Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>N1C=CC=CC=1>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])[CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc(C)c1
Yield: 90.5 %

Procedure:
Prepared according to the procedure described for Example 121 using 3-methylbenzenesulfonyl chloride (1.91 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (3.587 g); m.p. 195-197° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1=[O:18])(=[O:3])[CH3:2].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])(C)C)=[O:22]>CN(C=O)C.[Ag]=O>[C:1]([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1=[O:18])(=[O:3])[CH3:2].[CH3:1][CH2:2][CH2:27][CH2:24][O:23][C:21]([CH3:20])=[O:22]
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=[Ag]
Agent: CC(=O)N1CC(=O)NC(=Cc2ccccc2)C1=O
Solvent: CN(C)C=O
Product: CCCCOC(C)=O
Temperature: 45 °C

Procedure:
To a solution containing 6.36. g (26.00 mmol) of 1-Acetyl-3-benzylidene piperazine-2,5-dione described by D. Villemn, et al. (Synthetic Communications, 20:3325 (1990)), in 100 mL of DMF under nitrogen atmosphere was added 9.62 mL (65.10 mmol) of t-butyl bromoacetate and 7.55 g (32.60 mmol) of silver oxide. The reaction was heated to 45° C. overnight. The reaction was filtered through a plug of celite and the filtrate concentration under reduced pressure. The residue was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent under reduced pressure and column chromatography of the residue on silica gel with 1% methanol/dichloromethane gave 5.37 g of a tan solid. Further purification via preparative HPLC gave 2.5 g (27%) of the title compound. FAB MS [M+H] m/z: Calcd: 359, Found: 359.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:39])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:37])(=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:38])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:38][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:39])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:36])(=[O:37])[NH:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCc3ccc(OC)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(CNS(=O)(=O)c2ccc(-c3c(C)c(CC(=O)O)cc4ccc(Cl)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
Lithium hydroxide monohydrate (0.029 g, 0.68 mmol) was added to a solution {6-chloro-4-[4-(4-methoxy-benzylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.090 g, 0.18 mmol) in a 3:1 mixture of THF—H2O mixture (12 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave {6-chloro-4-[4-(4-methoxy-benzylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.086 g, 98%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43-12.61 (m, 1 H), 8.22 (t, J=6.30 Hz, 1 H), 7.98 (d, J=8.80 Hz, 1 H), 7.89-7.95 (m, 3 H), 7.49 (dd, J=8.80, 2.20 Hz, 1 H), 7.42 (d, J=7.83 Hz, 2 H), 7.15 (d, J=8.80 Hz, 2 H), 7.04 (d, J=1.96 Hz, 1 H), 6.81-6.86 (m, 2 H), 4.09 (d, J=5.87 Hz, 2 H), 3.86 (s, 2 H), 3.68 (s, 3 H), 2.06 (s, 3 H). MS calcd. for C27H23ClNO5S [(M−H)−] 508, obsd. 508.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C:9]2[C:10]([C:18]([OH:20])=[O:19])=[CH:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=2)=[CH:5][CH:4]=1>CN(C)C=O.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1
Reactant: COc1ccc(/C=C/c2cc(C(=O)O)ccc2C(=O)O)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CCc2cc(C(=O)O)ccc2C(=O)O)cc1

Procedure:
45 G. of a mixture of 3-(p-methoxybenzylidene)phthalide-5- and -6- carboxylic acids, obtained by the condensation of p-methoxyphenylacetic acid and benzene-1,2,4-tricarboxylic anhydride as described in Example 1, was hydrogenated for 20 hours in 250 ml of dimethylformamide containing 10.5 g. of 10% palladium on carbon catalyst. The solution was filtered and the filtrate evaporated. The residue was recrystallized from aqueous acetic acid to afford 3-(p-methoxybenzyl)phthalide-5- and -6- carboxylic acids. 24.1 G of this mixture was dissolved in 90 ml of dimethylsulfoxide and 30 g. of potassium tertbutoxide was added. After 15 minutes the solution was poured into water, acidified with acetic acid, and the product filtered off. Fractional crystallization from dioxan afforded 4'-methoxy-trans-stilbene 2,4-dicarboxylic acid as the less soluble isomer, and 4'-methoxy-trans-stilbene-2,5-dicarboxylic acid as the more soluble isomer. 2.4 G. of 4'-methoxy-trans-stilbene-2,5-dicarboxylic acid was hydrogenated for 41/2 hours in 20 ml dimethylformamide and 20 ml of acetic acid containing 0.3 g. of 10% palladium on carbon catalyst. The solution was filtered and evaporated and the residue recrystallized from aqueous ethanol to afford 2-(4-methoxyphenethyl)benzene-1,4-dicarboxylic acid. This compound was then cyclized by the procedure of part A of this example to give 2-carboxy-7-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 201°-203° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:28]([F:31])([F:30])[F:29])=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][C@H:16]([NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH2:15]3)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][C:6]1[C:7]([C:28]([F:29])([F:31])[F:30])=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][C@H:16]([NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH2:15]3)[CH:10]=1
Reactant: CCOC(=O)c1cn(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)nc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(S)-ethyl-1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.371 mmol, 630 mg) was dissolved in tetrahydrofuran (10 mL) and the vessel purged with nitrogen. Lithium aluminium hydride (1M, 1.371 mmol, 1.371 mL) was added dropwise and the mixture stirred at room temperature for 20 min. An additional quantity of lithium aluminium hydride (1M, 1.371 mmol, 1.371 mL) was added to complete the reaction. The reaction was quenched by addition of methanol followed by water before concentration. The residue was partitioned between 1N HCl and Ethylacetate and the organic phase collected. The aqueous phase was further extracted with EtOAc (×2). Combined organics were dried and concentrated before purification on silica eluting with 2% MeOH/DCM. Desired fractions were collected and concentrated to give (S)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide as a colourless glass. (0.505 g, 88%) MS (ESI): m/z [M+H]+ 418.5
Reaction SMILES: [CH:1]1[C:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([Br:15])[CH:2]=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[OH-].[K+]>Cl[Cu].C1(C)C=CC=CC=1>[CH:17]1[CH:22]=[CH:21][C:20]([N:7]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[C:6]2[CH:1]=[CH:2][C:3]([Br:15])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: Ic1ccccc1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Agent: Cl[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2ccccc2)c2ccc(Br)cc2)cc1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
In an oxygen-free glovebox, a 250 mL flask was charged with 4,4′-dibromodiphenylamine (15.0 g, 45.8 mmol), iodobenzene (18.7 g, 91.7 mmol), 1,10-phenanthroline (0.827 g, 4.59 mmol), CuCl (0.454 g, 4.59 mmol), KOH (15.4 g, 275 mmol), and toluene (125 mL). The flask was sealed and removed from the glovebox and heated to 130° C. and stirred for 24 hr. The flask was then removed from the oil bath and allowed to cool to room temperature. The solids were filtered off and the solvent was removed to yield a bluish oily substance, which was passed through silica gel column using toluene as the eluant. The fractions were collected and the solvent was removed followed by vacuum distillation at 160° C. for 30 min to remove the remaining iodobenzene to afford a blue solid. This solid was further purified by a second silica plug column using hexanes as the eluant. The colorless clear fractions were combined and the solvent removed to yield the desired product. Purity: 99+%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([NH2:24])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][CH2:26][C:27](=O)[C:28](=O)[CH2:29][CH3:30]>O.C(O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[C:28]([CH2:29][CH3:30])[C:27]([CH2:26][CH3:25])=[N:24]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: CCC(=O)C(=O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1nc2ccc3c(c2nc1CC)OC(COS(=O)(=O)c1ccc(C)cc1)CO3
Temperature: 60 °C

Procedure:
To a solution of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]-methyl 4-methylbenzenesulfonate (2.226 g, 5.258 mmole) in water (50 mL) was added a solution of 3,4-hexanedione (0.750 g, 6.572 mmole) in ethyl alcohol (50 mL) and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and was diluted with aqueous sodium hydrogen carbonate (250 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 7:3) gave 1.796 g (80%) of the (R)-enantiomer of the title compound as a tan crystalline solid. Rf=0.85 (silica, ethyl acetate:hexanes 7:3); mp 132–135° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:26]>ClCCl>[ClH:26].[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[N:15]=[C:14]([CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)[O:18][N:17]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2nc(-c3ccc(F)cc3)no2)C1
Agent: Cl
Solvent: ClCCl
Product: Fc1ccc(-c2noc(C3CNCCO3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carboxylic acid tert-butyl ester (0.325 g, 0.93 mmol) was dissolved in dichloromethane (3 mL) and 5 mL of HCl 4N (dioxane solution) were added dropwise. The resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure to afford 265 mg (yield: 100%) of 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine hydrochloride as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([CH:9]1[CH2:10][CH2:11][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCCN1C1CCCCC1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccccc2)CCN1C1CCCCC1
Yield: 69.9 %

Procedure:
Place 1-cyclohexyl-pyrrolidin-2-one (400 mg, 2.4 mmol) in THF (30 mL) and cool to −78° C. Slowly add LDA (2.0 M, 2.4 mL, 4.8 mmol) and stir for 15 minutes. Add benzyl bromide (1.23 g, 7.2 mmol) and stir for 3 hours. Quench with ammonium chloride and extract with dichloromethane. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (20-50% ethyl acetate in hexanes) to afford 432 mg (70%) of the title compound: Mass spectrum (apci) m/z=258.2 (M+H).
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]4=[O:36])=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+]>C1COCC1>[C:2]([C:4]1[C:5]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]4=[O:36])=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COCCOc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C=O)nc32)ncc1C#N
Reaction time: 0.33 h

Procedure:
Hydrochloric acid (4M, 8.6 ml) was added to a solution of N-(5-cyano-4-(2-methoxyethoxyl)pyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 107, 950 mg, 1.72 mmol) in THF (15 ml) at room temperature. After stirring for 4 h at room temperature saturated aqueous NaHCO3 was added, the mixture extracted with DCM (3×), the organic layers dried over MgSO4 and evaporated. The residue was stirred with EtOAc for 20 minutes then diluted with heptane and then filtered to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(Cl)cn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-chloropyridin-2-yl)oxy]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.04 (1H, d, J=2.6 Hz), 7.94 (1H, d, J=2.6 Hz), 7.91 (2H, d, J=8.3 Hz), 7.63 (1H, dd, J=8.8, 2.6 Hz), 7.43 (1H, dd, J=8.8, 2.6 Hz), 7.22 (2H, d, J=8.3 Hz), 7.18 (1H, d, J=8.0 Hz), 7.00 (1H, d, J=8.8 Hz), 6.80 (1H, d, J=8.8 Hz), 5.28–5.16 (1H, m), 3.91 (3H, s), 1.42 (3H, d, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
4-Bromophenol (2 g, 11.5 mmol) is placed in 10 ml of anhydrous DMF under nitrogen. Sodium hydride (0.51 g, 127 mmol) is added. After stirring for 20 min at ambient temperature, 2-fluoropyridine (1.05 ml, 12.1 mmol) is added and the reaction medium is heated at 105° C. for 7 h. After hydrolysis, the pH is adjusted to 8 with a 1N aqueous solution of HCl. The reaction medium is then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of ethyl acetate in heptane ranging from 0% to 30%. 2.22 g of expected 2-(4-bromo-phenoxy)pyridine are obtained,
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
A mixture of 91.7 parts of 4-(1-piperazinyl)phenol, 71.0 parts of 1-fluoro-4-nitrobenzene, 60.0 parts of potassium carbonate and 450 parts of N,N-dimethylacetamide was stirred over weekend at room temperature. Water was added and after standing for 5 hours, the product was filtered off. It was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 114.4 parts (76%) of 4-[4-(4-nitrophenyl)-1-piperazinyl]phenol; mp. 260.0° C. (intermediate 9).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[N:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[F:28][C:29]([F:58])([F:57])[C:30]1[C:34](B(O)O)=[CH:33][N:32]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:31]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:34]5[C:30]([C:29]([F:57])([F:58])[F:28])=[N:31][N:32]([C:38]([C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)([C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)[C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH:33]=5)[CH:25]=4)[N:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Reactant: O=C(Nc1ccc(F)cc1)C1CCN(c2ccnc3ccc(Br)cc23)CC1
Product: O=C(Nc1ccc(F)cc1)C1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Yield: 43.7 %

Procedure:
73 mg 1-(6-bromoquinolin-4-yl)piperidine-4-carboxylic acid (4-fluorophenyl)amide (compound in Production Example 457) and 94 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 54 mg 1-[6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl)quinolin-4-yl]-piperidine-4-carboxylic acid (4-fluorophenyl)amide. This product was reacted in the same manner as in Example 67 to give 54 mg of the title compound as pale gray crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[K+].[Br-].[N:25]([C:28]1[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1)=[C:26]=[O:27]>O1CCCC1>[C:10]([O:9][C:7]([CH:6]1[CH2:14][CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]1[C:3](=[O:4])[CH2:2][NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Yield: 59.4 %

Procedure:
By proceeding in a fashion similar to that described in Example 2, but starting from 6.2 g of tert-butyl (2RS,5SR)-1-(2-aminoacetyl)-5-phenylprolinate in solution in 150 cm3 of anhydrous tetrahydrofuran and 4.2 g of methyl 3-isocyanatophenylacetate, 6 g of methyl (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetate are obtained [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C.: 1.5 (s, 9H, (CH3)3); 3.6 (s, 2H, CH2CO); 3.65 (s, 3H, OCH3); 6.8 to 7.7 (m, 9H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3365, 3155, 3110, 3090, 3060, 3030, 2975, 2950, 2930, 2875, 1738, 1700, 1650, 1610, 1595, 1560, 1495, 1435, 1395, 1365, 1315, 1250, 1220, 1155, 1015, 905, 890, 860, 845, 780, 760, 700].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH3:20])[CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH2:32]Br>CN(C=O)C>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH2:32][N:7]1[C:6]2[CH:22]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH3:20])[CH:14]=2)[C:8]1=[O:21]
Reactant: CSc1cccc(N2C(=O)Nc3cc(F)ccc3S2(=O)=O)c1
Reactant: Fc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1cccc(N2C(=O)N(Cc3c(F)cccc3Cl)c3cc(F)ccc3S2(=O)=O)c1
Yield: 46.1 %

Procedure:
The title compound (74 mg, 0.15 mmol) was subsequently prepared from 6-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (110 mg), K2CO3 (180 mg, 1.30 mmol) and 2-chloro-6-fluorobenzyl bromide (89 uL, 0.65 mmol) in DMF (5 mL) using the methods of (115).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C1(C)C=CC=CC=1.Cl[Sn](Cl)(Cl)Cl.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>[OH-].[Na+]>[C:29]([C:5]1[CH:6]=[C:2]([CH3:1])[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[C:4]=1[CH3:7])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOc1ccc(-n2c(C)ccc2C)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOc1ccc(-n2c(C)cc(C(=O)c3ccccc3)c2C)cc1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (EXAMPLE 1) (1.0 g, 4.7 mmol) and toluene (15 mL) at 0° C. was added dropwise SnCl4 (4.7 mL, 4.7 mmol, 1.0M solution in CH2Cl2) and benzoyl chloride (0.54 mL, 4.7 mmol). The mixture was warmed to rt and heated at 50° C. overnight. After cooling to rt, the mixture was diluted with 1N NaOH (50 mL), extracted with EtOAc (2×50 mL), the combined extracts washed with brine (50 mL), dried MgSO4), filtered, concentrated in vacuo, and purified by flash chromatography on silica gel (0-25% EtOAc/hexanes) to give 3-benzoyl-2,5-dimethyl-1-(4ethoxyphenyl)pyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 7.84-7.82 (m, 2H), 7.52-7.43 (m, 3H), 7.14-7.12 (m, 2H), 7.01-6.98 (m, 2H), 6.18 (s, 1H), 4.10 (q, 2H), 2.33 (s, 3H), 1.98 (s, 3H), 1.47 (t, 3H). MS (ESI) 320 (M+H)+.