Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42](C=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.[C:57](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[NH4+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:50][N:51]6[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]6)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (0.033 g, 0.05 mmol) and 1-methylpiperazine (0.025 g, 0.25 mmol) were combined in CH2Cl2 (2 mL) and stirred for 30 min. Sodium triacetoxyborohydride (0.053 g, 0.25 mmol) was added and the mixture stirred overnight. Aqueous workup followed using a Gilson HPLC with an ammonium hydroxide system gave the title compound as a white solid. LC-MS m/z 743.2 (M+H)+, 1.42 min (ret time); mp 121-124° C.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:15][C:12]1[N:11]=[C:10]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:17])[C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)ccc1OCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc(Br)ccc1O
Reaction time: 12 h
Yield: 55.9 %

Procedure:
To a solution of 3-(benzyloxy)-6-bromo-N-(4-fluorobenzyl)picolinamide (50 mg, 0.11 mmol) in CH2Cl2 (5 mL) was added BBr3 (1.5 mL) dropwise at −78° C. under N2. The mixture was allowed to room temperature and stirred for another 12 hours. Then CH3OH was added and the mixture was adjusted to pH=7 by saturated K2CO3. The mixture was extracted with EtOAc and the combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (PE:EtOAc=5:1) to afford the product of 6-bromo-N-(4-fluorobenzyl)-3-hydroxypicolinamide (20 mg, yield: 57%). 1H-NMR (CDCl3, 400 MHz) δ 12.04 (s, 1H), 8.02 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.24˜7.28 (m, 2H), 7.15 (d, J=8.8 Hz, 1H), 6.96˜7.00 (m, 2H), 4.52 (d, J=6.4 Hz, 2H). MS (M+H)+: 325/327.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:34])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:15]([C:26]#[C:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]=1)=[O:11])C)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[CH:9]([NH:7][CH3:6])[CH3:34])=[N:14][C:15]=1[C:26]#[C:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C(=O)Nc1ccc(Cc2ccccc2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)Nc1ccc(Cc2ccccc2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-benzyl-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate E2d (26 mg, 0.6 mmol) and DCM:TFA (9:1, 2 ml) is stirred at RT for 90 minutes. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 4 mg (20%). HPLC-MS: M+H=370; tR=2.16 min (*Method—1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Si](C)(C)[CH3:16].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl.N1C=CC=CC=1>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:1][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])=[C:3]([CH:7]=1)[C:4]([O:6][CH3:16])=[O:5])([O-:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-5-nitrobenzoic acid (151 mg, 0.77 mmol) in dichloromethane (2.0 mL) was treated with chlorotrimethylsilane (1.70 mL of 1M solution in CH2Cl2, 1.70 mmol) and pyridine (2.0 mL), stirred at room temperature for 30 minutes, treated with benzenesulfonyl chloride (150 μL, 1.16 mmol), stirred overnight at room temperature, warmed to 40° C., stirred overnight, treated with 1N HCl (2.0 mL), and extracted with dichloromethane (2×). The combined extracts were washed with distilled water and brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(−)) m/e 335 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.58 (d, 1H), 8.39 (dd, 1H), 7.96 (m, 2H), 7.74-7.60 (m, 4H), 3.91 (s, 3H).
Reaction SMILES: CCC[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1.[Na].[NH:15]1[CH:19]=[CH:18]N=N1>CN(C=O)C.CO.C(Cl)Cl>[N:9]1([CH:7]2[CH:6]3[CH2:5][CH2:4][N:15]([CH2:19][CH2:18]3)[CH2:8]2)[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: c1nc[nH]n1
Reactant: c1c[nH]nn1
Reactant: CCCCCCCC
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ncn(C2CN3CCC2CC3)n1
Temperature: 25 °C

Procedure:
To a solution of (±)3-methanesulphonyloxy-1-azabiyclo[2.2.2]octane (1.3 g; 6.3 mmol) in dry DMF (20 mL) was added 1,2,4-triazole, sodium salt (1.5 g; 21 mmol). The resulting mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was taken up into 1M Na2CO3 and extracted into CH2Cl2 (3×50 mL). The organics were combined, dried (Na2SO4), filtered, and evaporated to yield 0.57 g of a crude yellow oil. MPLC (Al2O3 ; 2% MeOH/CH2Cl2) provided two fractions, the first containing a byproduct and the second containing the triazole. Yield 300 mg (27%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Na].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24].[H-].[Na+].C1(O)C=CC=CC=1>CN(C)C=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:19][C:18]=1[CH3:24]
Reactant: Cc1cc(O)ccc1Cl
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: COC(=O)c1cc(Oc2ccc(Cl)c(C)c2)ccc1[N+](=O)[O-]

Procedure:
Methyl 5-fluoro-2-nitrobenzoate was reacted with the sodium salt of 4-chloro-3-methylphenol (prepared from sodium hydride and the phenol) in dimethylformamide at 100° C. for 2.5 hours and the resulting methyl 5(4-chloro-3-methylphenoxy)-2-nitrobenzoate isolated in the usual way; the ester had a melting point of 85°-87° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[C:22]([O:39][CH3:40])[CH:21]=4)[CH:18]=3)[N:13]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:12]=2)[CH:8]=[N:7]1.CO.[ClH:56]>C(OCC)C>[ClH:56].[F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[C:22]([O:39][CH3:40])[CH:21]=4)[CH:18]=3)[N:13]([S:41]([C:44]3[CH:45]=[CH:46][C:47]([CH3:48])=[CH:49][CH:50]=3)(=[O:42])=[O:43])[CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCNCC1
Yield: 69 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)piperazine-1-carboxylate (190 mg, 0.257 mmol) was deprotected in methanol/HCl in diethyl ether (5/3 ml) to afford 120 mg (69.0% yield) of the titled compound. MS: m/z=637.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[CH:19]=[CH2:20]>[C].[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:6]=2[CH2:19][CH3:20])=[C:2]([F:1])[CH:24]=1
Reactant: C=Cc1c(Oc2ccc([N+](=O)[O-])cc2F)ccnc1NC(=O)OC(C)(C)C
Agent: [Pd]
Product: CCc1c(Oc2ccc(N)cc2F)ccnc1NC(=O)OC(C)(C)C
Yield: 88.6 %

Procedure:
A solution of tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridin-2-ylcarbamate (48 mg, 0.13 mmol) was hydrogenated over 10% palladium-carbon (10 mg) and Pt2O (5 mg) for 1.5 h using H2 from a rubber balloon. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to give the title compound (40 mg, 89%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 9.04 (s, 1H), 8.03 (d, 1H, J=5.6 Hz), 6.95 (dd, 1H, J=8.6, 8.6 Hz), 6.50 (dd, 1H, J=2.5, 13.2 Hz), 6.41 (dd, 1H, J=2.5, 9.4 Hz), 6.36 (d, 1H, J=5.6 Hz), 5.44 (s, 2H), 2.67-2.62 (m, 2H), 1.43 (s, 9H), 1.11 (t, 3H, J=7.1 Hz); MS(ESI+): m/z 348.22 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:3]1.[C:17]1([CH:23]([N:30]=[C:31]=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH:23]([NH:30][C:31]([N:7]1[CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:3][CH:2]1[CH3:1])=[O:32])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: CC1CN(CC2CCN(C)CC2)CC(C)N1
Solvent: ClCCl
Product: CC1CN(CC2CCN(C)CC2)CC(C)N1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
To a solution of 3,5-dimethyl-1-((1-methylpiperidin-4-yl)methyl)piperazine (0.2 g, 1 mmol) dissolved in methylene chloride (5 ml) was added diphenylmethyl isocyanate (0.227 g, 1.09 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.12 g of desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:9]([CH3:17])([CH3:18])[CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:28](=[O:30])[NH:19][C:4]=2[CH:3]=1
Reactant: CC(C)(CN1CCOCC1)Nc1ccc(Br)cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CN1CCOCC1)n1c(=O)[nH]c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 139.1 %

Procedure:
Mix 4-bromo-N1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-benzene-1,2-diamine (3.76 g, 11.5 mmol), triethylamine (4.6 mL, 34.4 mmol) in THF (150 mL). Cool to 0° C. and carefully add solid triphosgene (2.0 g, 6.9 mmol). Allow the reaction to warm to room temperature and stir for 18 h. Cautiously quench the reaction with aqueous K2CO3 and extract into EtOAc. Dry (MgSO4) and concentrate to give 3.4 g yellow solid. Purify by column chromatography using 3% 3N NH3 in MeOH/methylene chloride to give 2.25 g (55%) title compound as a white solid, MS (es) 354, 356 (M+1), 352, 354 (M−1). HPLC(ISO80-10M) t=1.55.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([CH3:17])[N:3]=1.O.O.O.O.O.O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CC(C)=O.O1CCOCC1>[CH3:17][C:4]1[N:3]=[C:2]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: C1CNCCN1
Reactant: Cc1nc(Cl)nc(N2CCOCC2)c1[N+](=O)[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(N2CCNCC2)nc(N2CCOCC2)c1[N+](=O)[O-]

Procedure:
A solution of 2.6 gm (0.01 mol) of 2-chloro-6-methyl-4-morpholino-5-nitro-pyrimidine (m.p. 127°-129°C, prepared from 2,4-dichloro-6-methyl-5-nitro-pyrimidine and morpholine) in 100 ml of acetone/dioxane (1:1) was added dropwise, while stirring and cooling, to a solution of 19.4 gm (0.1 mol) of piperazine hexahydrate in 300 ml of acetone/dioxane (1:1) at about 5°C. After about 1 hour the solvents were distilled off in vacuo, and the residue was taken up in about 100 ml of water. The insoluble reaction product was suction-filtered off, washed with water and dried. Yield: 3.0 gm (97% of theory). After one reprecipitation from about 0.2 N hydrochloric acid with 2 N ammonia, the reaction product of the formula ##SPC5##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[Cl:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1cc(Cl)ccc1Cl
Temperature: 50 °C
Yield: 50.1 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 444 mg, 2.0 mmol), 2,5-dichlorophenylboronic acid (Aldrich; 274 mg, 1.44 mmol), copper(II) acetate (363 mg, 2.0 mmol) and triethylamine (280 μL, 2.0 mmol) in 1,2-dichloroethane (3 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-benzyl-N′-(2,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (265 mg, 50%) as a colorless oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH:44]=O)[CH:42]=[CH:43][C:36]1=2>C(O)C.C(O)(=O)C.[C].[Pd]>[C@@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=2[C:32](=[O:34])[CH2:33][CH2:44][C:41]2[CH:42]=[CH:43][C:36]3[O:35][CH2:39][CH2:38][C:37]=3[CH:40]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: O=Cc1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(CCc1ccc2c(c1)CCO2)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 78.4 %

Procedure:
2'-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-hydroxyacetophenone (1268 mg) and benzo[b]furan-5-carbaldehyde (911 mg) are treated in the same manner as in Example 1 to give crude 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)acrylophenone. This product is dissolved in a mixture of ethanol (20 ml) and acetic acid (2 ml), and the mixture is subjected to catalytic hydrogenation by using 10% palladium-carbon (0.5 g) under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue are added ethyl acetate and water, and the mixture is stirred. The organic layer is collected, washed with a saturated aqueous sodium hydrogen carbonate solution, dried, and evaporated to remove the solvent. The residue is pulverized with chloroform-diisopropyl ether, and the obtained powder is collected by filtration and dried to give 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(2,3-dihydro-5-benzo[b]furanyl)propiophenone (920 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:20]1[N:29]=[C:28]([Cl:30])[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[N:21]=1>CN(C)C=O>[ClH:30].[CH3:9][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:28]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[N:21]=[C:20]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)[N:29]=1
Reactant: Clc1nc(N2CCc3ccccc3C2)nc2c1CCCC2
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2)nc2c1CCCC2
Product: Cl
Yield: 47.1 %

Procedure:
After 4-fluoro-2-methylaniline(0.3 ml, 2.7 mmol) was added to a mixture solution of 2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloro-5,6,7,8-tetrahydroquinazoline(0.3 g, 1.0 mmol) and dimethylformamide(5 ml), 0.2 g of the titled compound was prepared in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [OH:1][C:2]([C:35]([F:38])([F:37])[F:36])([CH2:18][C:19]([C:22]1[C:30]2[O:29][CH2:28][CH2:27][C:26]=2[CH:25]=[C:24]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:23]=1)([CH3:21])[CH3:20])[CH2:3][C:4]#[C:5][C:6]1[C:13]([N+:14]([O-])=O)=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:17].C(O)(=O)C>C(O)C.ClCCl.[Fe]>[NH2:14][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([CH3:17])[C:6]=1[C:5]#[C:4][CH2:3][C:2]([OH:1])([C:35]([F:37])([F:38])[F:36])[CH2:18][C:19]([C:22]1[C:30]2[O:29][CH2:28][CH2:27][C:26]=2[CH:25]=[C:24]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:23]=1)([CH3:21])[CH3:20])[C:10]#[N:11]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Temperature: 90 °C
Yield: 90 %

Procedure:
A stirred solution of 4-[4-hydroxy-6-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-ynyl]-3-methyl-5-nitrobenzonitrile. (165 mg, 0.3 mmol) in 6 mL of absolute ethanol was treated with 4 mL of glacial acetic acid and iron powder (335 mg, 6 mmol). The resulting mixture was heated at 90° C. for 30 minutes, cooled to room temperature, diluted with 200 mL of dichloromethane, and filtered through a pad of CELITE® filter aid. The filtrate was washed with three 50 mL portions of saturated aqueous sodium carbonate solution and two 25 mL portions of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 140 mg of 3-amino-4-[4-hydroxy-6-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-ynyl]-5-methylbenzonitrile as a light brownish oil (90% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH2:17]O)[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc2c(c3c1ncn3CCCO)CCCC2
Solvent: CN(C)C=O
Product: Nc1nc2c(c3c1ncn3CCCCl)CCCC2

Procedure:
Dimethylformamide was added dropwise to 4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-propanol (1.06 g) until a solution was obtained. Thionyl chloride (0.63 mL) was added and the reaction mixture was heated for 45 minutes before being evaporated to dryness. The residue was taken up in ice water then made basic with saturated sodium bicarbonate solution. The resulting precipitate was collected and dried to provide 0.32 g of a dark brown solid. This material was purified by silica gel column chromatography eluting with 85:15 methylene chloride:methanol to provide 0.28 g of the desired product as a solid m.p. 245°-247° C. Analysis: Calculated for C13ClH17N4 +1.5H2 0: % C, 53.51; % H, 6.91; % N, 19.2; Found: % C, 53.81; % H, 6.25; % N, 18.86.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1([CH2:20][CH3:21])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].ClC1C(=O)C(C#N)=C(C#N)C(=[O:31])C=1Cl>C1COCC1.O.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1([CH2:20][CH3:21])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:31])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Reaction time: 8 h

Procedure:
The ester produced in step A (0.5g, 1.66 mmol) was dissolved in 5 ml of a 90% THF/water solution, and to this was added 2,3-dichloro-5,6-dicyano-1,4 -benzoquinone (0.75 g, 3.3 mmol., previously dissolved in 5 ml THF). This mixture was stirred overnight. The solvent was evaporated and 50 ml of ethyl acetate was added. The organic phase was extracted sequentially with 2.5N NaOH, distilled water and brine. The organic layer was separated, dried (MgSO4) and evaporated to produce 0.56 g of crude oil. The oil was flash chromatographed using CH2Cl2 --EtOAc 98-2 as eluant to yield 0.15 g of the desired product as a solid, m.p. 187°-189° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](#[N:30])[CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH3:29].N12CCCN=C1CCCCC2>C(#N)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][C:23]#[N:30])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CCCCC=CC#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (6.1 g, 19 mmol) in acetonitrile (58 mL) was added crude hept-2-enenitrile (2.6 g, 23 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.49 mL, 23.4 mmol). The resulting mixture was stirred at room temperature over the weekend and then evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% of ethyl acetate in hexane, to give the desired product (6.90 g, 84%). LCMS calculated for C22H33N6OSi(M+H)+: m/z=425.2. Found: 425.4. The racemic mixture was applied on an OD-H column (3×25 cm, 5 μM), eluting with 15% ethanol and 85% hexane mixture at a flow rate of 28 mL/min to give the two desired enantiomers. First peak retention time of 9.46 min; second peak (3.45 g) retention time of 12.35 min.