Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[F-].[K+].[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:26]1[CH:27]=[C:22]([O:21][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:23]=[C:24]([CH3:30])[C:25]=1[C:41]1[CH:40]=[CH:39][C:38]([O:37][C:36]([F:35])([F:47])[F:48])=[CH:43][CH:42]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Product: CCCCCCC(Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Yield: 91.8 %

Procedure:
3-{4-[1-(4-Bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (isomer 1, 100 mg, 0.2 mmol), potassium flouride (35 mg, 0.6 mmol), 4-trifluoromethoxylphenyl boronic acid (83 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) are place in a flask. After the reaction is purged with N2 for several times, Toluene/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give 3-{4-[1-(2,6-Dimethyl-4′-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid, (105 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16].[C:30]1(=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:30]2([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:20][C:21]=1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16]
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(C2(O)CCCCC2)cc1NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 84253.7 %

Procedure:
Diisopropylamine (140 g, 1.39 mol) and 800 mL dry THF were added to a dry 12 L 4 neck flask with a mechanical stirrer under nitrogen. The solution was cooled to −40° C. and n-BuLi (1.29 mol) was added slowly while keeping the inside temperature around −40° C. The mixture was stirred for 45 min at −40° C. and then cooled to −78° C. To this solution, a solution of 3-tert-butoxycarbonylamino-thiophene-2-carboxylic acid methyl ester (99 g, 0.384 mmol) in 3.2 L THF was added drop wise. The mixture was stirred for 60 min at −78° C. and then cyclohexanone (118 g, 1.19 mmol) was added in 30 seconds. The mixture was stirred for 30 min at −78° C. The reaction mixture was quenched with 0.75 L of NH4Cl (sat). The aqueous phase was extract with 0.75 L of EtOAc. Combined the organic phase and washed them with 5 L of brine, Dried over Na2SO4, filtered and evaporated to a residue to afford 115 g (84%) of 3-tert-Butoxycarbonylamino-5-(1-hydroxy-cyclohexyl)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].O>N1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: COC(=O)CCc1ccc(N)nc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
To a solution of methyl 3-(6-aminopyridin-3-yl)propanoate (500 mg, 2.78 mmol) in pyridine (5 mL) was added 2-nitrobenzenesulfonyl chloride (924 mg, 4.17 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (365 mg, yield 36%) as yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Cl[C:29]1[C:30]2[C:37]([CH3:38])=[CH:36][S:35][C:31]=2[N:32]=[CH:33][N:34]=1.C1COCC1.[OH-].[Na+]>C(O)(C)C.Cl>[CH3:26][C:23]1[C:22]([NH:27][C:29]2[C:30]3[C:37]([CH3:38])=[CH:36][S:35][C:31]=3[N:32]=[CH:33][N:34]=2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Nc1ncnc2scc(C)c12
Temperature: 75 °C
Reaction time: 0.83 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.0583 g, 0.161 mmol) and 4-chloro-5-methyl-thieno[2,3-d]pyrimidine (0.0297 g, 0.161 mmol) were mixed in isopropyl alcohol (1 mL) and 1 drop of conc. HCl was added. The reaction was heated to 75° C. overnight, then THF (5 mL) was added, followed by NaOH (3N aq., 0.30 mL) and the reaction continued heating and stirring for 50 minutes. An additional portion of NaOH (3N aq., 0.10 mL) was added and the reaction was heated for 1 hour, then cooled. The reaction mixture was submitted to standard aqueous workup then purified on silica gel (30-100% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: C[OH:2].[C:3]([C:7]1[CH:12]=[C:11](C)[CH:10]=[C:9](C(C)(C)C)[C:8]=1[OH:18])(C)(C)[CH3:4]>C1CCCCC1>[CH2:4]=[CH:3][CH:7]=[CH2:8].[C:8]1(=[O:18])[O:2][CH2:7][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CO
Solvent: C1CCCCC1
Product: C=CC=C
Product: O=C1CCCCCO1

Procedure:
Steps I and II were carried out in a first 20 gal. capacity, jacketed, stirred reactor and the reaction mixture transferred to a second 20 gal. capacity, jacketed, stirred reactor for Steps III and IV. Following termination with methanol in Step IV, 0.5 parts by weight of 2,6-di-t-butyl-4-methylphenol was added as a 20 weight percent solution in cyclohexane, and the butadiene/ε-caprolactone block copolymer then isolated by steam stripping. The calculated molecular weight of this copolymer based on the relative amounts of initiator and monomers used in the polymerization was about 26,000.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][CH:35]([CH2:40][S:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:43])=[O:42])[CH2:36][C:37]([OH:39])=[O:38].CN(C1C=CC=CN=1)C>C(N(CC)CC)C.CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:34][CH:35]([CH2:40][S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH2:36][C:37]([OH:39])=[O:38])=[O:17])=[CH:9][CH:10]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: NC(CC(=O)O)CS(=O)(=O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: NN=Cc1ccc(NC(=O)CCC(=O)NC(CC(=O)O)CS(=O)(=O)c2ccccc2)cc1
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1(3.0 g, 11.3 mmol) was added to dry DMF (200 ml) followed by N-methylmorpholine (1.2 g, 11.3 mmol) and isobutyl chloroformate (1.5 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. 3-Amino-4-phenylsulfonyl butanoic acid (4.0 g, 11.3 mmol) was added followed by triethylamine (2.7 g) and dimethylaminopyridine. After 1 hr, the solvent was removed under reduced pressure and the solid mass was dissolved into a mixture of acetic acid:H2O:H2O2 30% (2:2:1) and stirred at 25° C. for 48 hr. The reaction mixture was concentrated in vacuo and the residue purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 3.5 g of a white solid: 1H NMR (d6-DMSO) 2.25 (m, 2H), 2.53 (m, 4H), 3.55 (m, 2H), 4.33 (m, 1H), 7.44 (m, 5H), 7.79 (s, 4H), 7.99 (d, 1H,J=8.1 Hz), 9.1 (bs, 2H), 9.19 (bs, 2H), 10.42 (s, 1H); MS (FAB) m/z 461.2 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:5]=2[N:4]([CH2:21][C:22]([N:24]2[CH2:30][CH:29]3[CH2:31][CH2:32][CH:26]([CH2:27][CH2:28]3)[CH2:25]2)=[O:23])[C:3]1=[O:33].[C:34](N1C=CN=C1)([N:36]1[CH:40]=[CH:39][N:38]=[CH:37]1)=[O:35].C(OCC)(=O)C.O>O1CCCC1>[CH:26]12[CH2:32][CH2:31][CH:29]([CH2:28][CH2:27]1)[CH2:30][N:24]([C:22]([CH2:21][N:4]1[C:5]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:8][CH:2]([NH:1][C:34]([N:36]3[CH:40]=[CH:39][N:38]=[CH:37]3)=[O:35])[C:3]1=[O:33])=[O:23])[CH2:25]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc2c1N(CC(=O)N1CC3CCC(CC3)C1)C(=O)C(N)N=C2c1ccccc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc2c1N(CC(=O)N1CC3CCC(CC3)C1)C(=O)C(NC(=O)n1ccnc1)N=C2c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.0 g) and 1,1′-carbonyldiimidazole (723 mg) in tetrahydrofuran (20 ml) was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture. The separated organic layer was washed with water twice, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-3-(imidazol-1-yl)carbonylamino-1H-1,4-benzodiazepin-2-one (1.27 g) as a crystalline powder.
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[C:7]([OH:11])(=[O:10])[CH:8]=[CH2:9].BrC1C=CC=CC=1B(O)O.O>C(Cl)Cl>[CH3:3][C:2]1[CH2:1][CH:8]([C:7]([OH:11])=[O:10])[CH2:9][CH2:5][C:4]=1[CH3:6]
Reactant: C=CC(=O)O
Reactant: C=C(C)C(=C)C
Agent: OB(O)c1ccccc1Br
Solvent: O
Solvent: ClCCl
Product: CC1=C(C)CC(C(=O)O)CC1
Yield: 76 %

Procedure:
2,3-Dimethylbuta-1,3-diene (2 equiv.) and acrylic acid (1 equiv.) were combined in the presence of 2-bromophenyl boronic acid (0.2 equiv.) and water (0.1 equiv.) in DCM at room temperature for 28 hours. The product, 3,4-dimethylcyclohex-3-enecarboxylic acid, was isolated in 76% yield. When the reaction was repeated without the addition of water, the yield was 90%.
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17](O)=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([N:27]=C=NC2CCCCC2)CCCCC1.N.C(O)(=O)C>C(Cl)Cl.C(Cl)(Cl)Cl>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([NH2:27])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1cccnc1S2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C(N)=O)c1ccc2c(c1)CCc1cccnc1S2
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
An amount of 50 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]-thiepin-8-yl)-propionic acid was dissolved in the mixed solvents of 20 ml of methylene chloride and 20 drops of chloroform by heating, and to this were added 50 mg of dicyclohexylcarbodiimide with ice-cooling, then dropwise 3 ml of methylene chloride saturated with liquid ammonia. The resulting mixture was stirred for 1.5 hours under a stream of nitrogen. After the completion of the reaction, to the mixture were added pieces of ice and acetic acid and the resulting mixture was extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution, then saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the residue, which was chromatographed over silica gel, eluted with n-hexane/acetone (4/1-1/1), and there was obtained colorless solid. This was recrystallized from ethyl acetate to give 38 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]-thiepin-8-yl)-propionamide as colorless crystals having a melting point of 173.5°-175° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](OCC)=[O:26].CC(C)([O-])C.[K+]>C(OCC)C>[OH:16][C:14]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25](=[O:26])[C:24]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1
Reactant: COC(=O)c1cccnc1Nc1ccccc1
Reactant: CCOC(=O)Cc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=c1c(-c2ccccn2)c(O)c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Yield: 78.6 %

Procedure:
To a stirred solution of 5.8 gm of methyl 2-phenylamino-3-pyridine carboxylate and 25 gm of ethyl 2-pyridylacetate there is added, portionwise, 5.7 gm of potassium tertiary butoxide under a nitrogen atmosphere. The system is heated to an internal temperature of 105° C. for 10 minutes. The reaction is cooled to room temperature, diluted with 100 ml of diethyl ether and the brown precipitate collected by filtration. The precipitate is washed with 200 ml water and the filtrate is acidified to pH 3-4 with a 15% HCl solution whereupon the product separates. The precipitate is filtered and dried to give 6.3 gm of crude 4-hydroxy-1-phenyl-3-(2-pyridyl)-1,8-naphthyridin-2(1H)one; recrystallization from pyridine yields the title product; m.p. 332°-333° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>[OH-].[Na+]>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)=[N:3][CH:4]=1
Reactant: CN1CCNCC1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3.2 g (12.2 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide in 6.7 ml (60.3 mmol) 1-methylpiperazine was stirred at 100° C. for 2.5 h. The reaction mixture was cooled to r.t., treated with 10 ml 0.1N NaOH and extracted. The aqueous phase was separated and extracted twice with THF and the organic phases were washed twice with brine. The combined organic phases were dried over Na2SO4, the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CH2Cl2: MeOH=99:1) to yield 3.3 g (83.7%) product as beige foam.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12](OC)=[O:13])=[CH:7]2.COCCO[AlH2-]OCCOC.[Na+].O.Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][OH:13])=[CH:7]2
Reactant: COC(=O)c1ccc2c(Br)cccc2c1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: OCc1ccc2c(Br)cccc2c1
Yield: 89.5 %

Procedure:
Methyl 5-bromo-2-naphthoate (6.0 g) in benzene (100 ml) was cooled at 7° and a 70% solution of Vitride (sodium dihydro bis-2-methoxyethoxy aluminate) (10 ml) in benzene (20 ml)) was added dropwise with stirring. The solution was stirred for 4 hours at this temperature and decomposed with water and dilute hydrochloric acid. The benzene solution was separated and washed successively with dilute acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated to give a solid (4.8 g), m.p. 76°-77°.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[OH:1]
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 0 °C
Yield: 93 %

Procedure:
20 g (109 mmol) of 2-hydroxy-3-nitrobenzoic acid was dissolved in 150 mL of methanol, 7 mL of strong sulfuric acid was added dropwise thereto. The mixture was stirred under heat-reflux for 24 hr. The mixture was cooled to 0° C., filtered and washed with distilled water, followed by drying under vacuum to obtain the title compound (20 g, yield: 93%)
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH3:37])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Product: CN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoro-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 273) and formaldehyde following General Procedure R.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[C@H](CCl)CBr
Product: C[C@H](CCl)COc1ccc(Cl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](I)=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:41]([O:45][CH3:46])(=[O:44])[CH:42]=[CH2:43]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](/[CH:43]=[CH:42]/[C:41]([O:45][CH3:46])=[O:44])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To a stirring solution of 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide (1.17 g, 2 mmol) in acetonitrile (4 mL) was added triethylamine (2 mL, 14.3 mmol) followed by palladium(II) acetate (22 mg, 0.1 mmol) and then methyl acrylate (0.36 mL, 4 mmol). The mixture was heated to 100° C. in a sealed tube. After 15 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with 20% ethyl acetate in dichloromethane, to give 0.96 g (88%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]CC)=O)=[C:20]([F:30])[CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:31].[Al]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:31])=[O:27])=[C:20]([F:30])[CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1F
Agent: [Al]
Solvent: CO
Product: Cl
Product: NC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1F
Temperature: 100 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
To a microwave vessel was added ethyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-fluorophenyl)acetate (0.075 g, 0.18 mmol) and ammonia in methanol (7.0 M, 3 mL) and the vessel was sealed with an aluminum cap. The resulting mixture was stirred at 100° C. for 24 h. After this time, the crude reaction solution was cooled, concentrated, and purified by column chromatography (silica, hexanes/ethyl acetate), followed by the formation of the hydrochloride salt to afford the title compound (0.374 g, 49% yield) as an off-white solid. MW=431.32. 1H NMR (DMSO-d6, 300 MHz) δ 14.10 (s, 1H), 9.80 (s, 1H), 7.93 (t, J=1.7 Hz, 1H), 7.77-7.71 (m, 1H), 7.71-7.60 (m, 2H), 7.59-7.52 (m, 1H), 7.42 (t, J=8.6 Hz, 1H), 7.31-7.20 (m, 2H), 7.14 (s, 1H), 7.02 (s, 1H), 3.48 (s, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.03 (quin, J=7.6 Hz, 2H); APCI MS m/z 396 [M+H]+.
Reaction SMILES: [C:1]([O:5][PH:6]([CH2:8][CH:9]([CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[C:27]([CH3:29])=[CH2:28].[H-].[Na+].O>C1COCC1.CCOCC>[CH2:32]([O:31][C:26]([CH:27]([CH3:29])[CH2:28][P:6]([CH2:8][CH:9]([CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCC(C[PH](=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(CP(=O)(CC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a solution of di-tert-butyl 2-[(tert-butoxyphosphinyl)methyl]pentane-1,5-dioate (13.62 g, 36.0 mmol) and benzyl methacrylate (6.35 g, 36.0 mmol) in THF (100 mL) under nitrogen was added sodium hydride (0.14 g, 60% dispersion in oil, 3.60 mmol). After three hours, the reaction mixture was poured into water (300 mL) and ether (100 mL) was added. The organic layer was separated and retained, and the aqueous layer was washed again with ether (100 mL). The combined organic extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography and the product was eluted with 2:3 EtOAc/Hexane. The solvent was removed under reduced pressure leaving a clear oil (10.5 g, 53%).