Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[CH:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]21
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Reaction time: 5 h

Procedure:
To a stirred solution of [10-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-a]benzimidazol-7-yl]methanol (113 mg, 0.284 mmol) in acetonitrile (2.8 mL) was added Dess-Martin reagent (145 mg, 0.341 mmol) at room temperature. After 5 h, the reaction mixture was diluted with ethyl acetate, quenched with aqueous sodium hydrogen carbonate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (88.1 mg, 0.223 mmol, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([OH:35])=O)[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:35])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(C(=O)O)ccc5N4)c3)CC2)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(C(=O)NS(C)(=O)=O)ccc5N4)c3)CC2)c(C)c1
Yield: 20 %

Procedure:
A mixture of 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-(2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-methanesulfonamide (23 mg, 20%) as a light yellow solid: MS (ESI) M+1=547.3.
Reaction SMILES: O.NN.[CH3:4]/[C:5](/[CH2:19][CH2:20]/[CH:21]=[C:22](\[CH3:34])/[CH2:23][CH2:24]/[CH:25]=[C:26](\[CH3:33])/[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:6]\[CH2:7][N:8]1C(=O)C2=CC=CC=C2C1=O>CCO>[CH3:4]/[C:5](/[CH2:19][CH2:20]/[CH:21]=[C:22](\[CH3:34])/[CH2:23][CH2:24]/[CH:25]=[C:26](\[CH3:33])/[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:6]\[CH2:7][NH2:8]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CN
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Hydrazine monohydrate (0.138 ml, 2.86 mmol) was added to a solution of intermediate 34 (0.80 g, 1.9 mmol) in EtOH (90 mL), and the resulting mixture was stirred at room temperature for 24 h. After filtration of a white solid, the solution was evaporated and the residue was extracted with Et2O (2×20 mL). The organic layers were filtered and evaporated to give intermediate 35 (0.520 g, 95%) as an oil, which was used for the following reaction without any further purification; 1H-NMR (CD3OI), 80 Mhz) δ 1.59 (s, 9H, 3×CH3), 1.65 (s, 6H, 2×CH3), 2.02 (m, 12H, 6×CH2), 3.27 (d, 2H, J=7.2 Hz, CH2), 5.12 (br, 3H, 3×CH), 5.25 (t, 1H, J=7.2 Hz, CH); MS (FAB+) m/e 290 (M+H)+.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([OH:19])=O.C(N(CC)CC)C.[NH2:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([NH:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19]
Reactant: O=C(O)C=Cc1cccs1
Reactant: CCOC(=O)c1ccccc1N
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Yield: 45.3 %

Procedure:
Under nitrogen stream, 2-chloro-1-methylpyridinium iodide (966 mg, 3.89 mmol) was suspended in dry methylene chloride (5 ml). To the suspension, a solution of 3-(2-thienyl)acrylic acid (500 mg, 3.24 mmol), triethylamine (1.08 ml, 7.78 mmol), and ethyl 2-aminobenzoate (0.48 ml, 3.24 mmol) in dry methylene chloride (5 ml) was added dropwise. After the addition, the mixture was heated under reflux for 39 hours. Then, the reaction mixture was diluted with methylene chloride, washed with 10% aqueous HCl, saturated aqueous sodium chloride, 1N-aqueous NaOH, and saturated aqueous sodium chloride successively, and dried. Removal of solvent gave a yellow solid, which was washed with n-hexane to give pale yellow solids of the title compound (442 mg, yield, 45%). m.p., 126°-127° C. (recrystallized from methanol)
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:26]([CH:27]([OH:37])[CH2:28][CH2:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=[CH:23][N:22]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C1COCC1.CCO>[OH:37][CH:27]([C:26]1[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4ncccc4C(O)CCCc4ccccc4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1(c2ccc(-c3ccc(-c4ncccc4C(O)CCCc4ccccc4)cc3)cc2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
1-{4′-[3-(1-Hydroxy-4-phenyl-butyl)-pyridin-2-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.258 g, 0.52 mmol) was dissolved in THF (2 mL) and EtOH (1 mL). NaOH (3N aq., 1.1 eq.) was added and the reaction stirred at 45° C. overnight. The reaction was concentrated to dryness, diluted with H20, washed with EtOAc, acidified and extracted with EtOAc. The solution was dried and concentrated to yield the title compound.
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[OH:17].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:23](O)=O.[ClH:35]>CCOCC>[ClH:35].[F:16][C:12]1[C:11]2[O:17][C:23]([C:22]3[CH:26]=[CH:27][C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[C:20]([O:19][CH3:18])[CH:21]=3)=[N:9][C:10]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Reactant: Nc1cccc(F)c1O
Agent: C[Si](C)(C)OP(=O)=O
Agent: Cl
Solvent: CCOCC
Product: COc1cc(-c2nc3cccc(F)c3o2)ccc1-c1ccccn1
Temperature: 200 °C

Procedure:
To 7 mL trimethylsilyl polyphosphate was added 2-amino-6-fluorophenol (166 mg, 1.31 mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (300 mg, 1.31 mmol). The mixture was heated at 200° C. for 2 h, quenched over ice, and made basic (pH 14) with 1N NaOH. The aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resultant oil was taken up in ether and reconcentrated to give a tan solid. The free base was dissolved in ether and HCl (1N in ether) was added. The solution was filtered to give 7-fluoro-2-(3-methoxy-4-pyridin-2-ylphenyl)-1,3-benzoxazole hydrochloride as a yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.71 (d, 1H), 8.00 (t, 1H), 7.97–7.84 (m, 4H), 7.70 (d, 1H), 7.49–7.37 (m, 3H), 4.00 (s, 3H); MS (ESI) 321 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([CH2:12][C:13]#[N:14])=[N:3]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>O1CCOCC1>[CH:9]1[CH:10]=[C:11]2[C:2]([NH:3]/[C:4](/[NH:5][C:6]2=[CH:7][CH:8]=1)=[C:12](/[C:25]([C:24]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:23]=1[Cl:22])=[O:26])\[C:13]#[N:14])=[O:1]
Reactant: N#CCc1nc(=O)c2ccccc2[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#C/C(C(=O)c1ccc(Cl)cc1Cl)=C1\NC(=O)c2ccccc2N1
Yield: 54.6 %

Procedure:
To solution of 2-(4-oxo-1.4-dihydroquinazolin-2-yl)acetonitrile (202 mg, 1.09 mmol) and triethylamine (167 μL, 1.20 mmol) in dioxane (8 mL) was added 2.4-dichlorobenzoyl chloride (152 μL, 1.09 mmol), and the resulting mixture was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with methanol, water, methanol, and dichloromethane. The solid was then dried to yield ciliobrevin A (1) (213 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46-7.50 (m, 1H), 7.52 (d. 1=8.2 Hz, 1H), 7.56 (dd, J1=8.2, J2=1.9 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.83-7.88 (m, 2H), 8.07 (d, J=8.1 Hz, 1H). 13C NMR (500 MHz, DMSO-d6) δ ppm 71.74, 117.43, 117.54, 118.71, 125.92, 126.68, 127.66, 129.21, 129.66, 130.49, 134.85, 135.85, 138.15, 139.25, 155.01, 158.3, 188.75. HRMS (m/z): [M+ calc. for C17H9N3O2Cl2Na, 379.9970; observed, 379.9967.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[C:12](=[O:27])[N:13]([CH3:26])[CH2:14][C:15]3[N:16]([CH:17]=[N:18][C:19]=3[C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(O)C[OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:2][CH2:1][O:3][C:4]([C:6]1[C:11]2[C:12](=[O:27])[N:13]([CH3:26])[CH2:14][C:15]3[N:16]([CH:17]=[N:18][C:19]=3[C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cccc2c1C(=O)N(C)Cc1c(-c3noc(C)n3)ncn1-2
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(C(=O)OCCO)cccc2-3)no1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
7-Ethoxycarbonyl-5,6-dihydro-5-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine (500 mg) was dissolved in ethylene glycol (20 ml) and 3 drops of concentrated sulphuric acid were added. The solution was then stirred at 130° C. for 24 hours, cooled and partitioned between water (150 ml) and CHCl3 (150 ml). The organic phase was separated, dried over Na2SO4, and evaporated to give the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[S:21].I[CH3:28]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:13]=2)[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[N:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:21][CH3:28]
Reactant: Cc1cc(Oc2nc(C(F)(F)F)cs2)cc(C)c1NC(=S)NC(C)(C)C
Reactant: CI
Solvent: CCO
Product: CSC(=NC(C)(C)C)Nc1c(C)cc(Oc2nc(C(F)(F)F)cs2)cc1C

Procedure:
5 g of N-[2,6-dimethyl-4-(4-trifluoromethylthiazol-2-yloxy)phenyl]-N'-tert-butylthiourea are heated in 30 ml of ethanol and 2.1 g of iodomethane for 5 hours to 50° C. The alcohol is subsequently removed by evaporation and the residue is taken up in methylene chloride. The methylene chloride solution is washed twice with dilute sodium carbonate solution and dried over sodium sulfate. The solvent is removed by evaporation and the residue is recrystallised from hexane, affording the title compound of formula ##STR35## with a melting point of 88°-90° C. (compound 4.01).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=C2N=C(CCC3NC(=O)CCCC3)NC2=NC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:52]([N:54]1[CH2:59][CH2:58][N:57]([S:60](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)(=[O:62])=[O:61])[CH2:56][CH2:55]1)[CH3:53]>>[CH2:52]([N:54]1[CH2:59][CH2:58][N:57]([S:60]([C:4]2[CH:3]=[CH:2][C:1]([C:7]3[CH:8]=[C:9]4[N:15]=[C:14]([CH2:16][CH2:17][CH:18]5[NH:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]5)[NH:13][C:10]4=[N:11][CH:12]=3)=[CH:6][CH:5]=2)(=[O:61])=[O:62])[CH2:56][CH2:55]1)[CH3:53]
Reactant: CCN1CCN(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Agent: O=C([O-])[O-]
Agent: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Agent: [Na+]
Product: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=O)N5)nc4c3)cc2)CC1

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound B1) from 300 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1), 2.67 ml of aqueous sodium carbonate solution (strength 2.0 M), 510 mg 1-ethyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-piperazine (compound C4), and 131 mg of trans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) at 110° C. for 18 hours. After aqueous work-up using 200 ml of dichloromethane and 75 ml of water, purification by chromatography on flash silica gel (eluent gradient dichloromethane/5-50 vol. % ethanol) yields 175 mg of the title compound as a waxy solid. ESI-MS: 511.3 (MH+). TLC: Rf=0.30 (dichloromethane/ethanol 8:1 parts by volume).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH2:17][CH3:18])[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=3)[C:6]([CH3:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[O:22]=[C:23]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:44]([O:46]C)=[O:45])[CH:39]=3)[CH:36]=2)[O:31][C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24]1>>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH2:17][CH3:18])[CH:9]=[C:10]([C:13]([N:28]4[CH2:29][CH2:30][C:25]5([CH2:24][C:23](=[O:22])[C:37]6[C:32](=[CH:33][CH:34]=[C:35]([C:38]7[CH:43]=[CH:42][N:41]=[C:40]([C:44]([OH:46])=[O:45])[CH:39]=7)[CH:36]=6)[O:31]5)[CH2:26][CH2:27]4)=[O:15])[CH:11]=3)[C:6]([CH3:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)ccn1
Reactant: CCOc1cc(C(=O)O)cc2c1c(C)cn2C1CC1
Agent: Cl
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4ccnc(C(=O)O)c4)ccc2O3)cc2c1c(C)cn2C1CC1

Procedure:
In the same manner as described in Example 42 except using 1-cyclopropyl-4-ethoxy-3-methyl-1H-indole-6-carboxylic acid and methyl 4-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)pyridine-2-carboxylate dihydrochloride, the title compound was obtained as a colorless amorphous substance. 1H-NMR (400 MHz, DMSO-d6) δ: 8.72 (1H, d, J=4.9 Hz), 8.25 (1H, d, J=1.5 Hz), 8.15-8.11 (2H, m), 7.94 (1H, dd, J=6.0, 2.0 Hz), 7.28 (1H, dd, J=6.0, 2.9 Hz), 7.12 (1H, d, J=1.0 Hz), 6.99 (1H, d, J=1.0 Hz), 6.48 (1H, s), 4.45-4.10 (1H, br m), 4.08 (2H, q, J=6.8 Hz), 3.67-3.19 (4H, m), 2.97 (2H, s), 2.32 (3H, s), 2.12-1.74 (4H, br m), 1.37 (3H, t, J=6.8 Hz), 1.03-0.98 (2H, m), 0.88-0.85 (2H, m); MS [M+H]+=580.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]=[C:7]([SH:9])[NH:6][N:5]=1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.O>CN(C)C=O>[NH2:3][C:4]1[N:8]=[C:7]([S:9][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[NH:6][N:5]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2nc(N)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To 60% sodium hydride-in-oil (3.89 g) in dimethylformamide (50 ml) was dropwise added a solution (100 ml) of 3-amino-5-mercapto-1H-1,2,4-triazole (10.0 g) in dimethylformamide under ice-cooling. After the dropwise addition, the mixture was stirred at 0° C.-room temperature for 30 minutes and ice-cooled again. A solution (50 ml) of 4-chlorobenzonitrile (13.0 g) in dimethylformamide was dropwise added. The mixture was stirred at 0° C.-room temperature for 30 minutes and at 100°-110° C. for 33 hours. After the reaction, the mixture was cooled to room temperature and added with water, followed by stirring for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The crude product was subjected to silica gel column chromatography (chloroform-methanol) to give 1.86 g of white crystals (yield 9.9%).
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:31])=O)=[N:27][CH:28]=1)=[O:21].[CH2:32]1[C:40]2[C:35](=[CH:36]C=CC=2)[CH2:34][N:33]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:34][CH:35]([CH3:36])[CH2:40][CH2:32][NH:33][C:29]([C:26]1[N:27]=[CH:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cn1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)cn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 5-(isoindoline-2-carboxamido)picolinic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (m, 2H), 8.57 (t, J=6.1 Hz, 1H), 8.17 (dd, J=8.5, 2.4 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.41-7.29 (m, 4H), 4.79 (m, 4H), 3.35 (m, 2H), 1.59 (m, 1H), 1.42 (q, J=7.1 Hz, 2H), 0.90 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 353 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12](N)[CH2:13][NH2:14]>>[NH:5]1[CH2:12][CH2:13][N:14]=[C:4]1[C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH2:1]
Reactant: COc1ccc(C#N)c(N)c1
Reactant: NCCN
Product: COc1ccc(C2=NCCN2)c(N)c1

Procedure:
The procedure used for the preparation of Intermediate C, Step 3 was used to prepare the title compound from 2-amino-4-methoxybenzonitrile (Step 1) and ethylene diamine. High vacuum drying gave the title compound (44 g, 92%). HPLC MS RT=1.04 min, MH+=192.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:26][CH:25]=1>>[NH2:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)=[CH:10][CH:9]=3)[C:14](=[O:22])[C@@H:15]2[CH2:19][CH2:20][CH3:21])=[O:33])=[CH:26][CH:25]=1
Reactant: Nc1ccc(C=CC(=O)O)cn1
Reactant: CCCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Product: CCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)C=Cc1ccc(N)nc1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-aminoquinazoline-7-ylmethyl)-3-propyl-piperazine-2-one, EXAMPLE 78 and 3-(6-amino-pyridin-3-yl)-acrylic acid, EXAMPLE 36. 1H NMR (d6-DMSO, 300 MHz) δ9.73 (bs, 2H), 8.81 (s, 1H), 8.36 (m, 2H), 8.22 (m, 3H), 7.62 (d, 1H), 7.52 (m, 1H), 7.39 (m, 1H), 7.21 (m, 1H), 6.91 (d, 1H), 5.00 (m, 1H), 4.78 (m, 1H), 4.60 (m, 2H), 4.34 (m, 1H), 3.30 (m, 2H), 1.87 (m, 2H), 1.24 (m, 2H), 0.90 (m, 3H). MS (ion spray), m/z, 446, 448 (M+H), (Cl pattern).
Reaction SMILES: Cl.[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].O.[CH3:15]COCC>C(N(CC)CC)C>[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([O:6][CH3:15])=[O:5]
Reactant: CC(N)(C(=O)O)c1ccccc1
Reactant: CCOCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(N)c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4.3 g of methyl DL aminophenylpropanoate hydrochloride, 43 ml of demineralized water, 86 ml of ether and 3 ml of triethylamine was stirred at 20° C. for 10 minutes and the aqueous phase was extracted with ether. The combined ether phases were dried and evaporated to dryness under reduced pressure to obtain 8.3 g of methyl aminophenylpropanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: OCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: OCC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 72.3 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (50 mg, 0.27 mmol), piperidin-4-ylmethanol (35 mg, 0.30 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, 85:15) to furnish the title compound as white solid (51 mg, 71%), LC-MS (ESI, 3.5 min) Rt 2.49 min, m/z 261 (100%, [M+H]+); m/z (ESI) C11H15Cl2N2O requires 261.0556 found [M+H]+ 261.0558; HPLC Rt 6.68 min, 100%.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])O2)=[CH:5][CH:4]=1.C(N(CC)C(=O)C1C=CC=CC=1C(O)C1C=CC(N(C)C)=CC=1)C.[CH2:44]([N:46]([CH2:50][CH3:51])[CH2:47][CH2:48][NH2:49])[CH3:45]>[Cl-].[Zn+2].[Cl-]>[CH2:44]([N:46]([CH2:50][CH3:51])[CH2:47][CH2:48][N:49]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:19])=[CH:8][CH:7]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18])[CH3:45]
Reactant: CN(C)c1ccc(C2OC(=O)c3ccccc32)cc1
Reactant: CCN(CC)CCN
Agent: CCN(CC)C(=O)c1ccccc1C(O)c1ccc(N(C)C)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccc(N(C)C)cc1

Procedure:
To a solution of 0.32 g of Compound A and 1.41 g of Compound B in 10 ml of N,N-diethylethylenediamine was added 0.15 g of anhydrous zinc chloride. After heating at reflux for 2.5 hours in a nitrogen gas atmosphere, the mixture was concentrated under reduced pressure. To the residue were added 15 ml of methylene chloride and 50 ml of water, and pH of the mixture was adjusted to 1 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 30 ml of methylene chloride was added to the aqueous layer. The pH was adjusted to 12 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent, ethyl acetate:hexane:triethylamine=10:20:1). A major fraction was concentrated under reduced pressure to give 1.13 g of 2-(2-diethylaminoethyl)-3-(4-dimethylaminophenyl)isoindolin-1-one (Compound 18).
Reaction SMILES: [C:1]1([P:7]([Cl:10])(Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[C:1]1([P:7]([Cl:10])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCO
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCP(=O)(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.5 %

Procedure:
To a solution of phenylphosphonic dichloride (3.0 g, 14.2 mmol) and triethylamine (2.4 mL, 17.1 mmol) in toluene (20 mL) at 0° C. is added dropwise a solution of 1-nonanol (2.05 g, 14.2 mmol) in toluene (5 mL). The mixture is allowed to warm slowly to room temperature and stirred for 2 hours. The mixture is filtered, and the filtrate is concentrated to afford 4.5 g of the title compound as a light yellow liquid; 1H NMR (200 MHz, CDCl3)δ7.40-7.15 (m, 5 H), 4.40-4.25 (m, 2 H), 1.90-1.65 (m, 2 H), 1.45-1.20 (m, 12 H), 0.89 (t, J=7 Hz, 3 H).