Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([C:25]([NH:27][C:28]3[C:29]([CH3:39])=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31]([O:33][CH3:34])=[O:32])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[C:17]([C:25]([NH:27][C:28]3[C:29]([CH3:39])=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31]([O:33][CH3:34])=[O:32])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:14]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)cc3ccccc23)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O)CC3)cc3ccccc23)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.8 %

Procedure:
To a solution of methyl 3-[[3-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]naphthalene-1-carbonyl]amino]-2,4-dimethyl-benzoate (0.30 g, 0.54 mmol) in THF (8.0 ml) is added Bu4NF 1.0 M in THF (0.35 g, 1.60 mmol) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 14 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) with ethyl acetate in hexanes to afford the title compound as a white solid (0.10 g, 55%). Mass spectrum (m/z): 433.0 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[N:16](COCCOC)[C:15]3[CH:23]=[C:24]([Cl:37])[C:25]([S:27](=[O:36])(=[O:35])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:26][C:14]=3[N:13]=2)[CH:11]=1)=[O:6])[CH3:3]>O1CCOCC1.C(O)C>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[NH:16][C:15]3[CH:23]=[C:24]([Cl:37])[C:25]([S:27](=[O:36])(=[O:35])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:26][C:14]=3[N:13]=2)[CH:11]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)Nc4ccccc4)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)Nc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
Hydrochloric acid in dioxane (4M, 0.241 mL) was added to 1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-phenylsulfamoyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (35.0 mg, 65.5 μmol) in ethanol (0.50 mL) and allowed to stir at 23° C. for 2.5 h. The solvent was evaporated and the residue was purified via FCC (5-100% EtOAc/hexanes) to yield the titled compound (28.7 mg, 98% yield). MS (ESI/CI): mass calcd. for C19H16ClN5O4S, 445.1; m/z found, 446.0 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][CH2:25][S:26][CH3:27])[C:10]1=[O:28].Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].Cl.Cl.[O:44]=[C:45]1[NH:53][C:48]2=[N:49][CH:50]=[CH:51][CH:52]=[C:47]2[N:46]1[CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>O1CCCC1.ClCCl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][CH2:25][S:26][CH3:27])[C:10](=[O:28])[C@H:9]([NH:8][C:30]([N:57]2[CH2:58][CH2:59][CH:54]([N:46]3[C:47]4[C:48](=[N:49][CH:50]=[CH:51][CH:52]=4)[NH:53][C:45]3=[O:44])[CH2:55][CH2:56]2)=[O:31])[CH2:15][CH2:14]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CSCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
Triethylamine (0.020 mL, 0.143 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]azepan-2-one (45 mg, 0.143 mmol) and 4-nitrophenyl chloroformate (29 mg, 0.143 mmol) in tetrahydrofuran (3 mL) at 0° C. After 15 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (46 mg, 0.157 mmol), triethylamine (0.080 mL, 0.572 mmol) and dichloromethane (5 mL) were added and the mixture was heated to 50° C. After 30 min, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave the title compound (60 mg). The title compound was converted to the HCl salt with 2M HCl in ether. MS 559.2 (M+1). NMR (500 MHz, CD3OD) δ 8.11 (dd, J=7.8 Hz, 1.0 Hz, 1H), 7.99 (dd, J=6.1 Hz, 1.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.18-7.14 (m, 3H), 4.76 (d, J=10.7 Hz, 1H), 4.61-4.54 (m, 1H), 4.31-4.26 (m, 2H), 4.15-4.09 (m, 1H), 3.85-3.80 (m, 1H), 3.67-3.58 (m, 1H), 3.37 (d, J=15.4 Hz, 1H), 3.20-3.16 (m, 1H), 3.08-2.96 (m, 2H), 2.75-2.70 (m, 2H), 2.49-2.41 (m, 1H), 2.34-2.26 (m, 1H), 2.21-2.16 (m, 1H), 2.14 (s, 3H), 2.11-2.07 (m, 2H), 1.90-1.85 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:30][CH3:31])=[CH:7][CH:8]=2)[N:3]=1.Br[C:33]1C=CC(N)=N[CH:38]=1.ClC1C2C(=CC(OC)=CC=2)N=C(C)N=1>>[CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:24]=[C:25]5[CH:38]=[CH:33][NH:29][C:26]5=[N:27][CH:28]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:30][CH3:31])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1ccc2c(N3CCOc4ccc(-c5ccc(N)nc5)cc4C3)nc(C)nc2c1
Agent: COc1ccc2c(Cl)nc(C)nc2c1
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc6[nH]ccc6c5)cc4C3)nc(C)nc2c1

Procedure:
(5-{4-[2-methyl-7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyridin-2-amine. Synthesized according to the method of example 3 using 5-bromo-2-aminopyridine in step 1 and 4-chloro-7-methoxy-2-methylquinazoline in step 3. 1H NMR (400 MHz, DMSO-d6): 11.9 (s, 1H, AcOH), 8.21 (d, 1H), 7.87 (d, 1H), 7.67 (dd, 1H), 7.55 (m, 1H), 7.38 (dd, 1H), 7.10 (d, 1H), 7.02 (dd, 1H), 6.96 (d, 1H), 6.52 (d, 1H), 6.03 (s, 2H), 4.96 (s, 2H), 4.38 (m, 2H), 4.13 (m, 2H), 3.87 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H, AcOH); MS (EI) for C24H23N5O2: 413.9 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:5][C:6](=O)[C:7]=1[CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].P(Cl)(Cl)([Cl:25])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:25][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Yield: 73 %

Procedure:
To a suspension of methyl 2-(4-methyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)pentanoate (0.900 g; 3 mmol) in dry toluene (6 mL) under a nitrogen atmosphere were carefully added phosphorus oxychloride (3 mL), dimethylaniline (0.3 mL) and the reaction mixture was heated to reflux for 3 h. The volatiles were removed under reduced pressure, the residue was cooled down in an ice-bath and quenched by adding crushed-ice and a saturated solution of sodium hydrogencarbonate until neutralization. The product was extracted with ethyl acetate, the combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.701 g (73%) of the title compound as a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([CH3:46])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:39]([CH3:46])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cn1cc(C(=O)CCCCCBr)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(C)c3ccccc23)CC1
Yield: 41.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.2 g) as starting compound, potassium carbonate (1.8 g) and 6-bromo-1-(1-methyl-1 H-indol-3-yl)-1-hexanone (1.0 g) were reacted and treated in the same manner as in Example 172 to give 0.71 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-methyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][NH2:14])[N:12]=2)=[CH:4][CH:3]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCc1coc(-c2ccc(F)cc2)n1
Product: O=C(NCc1coc(-c2ccc(F)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 26 %

Procedure:
This compound was synthesized from (2-(4-fluorophenyl)oxazol-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (65 mg, yield 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.35-9.32 (m, 1H), 8.60 (t, J=1.5 Hz, 1H), 8.25-8.19 (m, 2H), 8.12 (m, 1H), 8.04-8.00 (m, 2H), 7.77-7.73 (t, J=7.8 Hz, 1H), 7.41-7.36 (m, 2H), 4.48-4.47 (d, J=5.2 Hz, 2H). MS (ESI) m/z: Calculated for C20H12F4N4O3: 432.08. found: 433.2 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)C.Cl.[NH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>O>[OH:29][NH:28][C:20](=[NH:21])[C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[N:15][C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]3)=[CH:11][CH:12]=2)=[CH:23][CH:22]=1
Reactant: CC(C)N1CCN(c2ccc(-c3ccc(C#N)cc3)cn2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)N1CCN(c2ccc(-c3ccc(C(=N)NO)cc3)cn2)CC1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A mixture of 4-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)benzonitrile (330 mg, 1.1 mmol, prepared as described in Example 10), ethanol (15 mL), hydroxylamine hydrochloride (225 mg, 3.2 mmol), potassium carbonate (240 mg, 1.7 mmol) and water (1.5 mL) was stirred at reflux temperature overnight. The reaction mixture was allowed to cool to rt, and the solid was isolated by filtration and dried. The solid was then stirred with water (10 mL) to remove inorganic residues. The mixture was filtered and the solid was washed with water and a small portion of ethanol. Drying in vacuo afforded 260 mg (71%) of N-hydroxy-4-(6-(4-isopropylpiperazin-1-yl)pyridine-3-yl)benzamidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=1)#[N:2].[NH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.C[Al](C)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:12]([C:13]([NH:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:14])=[CH:11][N:10]=1)#[N:2]
Reactant: CCOC(=O)c1cnc(-c2ccccc2C#N)cc1NCCc1cccc(F)c1
Reactant: NCc1cccnc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1cc(NCCc2cccc(F)c2)c(C(=O)NCc2cccnc2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
To a solution of ethyl 6-(2-cyanophenyl)-4-(3-fluorophenethylamino)nicotinate (100 mg, 0.26 mmol) and 3-aminomethylpyridine (39 mg, 0.36 mmol) in toluene (1 mL) was added AlMe3 (0.2 mL, 2M in toluene, 0.39 mmol) at r.t. The reaction mixture was stirred at 70° C. overnight. The reaction was cooled, quenched with sat. NaHCO3, and diluted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude oil. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6-(2-cyanophenyl)-4-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (10 mg, 8.6%). LRMS (M+H+) m/z 452.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22]([CH3:24])=[O:23])=[N:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22]([CH3:24])(=[O:33])=[O:23])=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(S(C)=O)nn2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(C)(=O)=O)nn2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)-3-(methylsulfinyl)-1H-1,2,4-triazole (152 mg, 0.443 mmol) and m-chloroperbenzoic acid (115 mg, 0.664 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 6 hours. Dichloromethane and sat. sodium bicarbonate solution were poured into the mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane. A combined organic layer was washed with sat. sodium bicarbonate solution and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with diisopropyl ether and the precipitate was isolated by filtration, washed with diisopropyl ether, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(methylsulfonyl)-1H-1,2,4-triazole (130 mg, 81.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[C:34]([Cl:35])=[C:33]([CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[C:34]([Cl:35])=[C:33]([CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: CCc1ccnc(C(=O)CBr)c1Cl
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)OC)c1Cl

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-3-chloro-4-ethylpyridine hydrobromide (Preparation is described in Example 115).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=O)[NH:12][CH2:11][CH2:10]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2
Reactant: O=C1NCCc2cc(OCc3cccc(F)c3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(COc2ccc3c(c2)CCNC3)c1
Temperature: 60 °C

Procedure:
A mixture of 6-(3-fluoro-benzyloxy)-3,4-dihydro-2H-isoquinolin-1-one (1.2 g, 4.423 mmol) and lithium aluminum hydride (0.337 g, 8,84 mmol) in tetrahydrofuran (24 ml) was heated to 60° C. for 8 h. Water was added and an 15% aqueous solution of sodium hydroxide and the mixture was extracted with ethylacetate. After drying of the organic layer with MgSO4, filtration and evaporation, an oil was obtained (1.14 g, 99%). MS: m/e 258.0 (M+H+).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[C:9]1[S:10][C:11]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:16])=[C:12]([CH3:14])[N:13]=1>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([C:11]2[S:10][C:9]([N:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]3=[O:7])=[N:13][C:12]=2[CH3:14])=[O:16])=[CH:24][CH:23]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Reactant: O=c1cccc[nH]1
Product: Cc1nc(-n2ccccc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 2-bromo-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 45% yield: mp 170-172° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.80-8.77 (m, 1H), 7.47-7.42 (m, 1H), 7.34-7.28 (m, 2H), 7.03 (t, J=8.6 Hz, 2H), 6.75 (d, J=9.4 Hz, 1H), 6.44 (d, J=6.9 Hz, 1H), 6.06 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.9, 162.1, 160.6, 153.2, 152.5, 139.9, 133.5, 131.2, 129.6, 129.5, 122.9, 121.3, 115.8, 115.5, 107.8, 43.4, 17.3; (ES+) m/z 344.2 (M+1).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:15]([OH:17])=O)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.P(Cl)(Cl)([Cl:24])=O.C([N:30]([CH:33]([CH3:35])[CH3:34])CC)(C)C.C1(N)CC1>>[Cl:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:15]([NH:30][CH:33]3[CH2:35][CH2:34]3)=[O:17])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(O)nncc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
A suspension of 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoic acid (1.0 g, 3.6 mmol) in phosphorous oxychloride (4.9 mL, 54 mmol) was heated at 80° C. for 1 h. The solution was cooled and concentrated. Toluene (10 mL) was added and removed in vacuo. The brown syrup was resuspended in DCM (20 mL) and cooled to 0° C. Diisopropylethylamine (3.1 mL, 18 mmol) followed by cyclopropylamine (3.0 mL, 43 mmol) was added and the mixture was allowed to warm up to RT and stirred for 1 hour. The mixture was concentrated and the crude product was purified by silica gel chromatography (50-100% EtOAc in hexanes) to give 610 mg of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide as an off-white solid. MS (ES+)=338.1 (M+H)
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl.Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: COCCOCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1ccc(Cl)cc1C(=O)O
Reaction time: 18 h
Yield: 81.8 %

Procedure:
Sodium hydroxide (7.20 g, 180 mmol) was added to a solution of 5-chlorosalicylic acid (10.36 g, 60 mmol) in tetrahydrofuran (60 ml). (2-Methoxyethoxy)methyl chloride (15.1 ml, 132 mmol) was added to the mixture, and the mixture was stirred for 18 hours. 2N Aqueous sodium hydroxide (80 ml) was added to the reaction mixture, and the mixture was refluxed for 2 hours. The water layer was adjusted to pH=3 by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane ethyl acetate=1:1) to give the title compound (12.8 g, 82%) as a colorless liquid.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][N:21]1[CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([C:38](=[O:39])[CH2:37][N:21]3[CH2:22][CH2:23][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:20]3=[O:19])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,4-diphenylpiperidine (Matrix, 0.48 mg, 2.00 mmol) in dichloromethane was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.59 g, 2.00 mmol) under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.77 g, 4.00 mmol) and N,N-dimethylpyridin-4-amine (0.024 g, 0.20 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.25-7.37 (m, 12H), 7.14-7.24 (m, 8H), 4.20 (s, 2H), 3.61-3.67 (m, 2H), 3.50 (t, J=6.4 Hz, 2H), 3.42-3.47 (m, 2H), 2.80 (t, J=6.6 Hz, 2H), 2.35-2.41 (m, 2H), 2.26-2.31 (m, 2H); MS (DCI+) m/z 515 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[CH2:13]([NH:15][CH3:16])[CH3:14]>>[CH2:13]([N:15]([CH3:16])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)[CH3:14]
Reactant: CCNC
Reactant: O=C1NCCc2cc(F)ccc21
Product: CCN(C)c1ccc2c(c1)CCNC2=O
Temperature: 150 °C
Yield: 85.1 %

Procedure:
6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (2.00 g, 12.1 mmol) was deposited in a sealed tube with N-ethylmethylamine (4.0 mL, 47 mmol). This was heated at 150° C. for 24 hours. This was concentrated in vacuo and purified by flash chromatography (elution with ethylacetate) to yield 6-(Ethyl-methyl-amino)-3,4-dihydro-2H-isoquinolin-1-one (2.10 g, 10.3 mmol). MS (ESI) 205.1 (M+H)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:10][O:11][C:12](=[O:16])[CH2:13][NH:14][CH3:15].C(N(CC)C(C)C)(C)C>CCCC(C)C>[F:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:14]([CH3:15])[CH2:13][C:12]([O:11][CH3:10])=[O:16])[N:7]=1
Reactant: CNCC(=O)OC
Reactant: Fc1ccnc(F)n1
Agent: Cl
Solvent: CCCC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C)c1nccc(F)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,4-difluoropyrimidine (J.Heterocyclic Chem. 1985, 22, 149) (4.48 g) in isohexane (50 ml) at 0° C. was added sarcosine methyl ester hydrochloride (5.39 g) followed by N,N-diisopropylethylamine (13.45 ml). After 5 minutes, the ice bath was removed and the reaction mixture allowed to stir at room temperature for 3 hours. The solvents were evaporated under reduced pressure and the residue purified by chromatography eluting with ethyl acetate/isohexane mixtures. The first and minor component of the mixture to be eluted was the subtitle compound. Yield 0.68 g.