Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH2:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].C(Cl)Cl.CCN([CH2:27][CH3:28])CC>>[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH:11][C:3]([O:2][CH2:1][C:28]2[CH:27]=[CH:9][CH:10]=[CH:5][CH:6]=2)=[O:4])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1

Procedure:
(3R,4S)-4-Amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (540 mg, synthesized according to Duan, Jingwu et al, PCT Int. Appl. (2001), WO 2001070673 A2) and WO 2002002525) was dissolved in abs. DCM and NEt3 (0.39 ml) was added.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cccc(F)c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(F)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-fluorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.88-1.98 (m, 3H), 2.03 (s, 1H), 2.26-2.33 (m, 4H), 3.42 (s, 2H), 3.48-3.56 (m, 4H), 4.37 (s, 1H), 7.27-7.32 (m, 1H), 7.44-7.53 (m, 1H), 7.55-7.62 (m, 1H), 7.66 (d, J=8 Hz, 1H); MS (APCI/NH3) m/z 275 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccccc12
Yield: 117.6 %

Procedure:
0.37 g (8.84 mmol) of lithium hydroxide monohydrate and 45 cm3 of water are added at 25° C. to 0.89 g (2.95 mmol) of 3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole dissolved in 45 cm3 of tetrahydrofuran. After stirring at reflux for 17 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 30 cm3 of water and then triturated with 8.8 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 1 g of 3-carboxy-1-(quinol-4-yl)-1H-indole is obtained in the form of a yellow solid. Mass spectrum (EI): m/e 288 (M+·), m/e 243.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@@H](COC)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@@H](COC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 143-146° C.; 1H NMR (300 MHz, CDCl3): δ 7.16 (d, J=1.9 Hz, 1 H), 7.09 (d, J=1.9 Hz, 1 H), 7.03 (s, 1H), 4.93-4.88 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.65 (dd, J=10.6, 5.5 Hz, 1 H), 3.54 (dd, J=10.6, 3.5 Hz, 1H), 3.33 (s, 3 H), 3.11 (t, J=8.1 Hz, 2 H), 1.90-1.70 (m, 2 H), 0.91 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2Cl3 (M+H)+: 402.0543; found m/z 402.0520.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([C:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29])[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:16][CH2:15]1)=[O:4].[OH2:36].[OH-].[Li+].[ClH:39]>C1COCC1.O>[OH2:2].[OH2:36].[ClH:39].[CH:30]1([C:28]([N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])[CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:18][CH2:19]2)=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)c1ccccc1N(CCN1CCN(c2ccccc2OC)CC1)C(=O)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2C(=O)O)CC1
Yield: 84 %

Procedure:
A solution of 0.33 g of the compound of example 18 and 0.06 g of lithium hydroxide monohydrate in 5 mL of THF and 1 mL of H2O was stirred at 70° C. for 9 h. The solution was added with 2 N aq. HCl to pH≡1 and evaporated to dryness. The residue was taken up with 10 mL of boiling Me2CO and filtered to give 0.32 g (84%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH2:15](Br)[C:16]#[CH:17].O>O1CCCC1>[CH3:3][O:4][N:5]([CH2:17][C:16]#[CH:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: C#CCBr
Reactant: CONC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCN(OC)C(=O)c1ccc(Cl)cc1
Yield: 36.5 %

Procedure:
0.22 g of sodium hydride (60% in oil) was suspended in 10 ml of tetrahydrofuran, and 1.0 g of N-methoxy-p-chlorobenzamide and 0.68 g of propargyl bromide were added thereto in this order while being cooled with ice. The mixture was heat-refluxed for 8 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.44 g of N-methoxy-N-propargyl-p-chlorobenzamide.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]([CH3:29])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>O1CCCC1>[CH2:30]([O:32][CH2:33][N:5]1[C:6]([CH3:29])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]1[CH3:3])[CH3:31]
Reactant: CCOCCl
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCN1C(C)=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C1C

Procedure:
In 5 ml. of anhydrous tetrahydrofuran was suspended 193 mg. of a 50% oil dispersion of sodium hydride and after adding to the mixture 7 ml of anhydrous tetrahydrofuran solution of 1 g. of diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, the resultant mixture was stirred at room temperature for a while. The red-brown reaction product thus obtained was cooled to temperatures of from -40° C. to -50° C. and after adding thereto 5 ml. of anhydrous tetrahydrofuran solution of 380 mg. of ethoxymethyl chloride at the same temperature, the mixture was stirred for one hour and 45 minutes at the same temperature. By treating further the reaction product as in Example 1, 370 mg. of white crystals of diethyl 1-ethoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate melting at 125° C. was obtained. The product was confirmed in the infrared absorption spectra and the nuclear magnetic resonance spectra to completely coincide with the presumed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=2[CH3:20])=[C:6]([CH2:8]I)[CH:7]=1.CS(C)=O.[C-:25]#[N:26].[K+]>ClCCl.C(O)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=2[CH3:20])=[C:6]([CH2:8][C:25]#[N:26])[CH:7]=1
Reactant: COc1cccc(CCc2ccc(Br)cc2CI)c1C
Reactant: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CC(C)O
Product: COc1cccc(CCc2ccc(Br)cc2CC#N)c1C
Temperature: 42 °C
Reaction time: 16.5 h
Yield: 46 %

Procedure:
To 5-bromo-2-[2-(3-methoxy-2-methylphenyl)-ethyl]-phenyliodomethane 9 (5.56 g; 12.5 mmol) in dichloromethane (10 mL), isopropyl alcohol (10 mL), and DMSO (3 mL), was added potassium cyanide (1.22 g; 18.8 mmol). The mixture was stirred at 42° C. for 16.5 hours and concentrated in vacuo. The resultant residue was taken up in dichloromethane and water. The solution was shaken and the layers were separated. The organic layer was washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give an amber oil. The oil was chromatographed using SiO2 and hexane/ethyl acetate (3:2) as eluent to give compound 10, 1.99 g; 46% yield.
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].C(OC(C)C)(C)C>CCCCCC>[C:9]([N:2]([C:3]1[CH:8]=[CH:7][C:6]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:5][CH:4]=1)[CH3:1])(=[O:11])[CH3:10]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N(C)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
N-Methylacetanilide (25.0 g, 188.0 mmol) was added to chlorosulfonic acid (62.8 ml) under cooling with ice in portions at such a rate as not to raise the temperature of the resulting mixture to 50° C. or above, which took about 10 minutes. The obtained mixture was stirred at 80° C. for 2.5 hours and poured into a mixture comprising ice (200 ml), hexane (30 ml) and isopropyl ether (30 ml) under cooling with ice at 20° C. or below in portions to decompose excess chlorosulfonic acid. The precipitated crystal was recovered by filtration, washed with water and dissolved in ethyl acetate. The obtained solution was washed with water and a saturated aqueous solution of common salt. The organic layer was dried over magnesium sulfate and concentrated to give the title compound as a white crystal (19.4 g, yield: 42%).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([OH:16])=[C:9]([O:17]C)[CH:8]=1)[CH3:2].C(N(CC)CC)C.[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl>[CH2:22]([N:3]([CH2:1][CH3:2])[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([OH:16])=[C:9]([OH:17])[CH:8]=1)[CH3:23]
Reactant: CCN(CC)C(=O)C(C#N)=Cc1cc(OC)c(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A round-bottom flask under nitrogen atmosphere is loaded with N,N-diethyl-2-cyano-3-(-3-methoxy-4-hydroxy-5-nitrophenyl-)-acrylamide (134 g, 0.421 mol) dissolved in dichloromethane (0.65 l) and triethylamine (128 g, 1.26 mol). The solution is cooled to 0-5° C. and aluminium trichloride (67.4 g, 0.505 mol) is added in portions. After that, the mixture is refluxed for 3-4 hours, until completion of the conversion. The reaction mixture is cooled to 0-5° C., a 20% hydrochloric acid solution (0.5 l) is dropped in the mixture, which is left under stirring at room temperature for 30 minutes. The resulting solid is filtered, washing with water (0.1 l×3), and dried in a static dryer under reduced pressure at 50° C.; 126 g are obtained. Yield: 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([OH:23])=[C:7]([C:9](=[O:22])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=O)[CH:8]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[O:23][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)=[CH:10][C:9]2=[O:22]
Reactant: COc1ccc(O)c(C(=O)CC(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc2oc(-c3ccc([N+](=O)[O-])cc3)cc(=O)c2c1

Procedure:
A mixed solution consisting of compound 22 (2.92 g, 9.26 mmol), concentrated sulfuric acid (1 ml), and acetic acid (50 ml) was heated to reflux for 1 hour. The temperature of the resultant was returned to room temperature, and ice pieces were then added to the reaction solution. The precipitated crystal was collected by filtration, so as to obtain a product of interest, 6-methoxy-4′-nitroflavone (compound 23). Yield: 2.31 g (yield constant: 84.1%)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[CH3:24]>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: Cc1ccc([Mg]Br)cc1F
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cnccc2-c2cccc(C#N)c2)cc1F

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (41 mg, 0.20 mmol) in THF (2 mL) at −78° C. was added 0.5 M 3-fluoro-4-methylphenylmagnesium bromide in THF (0.8 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(3-fluoro-4-methyl-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:44][NH:45][C:46]([C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][CH:53]=1)=[O:47].C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl.CO>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>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:42]=[CH:43][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([C:52]3[CH:51]=[CH:50][CH:49]=[C:48]([C:46](=[O:47])[NH:45][CH3:44])[CH:53]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Reactant: CNC(=O)c1cccc(B(O)O)c1
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: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cccc(-c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c23)c1
Reaction time: 6 h
Yield: 35.6 %

Procedure:
A stirred mixture of N-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg, 0.144 mmol; prepared as in Example 7, Step C), 3-(N-methylaminocarbonyl)phenyl boronic acid (51.47 mg, 0.288 mmol), Pd(PPh3)4 (8.31 mg, 0.0072 mmol) dissolved in 3:1 DME:aqueous 2N Na2CO3 (8 mL) was heated at 70° C. Reaction was monitored by TLC (90/10 CHCl3/MeOH). After stirring for 6 hours, the reaction mixture was partitioned between ethyl acetate (25 mL) and water (50 mL). The organic layer washed with brine, dried over sodium sulfate, filtered and evaporated to afford crude product. The crude was purified by silica gel column chromatography (Biotage 12M) eluting with 2% MeOH/DCM to give the product as pale orange glass (36 mg, 35%). LRMS (APCI pos) m/e 703.2 (M+H).
Reaction SMILES: [NH3:1].[C:2]([C:4]([C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])=[CH:5]OCC)#[N:3]>CO>[NH2:1][C:11]1[C:10]2[C:9](=[CH:16][C:15]([F:17])=[CH:14][CH:13]=2)[C:4]([C:2]#[N:3])=[CH:5][N:12]=1
Reactant: CCOC=C(C#N)c1cc(F)ccc1C#N
Reactant: N
Solvent: CO
Product: N#Cc1cnc(N)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A solution of ammonia in MeOH (7 N, 20 mL) is added to 2-(1-cyano-2-ethoxy-vinyl)-4-fluoro-benzonitrile (0.88 g, 4 mmol). The reaction mixture is stirred at RT for 5 h. The orange precipitate is collected by vacuum filtration to afford 0.297 g (40%) of 1-amino-6-fluoro-isoquinoline-4-carbonitrile as an orange solid. LC/MS m/z=188 [M+H]+, RT=2.10-2.15 min. 1H NMR (CDCl3, 25 deg, 500 MHz): δ 8.44 (dd, 2H), 8.18 (t, 1H), 8.04 (bs, 4H), 7.73 (d, 1H), 7.63 (dt, 1H), 7.53 (dt, 2H), 7.43 (dd, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10]S([C@H](C)CC)=O)[CH3:9])=[N:6][CH:7]=1.[ClH:17]>O1CCOCC1>[ClH:17].[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1
Reactant: CC[C@@H](C)S(=O)N[C@@H](C)c1ncc(F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-(2R)-methylpropane-2-sulfinamide (Method 52, 655 mg, 2.67 mmol) in dry dioxane (20 ml) was added HCl (3.4 ml, 13.3 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours. The solvent was removed to give the title compound as white solid (quantitative). MS: Calcd.: 141. Found: [M+H]+142.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10](=[CH:16][NH:17][CH:18]2[CH2:20][CH2:19]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([CH3:21])[N:5]=[C:4]([Cl:22])[C:3]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:4]1[C:3]([Cl:23])=[C:2]2[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]2[CH:18]2[CH2:20][CH2:19]2)=[C:6]([CH3:21])[N:5]=1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)nc(Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(Cl)nc(C)c2c1=O
Temperature: 0 °C

Procedure:
4.8 g (0.01 mol) of ethyl 2-(4,5,6-trichloro-2-methyl-nicotinoyl)-3-cyclopropylamino-acrylate are heated with 2.2 g (0.016 mol) of potassium carbonate in 40 ml of DMF at 100° C. for four hours. Ice-water is added to the cooled mixture and the product is isolated, washed with ice-water and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17][O:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C[C@@H](CO)C[C@@H](C)CCCCC)(C)(C)C>>[C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17][O:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][C@@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Agent: CCCCC[C@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Product: CCCCC[C@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Yield: 64 %

Procedure:
A procedure similar to that used to prepare compound 159 was used except that (3S,5S)-3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167 (4.164 g, 15.29 mmol) was used as a reactant to give 168 as an oil (4.17 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=8.30 Hz, 2H), 7.31 (d, J=8.30 Hz, 2H), 3.97 (dd, J=9.52, 4.15 Hz, 1H), 3.90 (dd, J=9.52, 5.13 Hz, 1H), 2.42 (s, 3H), 2.28, 2.19-2.13 (m, 2H), 1.37 (s, 9H), 1.27-1.01 (m, 1H), 0.85 (t, J=7.08 Hz, 3H), 0.76 (d, J=6.35Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][C:16]=1[O:25][CH3:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:15]=1[C:14]#[C:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: COC(=O)c1ccc(C#CC2CCCN2C(=O)OC(C)(C)C)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C#CC2CCCN2)c(OC)c1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-(2-methoxy-4-methoxycarbonyl phenyl)ethynyl]pyrrolidine (395 mg, 1.1 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). The resulting mixture was stirred for 1 hr. The mixture was concentrated in vacuo and made basic by the addition of sat. NaHCO3, and extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated to give 238 mg (84%) 2-[2-(2-methoxy4-methoxycarbonylphenyl) ethynyl]pyrrolidine as a yellow oil. 1H-NMR (CDCl3) δ 1.81–2.16 (4 H, m), 2.97–3.17 (2 H, m), 3.91 (6 H, s), 4.13–4.15 (1 H, m), 7.41 (1 H, d, J=8.3 Hz), 7.51 (1 H, s), 7.56 (1 H, d, J=8.3 Hz).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1)[CH3:3].[CH3:14][S-:15].[Na+]>C(O)C>[CH3:14][S:15][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1)[CH3:3]
Reactant: CC(Br)c1ccc(C(F)(F)F)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSC(C)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(1-bromoethyl)-2-trifluoromethylpyridine (1.02 g, 4.0 mmol) in ethanol (30 mL) was cooled to 0° C. under an atmosphere of nitrogen. Sodium methyl mercaptide (364 mg, 5.2 mmol) was added batchwise. Once added, the ice bath was removed and the reaction stirred at room temperature under nitrogen overnight. TLC (9:1, hexane:EtOAc) showed complete reaction. The turbid solution was quenched with water and extracted with ether. The organic layer was then washed with brine and dried (MgSO4). The solvent was removed in vacuo to provide the crude product as a pale yellow liquid, 0.83 g (93%); 1H NMR (CDCl3) δ 8.65 (s, 1H), 7.89 (d, 1H), 7.67 (d, 1H), 3.93 (q, 1H), 1.94 (s, 3H), 1.62 (d, 3H).
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C(C)=CN=C(NCCC5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[CH:55]=[CH:54][N:53]=[C:52]([NH:56][CH2:57][CH2:58][CH2:59][CH:60]5[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1>>[ClH:1].[ClH:1].[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[CH:55]=[CH:54][N:53]=[C:52]([NH:56][CH2:57][CH2:58][CH2:59][CH:60]5[CH2:61][CH2:62][N:63]([CH3:3])[CH2:64][CH2:65]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:36][CH2:37]1
Reactant: Cc1cnc(NCCC2CCN(C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3ccnc(NCCCC4CCNCC4)n3)cc12
Agent: Cl
Product: CN1CCC(CCCNc2nccc(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1

Procedure:
Using the method of 2-{5-methyl-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 450 [M(free base)+H].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COCCOCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCOCCNc1ccc([N+](=O)[O-])c(N)c1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.6 g, 9.3 mmol), 2-(2-methoxy-ethoxy)-ethylamine (2.0 g, 16.8 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) in N,N-dimethylacetamide (3 ml) was stirred at 120° C. under nitrogen for 3 days. Sample NMR analysis showed 80% conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (30 ml) and extracted with ethyl acetate. The organic extract was washed with brine, dried and evaporated. The resulting orange yellow oil was subjected to a silica gel filtration on a 5 cm×6 cm silica gel plug, eluting first with 50% ethyl acetate/petroleum spirits (40-60° C.), followed by 100% ethyl acetate. Evaporation yielded an orange-red liquid, 1.1 g (45.8% yields).