Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]4[C:37](=[O:38])[N:36]([C:39]5[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[O:31])=[CH:25][C:24]=3[F:46])[NH:15][N:14]=2)[CH2:7]1)=O.Cl.CCOC(C)=O>[Li+].[OH-].C1COCC1.CO>[F:46][C:24]1[CH:25]=[C:26]([NH:29][C:30]([C:32]2[C:37](=[O:38])[N:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[N:35]=[CH:34][CH:33]=2)=[O:31])[CH:27]=[CH:28][C:23]=1[O:22][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[NH:15][N:14]=[C:13]([NH:12][CH:8]3[CH2:9][CH2:10][CH2:11][CH:6]([OH:5])[CH2:7]3)[C:21]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCCC(OC(=O)C(F)(F)F)C4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCCC(O)C4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 29.1 %

Procedure:
LiOH (2M solution, 2 drops) was added into a solution of 3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)cyclohexyl 2,2,2-trifluoroacetate (10 mg, 0.015 mmol, obtained from Example 131, Step C) in THF (0.5 mL) and MeOH (0.1 mL). HCl (5M, 0.1 mL). EtOAc was added to dilute the reaction mixture. The organic layer was separated, washed with brine, dried with Na2SO4, filtered and concentrated to afford the product (2.5 mg, 29% yield) as a yellow solid. LRMS (APCI pos) m/e 574.2 (M+H). 1H NMR (DMSO-d6, 400 MHz): δ 8.38 (d, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.05 (dd, 1H), 7.66-7.70 (m, 2H), 7.56-7.62 (m, 1H), 7.48-7.54 (m, 1H), 7.38-7.44 (m, 2H), 6.80-7.00 (m, 1H), 6.00-6.05 (m, 1H), 3.80-4.00 (m, 2H), 3.50-3.80 (m, 1H), 1.80-2.00 (m, 1H), 1.60-1.80 (m, 2H), 1.40-1.60 (m, 1H), 1.10-1.30 (m, 2H), 0.80-0.90 (m, 2H).
Reaction SMILES: [OH2:1].O.O.O.O.[Al:6].Cl>C(O)(=O)C>[O-2:1].[O-2:1].[O-2:1].[O-2:1].[O-2:1].[O-2:1].[O-2:1].[O-2:1].[Al+3:6]
Reactant: O
Reactant: [Al]
Agent: Cl
Solvent: CC(=O)O
Product: [Al+3]
Product: [O-2]
Temperature: 80 °C

Procedure:
Aluminum octaoxide was synthesized by the method disclosed by U.S. Pat. Nos. 4,242,271 and 4,202,870, and then hydrolyzed to prepare an alumina slurry. Water was added to the alumina slurry until it had 5% by weight of solid contents of an alumina hydrate. The alumina slurry was heated to 80° C. and reacted for 10 hours for aging, and a colloidal sol thus obtained was dried with a sprayer, thereby preparing Alumina Hydrate No. 1. The Alumina Hydrate No. 1 was mixed with water for dispersion therein, adjusted to pH 4 with hydrochloric acid and then stirred for some time. Subsequently, small components were eliminated by the ultrafiltration method (using ACV-3050 Module, trade name, manufactured by Asahi Chemical Corp.), thereby obtaining a colloidal sol. The colloidal sol was desalted and deflocculated by adding acetic acid. Alumina Hydrate No. 2 was prepared by drying the colloidal sol after the deflocculation, and X-ray diffractometry of the Alumina Hydrate No. 2 indicated the pseudo-boehmite structure. Furthermore, a measurement of a pore radius distribution by the nitrogen adsorption·desorption method indicated that a volume of pores having radii not exceeding 50 Å was not more than 6.0% of a volume of all pores as shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:13]=3[C:26]=2[CH3:27])=O)=[CH:4][CH:3]=1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:13]=3[C:26]=2[CH3:27])=[CH:30][CH:31]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(F)cc1)C(C)(C)O2
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1NCc1ccc(F)cc1)C(c1ccc(F)cc1)C(C)(C)O2
Yield: 66 %

Procedure:
By using 4-fluoro-N-[3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 66%. Melting point: 118-120° C. (Ethanol)
Reaction SMILES: [OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl.O.C(=O)([O-])O.[Na+].[CH2:20](O)[CH3:21]>>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH2:20][CH3:21])=[O:4]
Reactant: CCO
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(O)Cc1ccccc1
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 2-hydroxy-3-phenylpropanoic acid (2.10 g, 12.6 mmol) in ethanol (50 mL) was saturated with gaseous hydrochloric acid and allowed to stand at room temperature overnight. The reaction mixture was poured into water, neutralized with solid sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give ethyl 2-hydroxy-3-phenylpropanoate as a peach-colored oil (2.00 g, 82%); 1HNMR (200 MHz, DMSO-d6): δ7.15-7.35 (m, 5H), 5.4-5.6 (br, 1H), 4.15-4.3 (br, 1H), 4.05 (q, 2H, J=7.3 Hz), 2.75-3.0 (m, 2H), and 1.2 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([N:13]([CH2:17][CH2:18][CH2:19][Br:20])[C:14]=2[C:15]=1[CH3:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH3:22][Li].O>O1CCCC1.C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH2:22])[C:7]3[C:12]([N:13]([CH2:17][CH2:18][CH2:19][Br:20])[C:14]=2[C:15]=1[CH3:16])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: [Li]C
Reactant: Cc1ccc2c(=O)c3ccccc3n(CCCBr)c2c1C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=C1c2ccccc2N(CCCBr)c2c1ccc(C)c2C
Reaction time: 1 h

Procedure:
0.1 g of 3,4-dimethyl-10-(3-bromopropyl)-9-acridone was dissolved in 5 ml of dry tetrahydrofuran. Then 0.36 ml of methyllithium (a 1.4 M solution in diethyl ether) was added dropwise at −78° C. After stirring at the same temperature for 1 hr, water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 0.1 g of the title compound.
Reaction SMILES: CC(C)N=C=NC(C)C.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17]([O:21][C:22](=[O:35])[C@@H:23]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[CH2:24][C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)CCC=C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:26]=[C:25]([S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:24][C@H:23]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[C:22]([O:21][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:35]
Reactant: Sc1ccccc1
Reactant: C=CCCC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Agent: C=CCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCC(=O)N[C@@H](CC(=O)Sc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
DIC (2.43 ml, 15.6 mmol), DMAP (318 mg, 2.60 mmol) and benzenethiol (1.59 ml, 15.6 mmol) were added to a solution of the mixed crude product A (2.53 g, 13.0 mmol) of (S)-4-(tert-butoxy)-4-oxo-3-(pent-4-enamido)butanoic acid (Compound 1b-I) and pent-4-enoic acid (1:0.8) in CH2Cl2 (35 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, and the resulting filtrate was concentrated, diluted with ethyl acetate and then washed with a saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate and brine. The organic extract was then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100), and the resulting crude product was further purified by silica gel column chromatography (hexane/ethyl acetate=100/0→65/35) to afford (S)-tert-butyl 4-oxo-2-(pent-4-enamido)-4-(phenylthio)butanoate (Compound 1e-IF) (1.99 g, 79%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:8][CH2:7][CH:6]1[C:17]([OH:19])=[O:18])=[O:4].[NH2:20][CH:21]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([OH:24])=[O:23].Cl>[OH-].[Na+]>[C:22]([CH:21]([NH:20][CH2:2][C:3]([N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:8][CH2:7][CH:6]1[C:17]([OH:19])=[O:18])=[O:4])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([OH:24])=[O:23]
Reactant: O=C(O)C1CCC(c2ccccc2O)N1C(=O)CCl
Reactant: NC(CCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(CCc1ccccc1)NCC(=O)N1C(C(=O)O)CCC1c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
1-(Chloroacetyl)-5-(2-hydroxyphenyl)-2-pyrrolidinecarboxylic acid [mp 204°-206° C.(dec.), [α]D24 +24.5° (c=1.2, MeOH)] (2.8 g) was added to a stirred solution of 2-amino-4-phenylbutanoic acid (1.8 g) in N sodium hydroxide (40 ml). The reaction mixture was stirred overnight at room temperature. The solution was adjusted to pH 1.5 by 20% hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 3.0, and the separated solid was collected by filtration to give 1.0 g (24%) of the titled compound. IR (nujol, cm-1): 3425, 1735, 1625, 1588.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([CH3:16])(O)[CH3:14])[CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)[OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([NH:4][C:3](=[O:18])[CH2:2][Cl:1])([CH3:14])[CH3:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(O)Cc1cccc(Br)c1
Reactant: O=S(=O)(O)O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(Cc1cccc(Br)c1)NC(=O)CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chloroacetonitrile (6.63 ml, 105 mmol) was added to a stirred solution of 1-(3-bromophenyl)-2-methylpropan-2-ol) (Preparation 29) (12.0 g, 52.0 mmol) in acetic acid (25 ml) at room temperature. The resulting solution was cooled to 0° C. and concentrated sulfuric acid (25 ml) was added keeping the temperature<10° C. The resulting solution was left to stir for 1 hour and then poured onto ice and basified by the addition of solid potassium carbonate. The product was extracted with ethyl acetate (2×500 ml), the organics combined and washed with water (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to afford the title compound as an orange solid (16.08 g). 1H NMR (400 MHz, CDCl3) δ 7.39-7.32 (1H, d), 7.26 (1H, s), 7.1-7.13 (1H, t), 7.08-7.03 (1H, d), 6.17 (1H, bs), 3.94 (2H, s), 3.02 (2H, s), 1.37 (6H, s). CHN for C12H15BrClNO calc. (found): C, 47.32 (47.26); H, 4.96 (4.87); N, 4.60 (4.65). LRMS (electrospray) m/z 306 [M+H]+
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH2:38][C:39]([O:41]CC)=[O:40])[C:30]5[C:35]([C:36]=4[CH:37]=3)=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:24])=[O:23])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].Cl>O1CCOCC1.CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH2:38][C:39]([OH:41])=[O:40])[C:30]5[C:35]([C:36]=4[CH:37]=3)=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:24])=[O:23])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)Cn1c2ccccc2c2cc(S(=O)(=O)NC(Cc3ccc4[nH]cnc4c3)C(=O)N3CCC(C)CC3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc3c(c2)c2ccccc2n3CC(=O)O)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 0.6 g (0.001 Mol) of ethyl [3-[[1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]sulphamoyl]-carbazol-9-yl]-acetate in 5 ml of dioxane and 5 ml of methanol are added dropwise 4 ml of 1N sodium hydroxide solution and the mixture is stirred at 20° C. for one hour. It is then diluted with 20 ml of water and mixed with 4 ml of 1N hydrochloric acid. The organic solvent is eliminated in vacuo, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:19]([OH:20])=[C:18]([C:21]([CH3:23])=[O:22])[CH2:17][S:16]2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].S(Cl)(Cl)(=O)=O>O>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:16][CH:17]=[C:18]([C:21]([CH3:23])=[O:22])[C:19]=2[OH:20])=[CH:13][CH:14]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)C1=C(O)C(c2ccc(C(C)(C)C)cc2)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: -23 °C
Reaction time: 0.55 h
Yield: 87.4 %

Procedure:
A chloroform (250 mL) solution of 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (24.94 g, 64.6 mmol, purity: 78%) was cooled to −23° C., and to this solution, a chloroform (50 mL) solution of sulfuryl chloride (5.45 mL, 1.05 equivalent amounts) was dropwise added over a period of 27 minutes, followed by stirring at from −22 to −24° C. for 33 minutes. The temperature of the solution was raised to −3° C., and water (50 mL) was dropwise added over a period of 2.5 minutes, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was distilled in chloroform (80 mL) at 45° C., the solution was cooled to 0° C., and isopropanol (375 mL) was dropwise added, followed by stirring at 0° C. for 40 minutes. The formed crystals were subjected to filtration to give the desired product as a yellow solid (15.5 g, yield: 63%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:40])(C)C.CCOCC>CC(CC)=O>[ClH:40].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(c1ccc(F)cc1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(4-fluorobenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one (254 mg, 0.9 mmol) was dissolved in ethyl methyl ketone (2.0 mL), water (5 μL), TMSCl (77 μL), and ether (20 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(4-fluorobenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 242 mg (88%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:28]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:20](=[O:21])[O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:32][CH:31]=2)=[O:29])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)benzoic acid via Procedure G to yield tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 50 mg of the crude HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 443.3 (M)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>C1COCC1>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COC(=O)CBr
Reactant: NCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl bromoacetate (24.0 mL, 253.5 mmol) in anhydrous THF (264 mL) was added triethylamine (35.34 mL, 253.5 mmol). The cloudy mixture was treated rapidly with 4-fluorobenzylamine (30.3 mL, 263.7 mmol), and the resulting viscous mixture was stirred at ambient temperature under inert atmosphere for 18 h. TH was removed in vacuo, and the residue was suspended in diethyl ether. The mixture was filtered and the solids washed with excess diethyl ether. Concentration of the filtrate in vacuo afforded the product as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:25]=[C:24]([Cl:26])[C:6]([C:7]([C:9]2[C:17]3[C:12](=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[C:5]([Cl:27])[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH2:35]>C(#N)C.O>[Cl:27][C:5]1[CH:4]=[C:3]([CH2:2][NH:35][CH3:34])[CH:25]=[C:24]([Cl:26])[C:6]=1[C:7]([C:9]1[C:17]2[C:12](=[C:13]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[N:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1c(Cl)cc(CBr)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CNCc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Yield: 15.7 %

Procedure:
To a solution of N-{3-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropanecarboxamide (50 mg, 0.11 mmol) in acetonitrile, cesium carbonate (70 mg, 0.21 mmol) was added and stirred at same temperature. Methyl amine (6.8 mg, 0.21 mmol) was added at 0° C. The reaction mixture was then stirred at room temperature for 3 h. On completion, the reaction mixture was diluted with water and extracted with ethyl acetate, organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-(3-{2,6-dichloro-4-[(methylamino)methyl]benzoyl}-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (7.2 mg, 16%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][CH:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:29]2=[O:47])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:48].C(O)(=O)C>C(O)(=O)C.C(OCC)C>[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][CH:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([OH:42])=[O:41])[C:29]2=[O:47])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:16]1.[BrH:48]
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(CCCCC1CCNCC1)NC1CCc2ccccc2N(CC(=O)O)C1=O
Reaction time: 2 h

Procedure:
In 2 ml of acetic acid is dissolved 0.7 g of tert-butyl 3(RS)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(RS)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 2 hours. The reaction solution is diluted with 100 ml of ethyl ether, and after the mixture is allowed to stand, the supernatant layer is removed by decantation. The precipitate is rinsed with 50 ml of ethyl ether and dried to give 3(RS)-[5-(4-piperidyl)-1(RS)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid·hydrobromide. This product is dissolved in 20 ml of 1N aqueous sodium hydroxide, and the solution is allowed to stand at room temperature for 1 hour, made acidic with 2 ml of acetic acid and purified by XAD-2 column chromatography (methanol:water=1:1). The effluent is concentrated under reduced pressure, and the crystals, which separate out, are rinsed with 50 ml of acetone and collected by filtration to give 0.22 g of 3(RS)-[5-(4-piperidyl)-1(RS)-carboxypentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-acetic acid as colorless prisms. m.p. 240°-260° C. (decomp.).
Reaction SMILES: [K].CCOCC.[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>CCO>[CH2:15]([O:14][C:7](=[O:13])[C:8](=[O:10])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:18])[CH3:19])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29])[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [K]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared by adapting the procedure described by Gagliardi S., el al., in J. Med. Chem., 1998;41:1568 using potassium (1.66 g, 42.4 mmol), Et2O (200 mL), EtOH (10 mL), diethyl oxalate (7.56 g, 51.8 mmol), and 4-tert-butyl-1-methyl-2-nitrobenzene (prepared in ExampleWW; 10.0 g, 51.8 mmol). MS(APCI): 294 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9]Br)[CH:3]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1ccc(Br)cc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cc(Br)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 4-bromo-2-(bromomethyl)-1-chlorobenzene (4.76 g. 16.7 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (1.83 g, 12.9 mmol), and triethylamine (5 mL, 36.0 mmol) in absolute ethanol (200 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The solid residue was treated with water (500 mL). The solid product was recovered by filtration, washed with water (2×50 mL), diethyl ether (3×50 mL), and hexanes (3×50 mL), and then dried in vacuo, affording the title compound (3.23 g, 56% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.39 (s, 2H), 6.00 (s (br), 1H), 7.41 (d, 1H, J=8.4 Hz), 7.53 (dd, 1H, J=2.3 Hz, 8.4 Hz), 7.86 (d, 1H, J=2.0 Hz); M+347.