Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)CC)C.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=O)=CC=1.CO>C(Cl)(Cl)Cl>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCN(CC)CC
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of benzoic acid (1.22 g) and triethylamine (1.4 ml) in chloroform (15 ml) is added 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (3.44 g) and the mixture is allowed to stand for 1.5 hours. To the mixture are added methanol (1.6 ml) and triethylamine (1.4 ml), whereby exothermic reaction occurrs. After reacting them for 1 hour and 20 minutes, chloroform is distilled off and to the resulting residue are added water and ether. The ether layer is washed with water, an aqueous sodium hydrogen carbonate and water in order and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give methyl benzoate (1.26 g).
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br>>[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH:21][CH:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Reactant: COC(=O)CBr
Agent: Cl
Product: COC(=O)CNC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 20.1 %

Procedure:
The title compound (24 mg, 21%) was prepared from the compound from Example 12 (120 mg, 0.35 mmol) and 2-bromoacetic acid methyl ester (53 mg, 0.35 mmol) by the procedure described in step 1 of Example 1: MS (ESI) m/z 341 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.51-1.61 (m, 4H), 1.95 (br, 2H), 2.61 (m, 11H), 2.75 (dd, J=2.4, 12 Hz, 2H), 3.56 (m, 2H), 3.75 (s, 3H), 6.90-6.96 (m, 6H), 7.03 (m, 1H), 7.28 (m, 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.[C:41](=O)([O:47]C(C)(C)C)[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:43]([O:42][C:41](=[O:47])[NH:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:7]2[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8]2=[O:12])=[CH:19][CH:18]=1)(=[O:21])=[O:22])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NC(=O)OC(C)(C)C)cc1

Procedure:
To a mixture of 4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzenesulfonamide (2.0 g), triethylamine (1.1 ml), 4-dimethylaminopyridine (0.23 g) and methylene chloride (40 ml) was added di-t-butyl carbonate (1.1 ml) at room temperature with stirring, and the mixture was stirred at the same temperature for 1 hr. After the completion of the reaction, the reaction mixture was washed with 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=3/1-1/1), crystallized from hexane/ethyl acetate=3/1 to give the title compound (2.0 g) in pale-pink crystals. 1H NMR (CDCl3) δ: 0.46 (3H, t, J=6.9 Hz), 1.37 (9H, s), 1.62 (2H, q, J=6.9 Hz), 5.42 (2H, s), 7.14 (1H, br), 7.24-7.30 (2H, m), 7.39 (2H, d, J=8.4 Hz), 7.29-7.51 (4H, m), 7.69 (1H, dd, J=1.8, 8.4 Hz), 7.95 (2H, d, J=8.4 Hz), 8.41 (1H, d, J=8.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)CBr
Reactant: COc1ccc(N)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccc(OC)cc1OC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of 1.53 g (10 mmol) of 2,4-dimethoxyaniline and 2.76 g (20 mmol) of potassium carbonate in 10 mL of DMF are added 1.53 g (10 mmol) of methyl bromoacetate. The mixture is stirred at 60° C. for 3 h, then allowed to cool to RT. The mixture is poured into water and extracted with EtOAc. The organic phase is washed with water, brine and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue is chromatographed using CH2Cl2 as the eluant to give (2,4-dimethoxyphenylamino)-acetic acid methyl ester as an oil: 1H-NMR (CDCl3) δ 6.46 (d, J=2.20, 1H), 6.41-6.38 (m, 2H), 3.91 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[S:29])[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Solvent: Cc1ccccc1
Product: S=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Yield: 63.4 %

Procedure:
To 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one (9 g) in toluene (175 ml), under nitrogen, was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (12.6 g). The mixture was refluxed for 1 hr and concentrated under reduced pressure. Recrystallization of the residue from chloroform:hexane afforded 6 g (63%) of product, mp 196°-197° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30](O)=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1>C(Cl)Cl>[N:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[NH:53][C:30](=[O:31])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:18]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
3-[6-(4-t-Butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid (121 mg) was dissolved in methylene chloride (0.9 ml). Oxalyl chloride (27 mg) and dimethylformamide (1 droplet) were added, and the mixture was stirred for 30 minutes at room temperature. 2-Aminopyridine (38 mg) was added, and the mixture was stirred overnight at room temperature. After the solvent was evaporated, ethyl acetate was added. The organic layer was successively washed with 0.5N-HCl, sat. aq. NaHCO3, and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1), to thereby obtain 51 mg (yield: 37%) of the title compound as a white powder.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[S:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2ccc(Cl)cc2)no1

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide; hydrochloride (110 mg; 0.382 mmol) in DMF (1.5 mL) is added 4-chlorobenzenesulfonyl chloride (80.6 mg; 0.382 mmol) and N,N-diisopropylethylamine (0.133 mL; 0.764 mmol). The reaction mixture is left stirring at room temperature for 18 hours in the presence of catalytic amount of 4-dimethylaminopyridine. The reaction mixture is quenched with water and extracted with ethyl acetate twice. The combined organics are washed with water then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 426 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=O)[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(=O)NC(=O)C=C1.ClC1C=C(C=CC=1Cl)N.N1C=CC=CC=1.Cl.[CH3:47][O:48][NH2:49]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=[N:49][O:48][CH3:47])[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC2C(C=O)C2(c2ccc(Cl)c(Cl)c2)C1
Reactant: CON
Agent: Cl
Agent: Nc1ccc(Cl)c(Cl)c1
Agent: O=C1C=CC(=O)N1
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)c(Cl)c1
Yield: 90 %

Procedure:
To a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.50 g, 7.02 mmol, prepared from maleimide and 3,4-dichloroaniline according to the methods described in WO 2009141412 and WO 2008074716), in ethanol (40 mL) under nitrogen atmosphere, were added pyridine (2.82 mL, 35.04 mmol) and O-methylhydroxylamine hydrochloride (1.17 g, 14.01 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% HCl (5 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:9 EtOAc:Pet Ether) to afford pure tert-butyl 1-(3,4-dichlorophenyl)-6-((methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.45 g, 90%) as a viscous oil as a mixture of isomers.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[CH3:18][O:19][CH2:20][CH2:21]Cl>CN(C)C=O>[CH3:18][O:19][CH2:20][CH2:21][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: COCCCl
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Agent: [H-]
Solvent: CN(C)C=O
Product: COCCN1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 28.5 g (0.13 mol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), in 200 ml of N,N-dimethylformamide is added over 1.5 hours to a suspension of 6.24 g (0.13 mol) of solution hydride in 30 ml of N,N-dimethylformamide. The mixture is stirred for 1 hour at ordinary temperature and a solution of 14.7 g (156 mmol) of 2-methoxyethyl chloride in 100 ml of dimethylformamide is then run in. The mixture is heated at 70° C. for 5 hours and stirred at ordinary temperature for 15 hours and evaporated to dryness, the residue is taken up with 200 ml of 0.5N hydrochloric acid, extraction is carried out with benzene and the extract is washed with water and dried. After evaporation of the benzene layer, the residue is purified by chromatography on a silica column using a methylene chloride/ether mixture as the eluent. This gives 45% of a pure product of Rf=0.45 (A).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CC(C)=O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OCC1CO1
Yield: 12 %

Procedure:
A mixture of 15.2 g (0.10 mole) of methyl 2-hydroxybenzoate, 27.6 g (0.20 mole) of K2CO3 and 31 mL (0.40 mole) of epichlorohydrin in 250 mL of acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated under reduced pressure. The resulting oil was dissolved in 100 mL toluene and washed consecutively with 100 mL water, 2×100 mL 1.0N NaOH, and 2×100 mL water. The organic phase was then dried over MgSO4 and evaporated under reduced pressure to provide the crude product as an oil. Purification was effected by vacuum distillation to provide an oil in 12% yield: boiling point 148° C. (75 u). The NMR and IR spectra and elemental analysis were consistent with the assigned structure.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C1CCN2C(=NCCC2)CC1.C1CCCCC1>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:3]([C:4]([O:6][CH3:7])=[O:5])([C:2](=[O:1])[CH2:8][CH3:9])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC(=O)OC
Reactant: CCC(=O)CC(=O)OC
Solvent: C1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)C(CCC(=O)OC)(CCC(=O)OC)C(=O)OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 129 %

Procedure:
39.9 g (0.31 mol) of methyl 3-oxo-pentanoate and 1.9 g (0.012 mol) of DBU were mixed at room temperature in a three necked round bottom flask, equipped with a dropping funnel and a reflux condenser. 66.4 g (0.77 mol) of methyl acrylate was slowly added drop by drop. After the exothermal behavior has leveled off, the reaction mixture was stirred at 60° C. for an additional two hours. Cyclohexane was added and the mixture was washed with diluted hydrochloric acid and was subsequently washed with distilled water until the aqueous layer showed a neutral reaction. The organic layer was dried over sodium sulfate, the solvent was removed, and the addition product was isolated by fractional distillation in a vacuum. 21.4 g (0.20 mol) of 4-(methoxycarbonyl)-4-(1-oxopropyl)-heptanedioic acid 1,7-dimethyl ester was obtained (yield: 64%; boiling temperature: 130° C. at 0.02 mbar; colorless).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](O)=[O:14])[CH:9]=2)[N:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:26])=O>ClCCl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([Cl:26])=[O:14])[CH:9]=2)[N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2nc(C(F)(F)F)ccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2nc(C(F)(F)F)ccc2c1
Reaction time: 2 h

Procedure:
2-(Trifluoromethyl)quinoline-6-carboxylic acid (0.20 g) was dissolved in dichloromethane. To this solution, a small amount of N,N-dimethylformamide (300 μL) and oxalyl chloride (0.17 g) were added at room temperature and stirred for two hours. After refluxing for 20 minutes, the solvent was distilled off under the reduced pressure and 2-(trifluoromethyl)quinoline-6-carbonyl chloride was obtained as a crude product. To this crude product, 4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylaniline (0.49 g) dissolved in pyridine was added and refluxed for 5 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain N-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylphenyl]-2-(trifluoromethyl)quinoline-6-carboxamide (0.10 g, yield 24%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[C:17]([NH:19][CH3:20])=[O:18])=[CH2:6].[H][H]>CO.[Pd]>[NH2:3][CH2:4][CH:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[C:17]([NH:19][CH3:20])=[O:18])[CH3:6]
Reactant: C=C(CN)c1cccc2c(C(=O)NC)ccnc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC(=O)c1ccnc2c(C(C)CN)cccc12
Yield: 79.8 %

Procedure:
As shown in step 9-viii of Scheme 9, 8-[1-(aminomethyl)vinyl]-N-methyl-quinoline-4-carboxamide, dihydrochloride (compound 2036, 168.8 g, 537 mmol) was stirred in MeOH (1.688 L) and TEA (114.2 g, 157.3 mL, 1.129 mol) was added, followed by the addition of 5% Pd on BaSO4 (22.88 g, 10.75 mmol). The atmosphere of the reaction mixture was replaced with hydrogen gas and the reaction stirred at under 1 atmosphere of hydrogen atmosphere for 16 hours. After this time, the hydrogen atmosphere was removed and the mixture filtered through diatomaceous earth, concentrated under reduced pressure, and treated with 800 mL water and 250 mL DCM. The resulting biphasic mixture was stirred vigorously until most of the solids had dissolved, resulting in a thick mixture that separates on standing. The pH of the aqueous layer was checked and found to be pH=8. This layer was washed with 3×500 mL DCM, the pH adjusted to 14 with 500 mL 6N NaOH, and extracted with an additional 500 mL DCM. The aqueous solution was then treated with 500 g NaCl and it was extracted with an additional 500 mL DCM. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 8-(1-aminopropan-2-yl)-N-methylquinoline-4-carboxamide [compound 2037 (racemic mixture) 104.2 g, 80% yield]: LC-MS=244.43 (M+H); 1H NMR (300 MHz, methanol-d4) δ 8.94 (d, J=4.3 Hz, 1H), 8.02 (dd, J=8.3, 1.6 Hz, 1H), 7.72-7.59 (m, 2H), 7.50 (d, J=4.3 Hz, 1H), 4.30 (h, J=7.0 Hz, 1H), 3.04 (dd, J=12.7, 7.0 Hz, 1H), 3.01 (s, 3H), 2.90 (dd, J=12.7, 6.9 Hz, 1H), 1.40 (d, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:19]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:7]1[C:6]2[CH:19]=[C:2]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:3]=[CH:4][C:5]=2[NH:11][CH2:10][CH2:9][NH:8]1
Reactant: OB(O)c1ccncc1
Reactant: Fc1ccccc1C1NCCNc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1C1NCCNc2ccc(-c3ccncc3)cc21
Temperature: 160 °C
Yield: 40.2 %

Procedure:
A 5-mL microwave tube was charged with provided 7-bromo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (25 mg), 4-pyridylboronic acid (50 mg), dichlorobis(triphenyl-phosphine)palladium(II) (10 mg), potassium carbonate (50 mg), dimethylformamide (3.5 mL) and water (0.5 mL). The reaction was heated to 160° C. for 360 seconds using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water and extracted with ethyl acetate. The organic extracts were combined and dried over magnesium sulfate. The drying agent was filtered and the filtrate was concentrated to an oil. Silica gel purification provided the title compound 5-(2-fluorophenyl)-7-(4-pyridinyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (10 mg) as a white powder. H1 NMR (d6-dmso): 8.42 (d, 2H), 7.46 (m, 2H), 7.30 (m, 3H), 7.18 (m, 2H), 7.02 (d, 1H), 6.83 (s, 1H), 5.85 (br s, 1H), 5.22 (br s, 1H), 3.18-3.3 (m, 1H), 2.78-2.96 (m, 3H), 2.64 (br s, 1H). Mass (ES+)=320.2 (100%).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].S(O)(C1C=CC(C)=CC=1)(=O)=O.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 47.7 %

Procedure:
Boc-Phe-OH (79.6 g, 0.3 mole), Gly-OBzl-TosOH (111 g, 1.1 eq), and HOBt (44.6 g, 1.1 eq) were dissolved in DMF (300 ml). WSCI (60.4 ml, 1.1 eq ) was added dropwise while cooling, and the solution was stirred overnight. DMF was distilled off. The residue was dissolved in CHCl3, and the solution was washed with 5% NaHCO3, 10% Na2CO3, water, 1HCl, and water, in order, and dried over MgSO4. The CHCl3 was distilled off, and to the residue, Et2O was added. The thus-produced powder was obtained by filtration and recrystalized two times with AcOEt/Et2O to obtain the object product (59 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[N:17]1([CH2:22][CH2:23][O:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[C:11]1([C:10]2[C:5]3[CH:4]=[N:3][C:2]([N:29]4[CH2:30][CH2:31][CH:26]([CH2:25][O:24][CH2:23][CH2:22][N:17]5[CH2:21][CH2:20][CH2:19][CH2:18]5)[CH2:27][CH2:28]4)=[N:7][C:6]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: Clc1ncc2c(-c3ccccc3)csc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc(-c2csc3nc(N4CCC(COCCN5CCCC5)CC4)ncc23)cc1
Temperature: 150 °C
Yield: 26 %

Procedure:
2-Chloro-5-phenyl-thieno[2,3-d]pyrimidine (150 mg, 0.61 mmol), 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (293 mg, 0.92 mmol) and potassium carbonate (253 mg, 1.83 mmol) were combined in acetonitrile (2 mL) and heated in the microwave at 150° C. for 30 minutes. The reaction mixture was diluted with DCM (10 mL), washed with water (10 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by basic prep HPLC to afford 5-phenyl-2-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (67 mg). LCMS [M+H]+=423.2.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[C:8]2=[O:24])=[CH:4][CH:3]=1.[NH2:27][OH:28]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)/[C:19](/[NH2:20])=[N:27]/[OH:28])[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: COc1nn(-c2cccc(C#N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reactant: NO
Solvent: CCO
Solvent: O
Product: COc1nn(-c2cccc(/C(N)=N/O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 80 °C
Yield: 99 %

Procedure:
According to Scheme 9 Step 1: To a stirred solution of 3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile (1 50 mg, 0.41 mmol) in ethanol (5 ml) was added hydroxylamine (0.100 ml of a 50% solution in water, 1.2 mmol) and the mixture was heated at 80° C. overnight. The reaction mixture was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water, with brine,dried over MgSO4, filtered and concentrated to afford (Z)-3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-N′-hydroxybenzamidine (150 mg, 99%) which was used in the next step without any further purification.