Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH3+:23])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][N:10]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C1C=CC=CN=1)C.[CH3:38][N:39]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[N:41]=[CH:40]1>ClCCl.C(OCC)(=O)C>[CH2:2]([CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH:23][S:44]([C:42]3[N:41]=[CH:40][N:39]([CH3:38])[CH:43]=3)(=[O:46])=[O:45])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][N:10]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)N1CCCc2ccc(OCC[NH3+])cc2C1Cc1ccccc1
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N1CCCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccccc1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of 0.12 mmol 2-(1-benzyl-2-(ethoxycarbonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxy)ethanaminium chloride in 3 ml dichloromethane were added 0.33 mmol dimethylaminopyridine and 0.17 mmol 1-methyl-1H-imidazole-4-sulfonyl chloride. The mixture was stirred at room temperature over night. The mixture was diluted with ethyl acetate and washed with NH4Cl solution (2×), water (1×), and brine (1×). The organic layer was dried over MgSO4 and filtered. Evaporation of the solvent gave 66 mg of crude material that was purified by flash chromatography to yield 60 mg of ethyl 1-benzyl-8-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-4,5-dihydro-1H-benzo[c]azepine-2(3H)carboxylate (95%).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=C>C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH3:8]
Reactant: C=CC(=O)OCC
Solvent: ClC(Cl)Cl
Solvent: C=COC(C)=O
Product: CCOC(C)=O

Procedure:
Finely divided vinyl acetate-ethyl acetate copolymer is prepared exactly as described in Example 1 except that in place of the vinyl acetate there is used an 85:15 mixture of vinyl acetate and ethyl acrylate. The resulting dispersion contains 51.4% solids, and has a particle size of 0.45 micron. The polymer has a reduced specific viscosity of 1.32 determined in chloroform solution at 25° C., which indicates a molecular weight above 100,000, and has a second order transition temperature of 19° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl>COCCOC>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:22])(=[O:23])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Solvent: COCCOC
Product: CCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of methyl 7-(4-butoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (500 mg) in 1,2-dimethoxyethane (1Oml) was added 6N hydrochloric acid (5 ml), and the mixture was refluxed for 16 hours. To the mixture were added 1,2-dimethoxyethane (5 ml) and 6N hydrochloric acid (2 ml), and the mixture was refluxed for 4 hours, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals were washed with diisopropylether to give colorless crystals of 7-(4-butoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (388.9 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:27]([F:30])([F:29])[F:28])[C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([O:17][C@@H:18]([CH2:23][O:24][CH2:25][CH3:26])[C:19]([O:21][CH3:22])=[O:20])=[C:11]3[CH:10]=[N:9]2)=[N:6][CH:7]=1>[Pd].CO>[CH2:25]([O:24][CH2:23][C@H:18]([O:17][C:16]1[C:11]2[CH:10]=[N:9][N:8]([C:5]3[C:4]([C:27]([F:28])([F:29])[F:30])=[CH:3][CH:2]=[CH:7][N:6]=3)[C:12]=2[N:13]=[CH:14][N:15]=1)[C:19]([O:21][CH3:22])=[O:20])[CH3:26]
Reactant: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncc(Cl)cc1C(F)(F)F)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1C(F)(F)F)C(=O)OC
Yield: 54.3 %

Procedure:
(2S)-Methyl 2-(1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-ethoxypropanoate (Intermediate Q2) (800 mg, 1.79 mmol) and 10% palladium on carbon (200 mg) in MeOH (30 mL) was stirred under an atmosphere of hydrogen for 24 hours. The mixture was filtered, 10% palladium on carbon (200 mg) and ammonium formate (1.0 g) were added and the mixture was heated to reflux for 2 hours. The mixture was allowed to cool and was filtered and evaporated. The residue was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to afford the product (400 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.62-3.73 (2H, m), 3.79 (3H, s), 4.00-4.11 (2H, m), 5.84 (1H, dd), 7.63-7.66 (1H, m), 8.27-8.29 (1H, m), 8.38 (1H, s), 8.58 (1H, s), 8.88-8.89 (1H, m); m/z (ESI+) (M+H)+=412; HPLC tR=2.13 min.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[N:13]=[C:14]([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:54]=[CH:55][CH:56]=2)[C:23]([NH:25][C:26]2[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][S:44]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[CH:38]=[CH:37][C:27]=2[O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[O:24])[S:15][CH:16]=1)([CH3:11])([CH3:10])[CH3:9].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:8]([C:12]1[N:13]=[C:14]([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:54]=[CH:55][CH:56]=2)[C:23]([NH:25][C:26]2[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][S:44]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)(=[O:45])=[O:46])[CH:38]=[CH:37][C:27]=2[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:24])[S:15][CH:16]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCCc2nc(C(C)(C)C)cs2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1csc(CCOc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
Under ice-cooling, trifluoroacetic acid (1.2 ml) was added to a mixture of tert-butyl 2-[3-[2-(4-tert-butyl-2-thiazolyl)ethoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (185 mg, 0.25 mmol) and dichloromethane (2 ml), and the resulting reaction solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the resulting residue and the product formed was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in water, and the solution obtained was adjusted to pH 2 by adding 10% citric acid aqueous solution. Thereafter, the solid material formed was collected by filtration and purified by silica gel column chromatography (eluent=chloroform:methanol=50:1) to give 2-[3-[2-(4-tert-butyl-2-thiazolyl)ethoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetic acid 0.5 hydrate (58 mg, 0.086 mmol, 34%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([C:7]1[C:12]([NH2:13])=[C:11]([CH2:14][CH3:15])[N:10]=[C:9]([CH3:16])[N:8]=1)[CH3:6]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:14]([C:11]1[C:12]([N:13]=[C:1]=[S:2])=[C:7]([CH2:5][CH3:6])[N:8]=[C:9]([CH3:16])[N:10]=1)[CH3:15]
Reactant: CCc1nc(C)nc(CC)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(C)nc(CC)c1N=C=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Thiophosgene (2.53 mL, 33.2 mmol) was added dropwise to a stirred mixture of 4,6-diethyl-2-methylpyrimidin-5-amine (4.22 g, 25.5 mmol) in tetrahydrofuran (40 mL) and saturated aqueous sodium hydrogen carbonate (40 mL) at 0° C., and the mixture was stirred at 0° C. for 20 minutes. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow solid (5.28 g, 25.5 mmol, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:14][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CCCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Chloroethyl chloroformate (10.0 g, 69.9 mmol) and 1-hexanol (6.5 g, 63.6 mmol) were dissolved in chloroform (80 ml) at 0° C. Pyridine (5.5 g, 69.5 mmol) was added dropwise during 17 minutes maintaining the temperature below 10° C. After stirring at room temperature for 20 hours the organic phase was washed three times with 1 normal hydrochloric acid, once with a saturated sodium hydrogen carbonate solution and finally twice with water. The organic solution was dried with magnesium sulfate and the solvent was removed at reduced pressure. The residue (11.6 g) was distilled in vacuo (Bp. 61°-72° C., 3×10-3 mbar). Yield: 9.0 g. 1H-NMR (CDCl3): delta=0.89 (CH2CH3); 1.28-1.40 (CH2CH2CH×2CH3); 1.69 (OCH2CH2); 1.83 (CH3CH); 4.20 (OCH2); 6.43 ppm (CH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[CH:26]=[C:27]([S:31]([NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[CH:26]=[C:27]([S:31]([NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccc(S(=O)(=O)NC(C)(C)CO)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (336 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.6) (308 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (269 mg, 48%). MS (ISN) 561.3 [(M−H)−]; mp 204° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH2:33][C@@H:34]([OH:45])[CH2:35][NH:36][C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[O:38])=[CH:28][C:27]=2[Cl:46])[C:21]1=[O:47])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](N1C=CN=C1)(N1C=CN=C1)=[O:49]>C(#N)CCC.CN(C)C1C=CN=CC=1>[Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][C@H:34]([CH2:35][NH:36][C:37]([C:39]4[S:40][C:41]([Cl:44])=[CH:42][CH:43]=4)=[O:38])[O:45][C:48]3=[O:49])=[CH:28][C:27]=2[Cl:46])[C:21]1=[O:47])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)[Si](OCC1CCCN(c2ccc(NC[C@@H](O)CNC(=O)c3ccc(Cl)s3)cc2Cl)C1=O)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCCC#N
Product: CC(C)(C)[Si](OCC1CCCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2Cl)C1=O)(c1ccccc1)c1ccccc1
Reaction time: 15 h

Procedure:
A solution of 850 mg (1.196 mmol) of the compound from example 94A and 387 mg (2.39 mmol) of carbonyldiimidazole in 30 ml of butyronitrile is admixed with 3 mg (0.024 mmol) of 4-dimethylaminopyridine and heated to reflux. After 15 hours, the majority of the solvent is removed on a rotary evaporator. The product is isolated further by means of preparative HPLC with an acetonitrile/water mixture. This affords 605 mg (69% of theory) of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].P(=O)(O)(O)O>O>[NH2:1][C@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(CCCc1ccccc1)C(=O)O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@H](CCCc1ccccc1)C(=O)O
Temperature: 40 °C
Yield: 49.5 %

Procedure:
(±)-2-Amino-5-phenylpentanoic acid (35 g, from Example 40a) was suspended in water (3 L) and solubilized by adjust the pH to 12 with 7 N NaOH solution. The pH was readjusted to pH 8 with 1 M phosphoric acid while stiirng at 45° C. The solution was cooled to 40° C., and L-amino acid oxidase (Sigma, 0.7 unit/mg) was added. The reaction was stirred with good aeration for 2 weeks. The reaction mixture was concentrated to 500 mL under vacuum, the pH was adjusted to 5, and the precipitate was collected. The material was recrystallized from ethanol-water to afford 17.32 g of the title compound).
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([CH3:17])[C:10]=1[OH:18].O>CN(C=O)C.[I-].[K+]>[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([CH3:17])[C:10]=1[O:18][CH:2]1[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(C=O)cc(C)c1O
Reactant: BrC1CCC1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=O)cc(C)c1OC1CCC1
Temperature: 110 °C
Yield: 93.9 %

Procedure:
To a mixture of bromocyclobutane (1.39 g, 10.3 mmol), potassium iodide (43 mg, 5 mol %), and CsCO3 (3.84 g, 11.84 mmol) in DMF (18 mL) is added 5-formyl-2-hydroxy-3-methyl-benzoic acid methyl ester (1.0 g, 5.15 mmol). The reaction is placed in the microwave reactor and heated at 110° C. for 6 h. Water (50 mL) is added to the reaction and the solution is extracted with EtOAc (3×40 mL). The combined organic layers are dried over anhydrous MgSO4 and concentrated in vacuo to give product (282) as orange-yellow oil (1.20 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].[OH-].[Na+]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Cl)cc1C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 mL flask was charged with (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (10.0 g, 43.1 mmol) and pyridine (43 mL) under nitrogen. To the resultant solution was added methanesulfonyl chloride (7.06 mL, 90.5 mmol) and the reaction was stirred at room temperature overnight. The following morning, the organics were concentrated in vacuo at 60° C., followed by hydrolysis of the bis-sulfonamide employing THF (65 mL) and sodium hydroxide (65 mL, 4.0 M). The resultant homogeneous solution was stirred at room temperature for 120 min. Upon completion of the hydrolysis, the THF was removed under reduced pressure and the pH of the aqueous layer was adjusted to 5-6 with 6 M HCl. The resultant solution was diluted with EtOAc and the organics were washed with 10% HCl and saturated sodium bicarbonate, dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to generate the desired methanesulfonamide: MS (ES) (M+H)+ expected 311.0, found 311.1.
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.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCCC2=O)cc1Cl

Procedure:
A mixture of 500 mg of 2-chloro-4-florobenzonitrile, 821 mg of 2-pyrrolidinone and 3 g of cesium carbonate in 5 mL of DMF was heated to 100° C. in a sealed microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-80% ethyl acetate/hexane) to afford 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile. 890 mg of 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid. 80 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopyrrolidin-1-yl)benzamide. MS (Q1) 426.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:27][CH2:28][O:29]C)/[C:9](/[F:26])=[C:10](\[F:25])/[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](/[C:9](/[F:26])=[C:10](\[F:25])/[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[CH2:27][CH2:28][OH:29])=[CH:6][CH:7]=1
Reactant: COCCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: OCCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a stirred solution of 1-[(2E)-4-(4-chlorophenyl)-2,3-difluoro-6-methoxy-2-hexenyl]-3-phenoxybenzene (0.081 g, 0.189 mmol) in methylene chloride at −5° C. under nitrogen was added dropwise boron tribromide (0.5 ml of a 1 M solution in methylene chloride, 0.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was cooled to −5° C., diluted with methanol (10 ml) and concentrated in vacua. The residue was taken up in methanol (10 ml) and the solution again concentrated. The residue was taken up in methylene chloride (25 ml), washed successively with water, saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated in vacuo to a brown gum. Chromatography of this gum on silica gel afforded the title compound as a tan syrup (0.057 g) which was characterized by 1HNMR, 19FNMR and mass spectral analysis.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[N:5]=[C:4]([NH2:17])[N:3]=1.C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(O)C.C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:2]2[C:7]3[CH2:8][CH2:9][O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:6]=3[N:5]=[C:4]([NH2:17])[N:3]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1OCC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc3c2CCOc2ccccc2-3)CC1
Temperature: 90 °C

Procedure:
To a solution of Example 29D (29 mg, 0.12 mmol) in ethanol (0.5 mL) was added triethylamine (0.12 mL, 0.82 mmol), piperazine-1-carboxylic acid tert-butyl ester (33 mg, 0.18 mmol) and the mixture heated at 90° C. for 16 hours. The mixture was diluted with CH2Cl2 (25 mL) and washed with 1 M NaOH (10 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of CH2Cl2:EtOAc (5:1, 2:1 and 1:1) to provide the title compound. 1H NMR (CDCl3) δ 1.49 (s, 9H), 2.72 (t, J=5.93 Hz, 2H), 3.26-3.32 (m, 4H), 3.52-3.57 (m, 4H), 4.54 (t, J=5.93 Hz, 2H), 4.78 (s, 2H), 7.09 (dd, J=8.14, 1.36 Hz, 1H), 7.17-7.24 (m, 1H), 7.35-7.42 (m, 1H), 7.89 (dd, J=7.80, 1.70 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12](OC)=[O:13])[CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].[BH4-].[Li+].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([CH2:12][OH:13])[CH2:10][CH2:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1(n2cc([N+](=O)[O-])cn2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cnn(C2(CO)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.5 %

Procedure:
To a solution of methyl 1-(4-nitro-1H-pyrazol-1-yl)cyclopropanecarboxylate (1.0 g) obtained in Step A of Example 128 in tetrahydrofuran (50 mL) was added lithium tetrahydroborate (160 mg), and the mixture was stirred at room temperature for 10 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (620 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[C:29]([O:32][CH2:33][CH3:34])[CH:28]=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH2:33]([O:32][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[CH:31]=[C:22]([CH2:21][C:6]1[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH3:15])=[N:8][C:7]=1[OH:16])[CH:23]=[N:24]2)[CH3:34]
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CCOc1cccc2ncc(CCl)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cccc2ncc(Cc3c(O)nc(C)c4cc(OC)c(OC)cc34)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (51 mg, 233 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.22 mL, 0.44 mmol) at RT followed by CCH 29192 (50 mg, 194 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic layer was isolated and the aqueous layer was further extracted with CH2Cl2 (50 mL). Both organic layers were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 4-((5-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-((5-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 28 as a yellow solid (11 mg, 12% yield).