Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:22][N:23]1[C:27]([CH:28]=[O:29])=[CH:26][CH:25]=[N:24]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:28]([OH:29])[C:27]4[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: Cn1nccc1C=O
Product: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 87 %

Procedure:
Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with 1-methylpyrazole-5-carbaldehyde to afford 342 mg (87% yield) of the title compound.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[N:18]=[N:19][C:20]([O:23][C@@H:24]4[CH:29]5[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]5)[CH2:25]4)=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[Cl:32])=O)(C)(C)C.Cl>CC(O)C>[ClH:32].[Cl:32][C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([C:17]1[N:18]=[N:19][C:20]([O:23][C@@H:24]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25]3)=[CH:21][CH:22]=1)=[CH:14][CH:15]=2
Reactant: CC(C)(C)OC(=O)n1c(Cl)cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc21
Agent: Cl
Solvent: CC(C)O
Product: Clc1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1

Procedure:
The product of Example 47B (110 mg, 0.24 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 0.5 mL) in iPrOH at ambient temperature overnight. The title product was obtained as a yellow solid (50 mg, yield, 53%). 1H NMR (300 MHz, CD3OD) δ ppm 1.93-2.31 (m, 3H), 2.33-2.55 (m, 1H), 2.65-2.81 (m, 1H), 3.33-3.59 (m, 5H), 3.59-3.75 (m, 1H), 5.38-5.77 (m, 1H), 6.68 (d, J=4.07 Hz, 1H), 7.43-7.45 (m, 1H), 7.65 (d, J=8.80 Hz, 1H), 7.71-7.78 (dd, J=8.40, 2.10 Hz, 1H), 8.28 (d, J=1.36 Hz, 1H), 8.86 (s, 1H) ppm; MS (DCI/NH3) m/z 355, 357 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([CH2:32][OH:33])=[CH:30][CH:31]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(/C=C/c1ccc(CO)cc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Yield: 67 %

Procedure:
This product was prepared by stirring a solution of Example 23 (0.3 g, 0.66 mmol) in 40 mL of MeOH with NaBH4 (0.1 g, 4 equiv.) at rt for two hours. Evaporation of the solvent gave a residue which was dissolved in DCM (100 mL) and washed twice with water (50 mL). Extraction with DCM, drying over MgSO4 and evaporation in vacuo gave the title compound (0.2 g, 67%) as white crystals after recrystallization from EtOH. MP: 206° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].Cl.[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>>[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]3[C:8]([OH:10])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Yield: 24.8 %

Procedure:
According to the procedure of Example 10, Step 1, the reaction of 487 mg (3.4 mmol) of trans-2-amino-1-cyclohexanecarboxylic acid with 1.31 g of 4-(2-methyl-quinolin-4-ylmethoxy) -benzenesulfonyl chloride hydrochloride provided 382.7 mg of trans-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylic acid in 25% yield. MS: 455.1 (M+H)+
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:42]I>ClCCl>[I:42][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
tert-Butyl [4-(2-hydroxyethyl)phenyl]carbamate (6.45 g, 27.18 mmol) in dichloromethane (20 mL) was added drop-wise to a solution of imidazole (2.04 g, 30.0 mmol), triphenylphosphine (8.60 g, 32.8 mmol), and iodine (8.28 g, 32.6 mmol) in dichloromethane (80 mL) at 0° C. The reaction was allowed to warm to rt and was stirred overnight at room temperature. The reaction was cooled to 0° C. and quenched with water (100 mL). The organic layer was separated, washed with saturated aqueous sodium thiosulfate (100 mL), water (100 mL), and brine (100 mL). The organics were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified via flash chromatography using an Analogix SF40-150 g column eluting with 30% EtOAc in heptane to afford the title compound as a white solid (8.16 g, 86.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9H) 3.13 (t, J=8.00 Hz, 2H) 3.27-3.35 (m, 2H) 7.12 (d, J=8.59 Hz, 2H) 7.32 (d, J=8.59 Hz, 2H).
Reaction SMILES: CON(C)[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5].[CH2:20]([Mg]Br)[CH2:21][CH2:22][CH3:23]>O1CCCC1>[CH2:12]([N:8]1[CH2:9][CH2:10][O:11][CH:6]([C:4](=[O:5])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCC[Mg]Br
Reactant: CON(C)C(=O)C1CN(Cc2ccccc2)CCO1
Solvent: C1CCOC1
Product: CCCCC(=O)C1CN(Cc2ccccc2)CCO1
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
Compound 82 is prepared from 2 (0.87 g, 3.28 mmol) in anhydrous tetrahydrofuran (30 mL) and commercially available (Aldrich) n-butyl magnesium bromide (2M solution in THF, 5 mmol, 2.5 mL, 1.5 eq) following General Procedure 1. After stirring for 1 hour further n-butyl magnesium bromide (2M solution in THF, 1.6 mmol, 0.8 mL) is added and stirring continued for 30 minutes. The reaction is quenched by addition of ammonium chloride solution (30 mL) followed by EtOAc. The organic phases are combined, dried over magnesium sulphate and the solvent is removed in vacuo to give 82 (0.82 g, 96%). MW 261.37; C16H23NO2; LCMS (6 minute method): m/z 262.4 [M+H]+, RT 2.34 mm.
Reaction SMILES: B(O)O.Br[C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>>[F:13][C:11]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[CH:12]=1
Reactant: OB(O)c1ccco1
Reactant: O=Cc1ccc(F)cc1Br
Agent: OBO
Product: O=Cc1ccc(F)cc1-c1ccco1

Procedure:
4-fluoro-2-(furan-2-yl)benzaldehyde was prepared using the general boronic acid coupling procedure with 2-bromo-4-fluorobenzaldehyde and furan-2-ylboronic acid (20 mg, 94 mg theoretical, 21.3%). LC-MS m/z 191 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][OH:19])[N:14]=[CH:13]1>>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:11])[O:19][CH2:18][CH2:17][C:15]2[N:14]=[CH:13][NH:12][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NCCc1ccccc1
Reactant: OCCc1c[nH]cn1
Product: O=C(NCCc1ccccc1)OCCc1c[nH]cn1

Procedure:
The preparation is carried out as in Example 23 with 2-phenylethyl isocyanate and 2-(1H-imidazol-4-yl)ethanol. The title compound is extracted from water with dichloromethane, purified by chromatography and crystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]1[O:8][C:9]2[CH:14]=[CH:13][S:12][C:10]=2[N:11]=1.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:13]1[S:12][C:10]2[N:11]=[C:7]([CH3:6])[O:8][C:9]=2[CH:14]=1
Reactant: BrBr
Reactant: Cc1nc2sccc2o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2sc(Br)cc2o1
Temperature: 25 °C

Procedure:
Sodium acetate (1.4 g) and 2 g of 2-methylthieno[2,3-d]oxazole were dissolved in 24 ml of an acetic acid solvent, and a solution comprised of 15.8 ml of bromine and 7.2 ml of acetic acid was dropwise added thereto with stirring at room temperature. After stirring at room temperature for 2.5 hours, the reaction solution was added to 150 ml of water, followedby further stirring at room temperature for 2 hours. The crystals precipitated were recovered by suction filtration, and dried under reduced pressure, thereby 1.7 g of 5-bromo-2-methylthieno[2,3-d]oxazole was obtained as pale yellow powder (yield: 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[C:32]([NH2:38])=[C:31]([CH3:39])[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:38][C:32]1[C:33]([N+:35]([O-:37])=[O:36])=[CH:34][C:29]([O:28][C:24]2[N:25]=[CH:26][N:27]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:23]=2)=[CH:30][C:31]=1[CH3:39]
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc([N+](=O)[O-])c1N
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c([N+](=O)[O-])c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
496 mg (1.80 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 480 mg (1.71 mmol) 4-(6-chloro-pyrimidin-4-yloxy)-2-methyl-6-nitro-phenylamine and 0.697 mL (4.00 mmol) DIPEA were combined in 10.0 mL DMF and stirred overnight at RT. The reaction mixture was added to ice water, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(#N)C>[F:42][C:43]1[CH:44]=[C:45]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(F)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 59.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-fluorobenzenesulfonyl chloride (0.0260 mL, 0.195 mmol) to obtain 4-(3-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0241 g, yield 60%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[O:12]1[CH2:17][CH2:16][CH:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.CN(C)C(=O)C>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:18]([CH:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)=[O:19])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: O=C(Cl)C1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-iodoimidazo[1,2-b]pyridazin-2-amine (550 mg, 2.11 mmol), tetrahydro-2H-pyran-4-carbonyl chloride (320 mg, 2.15 mmol) and N,N-dimethylacetamide (5.0 mL) was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, washed with water, and air-dried to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)tetrahydro-2H-pyran-4-carboxamide as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH:3]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Br:20]N1C(=O)CCC1=O>ClCCl>[Br:20][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:3]([CH:2]([CH3:1])[CH2:18][CH3:19])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(C)C(C(=O)OC(C)(C)C)c1ccc(C)cc1
Solvent: ClCCl
Product: CCC(C)C(C(=O)OC(C)(C)C)c1ccc(CBr)cc1

Procedure:
15 g (59.1 mmol) of tert-butyl 3-methyl-2-(4-methylphenyl)pentanoate, 11 g (62 mmol) of N-bromosuccinimide and 97 mg (0.59 mmol) of 2,2′-azobis-2-methylpropanenitrile in 150 ml of dichloromethane were stirred under reflux for 2 h. After the reaction had gone to completion, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 16.22 g (47.5 mmol, 80% of theory) of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2SC=C(C(OC)=O)N=2)[CH2:18][CH2:17]1)=[O:13].ClCC1[O:35][CH:36]=[CH:37][C:38]=1[C:39]([O:41][CH3:42])=[O:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[O:35][CH:36]=[CH:37][C:38]=2[C:39]([O:41][CH3:42])=[O:40])[CH2:18][CH2:17]1)=[O:13]
Reactant: COC(=O)c1ccoc1CCl
Reactant: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Product: COC(=O)c1ccoc1CN1CCC(CNC(=O)c2n[nH]c3ccc(OC)cc23)CC1

Procedure:
Methyl 2-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}furan-3-carboxylate 14 was prepared, according to the procedure described for compound 7, using methyl 2-(chloromethyl)furan-3-carboxylate. Yield: 120 mg, 13%.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:10]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(-c2nc(=O)c3ccccc3s2)c1
Yield: 3.4 %

Procedure:
A mixture of isophthalonitrile (1.00 g, 07.8 mmol), methyl thiosalicylate (1.97 g, 12 mmol), triethylamine (1.34 g, 13 mmol) and toluene (5 ml) was heated and refluxed for 5 hours under a nitrogen flow. The precipitated crystals were taken by filtration and recrystallized from tetrahydrofuran-ethanol to give the title compound (0.07 g, 2%) as crystals.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:18])=O.N>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]3[O:13][CH2:14][CH2:1][O:2][C:3]=3[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc3c(cc12)OCCO3
Agent: N
Product: Clc1ncnc2cc3c(cc12)OCCO3
Temperature: 0 °C

Procedure:
A mixture of 25.3 g. of 6,7-ethylenedioxyquinazolin-4(3H)-one and 50 ml. of phosphorus oxychloride is refluxed for 10 minutes, cooled, and added with stirring to one liter of ice. After addition of concentrated ammonia the resulting mixture is extracted with chloroform and the chloroform solution chromatographed through 300 mls. of silica gel while eluting with chloroform. Evaporation of the eluent yields 4-chloro-6,7-ethylenedioxyquinazoline, m.p. 169°-174°C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4](/[C:7](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8]/[CH2:9][OH:10])=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:36]([O:38][C:39](=[O:52])[C@@H:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)[CH3:37]>C1C=CC=CC=1>[CH2:36]([O:38][C:39](=[O:52])[C@@H:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:10][CH2:9]/[CH:8]=[C:7](/[C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:5]=2)\[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:44][CH:43]=1)[CH3:37]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C(\c1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(-c3ccccc3)cc2)cc1)OCC
Yield: 83.1 %

Procedure:
Reaction of (E)-3-biphenyl-4-yl-3-phenyl-prop-2-en-1-ol (1.0 g, 3.49 mmol), tributylphosphine (1.3 ml, 5.24 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (0.92 g, 3.84 mmol) and azodicarboxylic dipiperidide (1.32 g, 5.24 mmol) in benzene in an identical manner to example 3 gave the title compound (1.47 g, 83%).
Reaction SMILES: C(OC(=O)[C:7]([C:36]#[N:37])=[C:8]([NH:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:20])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:27]=[C:22]([NH:21][C:8]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:20])=[CH:7][C:36]#[N:37])[CH:23]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:25]=1
Reactant: CC(C)(C)OC(=O)C(C#N)=C(NCCCN1CCCCCC1=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC=C(NCCCN1CCCCCC1=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 114.5 %

Procedure:
To a solution of 3-[3,5-bis(trifluoromethyl)phenylamino]-2-cyano-3-[3-(2-oxoazepan-1-yl)propylamino]acrylic acid tert-butyl ester (203 mg, 0.37 mmol) in DCM (6.0 mL) at 0° C. TFA (6.0 mL) was added. The resulting mixture was stirred at 0° C. for 30 min and then poured into an ice-cold, aqueous, saturated NaHCO3 -solution (100 mL). After dilution with DCM (30 mL) phases were separated, the aqueous layer was extracted (3×20 mL DCM), the combined extracts were washed with brine (2×50 mL), dried (magnesium sulfate) and concentrated, to yield 190 mg (100%) of the title compound as an oil (mixture of isomers). LCMS: elution at 9.97 min, MH+ : 449). 1H NMR (300 MHz, DMSO-d6): δ=1.45-1.80 (m, 8H), 2.40 (m, 2H), 2.95 (m, 1H), 3.21 (m, 2H), 3.35 (m, 6H), 3.58 (s, br, 1H), 7.35-7.70 (m, 3H).
Reaction SMILES: [F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20]([O:22]C)=[O:21])=[N:12]3)[C:4]=2[O:3]1.[OH-].[Na+]>CO>[F:24][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20]([OH:22])=[O:21])=[N:12]3)[C:4]=2[O:3]1
Reactant: COC(=O)c1nn(-c2cccc3c2OC(F)(F)O3)cc(OC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of methyl 1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.1 g, 12 mmol) in TI-IF (100 mL) and MeOH (50 mL) was added 1 M NaOH aqueous solution (18 mL, 18 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and acidified with 1 M HCl aqueous solution. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.8 g, 97% yield) as a yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 4.06 (3H, s), 7.22-7.26 (1H, m), 7.34 (1H, t, J=8.3 Hz), 7.72 (1H, dd, J=8.3, 1.1 Hz), 8.29 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CN1CCC(c2cn(C(=O)c3ccccc3)c3cc(Cl)ccc23)CC1

Procedure:
(25.4 mg, 72%); from 6-chloro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5b, 25 mg, 0.10 mmol) and benzoyl chloride (21.1 mg, 0.15 mmol), HRMS-FAB+ for C21H21ClN2O, calculated MH+ : 353.14206; found: 353.13873.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>C(Cl)Cl>[CH3:26][N:27]([O:28][CH3:29])[C:7](=[O:9])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
4-pyridinecarboxylic acid (18) (17.0 g, 0.138 mol) is slurried in methylene chloride (200 mL) and treated with 1,1′-carbonyldiimidazole (25 g, 0.154 mol). After a 1 minute induction period, CO2 evolution begins and the solution becomes homogeneous. After stirring at ambient temperature for 2 hours, the solution is treated with N,O-dimethylhydroxylamine hydrochloride (20 g, 0.20 mol) and stirred at room temperature overnight. The reaction mixture is quenched with 1 N NaOH and the phases separated. After a normal work-up, the organic phase is concentrated to leave an oil. Kugelrohr distillation provided the title compound (19) as a clear liquid (14.34 g, 62% yield); b.p. 120-135° C./0.5 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH2:20][NH:21][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[CH3:1])=[CH:15][CH:14]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: NCC(c1ccc(F)cc1)N1CCOCC1
Product: Cc1cccc(C(=O)NCC(c2ccc(F)cc2)N2CCOCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:34][C:35]([OH:37])=[O:36])[CH:6]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1)[CH2:7][N:8]([CH2:13][CH2:14][N:15]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:9][C:10]([OH:12])=[O:11])([OH:3])=[O:2]>O.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:6]([N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:34][C:35]([OH:37])=[O:36])[CH2:7][N:8]([CH2:13][CH2:14][N:15]([CH2:16][C:17]([OH:19])=[O:18])[CH2:20][C:21]([OH:23])=[O:22])[CH2:9][C:10]([OH:12])=[O:11])=[CH:26][CH:27]=1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Pd]
Solvent: O
Product: Nc1ccc(CC(CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1
Reaction time: 24 h
Yield: 119.9 %

Procedure:
To a solution of 5a (32 mg, 0.0502 mmol) in H2O (9 mL) at room temperature was added 10% Pd/C (13 mg) under Ar (g). The reaction mixture was placed under hydrogenation apparatus for 24 h. The resulting mixture was filtered via celite bed and washed thoroughly with H2O. The filtrate was concentrated to provide 6a (30 mg, 93%) as a yellowish solid. 1H NMR (D2O, 300 MHz) δ 2.43-4.25 (m, 22H), 7.21 (s, 4H).