Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.B(O)(O)[C:36]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][CH:37]=1>COCCOC.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>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:41]=3[C:42]([F:45])([F:44])[F:43])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3C(F)(F)F)c(-c3ccc(OC)cc3)c12
Reaction time: 15 h

Procedure:
Add 0.5 ml of 2 M aqueous potassium carbonate solution to a mixture of 224 mg (0.50 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 29 mg (0.03 mmol) tetrakis(triphenylphosphine)palladium(0) in 2.5 ml 1,2-dimethoxyethane. Next, add 119 mg (0.63 mmol) (2-trifluoromethyl)phenylboronic acid and stir the mixture for 15 h under reflux. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 118 mg (46% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH2:5][OH:6])[CH2:4][CH2:3]1.[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH3:1][C:2]1([CH2:5][O:6][C:14]2[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=2[C:12]#[N:13])[CH2:4][CH2:3]1
Reactant: CC1(CO)CC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC1(COc2cccc([N+](=O)[O-])c2C#N)CC1
Yield: 65 %

Procedure:
Prepared as in Example 166d from (1-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.44-0.46 (m, 2H), 0.57-0.59 (m, 2H), 1.22 (s, 3H), 4.06 (s, 2H), 7.67 (dd, J=1.6 Hz, J=8.0 Hz, 1H), 7.85-7.92 (m, 2H).
Reaction SMILES: [C:1](#[N:5])/[CH:2]=[CH:3]/[CH3:4].[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C.C(O)C>[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:3]([CH3:4])[CH2:2][C:1]#[N:5])[CH2:15][CH2:14]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C/C=C/C#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(CC#N)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
(E)-but-2-enenitrile (4.5 ml, 55.0 mmol) and triethylamine (2 drops) were added sequentially to a solution of piperidin-4-yl-carbamic acid tert-butyl ester (10 g, 50.0 mmol) in ethanol (120 ml) at 25° C. The reaction mixture was stirred at 60° C. for 1 week, then was cooled to 25° C. and concentrated under reduced pressure to afford crude [1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as tan oil. 1H NMR (400 MHz, CDCl3) δ 4.48 (s, 1H), 3.42 (s, 1H), 3.09-2.95 (m, 1H), 2.81-2.61 (m, 3H), 2.49 (dd, J=16.7, 6.0 Hz, 2H), 2.39-2.23 (m, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.44 (s, 9H), 1.18 (d, J=6.7 Hz, 3H). This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([C:25](=[O:27])[CH3:26])=[N:14][C:15]=2[C:16]2[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([C:25](=[O:27])[CH3:26])=[N:14][C:15]=2[C:16]2[CH:21]=[C:20]([S:22]([CH3:23])=[O:33])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(C)=O)nc2-c2cc(SC)nc(C)n2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncc(C(C)=O)nc2-c2cc(S(C)=O)nc(C)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(5-(6-methoxypyridin-3-ylamino)-6-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)ethanone (25 mg, 0.065 mmol) and 3-chloroperoxybenzoic acid (22.5 mg, 0.131 mmol, Aldrich) in dioxane (1 mL) was stirred at room temperature for 2 h. The reaction mixture was taken on directly to the next step without work-up.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][O:9][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cccc(CCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CCOc2ccc([N+](=O)[O-])cn2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 4.8 g of sodium hydride (50% oily suspension) in 130 ml of dimethylformamide, was added dropwise 13.6 g of 3-methylphenethyl alcohol in 20 minutes, and the resultant mixture was heated at 60° C. for 2 hours. After cooling, a solution of 15.9 g of 2-chloro-5-nitropyridine in 80 ml of dimethylformamide was added dropwise thereto at a temperature below 20° C. under ice-cooling. After standing at room temperature overnight, the reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extracts were washed with water and dried over magnesium sulfate. The oily products were purified by column chromatography on silica gel using benzene as an eluent to give 20.4 g of 2-(3-methylphenethyloxy)-5-nitropyridine as white crystals. M.P., 73.5°-74.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]O)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1.S(Cl)([Cl:47])=O.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][Cl:47])[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1
Reactant: CCc1cc(NC(CC)CCCCCCO)nc(Cl)n1
Reactant: O=S(Cl)Cl
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCc1cc(NC(CC)CCCCCCCl)nc(Cl)n1
Yield: 59.4 %

Procedure:
To a mixture of 0.9 g of dl-5-chloro-6-ethyl-4-(1-ethyl-7-hydroxyheptyl)aminopyrimidine and 0.28 g of pyridine was gradually added dropwise 0.42 g of thionyl chloride under cooling to -10° to -5° C. After dropwise addition, the mixture was heated at 60° to 70° C. for one hour and allowed to stand for cooling. The reaction mixture was neutralized with an aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=10:1) to give 0.55 g of the title compound as pale yellow oily liquid. nD22.8 1.5246.
Reaction SMILES: [ClH:1].O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].O.[CH2:15]([NH2:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(O)(C)C>[ClH:1].[CH2:15]([NH:33][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6.45 g of D-glucosamine hydrochloride were dissolved in 30 ml of isopropanol and 10 ml of water at 60° C., and 12.1 g of stearylamine were added. The resulting clear solution was subsequently stirred for a further 10 minutes and then cooled to room temperature. The product which crystallized out was filtered off with suction and washed first with ethanol/water (5:2, v/v), then with ethanol and finally with ether. The residue was dried under a high vacuum.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH2:18])[C:7]([NH2:17])=[CH:8][C:9]=1[N:10]1[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11]1.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][C:21]=1[N:34]=[C:35]=S.CCN(C(C)C)C(C)C>CC#N>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][C:21]=1[NH:34][C:35]1[NH:18][C:6]2[CH:5]=[C:4]([Cl:3])[C:9]([N:10]3[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11]3)=[CH:8][C:7]=2[N:17]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: Nc1cc(Cl)c(N2CCC(F)(F)C2)cc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(N4CCC(F)(F)C4)c(Cl)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-5-(3,3-difluoropyrrolidin-1-yl)benzene-1,2-diamine dihydrochloride (340 mg, 1.1 mmol) was added to N-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (300 mg, 1.1 mmol) in MeCN (10 mL) and stirred at rt overnight. After addition of DIPEA (0.41 μL, 2.3 mmol) the reaction mixture was stirred at rt for 4.5 h. The mixture was concentrated. The crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])(CC)C.B(OC)(OC)OC.C(=O)([O-])[O-].[Na+].[Na+].Br[C:25]1[CH:26]=[C:27]([O:31][CH2:32][C@@H:33]2[CH2:37][CH2:36][CH2:35][N:34]2[CH3:38])[CH:28]=[N:29][CH:30]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O.C1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:25]1[CH:26]=[C:27]([O:31][CH2:32][C@@H:33]2[CH2:37][CH2:36][CH2:35][N:34]2[CH3:38])[CH:28]=[N:29][CH:30]=1
Reactant: c1ccoc1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: COB(OC)OC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O
Product: CN1CCC[C@H]1COc1cncc(-c2ccco2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of furan (1.45 mL, 20.0 mmol) in THF (30.0 mL) was added sec-butyllithium (1.3M, 7.69 mL, 10.0 mmol) at -78° C. After half an hour at this temperature, trimethyl borate (2.27 mL, 20.0 mmol) was added. The reaction mixture was stirred at -78° C. for one hour and slowly warmed up to room temperature. Solvent was removed, and benzene (10.0 mL), sodium carbonate (2.0M, 5.0 mL), tetraids(triphenylphosphine)palladium(0) (175 mg) and 5-bromo-3-(1- methyl-2-(S)-pyrrolidinylmethoxy)pyridine (1.36 g, 5.0 mmol) were added. The reaction mixture was refluxed overnight, then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgS04, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (1.27 g, 99%). MS (CI/NH3) m/z 259 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.70-2.22 (m, 4H), 2.28-2.40 (m, 1H), 2.51 (s, 3H), 2.66-2.75 (m, 1H), 3.10-3.18 (m, 1H), 3.97-4.11 (m, 2H), 6.51 (dd, J=4.8 Hz, J=3.6 Hz, 1H), 6.74 (d, J=4.9 Hz,, 1H), 7.47 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 7.53 (d, J=3.6 Hz, 1H), 8.22 (d, J=3.0 Hz, 1H), 8.54 (d, J=2.1 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:17][C:18]1[S:19][CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:34]=[C:33]([Sn](C)(C)C)[CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][N:30]3S(C2C=CC=CC=2)(=O)=O)=[O:24])[N:22]=1.CN(C=O)C>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.CO>[CH:14]1([S:11]([NH:10][C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[C:31]4[C:27]([CH:28]=[N:29][NH:30]4)=[C:26]([NH:25][C:23]([C:21]4[N:22]=[C:18]([CH3:17])[S:19][CH:20]=4)=[O:24])[CH:34]=3)[CH:7]=[N:6][C:5]=2[O:8][CH3:9])(=[O:13])=[O:12])[CH2:16][CH2:15]1
Reactant: COc1ncc(Br)cc1NS(=O)(=O)C1CC1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)C1CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
N-[5-Bromo-2-(methyloxy)-3-pyridinyl]cyclopropanesulfonamide (208 mg, 0.371 mmol), 2-methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (128 mg, 0.417 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol) were weighed to a microwave vial. DMF (3 ml) was added and the reaction was heated in the microwave at 120° C. for 30 min. LCMS showed incomplete reaction, therefore the mixture was reheated at 120° C. for a further 30 min. The residue was passed through a 1 g silica cartridge, pre-conditioned with methanol, washing with methanol. The solvent was evaporated in the blow down unit. The residue was purified on a 40 g silica cartridge on the ISCO Companion, using a 0.5-6% methanol in DCM gradient over 14 mins at a flow rate of 40 ml/min. Fractions containing desired material were combined and concentrated in vacuo, then subjected to further purification on the ISCO companion using a reverse phase 13 g column, with 0.1% TFA in MeCN and 0.1% TFA in water as eluents and a gradient of 15-65% MeCN over 14 mins. Fractions containing desired material were combined and concentrated in vacuo. The residue was dissolved in IPA (3 ml) and 2M NaOH (aq., 3 ml) was added and the reaction mixture left overnight. The IPA was evaporated and the aqueous was acidified using 2M HCl (aq). The precipitate was filtered, washing with water, then dissolved in 1 ml DMSO:methanol (1:1, v/v) and purified by MDAP (Method E) to afford the title compound (27 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=1[CH2:18][NH:19][C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C(O)CO>C(O)(C)C.[Cu](I)I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:22]2[CH2:23][CH2:24][CH:20]([NH:19][CH2:18][C:17]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:16]=3[Cl:15])[CH2:21]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Reactant: Clc1ccc(I)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Clc1ccc(CNC2CCN(c3ccc(Cl)nc3)C2)c(Cl)c1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
Add 2-chloro-5-iodopyridine (193 mg, 0.84 mmol) to a mixture of potassium carbonate (344 mg, 1.61 mmol) and copper iodide (7 mg, 5% mol) and purge with nitrogen for 10 min. Add a solution of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (238 mg, 0.97 mmol) in ethylene glycol (0.09 mL, 1.61 mmol) and isopropanol (1 mL). Stir at 80° C. for 4 days. Add water (2 mL) and extract with ethyl acetate, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and chromatograph using preparative mass guided chromatography to give the title compound. Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (400 MHz, MeOH-d4) δ 7.79 (1H, d, J=2.69 Hz), 7.63-7.70 (2H, m), 7.49 (1H, dd, J=8.31, 1.96 Hz), 7.34 (1H, d, J=8.80 Hz), 7.21 (1H, dd, J=8.80, 2.93 Hz), 4.48 (2H, s), 4.17-4.24 (1H, m), 3.72-3.79 (1H, m), 3.61-3.68 (2H, m), 3.38-3.44 (1H, m), 2.59-2.69 (1H, m), 2.32-2.33 (1H, m), 2.32-2.40 (1H, m), MS (ES): m/z=356 [M+].
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:15]([O:19][C:20]([NH:22][C@H:23]1[CH2:28][O:27][CH:26]([CH2:29][C@@H:30]2[O:45][C:33]3[CH:34]=[N:35][C:36]4[CH:37]=[CH:38][C:39]([O:43][CH3:44])=[C:40]([F:42])[C:41]=4[C:32]=3[CH:31]2OC(=O)C)[CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:15]([O:19][C:20](=[O:21])[NH:22][C@@H:23]1[CH2:24][CH2:25][C@@H:26]([CH2:29][CH:30]2[O:45][C:33]3[CH:34]=[N:35][C:36]4[CH:37]=[CH:38][C:39]([O:43][CH3:44])=[C:40]([F:42])[C:41]=4[C:32]=3[CH2:31]2)[O:27][CH2:28]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: COc1ccc2ncc3c(c2c1F)C(OC(C)=O)[C@H](CC1CC[C@@H](NC(=O)OC(C)(C)C)CO1)O3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc2ncc3c(c2c1F)CC(C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1)O3
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (833 mg, 3.67 mmol, 5.0 eq) is added at room temperature to a stirred solution of acetic acid 2-(2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-ylmethyl)-9-fluoro-8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-1-yl ester (360 mg, 0.73 mmol, 1.0 eq) in toluene (60 mL). After 2 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×100 mL) and a saturated sodium carbonate aqueous solution (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: n-hexane:ethyl acetate, 10:1 to 1:1, v/v) to afford (3R,6S)-[6-(9-fluoro-8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-2-ylmethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester as a light yellow solid (75 mg, 24% yield).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[C:13]([Cl:37])=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[CH:19][CH:18]=[CH:17][CH:16]=2>>[CH2:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][CH2:23][N:22]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([Cl:37])[C:12]=2[N:11]=[CH:1]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(Cl)nc2ccccc2c1NCCCNC(=O)OCc1ccccc1
Product: O=C(NCCCn1cnc2c(Cl)nc3ccccc3c21)OCc1ccccc1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
0.52 ml (3.12 mmol) of triethyl ortho-formate was added to 0.12 g (0.312 mmol) of of 3-amino-4-[3-(benzyloxycarbonylamino)propylamino]-2-chloroquinoline. The mixture was heated at 100° C. and stirred for 3.5 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.12 g (0.304 mmol) of 1-[3-(benzyloxycarbonylamino)propyl]-4-chloro-1H-imidazo[4,5-c]-quinoline (shown below) as a pale yellow solid.
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[C:15]1[C:13]1[O:14][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cc3ccccc3[nH]2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc2nc(-c3cc4ccccc4[nH]3)oc12
Yield: 47.9 %

Procedure:
Methyl 2-hydroxy-3-(1H-indole-2-carboxamido)benzoate (170 mg, 0.5 mmol) and 4-methylbenzenesulfonic acid monohydrate (400 mg, 4.0 mmol) were added to xylene (10 mL) and the mixture was stirred at reflux for 10 hr. The resulting mixture was extracted with dichloromethane (100 mL×4) and concentrated. Then the crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1) to obtain methyl 2-(1H-indol-2-yl)benzo[d]oxazole-7-carboxylate as a solid (70 mg, yield 43%). LC-MS (ESI) m/z 293 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6]1.[BH4-].[Na+].O.CCCCCC>C(O)C.CCOCC>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]([CH:18]([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6]1
Reactant: CN(C)CCN1CCC(O)(c2ccccc2)C(C(=O)c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCN1CCC(O)(c2ccccc2)C(C(O)c2ccccc2)C1
Temperature: 50 °C

Procedure:
10.0 Parts of 1-(2-dimethylaminoethyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine is dissolved in 70 parts of ethanol. To this solution is slowly added 10.0 parts of sodium borohydride and the mixture heated to about 50°C. for 1/2 hour. After cooling to room temperature, the reaction mixture is poured into water. The resulting mixture is extracted three times with ethyl ether and the extracts are combined, dried over magnesium sulfate, and stripped of solvent under reduced pressure to give an oil. This oil is dissolved in ether and n-hexane added to the point of cloudiness. Cooling and filtration of the resulting crystals affords 1-(2-dimethylaminoethyl)-3-(α-hydroxybenzyl)-4-hydroxy-4-phenylpiperidine, melting at 157°-158°C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)O1.Cl[C:24]1[N:29]=[C:28]([C:30]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:27]=[C:26]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][C@@H:44]2[CH3:49])[N:25]=1.C(O)C>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([S:33]([C:30]([C:28]2[CH:27]=[C:26]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][C@@H:44]3[CH3:49])[N:25]=[C:24]([C:15]3[CH:16]=[CH:17][C:18]([NH2:19])=[CH:20][CH:21]=3)[N:29]=2)([CH3:32])[CH3:31])(=[O:34])=[O:35])=[CH:37][CH:38]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(Cl)cc2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
Sodium carbonate (2M in water, 6.69 mL, 13.38 mmol) was added to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.815 g, 3.72 mmol) and 2-chloro-4-[2-(4-chlorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.60 g, 3.72 mmol) in a mixture of DME (10 mL), ethanol (10.00 mL), DMF (10.00 mL) and water (20 mL) at RT under nitrogen. The mixture was degassed and purged with nitrogen three times. Bis(triphenylphosphine)palladium(II) chloride (0.130 g, 0.19 mmol) was added and the mixture was degassed and purged with nitrogen a further three times. The resulting suspension was stirred under nitrogen at 80° C. for 90 minutes. The reaction mixture was concentrated and diluted with ethyl acetate (150 mL) and washed with water (2×150 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 45% ethyl acetate in isohexane, to give the desired material as a white solid (1.502 g).