Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9](O[C@@H](C)CC)=[N:10][C:11]=2[NH2:17].FC(F)(F)C(O)=O.[CH3:30][C@H:31]([NH:35]C1NC2C(N=C(OC)N=2)=C(N)N=1)[CH2:32][CH2:33][CH3:34].BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:35][C@@H:31]([CH3:30])[CH2:32][CH2:33][CH3:34])=[N:10][C:11]=2[NH2:17]
Reactant: CCC[C@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from N2-[(1S)-1-methylbutyl]-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:24][C:25]4[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Cc1ncccc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Nc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 160 °C
Yield: 24.4 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 3-amino-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 21 mg, 0.19 mmol), and potassium tert-butoxide (22 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(2-methyl-pyridin-3-ylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15 mg, 24%) as a white powder. Mass spectrum (ES) MH+=410. HRMS Calcd. for C21H28N7O2 (MH+): 410.2299. Found: 410.2299.
Reaction SMILES: [I-].[Na+].[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24]Cl)[CH:11]=1)(=[O:5])[CH3:4].[F:27][C:28]([F:44])([F:43])[C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][CH:42]=1)[CH2:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C1COCC1.C(#N)C>[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24][N:36]2[CH2:37][CH2:38][CH2:39][N:33]([CH2:32][C:31]3[CH:40]=[CH:41][CH:42]=[C:29]([C:28]([F:43])([F:44])[F:27])[CH:30]=3)[CH2:34][CH2:35]2)[CH:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Reactant: FC(F)(F)c1cccc(CN2CCCNCC2)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCCN(Cc3cccc(C(F)(F)F)c3)CC2)nc(-c2ccccc2)n1

Procedure:
Sodium iodide (903 mg; 6.02 mmol) was added to a solution of chloroacetamide 6 (2.088 g; 6.00 mmol), 1-(3-trifluoromethylbenzyl)-[1,4]diazepane (7.40) (1.863 g; 7.21 mmol) and DIPEA (1.45 mL; 8.32 mmol) in 3:1 acetonitrile:THF (30 mL). After 21 h the reaction was concentrated on a rotary evaporator. EtOAc (90 mL) was added and the suspension was washed with 50% saturated NaHCO3 (25 mL), water (3×25 mL) and saturated NaCl (2×25 mL). The solution was dried (MgSO4), filtered, concentrated to an oil then purified on silica gel (340 mL), eluting with 9:1 EtOAc:methanol. Pure product was obtained as a hard white foam (3.10 g; 91%). LC (method B) tR=12.6 min; 1H NMR (200 MHz, CDCl3) δ 9.64 (s, 1H), 8.36 (m, 2H), 7.7-7.3 (m, 7H), 7.22 (s, 1H), 6.56 (brs, 1H), 5.42 (brt, J=5.8 Hz, 1H), 3.75 (s, 2H), 3.68 (m, 2H), 3.54 (m, 2H), 3.32 (s, 2H), 3.0-2.7 (m, 8H), 1.93 (m, 2H), 1.65 (s, 3H). ESIMS 570 (12) [MH+], 286 (100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[N:25]=1>N1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:32]#[C:31][C@:29]([C:26]4[N:25]=[C:24]([CH3:23])[O:28][N:27]=4)([OH:33])[CH3:30])[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: CC(C)(O)c1nn(-c2nc(N)ncc2Cl)c2cc(I)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(C)(C)O)nn(-c4nc(N)ncc4Cl)c3c2)no1
Temperature: 35 °C

Procedure:
To a solution of 2-[1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol (150 mg, 0.35 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (40.3 mg, 0.02 mmol), copper(I) iodide (6.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (106 mg, 0.70 mmol). The reaction was warmed to 35° C. for 1.5 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (heptane/EtOAc gradient) to furnish the title compound as a dark red solid: 1H NMR (500 MHz, DMSO-d6) delta 1.69 (6H, s), 1.93 (3H, s), 2.69 (3H, s), 5.65 (1H, s), 6.85 (1H, s), 7.34 (2H, br. s.), 7.39 (1H, dd, J=8.35, 1.10 Hz), 8.21 (1H, d, J=8.35 Hz), 8.26 (1H, s), 8.51 (1H, s); LC-MS: m/z=+454.05/456.05 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:48]=[CH:47][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][C:39]([CH3:46])=[C:40]([CH:45]=4)[C:41]([O:43]C)=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:49][CH3:50])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCC[CH2:52]1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:48]=[CH:47][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][C:39]([CH3:46])=[C:40]([CH:45]=4)[C:41]([OH:43])=[O:42])[O:33][C:34]=3[CH2:35][CH3:52])=[C:26]([O:49][CH3:50])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C)c(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C)c(C(=O)O)c3)oc2CC)c(OC)c1)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a mixture of methyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-methylbenzoate (0.46 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-ethyl-1,3-oxazol-2-yl]-2-methylbenzoic acid as colorless crystals (0.39 g, yield 87%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 165-166° C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[Cl:24][CH2:25][C:26]([CH2:28][Cl:29])=O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:24][C:25]1[C:26]([CH2:28][Cl:29])=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2
Reactant: O=C(CCl)CCl
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(Cl)c(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 110 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
A mixture of 2-amino-4,5,3',4'-tetramethoxy-benzophenone (25.0 g), 1,3-dichloroacetone (11.0 g), conc. sulfuric acid (1.2 ml) and acetic acid (200 ml) was stirred at 110° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water, made alkaline with 2N NaOH, and extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (10:1, v/v) gave 3-chloro-2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (12.0 g, 38%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 206°-207° C.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6]O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.ClCCl>[CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][N:33]1[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]2[C:29]1=[O:39])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C/C=C(/C=C/CO)CC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC=C(C=CCN1C(=O)c2ccccc2C1=O)CC
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a mixture of (E,E)-4-ethyl-2,4-hexadien-1-ol (1.0 g), triphenylphosphine (2.29 g), phthalimide (1.17 g), and tetrahydrofuran (30 ml) at room temperature was added a solution of diethyl azodicarboxylate (1.52 g) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (hexane-dichloromethane, 2:3) to give 0.42 g of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][NH:16][CH2:17][C:18]([O-:20])=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Na+].NC1C=CC=CC=1.CN(C([O:38]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)(Cl)Cl>[C:6]([NH2:7])(=[O:38])[C:5]1[CH:21]=[CH:22][CH:2]=[CH:3][CH:4]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:21][CH:22]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C([O-])CNNC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Product: O=C(O)CNNC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 47.6 %

Procedure:
Sodium N-(1-(4-chlorobenzyl)-piperazine-4-carboxamido)glycinate (20 mg, 0.060 mmol) and aniline (6.2 mg, 0.66 mmol) were dissolved in CHCl3 (1 mL). HBTU (25 mg, 0.066), HOBt (8.1 mg, 0.066 mmol) and Et3N (17 μL, 0.12 mmol) were added and the reaction mixture was stirred for 16 hr. The solvent was removed and the compound was dissolved into CH2Cl2 (2 mL). The organic layer was washed with 2N aqueous NaOH solution (2N mL), brine (1×1 mL) and concentrated. Purification via RPLC/MS afforded the desired material (6.4 mg, 21%). ESI/MS 385 (M++H, C26H24ClN3O2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][OH:14])[NH:8]2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>C(Cl)Cl>[Si:24]([O:14][CH2:13][CH2:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([N+:17]([O-:19])=[O:18])=[C:2]([F:1])[CH:10]=2)([CH3:16])[CH3:15])([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(CCO)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52558400 %

Procedure:
To a solution of 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutan-1-ol (6.6 g, 25 mmol) in CH2Cl2 (80 mL) was added TBSCl (3.7 g, 25 nmol) and imidazole (4.2 g, 62 nmol) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The precipitate was filtered off and washed with the methanol. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give the desired product as a brown solid (5.0 g, 53%). 1H NMR (300 MHz, CDCl3) δ 9.80 (brs, 1H), 8.30 (d, J=7.2 Hz, 1H), 7.05 (d, J=11.7 Hz, 1H), 6.33 (t, J=1.2 Hz, 1H), 3.7 (t, J=6.0 Hz, 2H), 1.91 (t, J=6.0 Hz, 2H), 1.42 (s, 6H), 0.94 (s, 9H), 0.12 (s, 6H). MS (ESI) m/z (M+H+): 381.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][OH:15])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:15][CH2:14][CH2:13][NH:12][C:4]1[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=[C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1
Reactant: OCCNc1nc(Cl)nc2c1SCCC2
Reactant: C1CNCCN1
Product: OCCNc1nc(N2CCNCC2)nc2c1SCCC2

Procedure:
In the same manner as described in Example 17, 2-chloro-4-(2-hydroxyethyl)amino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine was reacted with anhydrous piperazine to obtain 4-(2-hydroxyethyl)amino-2-piperazino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine which was then recrystallized from ethanol. Colorless needles. Melting point: 116°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20]5[C:21]([C:27]#[N:28])([CH2:22][CH2:23][C:24](=[O:26])[CH:25]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1.O[Pd]O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@H:20]5[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][C@:21]5([C:27]#[N:28])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@@H:20]5[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][C@@:21]5([C:27]#[N:28])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CC12CCC(=O)C=C1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: [H][H]
Agent: O[Pd]O
Solvent: Cc1ccccc1
Product: N#C[C@@]12CCC(=O)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Product: N#C[C@]12CCC(=O)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A solution of 9-(4-fluorophenyl)-3-oxo-1,2,3,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (30, R1=4-Fluorophenyl) (28.0 g, 67.9 mmol) in toluene (600 mL) containing dihydroxypalladium (4.29 g, 3.05 mmol) was hydrogenated on a Parr shaker at about 55° C. and about 50 psi of hydrogen for about 10 h. The reaction was cooled to rt and filtered (Celite®), rinsing with DCM (3×200 mL). The combined organics were concentrated to about 100 mL, the product was filtered off and dried under reduced pressure to yield (4aR,12bS)-9-(4-fluorophenyl)-3-oxo-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile; compound with (4aS,12bR)-9-(4-fluorophenyl)-3-oxo-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (31, R1=4-Fluorophenyl) (18.2 g, 72%) as an off-white solid. LC/MS, method 3, Rt=2.41 min, MS m/z 374 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.06 (s, 1H), 7.85-7.79 (m, 2H), 7.71 (s, 1H), 7.47-7.40 (m, 2H), 3.47-3.36 (m, 1H), 3.15-3.04 (m, 1H), 2.93-2.63 (m, 4H), 2.44-2.30 (m, 2H), 2.26-2.14 (m, 1H), 2.10-1.99 (m, 1H), 1.95-1.84 (m, 2H), 1.40-1.27 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH3:19]I.[H-].[Na+]>CS(C)=O.CCCCC>[Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[N:6]([CH3:19])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: O=[N+]([O-])c1cc(Br)cc2c1[nH]c1ccc(Br)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CS(C)=O
Product: Cn1c2ccc(Br)cc2c2cc(Br)cc([N+](=O)[O-])c21
Reaction time: 0.03 h

Procedure:
3,6-dibromo-1-nitrocarbazole (3.56 g, 0.01 mole) was dissolved in 30 ml of warm DMSO followed by the addition of 30 ml of CH3I. Then 2.0 g of 50% NaH dispersion in mineral oil (0.02 mole) was washed under N2 with 2×50 ml of pentane, dried under N2 and added rapidly to the DMSO solution. The solution turned purple immediately with H2 evolution and became yellow in two minutes. Addition of 0.25 g of NaH did not cause the yellow slurrY to turn purple indicating that the reaction was complete. Methanol (200 ml) was added cautiously to precipitate the product. The product was recovered by filtration, washed with 25 ml of methanol, 10×25 ml of water, 25 ml of methanol and air dried to give 3.40 g of product, m.p. 225°-226° C. (corrected). [H. Lindemann & F. Muhlhaus, Ber., 58, 2371 (1925) report a m.p. of 221° C. for the product].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([O:13][C:14](=[O:22])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14](=[O:22])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2cccc(Br)n2)C1

Procedure:
The preparation is carried out analogously starting from 1 g (4.23 mmol) of 2,6-dibromopyridine and 845 mg (4.22 mmol) of piperidin-3-ylcarbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:43]=[CH:42][C:38]([CH2:39][CH2:40][NH2:41])=[CH:37][CH:36]=1>CN(C=O)C.C(OCC)(=O)C.Cl>[F:34][C:35]1[CH:43]=[CH:42][C:38]([CH2:39][CH2:40][NH:41][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([CH2:10][S:9][CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:12]=2)=[CH:37][CH:36]=1
Reactant: O=C(O)c1cccc(CSCCc2ccccc2)c1
Reactant: NCCc1ccc(F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCc1ccc(F)cc1)c1cccc(CSCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 3-(phenethylthiomethyl)benzoic acid (0.5 g, 1.84 mmol) in DMF (8 mL) were added EDC (0.49 g, 2.57 mmol), HOBT (0.28 g, 1.84 mmol) and 4-fluorophenethylamine (0.24 mL, 1.84 mmol). The clear reaction mixture was stirred at rt for 2 h and diluted with ethyl acetate and 1 N aqueous HCl solution. The organic layer was separated, washed with brine and dried over MgSO4. The filtrate was concentrated in vacuo. The residue was dissolved in DCM and purified by flash chromatography on silica gel eluting with 20% ethyl acetate in dichloromethane to give the desired product (0.34 g, 47%) as a white solid. 1H NMR (CDCl3) δ 7.61 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.20-7.11 (m, 5H), 6.97 (t, J=8.0 Hz, 2H), 6.11 (s, 1H), 3.69 (s, 2H), 3.67-3.63 (m, 2H), 2.94-2.79 (m, 4H), 2.63-2.61 (m, 2H). MS (ESI): 394.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:29])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37]C(NC1C(=O)N2[C@H](C(OC(C)(C)C)=O)CCC2=NC=1)=O)C1C=CC=CC=1.COCCl>>[C:1]([O:5][C:6]([C:8]1([CH2:29][O:37][CH3:30])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: COCCl
Product: COCC1(C(=O)OC(C)(C)C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 36 %

Procedure:
According to the procedure for the preparation of intermediate 19a, alkylation of intermediate 1g (250 mg, 0.649 mmol) with methoxymethylchloride afforded 101 mg (36%) of intermediate 23a. MS (ESI) 430.4 (M+H+), 452.4 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:19](#[N:21])[CH3:20]>>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:20][C:19]#[N:21])[CH:11]=[CH:12][CH:13]=1
Reactant: CC#N
Reactant: Cc1cccc(Cl)c1/C=C/c1cccc(C=O)c1
Product: Cc1cccc(Cl)c1/C=C/c1cccc(C(O)CC#N)c1

Procedure:
(E)-3-(2-Chloro-6-methylstyryl)benzaldehyde was reacted with acetonitrile according to the procedure used in Example 50. Purification by flash chromatography (10 to 70% EtOAc-hexanes gradient) gave (E)-3-(3-(2-chloro-6-methylstyryl)phenyl)-3-hydroxypropanenitrile as an oil. Yield 0.0708 g, 77%): 1H NMR (400 MHz, CDCl3) δ 7.51-7.53 (m, 2H), 7.41 (t, J=8.0 Hz, 1H), 7.25-7.33 (m, 2H), 7.07-7.20 (m, 3H), 6.80 (d, J=16.8 Hz, 1H), 5.08 (t, J=6.4 Hz, 1H), 2.80 (dd, J=6.4, 0.8 Hz, 2H), 2.43 (s, 3H).
Reaction SMILES: NC1(C2C=CC(C3[C:13](=[O:36])C4C(OC=3C3C=CC=CC=3)=C(C3C(C)=NN(C)C=3C)N=CC=4)=CC=2)CCC1.C([C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1[C:46]1[N:47]=[CH:48][CH:49]=[C:50]2[C:55](=[O:56])[C:54]([C:57]3[CH:62]=[CH:61][C:60]([C:63]4([NH:67]C(=O)OC(C)(C)C)[CH2:66][CH2:65][CH2:64]4)=[CH:59][CH:58]=3)=[C:53]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)[O:52][C:51]=12)#N.Cl.S(=O)(=O)(O)[OH:83]>O1CCOCC1>[NH2:67][C:63]1([C:60]2[CH:61]=[CH:62][C:57]([C:54]3[C:55](=[O:56])[C:50]4[C:51]([O:52][C:53]=3[C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)=[C:46]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:39]=3[C:13]([OH:36])=[O:83])[N:47]=[CH:48][CH:49]=4)=[CH:58][CH:59]=2)[CH2:66][CH2:65][CH2:64]1
Reactant: Cc1nn(C)c(C)c1-c1nccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccc(F)c5C#N)nccc4c3=O)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccc(F)c5C(=O)O)nccc4c3=O)cc2)CCC1

Procedure:
Following the procedure used to prepare 3-(4-(1-aminocyclobutyl)phenyl)-2-phenyl-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4H-pyrano[2,3-c]pyridin-4-one, tert-butyl (1-(4-(8-(2-cyano-3-fluorophenyl)-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl)carbamate was reacted with HCl in dioxane and further heated 5 min with concentrated sulphuric acid (0.1 mL) to give the title compound. (5 mg, 20%). 1H NMR (500 MHz, CD3OD): δ 8.65 (d, J=8.2 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.71-7.65 (m, 1H), 7.58-7.54 (m, 1H), 7.50-7.45 (m, 2H), 7.40-7.25 (m, 6H) 7.20-7.15 (m, 2H), 2.85-2.75 (m, 2H), 2.62-2.55 (m, 2H), 2.28-2.19 (m, 1H), 2.05-1.91 (m, 1H). LCMS (Method I): RT=4.25 min, [M+2]+=508.