Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([C:26]1[CH:27]=[C:28]([O:36][CH3:37])[C:29]([OH:35])=[C:30](B(O)O)[CH:31]=1)[CH:24]=[CH2:25]>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:30]3[CH:31]=[C:26]([CH2:23][CH:24]=[CH2:25])[CH:27]=[C:28]([O:36][CH3:37])[C:29]=3[OH:35])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Reactant: C=CCc1cc(OC)c(O)c(B(O)O)c1
Product: C=CCc1cc(OC)c(O)c(-c2cccc(-c3cccc(-c4cc(OC)ccc4O)n3)n2)c1
Yield: 42 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(5-allyl-2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 5-allyl-2-hydroxy-3-methoxyphenylboronic acid in 42% yield using method F; δH [2H6]-DMSO 13.41,(1H, s), 12.52,(1H, s), 8.38,(1H, d), 8.27,(1H, d), 8.24-8.12,(4H, m), 7.65,(1H, s), 7.52,(1H, s), 6.99,(1H, d), 6.93,(2H, m), 6.05,(1H, m), 5.14,(1h, d), 5.07,(1H, d), 3.83,(6H, s), 3.40,(2H, d).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][O:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[NH:40][C:41](=[O:43])[CH3:42]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][C:2]([C:29]4[CH:28]=[CH:27][C:26]([NH:40][C:41](=[O:43])[CH3:42])=[C:25]([O:24][CH3:23])[CH:30]=4)=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:16][CH2:15]1
Reactant: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2ccc(N3CCN(C4CC4)CC3)nn2)ccc1NC(C)=O

Procedure:
The title compound was prepared from 3-chloro-6-(4-cyclopropyl-piperazin-1-yl)-pyridazine (4.6 g, 19.3 mmol), 1 M sodium carbonate solution (50 mL, 100.5 mmol), acetonitrile (50 mL), bis(triphenylphosphine)palladium(II) chloride (0.68 g, 0.96 mmol) and N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (6.73 g, 23.1 mmol), yield 3.39 g (40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5]([I:34])=[CH:4][N:3]=1.[OH-].[NH4+:36]>O1CCOCC1>[NH2:36][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5]([I:34])=[CH:4][N:3]=1
Reactant: C[C@H](Nc1nc(Cl)ncc1I)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)ncc1I)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of (S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (64) (964 mg, 1.65 mmol) in anhydrous 1,4-dioxane (5 mL) in a sealed tube, ammonium hydroxide (6 mL) was added and the resulting mixture was stirred at 110° C. for 16 h. An additional amount of ammonium hydroxide (3 mL) was added to the reaction mixture and stirring was continued for 16 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-8% MeOH-DCM) to afford the product, (S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (65) (532 mg, 57% yield) as a light tan solid. ESI-MS m/z: 564.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][C:5](=O)[CH2:4][O:3]1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=O.[NH2:20]/[C:21](/[CH3:27])=[CH:22]\[C:23]([O:25][CH3:26])=[O:24]>C(O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:27])[NH:20][C:5]3[CH2:4][O:3][CH:2]([CH3:1])[C:7](=[O:8])[C:6]2=3)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC1OCC(=O)CC1=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)C(C)OC2)C1c1ccc(F)c(Br)c1
Temperature: 25 °C

Procedure:
The product from Example 84C (1.3 g, 10 mmol), 3-bromo-4-fluorobenzaldehyde (2.4 g, 12 mmol) and methyl 3-aminocrotonate (1.2 g, 10 mmol) in ethanol (10 mL) were heated at 80° C. in a sealed tube for 60 hours. After cooling to ambient temperature, the mixture was filtered and the filtercake washed with ethanol and dried to provide the title compound. The filtrate was concentrated and chromatographed on silica gel eluting with 1% and then 2% and then 5% methanol in dichloromethane to provide additional quantities of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([O:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:6]=[CH:5][C:4]1=2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:8]=[C:7]([O:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:6]=[CH:5][C:4]2=3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCC1CCCc2cc(OCC(N)=O)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)COc1ccc2c(c1)CCCC2CNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
0.1 mol of 5-aminomethyl-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetamide (Example 7), 0.11 mol of 4-chlorobenzenesulphonyl chloride and 0.11 mol of triethylamine are stirred in 200 ml of tetrahydrofuran at room temperature for 3 hours. The mixture is filtered, the filtrate is evaporated, the residue is taken up in CH2Cl2 and the mixture is washed with 1N HCl, saturated NaHCO3, 1N HCl and saturated NaCl solution, dried over Na2SO4 and evaporated. The residue is purified by flash chromatography over silica gel using CH2Cl2MeOH 5:1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Li+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](Cl)(=[O:16])[CH3:15]>ClC(Cl)C>[CH3:13][C:7]1[CH:12]=[CH:11][C:10]([C:14]([CH3:15])=[O:16])=[CH:9][CH:8]=1
Reactant: Cc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an agitated mixture of aluminium chloride (20 g., 0.15 mole) and lithium chloride (3.18 g., 0.075 mole) and dichloroethane (20 ml) at -15° C. was slowly added toluene (4.6 g., 0.05 mole) and acetyl chloride (3.93 g., 0.05 mole) in dichloroethane (10 ml). The reaction mixture was left at -15° C. for one hour then allowed to warm up to room temperature overnight. After working up as described in Example 1, the 4-methylacetophenone obtained (7.17 g.), had a 1H NMR estimated purity of about 95%. 1H NMR showed less than 2% ortho isomers.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10]([NH2:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[S:33])[NH2:12])[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Temperature: 60 °C
Reaction time: 12 h
Yield: 157.2 %

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid amide (1.058 g; 3.36 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (0.71 g; 1.76 mmol) were dissolved in dioxane (6 ml). The reaction mixture was heated 30 min at 60° C. and stirred 12 hours at room temperature. The solvent was removed in vacuo and to the residue was added a mixture of water/sodium hydrogencarbonate (1:1; 15 ml) and stirred 30 min at room temperature. The mixture was filtered. The solid was washed with water (2×5 ml) and chromatographed on silica (2×15 cm) using ethyl acetate/heptane (2:1) to afford 0.914 g of ((1R)-2-(2-naphthyl)-1-thiocarbamoylethyl)carbamic acid tert-butylester.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[CH2:17]1[O:29][C:28]2[CH:27]=[C:26]3[C:21]([C:22]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:18]1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:17]1[O:29][C:28]2[CH:27]=[C:26]3[C:21]([C:22]([N:30]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:10](=[O:12])[C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[I:7])=[CH:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:18]1
Reactant: O=C(O)c1ccccc1I
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C)CCN(C(=O)c1ccccc1I)c1ccnc2cc3c(cc12)OCO3
Yield: 84 %

Procedure:
Oxalyl chloride (1.05 g, 8.1 mmol) was added to a solution of o-iodobenzoic acid (0.57 g, 2.3 mmol) in methylene chloride (20 mL) under nitrogen, and the stirred mixture refluxed for 4 h. The mixture was then concentrated to dryness under vacuum. The acid chloride was redissolved in methylene chloride (20 mL) and added to a solution of compound 7 and triethylamine (2.0 g, 20.0 mmol) in methylene chloride (20 mL). The reaction was stirred at reflux under nitrogen for 2 h. The mixture was then cooled and washed with a saturated solution of sodium bicarbonate (3×75 mL), and extracted into dilute HCl (3×75 mL), and the combined aqueous extracts were washed with chloroform (75 mL), made basic using 30% NaOH, then extracted with chloroform (3×75 mL). The combined organic extracts were washed with brine (100 mL), dried (anhydrous MgSO4), and concentrated in vacuo, to give 795 mg, in 84% yield; IR (CHCl3) 1653; 1H NMR (CDCl3) δ 2.23 (s, 6H), 2.60 (m, 2H), 3.52 (m, 1H), 4.57 (m, 1H), 6.13 (d, 1H, J=0.7), 6.16 (d, 1H, J=0.7), 6.78 (m, 3H), 7.32 (m, 2H), 7.36 (s, 1H), 7.64 (d, 1H, J=7.6), 8.48 (d, 1H, J=4.8); 13C NMR (CDCl3) δ 45.6, 46.8, 56.5, 93.9, 98.4, 102.3, 106.5, 120.2, 122.8, 126.5, 127.2, 128.3, 130.2, 139.5, 141.5, 145.6, 148.2, 149.2, 151.2, 170.0.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[C:7]([CH2:9][O:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)[CH3:13])[CH:6]=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].CCN(CC)CC.[BH4-].[Na+]>O1CCOCC1.O=[Mn]=O>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:8]=[C:7]([CH2:9][O:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:16][CH:15]=2)[CH3:13])[CH:6]=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: CC(=NOCc1ccc(-c2ccccc2)c(C(F)(F)F)c1)c1ccc(CO)cc1
Agent: O=[Mn]=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=NOCc1ccc(-c2ccccc2)c(C(F)(F)F)c1)c1ccc(CNCCC(=O)O)cc1
Temperature: 50 °C

Procedure:
To a suspension of MnO2 (10 eq) in dioxane is added 1-(4-hydroxymethyl-phenyl)-ethanone O-(2-trifluoromethyl-biphenyl-4-ylmethyl)-oxime (1 eq). The resulting mixture is refluxed for 10 minutes. After filtration and concentration, the residue is dissolved in MeOH and treated with β-alanine (2 eq) and Et3N (1.5 eq). The resulting mixture is heated at 50° C. for 30 minutes. After cooling to room temperature, NaBH4 (3 eq) is added in portions. Purification by preparative LCMS results in 3-{4-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid; 1H NMR (400 MHz, CD3OD) δ 2.28 (s, 3H), 2.75 (t, J=6.8 Hz, 2H), 3.26 (t, J=6.8 Hz, 2H), 4.22 (s, 2H), 5.30 (s, 2H), 7.26-7.77 (m, 12H). MS: (ES+): 471.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:21](O)=[O:22])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:44][O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[NH2:48].Cl>O.CN(C=O)C>[CH3:44][O:45][C:46](=[O:51])[C:47]([NH:48][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[O:10][CH2:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22])([CH3:50])[CH3:49]
Reactant: COC(=O)C(C)(C)N
Reactant: COc1ccc(COc2c(C(=O)O)ccc3ccccc23)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to 150 mg 1-[6-methoxy-pyridin-3-ylmethoxy]-naphthalene-2-carboxylic acid in 2 mL of abs. DMF 130 mg EDC, 72 mg 1-hydroxybenzotriazole and 81 mg N,N-diisopropylethylamine were added. After 30 min at 0° C. 89 mg of 2,2-dimethylglycine methyl ester hydrochloride and 81 mg N,N-diisopropylethylamine were added. The mixture was stirred for 1 h at room temperature. The mixture was poured into cold water, acidified to pH 3 with 2 M HCl, extracted with ethyl acetate twice, washed with sat. sodium hydrogen carbonate solution and brine. The combined organic layers were dried over magnesium sulphate, filtrated and concentrated in vacuo to provide 191 mg of 2-{[1-(6-methoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([N:21]([CH3:30])[CH3:20])=[CH:23][CH:24]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-dimethylaminobenzylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: FC1C=CC(S(Cl)(=O)=O)=CC=1C(O)=[O:5].[CH3:15][CH:16]1[CH2:21]CCNC1.F[C:23]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][CH2:38][CH:37]([CH3:41])[CH2:36]2)(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26].[H-].[Na+]>C(O)(C)C>[CH:16]([O:5][C:23]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][CH2:38][CH:37]([CH3:41])[CH2:36]2)(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26])([CH3:21])[CH3:15]
Reactant: CC1CCCN(S(=O)(=O)c2ccc(F)c(C(=O)O)c2)C1
Reactant: CC1CCCNC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1CCCN(S(=O)(=O)c2ccc(OC(C)C)c(C(=O)O)c2)C1

Procedure:
2-Fluoro-5-chlorosulfonylbenzoic acid is reacted with 3-methylpiperidine bythe method of Example 1, and the resulting 2-fluoro-5-(3-methylpiperidinosulfonyl)benzoic acid (5 millimoles) is heated on a steam bath for 31/2 hours in isopropyl alcohol (50 ml.) with 5 millimoles of sodium hydride (56.6% suspension in mineral oil). The reaction mixture is evaporated to dryness, and then dissolved in 50 ml. ofwater. After washing with ether, the aqueous solution is acidified with concentrated HCl. The acid solution is then extracted with ether, and the ether extract washed with water and evaporated to an oil. The oil crystallizes from isopropyl ether-hexane. Recrystallization from the same solvent mixture affords the product, m.p. 102°-104° C.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:11]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)C(OC(C)(C)C)=O)=[CH:23][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C1C(CC(O)=O)CC2C=CC(OCCCN(C3C=CC=CN=3)C(OC(C)(C)C)=O)=CC=2CN1CC1C=CC(C(F)(F)F)=CC=1.C(C(O)=O)(F)(F)F>O>[CH2:1]([N:8]1[C:14](=[O:15])[CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:11]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:23][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccccc1)C(=O)C(CC(=O)O)C2)c1ccccn1
Agent: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C(CC(=O)O)C2)c1ccccn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(Cc2ccccc2)C1=O
Yield: 40 %

Procedure:
According to the procedure of Example 25(a) except substituting (±)-2-benzyl-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid for the (±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, the title compound (0.014 g, 40%) was prepared: MS (ES) m/e 460.4 (M+H)+. Anal. Calcd for C27H29N3O4.CF3CO2H.2 H2O: C, 57.14; H, 5.62; N, 6.89. Found: C, 57.44; H, 5.32; N, 6.87.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=3)[C:16]([S:27][CH3:28])=[CH:15]2)=[N:12][CH:13]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(O)C>COCCOC.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>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=4)[C:16]([S:27][CH3:28])=[CH:15]3)=[N:12][CH:13]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cccc(OC)c4)cn3)c2c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol) and a 2M solution of sodium carbonate (8 mL) were added at room temperature and under an argon atmosphere to methyl 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylate (3.0 g, 7.96 mmol) in DME (50 mL). The addition of 3-methoxy phenyl boronic acid (1.53 g, 9.94 mmol) and ethanol (50 mL) followed 10 min later, and the resulting mixture was heated at 90° C. for 5 h. The reaction mixture was then cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by flash column chromatography [silica; ethyl acetate/hexane=3:7]. Yellow solid. Yield: 2.6 g (80% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Cl)nc1Cl

Procedure:
To a solution of 2,6-dichloronicotinic acid (52 g, 0.27 mol) in benzene: MeOH (7:1, 1.0 L) was added dropwise a solution of (trimethylsilyl)diazomethane (1 M in heptane) until gas evolution ceased and the yellow color persisted (ca. 320 mL, 1.2 equiv.). The volatiles were removed and the residue was purified by chromatography on silica gel eluting with 7:1 hexane:ethyl acetate to give the product as a white solid.
Reaction SMILES: C([C:4]1[NH:5][C:6](C(OCC)=O)=[C:7]([CH3:16])[C:8]=1[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(O)=O>[OH-].[Na+]>[C:11]([CH2:10][CH2:9][C:8]1[C:7]([CH3:16])=[CH:6][NH:5][CH:4]=1)([OH:13])=[O:12]
Reactant: CCOC(=O)CCc1c(C(=O)O)[nH]c(C(=O)OCC)c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[nH]cc1CCC(=O)O
Temperature: 10 °C
Yield: 474.7 %

Procedure:
2-Carboxy-5-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)-4-methylpyrrole (50.5 g) and 400 ml 10% sodium hydroxide solution was heated to 180° C. in a Parr autoclave for 90 minutes. This process was repeated 4 more times until a total of 252.5 g of 2-carboxy-5-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)-4-methylpyrrole had been treated. The five solutions were combined and rotary evaporated to a volume of about 1.8 L of thick black residue. The mixture was cooled to 10° C. in a water bath and 50% sulfuric acid was slowly added so as to keep the temperature at <20° C. until the pH was 2. Ethyl ether (1400 mL) was added, the mixture filtered and the precipitate saved. The precipitate was extracted in a Soxhlet extractor with 500 mL of ether. The combined ether layers were washed with 250 mL water followed by 150 mL of water. The combined water layers were back extracted with 150 mL of ether. All the ether layers were rotary evaporated and the residue dried to give 123.5 g of 3-(2-carboxyethyl)-4-methylpyrrole.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][C:49]1[S:53][C:52]([CH2:54][NH2:55])=[CH:51][CH:50]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:52]4[S:53][C:49]([CH3:48])=[CH:50][CH:51]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1ccc(CN)s1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1ccc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)s1
Yield: 41 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-methylthiophen-2-yl)methanamine, the title compound was obtained as a colorless solid in 41% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.78 (d, J=3.2 Hz, 1H), 6.58 (d, J=3.2 Hz, 1H), 6.09 (s, 1H), 5.94 (t, J=5.1 Hz, 1H), 4.64 (d, J=5.1 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.39 (m, 2H), 2.49 (s, 3H), 2.44 (s, 3H); MS (ES+) m/z 466.2 (M+23).