Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[CH:3]=1.ClC1C=C(C(F)(F)F)C=[C:16]([O:24]C)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[CH:16]=[O:24]
Reactant: COc1cc(Cl)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(Cl)cc(Cl)c1
Product: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
The title compound was prepared as described in Example 159 substituting 1,3-dichloro-5-(trifluoromethyl)benzene for 1-chloro-3-methoxy-5-(trifluoromethyl)benzene.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH:13]2[OH:22])=[C:8](F)[C:7]=1[F:24])[CH3:4].O.Cl>CCCCC.C1(C)C=CC=CC=1.CN(C=O)C>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]2[CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH:13]3[O:22][C:8]=2[C:7]=1[F:24])[CH3:4]
Reactant: CCOc1ccc(C2CCC3(CC2O)OCCO3)c(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCC
Product: CCOc1ccc2c(c1F)OC1CC3(CCC21)OCCO3
Temperature: 90 °C
Reaction time: 30 h

Procedure:
50.0 g (1.25 mol) of sodium hydride (60% suspension in mineral oil) are washed repeatedly with n-pentane and suspended in 3000 ml of toluene. The suspension is heated to 90° C., and a solution of 145.0 g (0.46 mol) of 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol in 700 ml of DMF is slowly metered in. The batch is stirred at 90° C. for 30 h, cooled and hydrolysed using water. The mixture is neutralised by addition of 2 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness under reduced pressure. The crude product obtained is recrystallised from ethanol at 5° C., giving (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-spiro-[dibenzo[b,d]-furan-3,2′-1,3-dioxolane] as colourless solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:31]([O-:33])=[O:32])=[C:13]([CH:30]=1)[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15]>>[CH:26]1([NH:25][C:23]([C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([NH:16][C:14](=[O:15])[C:13]3[CH:30]=[C:9]([N:6]4[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]4)[CH:10]=[CH:11][C:12]=3[N+:31]([O-:33])=[O:32])[CH:22]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN[C@H](C)C2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (13) in the portion of Example 1 which is concerned with the preparation of starting material (R)-2-methylpiperazine was reacted with 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(3R)-3-methylpiperazine-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 1.04 (d, 3H), 2.30 (s, 3H), 2.52 (m, 2H), 2.71 (m, 2H), 2.84 (m, 2H), 2.98 (d, 1H), 3.92 (t, 2H), 7.04 (m, 2H), 7.27 (d, 1H), 7.56 (d, 1H), 7.97 (s, 1H), 8.03 (d, 2H), 8.35 (d, 1H), 9.88 (s, 1H); Mass Spectrum: M+H+ 438.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][C:14]=4[F:17])[NH:9][C:8]=3[C:6]=2[N:7]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Reactant: O=Cc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc2[nH]c3c(c12)C(c1cccs1)Oc1ccc(Cl)nc1-3
Temperature: 60 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A mixture of compound 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (60 mg, 0.224 mmol), thiophene-2-carbaldehyde (50 mg, 0.448 mmol) and PTSA (85 mg, 0.448 mmol) in toluene (1 mL) was stirred at 60° C. for 4 hours. The mixture was then diluted with water (20 mL) and extracted with EtOAc (15 mL*3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=20:1) to provide 2-chloro-7-fluoro-6-(thiophen-2-yl)-6,11-dihydropyrido[2′,3′:5,6]pyrano[4,3-b]indole (40 mg, yield: 50.0%). 1H-NMR (CDCl3, 400 MHz) δ 9.28 (s, 1H), 7.07˜7.18 (m, 5H), 6.98 (d, J=8.4 Hz, 1H), 6.81˜6.86 (m, 2H), 6.66˜6.70 (m, 1H). MS (M+H)+: 357/359.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:32])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:66]([O:70][C:71]([NH:73][C@H:74]([CH2:77][CH:78]([CH3:80])[CH3:79])[CH2:75]O)=[O:72])([CH3:69])([CH3:68])[CH3:67]>C1C=CC=CC=1>[C:66]([O:70][C:71]([NH:73][C@H:74]([CH2:77][CH:78]([CH3:80])[CH3:79])[CH2:75][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]2=[O:32])=[CH:33][CH:34]=1)=[O:72])([CH3:68])([CH3:69])[CH3:67]
Reactant: CC(C)C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CC(C)C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 35 %

Procedure:
2.1 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in Preparation 11] were added to a mixture of 2.28 g of 1,1'-azodicarbonyl-dipiperidine, 3.34 ml of tributylphosphine and 100 ml of anhydrous benzene. The resulting mixture was stirred at room temperature for one and a half hours, after which 2 g of 2(R)-t-butoxycarbonylamino-4-methylpentanol [prepared as described in Preparation 15] were added. The mixture was then stirred for a further five hours at the same temperature. At the end of this time, insolubles were filtered off and the filtrate was concentrated. The resulting residue was then purified by column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to obtain 1.05 g of the title compound, having an Rf=0.54 (thin layer chromatography on silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C@@H:1]12[CH2:10][C@@H:5]([CH2:6][C:7](=[O:9])[NH:8]1)[CH2:4][CH2:3][C@@H:2]2[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][CH:14]=[N:15][C:16]=2[NH2:20].C(O[CH:24](OCC)[N:25]([CH3:27])[CH3:26])C>CN(C=O)C>[C@@H:1]12[CH2:10][C@@H:5]([CH2:6][C:7](=[O:9])[NH:8]1)[CH2:4][CH2:3][C@@H:2]2[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][CH:14]=[N:15][C:16]=2[N:20]=[CH:24][N:25]([CH3:27])[CH3:26]
Reactant: Nc1ncnc2c1ncn2[C@H]1CC[C@@H]2CC(=O)N[C@H]1C2
Reactant: CCOC(OCC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ncnc2c1ncn2[C@H]1CC[C@@H]2CC(=O)N[C@H]1C2
Temperature: 80 °C

Procedure:
A 500 ml round-bottomed flask was loaded with 5.58 g of A lactam 15b (20 mmol), 200 ml of dry DMF and 17.1 ml of dimethylformamide diethyl acetal (100 mmol). The mixture was heated at 80° C. for 3 h. The resulting clear solution was concentrated under reduced pressure (0.4 mbar, 60° C. bath temperature) to afford 6.9 g of crude 15c, which was used without further purification.
Reaction SMILES: [Sn](Cl)Cl.[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[NH:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)[CH3:16])[CH:10]=[CH:11][CH:12]=1)([O-])=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH:13]([NH:14][CH:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=2)[CH3:16])[C:9]2[CH:8]=[C:7]([NH2:4])[CH:12]=[CH:11][CH:10]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C(NC(C)c2ccc(OC(C)=O)cc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(NC(C)c2ccc(OC(C)=O)cc2)c2cccc(N)c2)cc1
Yield: 91.5 %

Procedure:
Tin (II) chloride (451 mg) was added to a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[1-(4-acetoxyphenyl)ethyl]amine (200 mg) [prepared as described in step (a) above] in ethanol (10 ml). The mixture was heated under reflux for 1 hour. At the end of this time, ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture. The insoluble material was removed by filtration. The filtrate was separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer and extract were combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. It was then concentrated by evaporation under reduced pressure, to afford the title compound (170 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:17][CH2:16][CH2:15]1)[CH2:6]2.[Br:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:18][CH2:19][CH2:20][N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[C:11]=2[CH3:14])[CH2:6][C:7]2([CH2:15][CH2:16][CH2:17]2)[CH2:8]1
Reactant: BrCCBr
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(c(C)c1C)N(CCBr)CC1(CCC1)C2

Procedure:
A solution of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (1.12 g), 1,2-dibromoethane (2 mL) and Cs2CO3 (3.16 9) in DMF (7 mL) was heated in a bath of 110° C. for 6 hours. The mixture was cooled, water was added, and extracted with dichloromethane. The organic phase was then washed with brine, dried and evaporated. The residue was passed through a column (Hexane/EtOAc, 10:0.6) to give 1′-(2-bromoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] which was then added NaN3 (1.1 g) and dissolved in dichloromethane (7 mL). After heating the solution in a bath of 90° C. for 1 hour, the mixture was cooled, mixed with water and extracted with dichloromethane. The organic phase was washed with brine, dried and evaporated. The residue was passed through a column (Hexane/EtOAc, 10:0.5-10:0.6) to give 1′-(2-azidoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (340 mg) as an oil. 1′-(2-azidoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (340 mg) was dissolved in methanol (7 mL) and ethylacetate to which 50 mg Pd/C (10%) was added. The flask was then flushed evacuated and flushed with hydrogen. Under a balloon of hydrogen for 1 hour, the mixture was filtered and evaporated to give 2-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)ethanamine (278 mg) as an oil. 1H-NMR (300 MHz, C2D6O) δ=6.414 (s, 1H); 3.77 (s, 3H); 3.52 (s, 2H); 3.16-2.92 (m, 4H); 2.81 (s, 2H); 2.18 (s, 3H); 2.12 (s, 3H); 2.03-1.86 (m, 4H); 1.84-1.64 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.CS(O[CH2:31][C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=O)=O>O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:31][C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[N:13]=2)=[N:4][CH:3]=1
Reactant: O=c1ccc(-c2ncc(Br)cn2)n[nH]1
Reactant: CCCCCCCC#CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCC#CCn1nc(-c2ncc(Br)cn2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12843.9 %

Procedure:
To a 20 mL 1 neck flask equipped with magnetic stirrer, and nitrogen inlet was charged 30 milligrams (mg) of 6-(5-bromopyrimidin-2-yl)pyridazin-3(2H)-one (0.12 mmol), 33 mg of potassium carbonate (0.24 mmol), and 5 mL of dry DMF. The reaction mixture was stirred for about 30 minutes at ambient temperature followed by the addition of 100 mg of dec-2-ynyl methanesulfonate (0.43 mmol) in one portion. The reaction was stirred overnight at ambient temperature. The reaction was poured into about 10 mL of water, and extracted with 3×10 mL of ethyl acetate. The combined organic extract was washed with 10 mL of water, 10 mL of saturated aqueous sodium chloride solution, dried, and stripped to the crude product which was purified by silica gel column chromatography (20% ethyl acetate/80% hexanes). The pure fractions were combined and concentrated under vacuum on a rotary evaporator to afford 6 g of a white solid consistent with the title compound upon analysis by NMR. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 0.85 (m 3H); 1.25 (m, 6H); 1.60-1.65 (m, 4H); 2.15 (m, 2H); 5.05 (s, 2H); 7.05 (d, 1H); 8.35 (d, 1H); 9.00 (s, 2H).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[N:11][C:10]=1Br)[CH:2]=[CH2:3].[Br-].[CH2:26]([Zn+])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[N:11][C:10]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Br
Reactant: [Zn+]Cc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
To a solution of N-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-bromo-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.0500 g, 0.124 mmol) in tetrahydrofuran (0.86 mL) was added benzylzinc bromide (0.50M solution in tetrahydrofuran, 0.495 mL, 0.247 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.00474 g, 0.00928 mmol) under argon. The solution was stirred at 60° C. for 2 hours then cooled to room temperature. The solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (0.0110 g, 21%). LCMS: (FA) ES+ , 416. 1H NMR (400 MHz, d4-methanol) δ: 8.70-8.65 (m, 1H), 8.41-8.36 (m, 1H), 7.66-7.61 (m, 1H), 7.34-7.05 (m, 7H), 5.81-5.70 (m, 1H), 5.16-5.10 (m, 1H), 4.95-4.88 (m, 1H), 4.38-4.33 (m, 2H), 4.13 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.CO>C1C=CC=CC=1.CCOCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2=CC(=O)CC2)cc1OC1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc(C2=CC(O)CC2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution 3-(3-Cyclopentyloxy-4-methoxyphenyl)cyclopent-2-en-1-one (275 mg, 1.01 mmol) (E7) in benzene (5 ml) at 0° C. under an argon atmosphere was added a toluene solution of diisobutylaluminum hydride (1M, 1.5 ml, 1.5 mmol) and the resulting mixture was stirred at 0° C. for 1 hr. The mixture was treated with methanol (5 ml) , poured into ether (100 ml) , filtered and concentrated under reduced pressure. The crude product was combined with the product to a similar reaction conducted on 55 mg of ketone and was purified by flash chromatography, eluting with 5:3.5:1 hexanes/ether/methylene chloride to provide a solid. Recrystallization from hexanes/ether provided the title compound (92 mg, 27.7%): m.p. 105°-107° C.; an additional 150 mg was recovered from the mother liquor.
Reaction SMILES: O[C:2]1[C:3]([NH:24][C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])=[CH:4][C:5]2[C@@:12]3([CH3:16])[C:13]([CH3:15])([CH3:14])[C@H:8]([N:9]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11]3)[CH2:7][C:6]=2[CH:23]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH:27]1([C:25]2[O:26][C:2]3[C:3]([N:24]=2)=[CH:4][C:5]2[C@@:12]4([CH3:16])[C:13]([CH3:14])([CH3:15])[C@@H:8]([CH2:7][C:6]=2[CH:23]=3)[N:9]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11]4)[CH2:28][CH2:29]1
Reactant: CC1(C)[C@H]2Cc3cc(O)c(NC(=O)C4CC4)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC1(C)[C@H]2Cc3cc4oc(C5CC5)nc4cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of cyclopropanecarboxylic acid [(2R,6S)-9-hydroxy-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-amide (0.62 g) and pyridinium p-toluenesulfonate (76 mg) in xylene (6 mL) is stirred at reflux temperature for 5 h. After cooling to room temperature, the solution is concentrated, ethyl acetate is added to the residue, and the resulting mixture is washed with water and brine. The organic solution is dried (MgSO4) and the solvent is evaporated to afford the title compound.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(N1[CH:52]=[C:51]([CH2:53][CH2:54][NH2:55])[N:50]=[CH:49]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[C@H:54]12[CH2:53][C@H:51]([NH:50][CH2:49]1)[CH2:52][N:55]2[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5C[C@@H]6C[C@H]5CN6)n4)n[nH]c3cn2)cn1
Yield: 69.7 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 2-(1-trityl-1H-imidazol-4-yl)-ethylamine were reacted. The product was deprotected to give 216 as a white solid (69.7% over two steps). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 6.64 (broad s, 1H), 6.50 (d, J=8.2 Hz, 1H), 4.76 (s, 1H), 3.91 (s, 3H), 3.75 (s, 1H), 3.69 (d, J=8.5 Hz, 1H), 3.49-3.32 (m, 2H), 3.00 (s, 2H), 1.89 (d, J=8.5 Hz, 1H), 1.78 (d, J=9.1 Hz, 1H). LC/MS: m/z 373.1 [M+1]
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][C:27]1[N:28]=[C:29]([NH2:42])[S:30][C:31]=1[S:32]([N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[CH3:26][C:27]1[N:28]=[C:29]([NH:42][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[S:30][C:31]=1[S:32]([N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)N1CCN(C)CC1
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N1CCN(C)CC1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine (example B.19) according to general procedure II.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=4)[N:21]=3)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Cc1ccnc(C2(O)CCNCC2)c1
Product: Cc1ccnc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Yield: 81 %

Procedure:
A mixture of 4-(4-methylpyridin-2-yl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(4-methylpyridin-2-yl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 81% yield.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][O:7][CH2:6][C@@H:5]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N+]=[N-]>[Pt]=O>[NH2:1][C@@H:4]1[CH2:9][CH2:8][O:7][CH2:6][C@@H:5]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N=[N+]=[N-]
Agent: O=[Pt]
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Temperature: 20 °C
Yield: 101.4 %

Procedure:
A mixture of platinum oxide and 1,1-dimethylethyl [(3R,4R)-4-azidotetrahydro-2H-pyran-3-yl]carbamate (42 g) was purged with nitrogen (×3) and ethanol (1 l) was added. The vessel was purged (×3), charged with hydrogen and stirred at 400 rpm while cooling at 20° C. and stirred for 3 h. The vessel was purged with nitrogen (×3), refilled with hydrogen and stirred for a further 3.5 h. The vessel was purged and refilled with hydrogen at 15 psi and stirred overnight. The vessel was purged and refilled and stirred for 1.5 h. The mixture was filtered through Celite under a nitrogen atmosphere, the filter cake washed with ethanol (2×500 ml) and the filtrate reduced to dryness in vacuo to give 1,1-dimethylethyl [(3R,4R)-4-aminotetrahydro-2H-pyran-3-yl]carbamate (38 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1.C[CH2:17][C@@H:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[ClH:2].[C:19]1([C@H:18]([NH:25][C:3]2[C:4]3[NH:15][C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:5]=3[N:6]=[CH:7][N:8]=2)[CH3:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC[C@@H](N)c1ccccc1
Reactant: Clc1ncnc2c1[nH]c1ccccc12
Agent: Cl
Product: C[C@@H](Nc1ncnc2c1[nH]c1ccccc12)c1ccccc1
Reaction time: 16 h
Yield: 11 %

Procedure:
4-Chloroindolo[3,2-d]pyrimidine hydrochloride 240 mg, 1 mmol) and (R)-(+)-methylbenzylamine (1 ml) are stirred under a dry nitrogen atmosphere at 150 for 5 hours, and then concentrated under reduced pressure to an oil. This oil is dissolved in EtOAc (20 ml), and stirred for 16 h. The precipitate which forms is collected by filtration, washed with EtOAc, and dried at 90 in vacuo to give 4-([R]-1-phenylethylamino)indolo[3,2-d]pyrimidine hydrochloride (37 mg, 11%). 1H NMR (DMSO): δ10 (1H, s), 9.14 (1H, brs), 8.64 (1H, s), 8.16 (1H, d, J=8.0 Hz), 7.74 (1H, d, J=8.5 Hz), 7.63-7.59 (1H, m), 7.50 (2H, d, J=7.2 Hz), 7.38-7.24 (4H, m), 5.59 (1H, p, J=7.0 Hz); 1.64 (3H, d, J=7.0 Hz).