Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:33]([CH2:34][CH3:35])[CH2:31][CH3:32])[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1
Reactant: CCNCC
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A 25° C. mixture of 500 mg of 2-(5-fluoro-2-nitrophenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 14d, 131 mg of diethylamine, and 329 mg of K2CO3 in 4 mL of DMF was stirred for 16 h and then stirred for an additional 24 h at 60° C. The mixture was diluted with ethyl acetate, and the resulting solution was washed with water, and then with brine. The solution was dried (Na2SO4) and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel to give 500 mg of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]CC)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:20]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]([NH2:14])=[O:20])=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2cccc(Br)c2)c1C#N
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Br)c1

Procedure:
A 14 g. portion of ethyl 1-(3-bromophenyl)-5-cyano-4-pyrazolecarboxylate was hydrolyzed by stirring under reflux in 200 ml. of ethanol with 6 g. ofpotassium hydroxide for 2 hours. The mixture was then poured over ice, acidified and filtered, and the solids were crystallized from ethanol/water and dried at 168° to obtain 10 g. of the desired product, m.p. 215°-217° dec. The product was identified by NMR analysis in CDCl3 /DMSOd6. δ7.06 (s, 1), carboxamide; 7.30-7.64 (m, 4), aromatic; 8.08 (s, 1), pyrazole; 9.10 (s, 1), carboxamide.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=[O:30].C([BH3-])#N.[Na+].[BH4-].[Na+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl>[OH:30][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[N:3]1[C:2](=[O:1])[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4]1
Reactant: O=Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzaldehyde (Example 529, 75 mg, 0.17 mmol) was suspended in tetrahydrofuran (5 mL) and cooled to 0° C. Sodium cyanoborohydride (0.067 mL, 1 M tetrahydrofuran solution, 0.067 mmol, 0.4 equiv) was added dropwise and the mixture was stirred for 1 hour at 0° C. The mixture was diluted with dichloromethane (3 mL) until homogeneous and stirred for an additional 1 hour at 0° C. Sodium borohydride (1 spatula tip, excess) was added and the mixture was stirred at 0° C. for 30 minutes. The mixture was warmed to ambient temperature, opened to the air and treated with dichloro-5,6-dicyanobenzoquinone (DDQ, 40 mg, 0.17 mmol, 1 equiv). After stirring for 30 minutes, the mixture was poured into sodium bicarbonate (50 mL, aqueous saturated) and extracted with ethyl acetate (3×50 mL) and chloroform (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100 hexanes:ethyl acetate; then 100:0 to 0:100 ethyl acetate:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.61 (1H, s), 8.35 (1H, d, J=7.4 Hz), 7.90 (1H, d, J=2.6 Hz), 7.72-7.70 (3H, m), 7.61 (1H, d, J=7.6 Hz), 7.57 (1H, d, J=7.5 Hz), 7.53 (1H, dd, J=7.6, 1.9 Hz), 7.51-7.47 (1H, m), 7.42 (1H, td, J=7.4, 1.5 Hz), 7.37 (1H, t, J=7.4 Hz), 7.29 (2H, d, J=8.6 Hz), 7.27 (1H, m), 6.47 (1H, m), 5.53 (2H, s), 5.21 (1H, br t, J=6.5 Hz), 4.53 (2H, d, J=5.8 Hz) ppm; high resolution mass spectrometry (ES+) m/z 448.1781 [(M+H)+; calculated for C27H22N5O2: 448.1768].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>OS(O)(=O)=O>[Br:18][C:7]1[C:6]([CH3:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1cccc(F)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2-fluoro-6-methylbenzonitrile (5.0 g, 37 mmol) in 100 mL of concentrated H2SO4 was added NBS (6.93 g, 38.9 mmol). Then the mixture was stirred at 0° C. for 3 hrs and poured into ice-water (1 L). The solution was extracted three times with EtOAc (200 mL) and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography to give 3-bromo-6-fluoro-2-methylbenzonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:26]([O:41][C@H:42]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:43][C:44](O)=[O:45])(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(Cl)CCl.CI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:26]([O:41][C@H:42]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:43][C:44]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:45])(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC(C)(C)[Si](OCCCCCCN)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCCl
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NCCCCCCO
Yield: 30.5 %

Procedure:
In the same manner as described in Example 20-(1), 6-amino-1-(t-butyldiphenylsilyloxy)hexane (1.48 g, 4.15 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (2.07 g, 4.56 mmol) in the presence of EDC·MeI (1.35 g, 4.56 mmol) and then deprotected with TBAF (1.0 M in THF, 1.53 mL, 1.53 mmol) in THF (46 mL) to afford 700 mg (30%) of 6-[(R)-3-tetradecanoyloxytetradecanoylamino]-1-hexanol as an off-white solid.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C1C=CC=CC=1.CN(C)C=O>[O:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCCOc1ccccc1
Reactant: C=CC(N)=O
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C=CC(=O)NCCCCOc1ccccc1
Yield: 81.7 %

Procedure:
Added to 20 ml of N,N-dimethylformamide were 1.34 g of acrylic amide and 3.4 g of (4-bromobutoxy)benzene. With stirring, 0.88 g of flaky potassium hydroxide which had been ground in a mortar was added. Phenothiazine was added in an amount of 0.5% based on the acrylic amide. After they were reacted at 0°-5° C. for 6 hours, insoluble matter was filtered off from the liquid reaction mixture. The solvent and unreacted raw materials were distilled off from the filtrate. The residue was extracted with benzene-water, thereby obtaining the intended product in the benzene layer. Benzene was then driven off from the benzene layer to obtain 2.66 g of N-(4-phenoxybutyl)acrylic amide (yield: 81%). It was purified further with column chromatography in which silica gel and benzene were used as an adsorbent and developer respectively. Its melting point was measured and its elementary analysis was also conducted. The following results were obtained. Melting point: 46°-47° C. Elementary analysis data: C, 71.29% (Calculated: 71.19%); H, 7.31% (7.82%); N, 6.15% (6.38%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[N:2]=1.C(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC1C=CC(C(C)C)=CC=1>[OH:9][CH:7]([C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccnn1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccc(C(C)C)cc1
Product: OC(c1ccccc1)c1cccnn1
Temperature: 135 °C
Yield: 18.6 %

Procedure:
Pyridazine-3-carboxylic acid [prepared as described by Leanza, Becker and Rogers, J.A.C.S., 75, 4086 (1953); 18.6 g.] was mixed with benzaldehyde (44 g.) and p-cymene (360 ml.) and decarboxylated by heating for 3 hours at 135° C. The hot solution was then filtered, cooled and the precipitate collected to give (±) 3-α-hydroxybenzylpyridazine (5.2 g.), m.p. 130°-135° C., in the form of fawn coloured needles.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+]>CCO.O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[CH:6]([CH2:5][C:4]([OH:17])=[O:3])[CH2:7][CH2:8]2
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCC2CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of the crude ester (416 g, 1.77 mol) prepared in Example 2 in EtOH (1 L), was added a solution of NaOH (142 g, 3.54 mol) in water (1.5 L). The reaction mixture was heated to reflux, during which time the color changed to dark red, and the reaction became homogeneous. After 1 h, the reaction was cooled to rt, and the EtOH was removed under reduced pressure. The remaining basic aqueous layer was washed with Et2O (3×500 mL), then acidified with HCl (conc. aqueous solution) to pH˜4 at which point an oily residue formed. The mixture was then extracted with Et2O (4×500 mL), the combined extracts washed with water (2×300 mL) and brine, and then dried over Na2SO4. Filtration and evaporation of the solvents under reduced pressure gave the title compound (305 g, 83%) as a yellow solid after drying for 12 h under vacuum. 1H NMR (CDCl3) δ 7.34 (d, 1H), 6.71 (s, 1H), 6.65 (dd, 1H), 3.71 (s, 3H), 3.47 (m, 1H), 2.80 (m, 3H), 2.35 (m, 2H), 1.71 (m, 1H). MS (CI) m/z 207 [M+H]+.
Reaction SMILES: Br[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5]Br.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O>[CH:8]1([N:14]2[CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: OC(CBr)CCBr
Reactant: NC1CCCCC1
Solvent: O
Product: OC1CCN(C2CCCCC2)C1
Temperature: 130 °C

Procedure:
With stirring 1,4-dibromo-2-butanol (696 g, 3 mol) was added dropwise to cyclohexylamine (595 g, 6 mol). The addition was rapid until the reaction temperature reached 130° C. and then slowed so as to maintain the temperature at 130°-135° C. When the addition was completed the mixture was heated at 130° C. for 2 h. The mixture was then poured into 3 L of water with stirring. The aqueous mixture was filtered and the filtrate extracted with 1 L of ether. The aqueous solution was basified with 50% sodium hydroxide solution. The oil which separated from solution was removed. The aqueous layer was extracted with three 400 ml portions of ether and the extract combined with the oil. The ether solution was dried (Na2SO4) and concentrated. The residual oil was distilled and the fraction boiling at 165°-180° C./39 mm was collected. A higher boiling fraction (180°-190° C./39 mm) was collected and redistilled to give some additional material boiling at 165°-180° C./39 mm for a total yield of 329.6 g (77%).
Reaction SMILES: O=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:9]([CH:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[CH3:10].[OH-].[Na+]>N#N.C1COCC1.O>[CH2:9]([CH:11]([CH:15]([OH:17])[CH3:16])[CH:12]([OH:14])[CH3:13])[CH3:10]
Reactant: CCC(C(C)=O)C(C)=O
Agent: N#N
Agent: O=O
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(C)O)C(C)O
Reaction time: 48 h
Yield: 64.3 %

Procedure:
In N2 atmosphere free of water and oxygen, to a reactor were successively added 0.024 mol LiAlH4 and 100 ml THF, followed by adding dropwise 0.04 mol 3-ethyl-2,4-pentandione while cooling the mixture with ice-bath. The reaction was allowed to continue at room temperature for 48 hours. Aqueous solution of sodium hydroxide was added carefully to stop the reaction. The reaction mixture was filtered and the cake was washed with anhydrous ethyl ether for three times. The organic phase was combined and dried over anhydrous sodium sulfate. Removing the solvent gave 3.4 g product.
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[C:6]([C:15]#[N:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:48][C:49]1[NH:53][N:52]=[C:51]([NH2:54])[CH:50]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([NH:54][C:51]2[CH:50]=[C:49]([CH3:48])[NH:53][N:52]=2)[C:10]2[C:5](=[C:6]([C:15]#[N:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C#N)cccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(C#N)cccc23)n[nH]1
Reaction time: 0.83 h
Yield: 41.1 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carbonitrile (168 mg, 0.48 mmol) in DCM (6 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 203 mg, 0.83 mmol) and the mixture stirred for 50 min. The mixture was diluted with DCM and then aq sodium thiosulfate solution was added followed by addition of saturated aq sodium bicarbonate. The organic layer was separate, dried over sodium sulfate and concentrated under reduced pressure. To the residue were added THF (3 mL) and 5-methyl-1H-pyrazol-3-amine (139 mg, 1.44 mmol) and the mixture was stirred at rt for 25 min. The mixture was concentrated under reduced pressure and purified by reverse phase HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/CH3CN and solvent A=0.05% aq formic acid/5% CH3CN) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazoline-8-carbonitrile (78 mg, 41%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 5.97 (s, 1H) 7.77 (t, J=7.91 Hz, 1H) 8.03 (dd, J=6.40, 1.32 Hz, 2 H) 8.45 (d, J=7.16 Hz, 1H) 8.68 (s, 1H) 8.99 (d, J=8.29 Hz, 1H) 11.04-11.20 (m, 1H) 12.18-12.37 (m, 1H); LC-MS (ESI) m/z 396 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:16]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1
Reactant: CCc1cnc(Cl)nc1
Reactant: Brc1ccc2oc(C3CCNCC3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4o3)CC2)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 7.2 %

Procedure:
Intermediate 5 (800 mg, 2.85 mmol) and 2-chloro-5-ethylpyrimidine (447 mg, 3.14 mmol) were dissolved in propan-2-ol (25 ml). To this mixture N,N-Diisopropylethyl amine (3.1 ml, 17.12 mmol) added and stirred at 90° C. for 12 h. After completion of the reaction, propan-2-ol was removed to obtain the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (8:92) as eluent to afford the titled compound (80 mg) as a pale-yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.19 (s, 2H), 7.81 (s, 1H), 7.41 (dd, J 1.6, 8.6, 1H), 7.35 (d, J 8.6, 1H), 4.72 (d, J 13.6, 2H), 3.27-3.11 (m, 3H), 2.47 (q, J 7.6, 2H), 2.21 (dd, J 2.6, 13.1, 2H), 2.02-1.90 (m, 2H), 1.19 (t, J 7.6, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>CO>[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a mixture of tert-butyl N-(piperidin-4-yl)carbamate (25 g, 125 mmol, 1.0 eq) and 3-nitrobenzaldehyde (19 g, 125 mmol, 1.0 eq) in MeOH (500 mL) were added NaBH(OAc)3 (53 g, 250 mmol, 2.0 eq) and acetic acid (1 mL). Then the resulting mixture was stirred at 30° C. overnight. LC-MS indicated complete conversion. The solvent was removed under vaccum and the residue was purified by column chromatography (DCM:MeOH=15:1), to provide tert-butyl N-{1-(3-nitrobenzyl)piperidin-4-yl}carbamate (32 g, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCO>[CH2:26]([O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:8][C:5]2[C:4]([C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:24])[CH3:27]
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Yield: 21.7 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (100 mg, 0.38 mmol, 1 eq) and ethyl 3-cyclopropyl-3-oxopropanoate (89.4 mg, 0.57 mmol, 1.5 eq) in anhydrous EtOH (5 ml), was added p-TsOH.H2O (72.6 mg, 0.38 mmol, 1 eq) and the mixture was refluxed for 16 h. After cooling, the reaction mixture was concentrated in vacuo and then diluted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (elution with 3% ethyl acetate in hexane) to give 6-chloro-4-(2-chloro-benzyl)-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (33 mg, 22%) as a pale yellow solid. MS (ESI): 400.0 (M+H)+.
Reaction SMILES: NC1SC=CN=1.C(OCC)(=O)CC(C)=O.FC1C=C([C:24]2[C:29](=[O:30])[N:28]3[CH:31]=[CH:32][S:33][C:27]3=[N:26][C:25]=2[CH3:34])C=C(F)C=1>C(O)(=O)C>[CH3:34][C:25]1[N:26]=[C:27]2[S:33][CH:32]=[CH:31][N:28]2[C:29](=[O:30])[CH:24]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: Nc1nccs1
Solvent: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n2ccsc2n1

Procedure:
A solution of 2-aminothiazole (50 g, 499.301 mmol), ethyl acetoacetate (96 ml, 748.885 mmol) and acetic acid (400 ml) was reacted together according to the procedure described in Intermediate 3, Step 1 to afford a crude product which was purified by silica gel column chromatography using 1% methanol in chloroform to give 40 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[CH:19]=[CH:18][NH:17][C:11]=4[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:29]([N:31]=[C:32]=[S:33])[CH3:30]>CN(C)C=O>[CH2:29]([NH:31][C:32]([N:17]1[C:11]2[NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:10]=2[CH:19]=[CH:18]1)=[S:33])[CH3:30]
Reactant: O=c1c2c[nH]c3[nH]ccc3c-2nn1-c1ccccc1
Reactant: CCN=C=S
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=S)n1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of pyrrolo-pyridine 16 in dimethylformamide under an atmosphere of nitrogen and 3 equivalents of di-iso-propylethylamine (3 eq.) was added 3 equivalents of ethylisothiocyanate. The reaction mixture was stirred in a microwave at 100° C. for 3 hours. The crude reaction mixture was concentrated in vacuo and purified by column chromatography to afford compound 17e. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.42 (m, 3H) 3.68-3.93 (m, 2H) 6.72-6.90 (m, 1H) 7.19-7.38 (m, 1H) 7.42-7.64 (m, 2H) 7.77-7.96 (m, 2H) 8.27-8.59 (m, 1H) 8.61-8.81 (m, 1H) 12.10-12.38 (m, 1H) 12.37-12.57 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:16]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=2[C:14]#[N:15])[CH:3]=1
Reactant: Cc1cc(CO)no1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: Cc1cc(COc2cccc([N+](=O)[O-])c2C#N)no1
Yield: 86 %

Procedure:
Prepared as in Example 187c from (5-methylisoxazol-3-yl)methanol and 2,6-dinitrobenzonitrile in 86% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.43 (d, J=0.8 Hz, 3H), 5.50 (s, 2H), 6.38 (d, J=0.4 Hz, 1H), 7.83 (dd, J=1.2, 8.4 Hz, 1H), 7.91-7.98 (m, 2H). MS 260 (MH+).
Reaction SMILES: [CH2:1]([CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH:9]([OH:21])[CH2:10][CH:11]([C:18](=[NH:20])[NH2:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:20]=[C:18]([NH2:19])[CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([OH:21])[CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=N)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N=C(N)C(CCC(C)(C)F)CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.0 equivalents of quinoxaline-2-carboxylic acid (1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide in methylene chloride is added 1.0 equivalents of triethylamine followed by 1.0 equivalents of acetyl chloride. The reaction is stirred at ambient temperature for approximately 5 hours. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[NH2:13])=CC=1.ClC1C2C=COC=2C=CN=1>>[O:2]1[C:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH2:13])[C:11]=2[CH:12]=[CH:3]1
Reactant: COc1ccc2ccnc(N)c2c1
Agent: Clc1nccc2occc12
Product: Nc1nccc2occc12

Procedure:
The procedure described to prepare 7-methoxyisoquinolin-1-ylamine was used to convert 15.3 g of 4-chloro-furo[3,2-c]pyridine into 12.2 g of the title compound as a brownish solid. m.p. 122-124° C.; EI-MS: 134 (M+).