH3:4]
Reactant: [Li]CCCC
Reactant: CN1CCN(c2cc3ccccc3c(=O)c3ccccc23)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC=C1c2ccccc2CC(=O)c2ccccc21
Yield: 98 %

Procedure:
To a stirred slurry of ethyltriphenylphosphonium bromide (21 g, 0.057 mole) in ether (400 ml) was added dropwise butyllithium in hexane (48 ml, 1.3 M). To the resulting solution was added a solution of 1-(5-keto-5H-dibenzo[a,d]cyclohepten-10-yl)-4-methylpiperazine (13.5 g, 0.044 mole) in THF (100 ml). The resulting mixture was stirred and heated under reflux for 3.5 hours, cooled and poured into ice H2O (300 ml). The organic phase was separated and the aqueous phase extracted with ether (2×150 ml). The combined organic solutions were concentrated under reduced pressure. The concentrate was stirred with a mixture of 1 N aqueous hydrochloric acid (300 ml) and ether (300 ml). The ether phase was separated, the aqueous phase extracted with ether, and the combined ether solutions dried over Na2SO4, filtered and the filtrate concentrated to 100 ml. Triphenylphosphine oxide was removed by filtration and the filtrate was chromatographed on silica-gel which was eluted with chloroform to yield 10.1 g (98%) of 5-ethylidene-10-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, m.p. 93°-95° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (150 mg) and 3-acetyl-1H-pyrazole-5-carboxylic acid (94 mg) using the method of Example 34(d). Yield 84 mg. 1H-NMR (400 MHz; d6-DMSO): δ 3.30 (s, 3H), 3.71 (q, 2H), 4.39 (t, 2H), 7.05 (d, 1H), 7.27 (br. s, 1H), 7.88 (d, 1H), 8.18 (d, 1H), 8.33 (d, 1H), 8.45-8.75 (m, 1H), 8.66 (d, 1H), 14.16 (s, 1H).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:36])[CH2:13][C:14]1[N:15]=[C:16]([N:19]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[S:17][CH:18]=1)[CH3:10].CI>C1COCC1>[CH2:9]([O:11][C:12](=[O:36])[CH:13]([C:14]1[N:15]=[C:16]([N:19]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[S:17][CH:18]=1)[CH3:1])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of lithium diisopropylamide (prepared in situ) (4.24 g, 39.6 mmol) in dry THF (40 mL) was added the solution of {2-[tert-butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester (8.0 g, 19.68 mmol) in 20 mL of dry THF in a dropwise fashion at −78° C. The reaction mixture was continued to stir at −78° C. for 1 hour followed by the addition of methyl iodide (4.19 g, 29.52 mmol) at the same temperature. The reaction mixture was kept on stirring and slowly allowed to come to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo to get the sticky compound (8.2 g). The compound was used for the next reaction without any purification.
Reaction SMILES: Br.Br[CH:3]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20]C(OC(C)(C)C)=O)[CH:15]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.C(OC(NC1C=C(CC(C2C=CC(OC)=CC=2)=O)C=CN=1)=O)(C)(C)C.[NH2:53][C:54]([NH2:56])=[S:55].C(N(CC)CC)C>C(#N)C>[NH2:20][C:16]1[CH:15]=[C:14]([C:3]2[S:55][C:54]([NH2:56])=[N:53][C:4]=2[C:6]2[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(Br)c2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Agent: Br
Agent: COc1ccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-c2nc(N)sc2-c2ccnc(N)c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 2-bromo-2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone hydrobromide (synthesized from 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (4.5 g, 13 mmol) according to the method described in Reference Example 20) in acetonitrile (40 mL) were added thiourea (1.1 g, 14 mmol) and triethylamine (1.9 mL, 14 mmol), and the mixture was stirred for 2 hours at 80° C. The reaction mixture was cooled to room temperature, then, concentrated. To the residue was added a saturated aqueous sodium hydrogen carbonate solution (200 mL), and the resulting solid was filtrated, and washed with water. To this solid was added 2N-hydrochloric acid (35 mL), and the mixture was stirred for 45 minutes at 100° C. The reaction mixture was cooled to room temperature, then, 8N-sodium hydroxide aqueous solution (10 mL) and aqueous sodium hydrogen carbonate solution (100 mL) were added. The resulted crude crystal was filtrated, and washed with water. This crude crystal was recrystallized from ethanol to obtain a title compound (2.7 g, yield 69%).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24](Br)=[O:25].[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:23][C:24]([NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[Cl:27])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1)NCC2
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1Cl
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)N(CC(=O)NCc1ccccc1Cl)CC2

Procedure:
prepared by reaction of 1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-chlorobenzylamine
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.Cl>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3]
Reactant: Cc1cc(OCC(=O)Cl)cc(C)c1S(=O)(=O)Cl
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
Referring to FIG. 37, to a solution of 2-(4-(chlorosulfonyl)-3,5-dimethylphenoxy)acetyl chloride (6 g, 20.3 mmol) in THF (60 mL) were added dropwise a solution of BnOH (2.2 g, 20.3 mmol). Et3N (3.44 mL, 24.3 mmol) and DMAP (25 mg, 0.2 mmol) in THF (30 mL) at −78° C. The reaction mixture was stirred for 5 h at −78° C. and then poured into HCl solution (1 N, 100 mL). The resulting mixture was extracted with ethyl acetate (100 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc=60:1) to give product as a white powder (1.2 g, 16% yield). 2-(4-(Chlorosulfonyl)-3,5-dimethylphenoxy)acetyl chloride (2.0 g) was recovered. 1H NMR (CDCl3, 300 MHz): δ 7.42-7.32 (m, 5H), 6.67 (s, 2H), 5.32 (s, 2H), 4.74 (s, 2H) 2.72 (s, 6H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]([CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][O:27]2)[OH:25])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]([CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][O:27]2)=[O:25])[CH2:22][CH2:23]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC(C1CCN(Cc2ccccc2)CC1)C1OCc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(C1CCN(Cc2ccccc2)CC1)C1OCc2ccccc21
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
After adding 0.511 ml of dimethylsulfoxide dropwise to a dichloromethane solution (15 ml) containing 0.315 ml of oxalyl chloride at −70° C., the mixture was stirred for 10 minutes, a solution of 597 mg of (1-benzylpiperidin-4-yl)-(1,3-dihydroisobenzofuran-1-yl)methanol in dichloromethane (5 ml) was added dropwise, and stirring was continued for 1 hour. Next, 2.5 ml of triethylamine was added dropwise to the reaction solution, the cooling bath was removed, and the mixture was stirred at room temperature. Water was added to the reaction solution, and extraction was performed with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (517 mg, 33% yield).
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[C:5]1=O)(=O)[CH3:2].Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1>C(O)C.O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:1]([CH3:2])=[C:4]3[C:5]([CH:6]4[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]4[CH2:12][CH2:13]3)=[N:25]2)=[CH:20][CH:19]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:5]3[CH:6]4[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]4[CH2:12][CH2:13][C:4]=3[C:1]([CH3:2])=[N:25]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)C1CCC2CCCCC2C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2nc(C)c3c2C2CCCCC2CC3)cc1
Product: COc1ccc(-n2nc3c(c2C)CCC2CCCCC32)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-Acetyloctahydronaphthalen-1-one (0.96 g, 4.95 mmol) was dissolved in absolute ethanol (10 mL), and 4-methoxyphenylhydrazine hydrochloride (0.95 g, 5.44 mmol) was added. The reaction was stirred overnight at 70° C. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried over MgSO4 and concentrated. SiO2 chromatography with 5-40% ethyl acetate/hexanes gave 0.15 g of 2-(4-methoxyphenyl)-3-methyl-4,5,5a,6,7,8,9,9a-octahydro-2H-benzo[g]indazole and 0.66 g of 1-(4-methoxyphenyl)-3-methyl-4,5,5a,6,7,8,9,9a-octahydro-1H-benzo[g]indazole. Regiochemistry was determined by x-ray crystal structure of 1-(4-methoxyphenyl)-3-methyl-4,5,5a,6,7,8,9,9a-octahydro-1H-benzo[g]indazole. LC-MS (C19H24N2O calculated 296) m/z 297 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1([C:33](OCC)=[O:34])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:22]=[CH:21]3)=[CH:15][CH:16]=1)=[O:5])C.C(OC(=O)C(NC1C=[N:51][C:52]([O:55]C2C=C3C(=CC=2)N(C2C=NC=CC=2)N=C3)=CC=1)C(OCC)=O)C.BrCCCBr.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:84](C)C=O>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][C:14]4[N:13]=[CH:12][C:11]([N:7]5[C:6]6([C:4](=[O:5])[NH:84][C:52](=[O:55])[NH:51][C:33]6=[O:34])[CH2:10][CH2:9][CH2:8]5)=[CH:16][CH:15]=4)=[CH:26][CH:25]=3)[CH:21]=[N:22]2)[CH:28]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(Nc1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1)C(=O)OCC
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1NC(=O)C2(CCCN2c2ccc(Oc3ccc4c(cnn4-c4cccnc4)c3)nc2)C(=O)N1
Temperature: 55 °C

Procedure:
1-[6-(1-Pyridin-3-yl-1H-indazol-5-yloxy)-pyridin-3-y]-pyrrolidine-2,2-dicarboxylic acid diethyl ester can be prepared by dissolving 2-[6-(1-Pyridin-3-yl-1H-indazol-5-yloxy)-pyridin-3-ylamino]-malonic acid diethyl ester (9.25 mmol) in dimethylformamide (90 mL), followed by addition of 1,3 dibromopropane (938 μL, 9.25 mmol) and cesium carbonate (6 grams, 18.5 mmol). The reaction mixture is stirred for approximately 24 hours to 48 hours. The mixture is filtered through celite, and then concentrated under vacuum while heating to 55° C. to remove the dimethylformamide (azeotroping with toluene). The crude product obtained is chromatographed on silica gel (ISCO MPLC purification, 40 minutes, 0-50% ethyl acetate gradient, Biotage flash 40m column) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.N1C2C(=CC=CC=2)C=C1.[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>ClCCl.CN(C1C=CN=CC=1)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:36])[C:27]1[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:29]([OH:31])=[O:30]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)Nc1ccccc1-c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A 100-mL, one-necked, round bottomed flask with a magnetic stirring bar and a septum was charged with 2-(2-aminophenyl) indole (210 mg; 1.01 mmol). The indole was dissolved in ca. 7 mL of dichloromethane to give a very pale yellow solution. DMAP (143 mg; 1.17 mmol; 1.16 equiv) and phthalic anhydride (179 mg; 1.21 mmol; 1.20 equiv) were added sequentially each dissolving completely with a resulting yellow solution. The solution was stirred at room temperature, and the reaction was followed by TLC, and showed complete conversion in ca. 30 min as indicated by the disappearance of the 2-(2-aminophenyl) indole. The reaction mixture was poured into a 125-mL separatory funnel and extracted with 15 mL HCl (aq, ca. 1 M). The aqueous layer was washed with 2×5 mL CH2Cl2, and the combined organic layer was dried (anhydrous Na2SO4), filtered, and concentrated by rotary evaporation to yield a canary yellow foamy solid (0.377 g) of N-[2-(1H-indol-2-yl)-phenyl]phthalamic acid. MS (M+H+: calcd 357; found 357).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@:7]12[CH2:15][CH2:14][C:13]3[C:16]4[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[CH:20][C:21]=4[CH2:22][CH2:23][C:12]=3[C@@H:11]1[CH2:10][CH2:9][C:8]2=[O:26])[CH:4]([CH3:6])[CH3:5].C(O)(=O)C>CO>[CH2:3]([C@:7]12[CH2:15][CH2:14][C:13]3[C:16]4[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[CH:20][C:21]=4[CH2:22][CH2:23][C:12]=3[C@@H:11]1[CH2:10][CH2:9][C@@H:8]2[OH:26])[CH:4]([CH3:6])[CH3:5]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)[C@@H](O)CC[C@@H]12
Reaction time: 1 h

Procedure:
To a stirred solution of sodium borohydride (6.0 g.) in methanol (500 cc. under nitrogen) add 13β-isobutyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (17 g.). Gently heat the reaction mixture for one minute to initiate the reaction and then allow to stand for one hour at room temperature. After adding cautiously glacial acetic acid (20 cc.), concentrate the solution in vacuo to 1/3 of its volume followed by addition of water. Extract the product with ether. Wash the ethereal solution successively with water, sodium bicarbonate, and water, and dry. Evaporate the ether to obtain 13β-isobutyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol as a gum, (17.0 g.; 99%); ultraviolet absorption peak at 278 mμ (ε14,560).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[CH:30]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1.CCN(CC)CC>CC#N>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[CH:30]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1
Reactant: Nc1nc(NCC2CCCN2)nc2cc(-c3ccco3)nn12
Reactant: Cc1cc(CCl)no1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(CN2CCCC2CNc2nc(N)n3nc(-c4ccco4)cc3n2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 7-furan-2-yl-N2-pyrrolidin-2-ylmethyl-pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.3 (s, 1H) 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 3 H). MS: m/z: 395 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[ClH:16].[CH3:17][NH:18][CH3:19].[CH2:20]=O.Cl>CC(C)=O.C(O)C>[ClH:16].[CH3:17][N:18]([CH2:20][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=2)[C:9]1=[O:13])[CH3:19]
Reactant: O=C1CCCc2cc(C(F)(F)F)ccc21
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: CN(C)CC1CCc2cc(C(F)(F)F)ccc2C1=O
Yield: 77.3 %

Procedure:
A mixture of 6-(trifluoromethyl)-1-tetralone (0.90 g), dimethylamine hydrochloride (0.42 g), paraformaldehyde (0.16 g), and 95% ethanol (2 ml) containing concentrated hydrogen chloride (0.02 ml) is heated on a steam bath for 1 1/2 hours. The reaction mixture soon becomes homogeneous and the paraformaldehyde dissolves. The warm solution is diluted with acetone (15 ml) and cooled to yield the title compound as white needles (1.0 g) melting point 137°-138° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[F:25]>C(O)C>[F:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Fc1cnccc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccncc2F)n1
Temperature: 25 °C
Yield: 5.1 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (152 mg, 1.1 mmol) was dissolved in absolute ethanol (20 mL), then triethylamine (200 pt, 1.4 mmol) and 4-(bromomethyl)-3-fluoropyridine (260 mg, 1.4 mmol) were added. The mixture was stirred over the weekend at room temperature. The solid was removed by filtration and washed with methanol. The filtrate was evaporated, and the residue was triturated in methanol, filtered, washed with water and diethyl ether, and then dried in vacuo to afford to 2-{[(3-fluoropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (14 mg, 7% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.41 (s, 2H), 6.00 (bs, 1H), 7.58 (t, J=5.7 Hz, 1H), 8.37 (dd, J=0.8 Hz, J=4.9 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H); LRMS (ES+) m/z 252 (100%, M+1).