Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]#[C:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[C:22][CH2:23][NH:24]C(=O)OCC2C=CC=CC=2)=[N:19][CH:20]=1)=O)C1C=CC=CC=1.[H][H]>CO>[NH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[N:19][CH:20]=1
Reactant: [H][H]
Reactant: O=C(NCC#Cc1ccc(C#CCNC(=O)OCc2ccccc2)nc1)OCc1ccccc1
Solvent: CO
Product: NCCCc1ccc(CCCN)nc1
Yield: 104.4 %

Procedure:
A solution of 2,5-di(3-benzyloxycarbonylaminoprop-1-ynyl)pyridine (8-1) (8.0 g) in methanol (160 mL) was hydrogenated under 20 psi of hydrogen gas pressure in the presence of 5%-Pd/Al2O3 (1.1 g) for 16 hours. The catalyst was filtered through Solka-flok and washed with methanol. The filtrate and wash were combined and concentrated under reduced pressure to give 12-1 (3.56 g) as a crystalline compound; m.p. 116-119° C.
Reaction SMILES: [Li+].[BH4-].[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20](OCC)=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[CH2:20][OH:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: O=C1N2C[C@@H](CC[C@H]2CO)N1OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
LiBH4 (0.54 g, 24.67 mmol) was added to a solution of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (5 g, 16.44 mmol) in MeOH (50 mL) at −10° C. After 15 min, another portion of LiBH4 (0.54 g, 24.67 mmol) was added and the mixture was stirred at −10 to 0° C. for 4-5 h. The reaction mixture was carefully quenched by addition of sat. NaH2PO4 (50 mL) at 0° C. The mixture was diluted with water (20 mL) and extracted with DCM three times. The combined organic layer was concentrated and purified by silica gel column chromatography (gradient elution 0-100% petroleum ether/EtOAc, then 0-2% MeOHEtOAc) to give (2S,5R)-6-(benzyloxy)-2-(hydroxymethyl)-1,6-diazabicyclo[3.2.1]octan-7-one (3.8 g, 88%) as a white solid. ESI-MS (EI+, m/z): 263.1. 1H-NMR (500M, CDCl3): 7.44-7.35 (m, 5H), 5.05 (d, J=11.5 Hz, 1H), 4.90 (d, J=11.5 Hz, 1H), 3.73-3.69 (m, 1H), 3.61-3.58 (m, 2H), 3.33 (m, 1H), 3.01 (br d, J=12.0 Hz, 1H), 2.91 (m, 1H), 2.03-1.95 (m, 2H), 1.58-1.54 (m, 1H), 1.39-1.24 (m, 1H).
Reaction SMILES: CN(C)CCC[OH:6].[OH-].[K+].Cl/[C:11](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:12]\[C:13]1[C:18]([C:19]#[N:20])=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)[N:16]=[C:15]2[NH:29][N:30]=[C:31]([CH3:32])[C:14]=12.B(Br)(Br)Br>CS(C)=O.O>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[N:16]=[C:15]3[NH:29][N:30]=[C:31]([CH3:32])[C:14]3=[C:13]([CH2:12][C:11](=[O:6])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:18]=2[C:19]#[N:20])=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2nc3[nH]nc(C)c3c(/C=C(\Cl)c3ccccc3)c2C#N)cc1
Reactant: CN(C)CCCO
Agent: BrB(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)c(C#N)c(CC(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
36 g (350 mmol) of 3-(dimethylamino)propan-1-ol and 12 g (21.4 mmol) of potassium hydroxide are added to 12 g (30 mmol) of Z-4-(2-chloro-2-phenylvinyl)-6-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile dissolved in 100 ml of dimethylsulfoxide and 36 ml of water. The reaction mixture is carried at 120° C. for 3 hours. The reaction medium is cooled to room temperature and then poured over crushed ice. The product is extracted with ethyl acetate. The organic phases are dried on sodium sulfate, filtered and then concentrated. The residue is purified immediately by silica gel chromatography (eluent: 95:5 dichloromethane/methanol). The product is then dissolved in 100 ml of dichloromethane. The reaction medium is cooled in an ice bath before 36 ml (376.5 mmol) of boron tribromide is added slowly. The reaction medium is stirred at room temperature for 3 hours and then added slowly to crushed ice. The solid is filtered, rinsed with water, dried and then purified by silica gel chromatography (eluent: 5:5 cyclohexane/ethyl acetate) to yield 6 g (54%) of 6-(4-hydroxyphenyl)-3-methyl-4-(2-oxo-2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:10]=2[NH2:11])=[CH:5][CH:4]=1>C(O)(=O)C.C(O)C.[Fe]>[NH2:11][C:10]1[C:9]([O:8][CH2:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:16]
Reactant: COc1ccc(COc2cccc([N+](=O)[O-])c2N)cc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(COc2cccc(N)c2N)cc1
Yield: 84.2 %

Procedure:
To a solution of 2-(4-methoxybenzyloxy)-6-nitroaniline (3 g) in acetic acid (6 ml) and ethanol (24 ml) was added iron (3.06 g), and the mixture was refluxed for 3 hours. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue was added saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diethyl ether to give 2-amino-3-(4-methoxybenzyloxy)aniline (2.25 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:16]=3)=[CH:13][CH:12]=[C:11]([CH3:41])[N:10]=2)[CH:5]=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O.OS(C(F)(F)F)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][CH:12]=[C:11]([CH3:41])[N:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(C)nc3Nc3cncc(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(C)nc(N)n2)c(Nc2cncc(F)c2)n1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
A solution of 4-(2-(5-fluoropyridin-3-ylamino)-6-methylpyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (118 mg, 0.214 mmol) in 2 mL of TFA was treated with 2 drops of triflic acid. The brown solution was heated in an oil bath at 80° C. for 8 h. The solution was concentrated and the residue was stirred in 5 mL of EtOAc and 2 mL of 0.5 N NaOH. The precipitated solid was collected by filtration, rinsed with 2×2 mL of water, followed by 2 mL of EtOAc and 2×2 mL of DCM. The yellow crystalline solid was collected and dried in a vacuum oven at 40° C. for 18 h to give 4-(2-(5-fluoropyridin-3-ylamino)-6-methylpyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (60 mg, 0.193 mmol, 90% yield). 1H NMR (400 MHz, d6-DMSO) δ 12.33 (1H, s); 8.66 (1H, s); 8.73 (1H, d, J=8.2 Hz); 8.60 (1H, d, J=12.9 Hz); 8.16 (1H, s); 7.90 (1H, br.); 7.75 (1H, br.); 6.91 (1H, d, J=8.0 Hz); 2.48 (3H, s); 2.44 (3H, s). m/z (ESI, +ve ion) 312 (M+H)+.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[O:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:16][C:15]=1[O:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(=O)C(=CNc1ccc(O)cc1OC)C(=O)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)C(=CNc1ccc(OC(=O)c2ccccc2)cc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Ethyl 2-butyryl-3-(4-hydroxy-2-methoxyphenylamino)acrylate (34.5 g) and pyridine (100 ml) were stirred in dichloromethane (500 ml) at 0°-5°. Benzoyl chloride (20 ml) in dichloromethane (100 ml) was added dropwise (below 10°) and the mixture was stirred overnight at room temperature. The reaction mixture was washed successively with water, 2M HCl (×2) and sodium hydrogen carbonate solution (×2). The organic layer was dried, filtered and evaporated to an oil which crystallized on standing to give ethyl 2-butyryl-3-(4-benzoyloxy-2-methoxyphenyl-amino)acrylate (24 g, 52%) m.p. 85°-87°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([NH:8][C:17](=[O:18])[O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1ncccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-diaminopyridine in tetrahydrofuran/pyridine (10/1) at 0° C. benzylchloroformate was added dropwise. The suspension was stirred at room temperature and after 2 hours partitioned between water and EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over sodium sulfate and the filtrate concentrated to dryness under reduced pressure. To the residue was added Et2O-MeOH and the solid was filtered.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:19]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]3[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:20]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)#[N:2].[ClH:41]>O1CCOCC1>[ClH:41].[N:6]1([CH2:5][CH:4]([N:19]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]4[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])[C:26]=4[N:27]=[CH:28][N:29]=3)=[CH:20]2)[CH2:3][C:1]#[N:2])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(CC#N)n2ccc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C(CC#N)CN4CCNCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-{3-cyano-2-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazine-1-carboxylate (1.9 g, 0.0034 mol; peak 2 of Step 1) in 1,4-dioxane (20 mL) was added 4.0 M of HCl in p-dioxane (12 mL, 48 mmol). The mixture was stirred at room temperature for 80 minutes. Solvent was removed in vacua, to afford product as a light yellow solid (1.90 g, 100%). LCMS (M+H)+: 466.3.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:25][NH:26][C:27](=[O:33])[CH:28]([F:32])[C:29](O)=[O:30]>>[F:21][C:22]1[CH:23]=[C:24]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:25][NH:26][C:27](=[O:33])[CH:28]([F:32])[C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30]
Reactant: O=C(O)C(F)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CN1C(=O)C(NC(=O)C(F)C(=O)NCc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
The title compound, MS: m/e=495.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-fluoro-malonamic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccncc1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Agent: Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccncc1
Reaction time: 15.5 h
Yield: 50.4 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (163 mg, 0.609 mmol), 4-(bromomethyl)pyridine hyrdobromide (185 mg, 0.730 mmol), DIPEA (256 μL, 1.52 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (6 mL) was warmed to 50° C. and stirred for 15.5 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded COMPOUND 74 (110 mg, 37%) as an orange oily solid. 1H NMR (CDCl3) δ 1.63-1.73 (m, 3H), 2.08-2.20 (m, 2H), 2.28-2.42 (m, 2H), 2.46 (s, 6H), 3.56 (s, 2H), 4.22 (d, 2H, J=11.8 Hz), 6.14 (d, 2H, J=5.3 Hz), 6.96 (dd, 2H, J=7.5, 4.8 Hz), 7.22 (d, 2H, J=7.9 Hz), 8.00 (d, 2H, J=4.4 Hz), 8.37 (d, 2H, J=4.4 Hz); ES-MS m/z 359 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)=O)[C:5](=O)[CH2:4][CH2:3]1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1>>[CH3:1][CH:2]1[CH2:3][CH2:4][C:5]2[N:23]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[C:9]([C:11]3[CH:12]=[CH:13][C:14]4[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=4[CH:21]=3)=[CH:8][C:6]=2[CH2:7]1
Reactant: CC1CCC(=O)C(CC(=O)c2ccc3c(c2)NC(=O)CO3)C1
Reactant: Nc1ccc(C(=O)O)cc1
Product: CC1CCc2c(cc(-c3ccc4c(c3)NC(=O)CO4)n2-c2ccc(C(=O)O)cc2)C1
Yield: 60 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 6-[(5-methyl-2-oxocyclohexyl)acetyl]-2H-1,4-benzoxazin-3(4H)-one and 4-aminobenzoic acid, the title compound was isolated in 60% yield (98% purity by HPLC). MS(ESI+): 403.7; MS(ESI−): 401.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11].N(C1C2CCCCC=2C(C#N)=CC=1)=[C:13]=[O:14]>>[F:10][C:4]1[C:3]([CH3:11])=[C:2]([N:1]=[C:13]=[O:14])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N=C=O)c2c1CCCC2
Reactant: Cc1c(N)ccc(C#N)c1F
Product: Cc1c(N=C=O)ccc(C#N)c1F

Procedure:
2-Fluoro-4-isocyanato-3-methylbenzonitrile was prepared from 4-amino-2-fluoro-3-methyl-benzonitrile (72D) following a procedure analogous to the procedure used in the preparation of compound 2E (Example 2).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][NH:5][N:4]=1.[OH-].[Na+].Cl>C(O)C>[F:14][C:2]([F:1])([F:13])[C:3]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][NH:5][N:4]=1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A mixture of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (100 mg, 0.48 mmol, 1 eq.), ethanol (5 mL) and 5N NaOH (5 mL) was heated to reflux for 72 h. The reaction was cooled to RT, acidified to pH 2 with 5 N HCl and the product extracted into ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated to provide 3-(trifluoromethyl) H-pyrazole-4-carboxylic acid (1a) as a white solid (80 mg, 93% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.95 (broad s, 1H), 8.49 (s, 1H), 3.50 (broad s, 1H). ES-LCMS m/z 181.16 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:49].[ClH:49].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][NH:27][CH2:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CNCC2
Yield: 10 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (210 mg, 0.429 mmol) was deprotected and converted to the dihydrochloride salt according to Example 2 (step g) to provide the title compound (19 mg, 10%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 12.90-11.93 (br s, 1H), 9.49 (s, 2H), 8.69 (d, J=3.9 Hz, 1H), 8.15-8.06 (m, 1H), 7.71-7.65 (m, 1H), 7.61-7.55 (m, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.42 (d, J=1.5 Hz, 1H), 7.02-7.00 (dd, J=8.4, 1.6 Hz, 1H), 4.30 (s, 2H), 4.05 (s, 2H), 4.04-3.99 (m, 2H), 3.78-3.72 (m, 2H), 3.72-3.62 (m, 5H), 3.53-3.42 (m, 4H), 3.10-3.04 (m, 2H); ESI MS m/z 390 [M+H]+; HPLC (Method B) 97.7% (AUC), tR=11.6 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:20].[Cl:20][C:19]1[C:14]([C:11]2([OH:21])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ncccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2ncccc2Cl)CCNCC1
Reaction time: 0.5 h
Yield: 209.3 %

Procedure:
3-Chloro-4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.18 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 2 mL). The mixture was stirred for 0.5 hours and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound (0.15 g). LCMS m/z 213.1 [M+H]+. R.T.=0.79 min (Analytical Method 3).
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[C:15]([CH3:18])[C:14]([OH:19])=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([C:20]([O:22]C)=O)=[CH:9][CH:8]=[C:7]1[OH:24])=O.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:20]([C:10]1[C:11]2[C:6](=[N:5][C:4]3[C:13]([N:12]=2)=[C:14]([OH:19])[C:15]([CH3:18])=[C:16]([OH:17])[C:3]=3[CH:1]=[N:30][CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])[C:7]([OH:24])=[CH:8][CH:9]=1)=[O:22]
Reactant: COC(=O)c1ccc(O)c2nc3c(C=O)c(O)c(C)c(O)c3nc12
Reactant: CN(C)CCCN
Product: Cc1c(O)c(C=NCCCN(C)C)c2nc3c(O)ccc(C(=O)NCCCN(C)C)c3nc2c1O
Reaction time: 0.08 h

Procedure:
6-Formyl-4,7,9-trihydroxy-8-methyl-1-phenazinecarboxylic acid, methyl ester (1.107 g, 3.27 mmol), was stirred with 50 g of 3-(dimethylamino)propyl amine (Aldrich Chemical Company, Milwaukee, Wis., USA) at 60° C. for 1.5 hours. The reaction mixture was then cooled in an ice bath for 20 minutes and the crude imine amide product precipitated from solution. The precipitated solid was collected by filtration and washed with 50 ml of acetonitrile. The retention time for this product, employing the HPLC system and method described in Example 3 above, was 4.6 minutes.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C:6]([F:9])([F:8])[F:7])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH:23]1[C:28]([OH:29])=[CH:27][CH:26]=[C:25]([Br:30])[CH:24]=1>CN(C=O)C>[Br:30][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:5][C:6]([F:9])([F:8])[F:7])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Br)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
To a stirred solution of trifluoroethyl tosylate (1.5 g, 5.8 mmol) in DMF (20 mL) was added K2CO3 (4 g, 29.4 mmol) followed by p-bromo phenol (1.1 g, 6.46 mmol) at RT under an inert atmosphere. The reaction mixture was stirred at 120° C. for 6 h. The volatiles were evaporated under reduced pressure; the residue was diluted with water (5 mL) and extracted with EtOAc (3×30 mL). The organic layer was washed with water and brine, was dried over anhydrous Na2SO4, was filtered and was concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with 5% EtOAc/hexane to afford the desired product (0.8 g, 3.13 mmol, 53.3%) as semi solid. 1H NMR (200 MHz, CDCl3): δ 7.44-7.38 (m, 2H), 6.86-6.80 (m, 2H), 4.38-4.25 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1.C(=O)=O.C(#N)C>C1COCC1>[Cl:1][C:2]1[C:11]([C@H:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)c1cc2ccc(F)cc2nc1Cl
Agent: O=C=O
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc2ccc(F)cc2nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A solution of 1-(2-chloro-7-fluoroquinolin-3-yl)ethanone (164 g, 733 mmol) in THF (1.34 L) was added to a solution of (+)-DIP-Cl (517.5 g, 2.2 eq) in THF (3.5 L) at −45° C. (dry ice and acetonitrile) dropwise. The reaction was slowly warmed up to rt overnight. The reaction was then quenched with acetone (750 mL) and 10% Na2CO3 (750 mL) at 0° C. and stirred at rt for 1 h before the addition of EtOAc (3.5 L). The mixture was warmed up to rt and washed with 10% Na2CO3 and water. The organic layer was dried with brine, concentrated and treated with hexane (1.0 L) and water (1.8 L). The mixture was stirred at rt for 40 min and filtered. The white solid was washed with water and hexane, dried in the air over night (143 g). This material was dried on the roto-evaporator at 60° C. for 4 h under high vacuum (2 mm Hg) to give a white powder of (R)-1-(2-chloro-7-fluoroquinolin-3-yl)ethanol (122 g, 73.7%). Chiral HPLC on AD column (isopropanol in hexane, 10%) showed ee>99%. Mass Spectrum (ESI) m/e=226 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](C(C3CCCN3)C)[NH:8]2)=[CH:4][CH:3]=1.B1([C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)OCCCO1>>[NH:8]1[CH2:7][CH2:6][CH2:5][CH:9]1[CH:10]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:28]3[CH:27]=[N:26][CH:25]=[CH:24][CH:29]=3)[CH:10]=2)[CH:6]=[CH:7]1)[CH3:2]
Reactant: CC(c1cc2ccc(Br)cc2[nH]1)C1CCCN1
Reactant: c1cncc(B2OCCCO2)c1
Product: CC(C1CCCN1)n1ccc2ccc(-c3cccnc3)cc21

Procedure:
(9.3 mg, 49%); from 6-Bromo-1-(2-pyrrolidinyl)ethyl indole (19.0 mg, 0.065 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (21.0 mg, 0.130 mmol).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1(C)[CH:12]=[CH:11][O:10][NH:9]1)([OH:3])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:20]C1ON=C(CCCO)C=1>>[OH:3][CH2:1][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:12]=[C:11]([CH3:20])[O:10][N:9]=1
Reactant: Cc1cc(CCCO)no1
Reactant: CC1(CCCCC(=O)O)C=CON1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(CCCCCO)no1
Yield: 84 %

Procedure:
3-(5-Hydroxypentyl)-5-methylisoxazole was prepared by reduction of 3-(4-carboxybutyl)-3-methylisoxazole with lithium aluminum hydride according to the procedure of part (e) above, and was obtained in 84% yield as an oil, b.p. 115°-125° C.(0.1 mm).