Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.066 mmol), β-alanine (589 mg, 6.6 mmol) and NaOMe solution (10.6 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound as a light yellow solid. MS: (+) m/z 512.34 (M+1).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC1(c2ccc(F)c(Cl)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COC1(c2ccc(F)c(Cl)c2)CCNC1
Yield: 51.4 %

Procedure:
Preparation according to Example 1: (+)-1-benzyl-3-(3-chloro-4-fluorophenyl)-3-methoxypyrrolidine (0.405 g, 1.27 mmol), 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (0.72 g, 5.06 mmol). Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound 0.15 g (51%). [a]D=+3.3° (methanol). MS m/z (relative intensity, 70 eV) 229 (M+, 1), 214 (37), 199 (77), 187 (bp), 157 (38).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[NH2:10][C:11]1[C:37]([Br:38])=[CH:36][C:14]2[C:15]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:16]([Sn](CCCC)(CCCC)CCCC)[O:17][C:13]=2[CH:12]=1>C1(C)C=CC=CC=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>[NH2:10][C:11]1[C:37]([Br:38])=[CH:36][C:14]2[C:15]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:16]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[O:17][C:13]=2[CH:12]=1
Reactant: Fc1ccc(I)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1oc2cc(N)c(Br)cc2c1C(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2F)oc2cc(N)c(Br)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
2,4-difluoro-1-iodobenzene (2.09 g, 8.72 mmol) and Pd(PPh3)4(20 mg) were added into a solution of ethyl 6-amino-5-bromo-2-(tributylstannyl)benzofuran-3-carboxylate (5 g, 8.72 mmol, prepared from ethyl 6-amino-5-bromobenzofuran-3-carboxylate with LDA and Bu3SnCl) in toluene (10 mL) under N2, then the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with H2O, brine, dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography (petroleum ether:EtOAc=6:1) to provide the product of ethyl 6-amino-5-bromo-2-(2,4-difluorophenyl)benzofuran-3-carboxylate (310 mg, yield: 9%). 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 6.95˜7.01 (m, 2H), 6.92 (d, J=8.0 Hz, 1H), 4.37 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H). MS (M+H)+: 396/398.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:37]1([C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a solution of Boc Gly-OH (80) (4.0 g, 22.83 mmol) in dry CH2Cl2 (50 mL) at 0° C. under N2 was added HATU (8.70 g, 22.9 mmol). After stirring for 15 min at r.t., 1,2,3,4-tetrahydroquinoline (2.9 mL, 23.0 mmol), and DIPEA (12 mL, 68.8 mmol) were added. The reaction was stirred for 36 h at room temperature. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated NaHCO3, 5% HCl, water, and saturated NaCl. Dried over MgSO4, and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-50% EtOAc in hexanes) to afford 81 as a solid (5.76 g, 87%). 2-Amino-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone, TFA salt (82): Compound 81 (2.8 g, 9.66 mmol) was dissolved in 20 mL of TFA/CH2Cl2 (1:3) at 0° C. under N2 After stirring for 1 h, the solvents were removed under reduced pressure. 5 mL of CH2Cl2/hexanes were added and removed again under reduced pressure to afford 82 (3.0 g). This crude material was used in the next step with out further purification. 2-(Benzo[d]thiazol-2-ylamino)-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone (83): To a 0° C. solution of 2-chlorobenzothiazole (1.20 mL, 9.66 mmol) in 1-butanol (25 mL) was added compound 82 (2.94 g, 9.66 mmol)) followed by dropwise addition of Et3N (4.5 mL, 32 mmol). The reaction was heated to reflux for 24 h under N2. The solvent was removed under reduced pressure and the product was purified by column chromatography (20-50% EtOAc in hexanes) to afford 83 as a white foam (2.58 g, 82%); MS m/z: 324 (M+H)+. Anal. Calcd. For, C18H17N3OS: C, 66.85; H, 5.30; N, 12.99; S, 9.91. Found: C, 67.01; H, 5.42; N, 12.78; S, 9.85. Benzo[d]thiazol-2-yl(2-(3,4-dihydroquinolin-1(2H)-yl)-2-oxoethyl)cyanamide (84): To a suspension of compound 83 (340 g, 1.05 mmol) in dry CH3CN (10 mL) were added cyanogen bromide (5M in CH3CN) (0.42 mL, 2.1 mmol) and K2CO3 (580 g, 4.2 mmol). The reaction was heated to reflux for 4 h under N2. 0.84 mL (4.2 mmol) of cyanogen bromide was added and the reflux was continued for 12 h. The reaction mixture was diluted with EtOAc (50 mL). The solids were filtered off, filtrate was concentrated, and the yellow residue was purified by column chromatography (20% EtOAc in hexanes) to afford 84 as an off-white solid (80 mg, 28%). MS m/z: 349 (M+H)+. Anal. Calcd. For, C19H16N4OS.0.6H2O: C, 63.53; H, 4.83; N, 15.60; S, 8.92. Found: C, 63.24; H, 4.67; N, 15.25; S, 8.76.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:17])[N:10]=[C:9](Cl)[N:8]=1.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][SH:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:17])[N:10]=[C:9]([S:31][CH2:30][C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)[N:8]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)nc(SCc2ccccc2)nc1NCc1ccc(OC)c(Cl)c1

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-2,6-dichloropyrimidine (prepared in the above (2)) 150 mg, a 1.0M solution of benzylthiol in dimethylformamide 0.40 ml, triethylamine 40 mg and dimethylformamide 2.5 ml is stirred at room temperature for 2.5 days. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The residue is separated with preparative thin-layer chromatography (solvent; hexane:chloroform:ethyl acetate=30:30:4) and crystallized from isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-benzylthiopyrimidine as a colorless crystalline powder 125 mg. mp 89–90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([O:25]C)=[O:24])=[CH:13][C:12]=2[N:11]=1.[OH-].[Na+].C(O)(=O)C>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 62.1 %

Procedure:
To a solution of methyl 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylate (0.100 g, 0.256 mmol) in MeOH (15 mL), sodium hydroxide (0.052 g, 1.3 mmol) was added. The reaction mass was refluxed for 3 h. Methanol was removed under vacuum. Water was added and reaction mixture was acidified with dilute acetic acid. The reaction mixture was filtered and obtained solid was dried to afford 0.060 g of the desired product. 1HNMR (DMSO-d6): δ 2.62 (s, 3H), 7.37 (m, 1H), 7.60 (d, J=7.8 Hz, 2H), 7.65 (s, 1H), 9.80 (s, 1H), 11.53 (s, 1H), 13.00 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:12]3[CH:13]=[N:14][NH:15][C:16]=3[CH3:17])[S:11][C:7]=2[C:6](=[O:18])[NH:5][C:4]1([CH3:24])[CH2:19]C(F)(F)F)[CH3:2].C(O)(C(F)(F)F)=O.COC(OC)(C)C.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+].Cl>CC(N(C)C)=O.CO>[CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:12]3[CH:13]=[N:14][NH:15][C:16]=3[CH3:17])[S:11][C:7]=2[C:6](=[O:18])[NH:5][C:4]1([CH3:19])[CH3:24])[CH3:2]
Reactant: CCN1c2cc(-c3cn[nH]c3C)sc2C(=O)NC1(C)CC(F)(F)F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Agent: O=C([O-])O
Solvent: COC(C)(C)OC
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCN1c2cc(-c3cn[nH]c3C)sc2C(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.7 %

Procedure:
A mixture of 1-ethyl-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (120 mg, 0.335 mmol) and TFA (1.0 mL) was stirred at room temperature for 1 day. After removal of the solvent at reduced pressure, the residue was treated with saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, EtOAc) to give a yellow crystalline solid. The solid was dissolved in DMA (1.5 mL). To the mixture, 2,2-dimethoxypropane (1.5 mL), CSA (15 mg) and MgSO4 (100 mg) were added. The mixture was stirred at 80° C. for 2 h. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, EtOAc) to give a yellow crystalline solid. The solid was mixed with MeOH (1.0 mL) and 1 M aqueous HCl (1.0 mL). After stirring at 50° C. for 1 h, saturated aqueous NaHCO3 was added to the mixture. The organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in acetic acid (0.50 mL). To the solution were added acetone (1.0 mL) and PTSA (10 mg). After stirring at 60° C. for 1 h, saturated aqueous NaHCO3 and EtOAc were added to the mixture. The organic materials were extracted with EtOAc. The combined extracts were washed with brine, and then dried over Na2SO4. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to EtOAc), then crystallized from EtOAc/heptane to give the title compound (24 mg, 24%) as a colorless solid:
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[Cl:16][C:17]1[CH:18]=[C:19]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[N:21][CH:22]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][C:19]2[CH:20]=[N:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH2:27][CH2:28]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: Clc1cncc(OCCN2CCNCC2)c1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cncc(Cl)c2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(5-chloro-3-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:14](OCC)=O)[C:10]([CH3:30])([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10]([CH3:30])([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2C)cc1OC
Reaction time: 2 h
Yield: 97 %

Procedure:
14.5 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-carbethoxy-piperazine (cf. Example 5) are dissolved in 170 ml of dry tetrahydrofuran and added dropwise, with stirring over a period of two hours, to a boiling suspension of 3.42 g of lithium aluminum hydride in 150 ml of dry tetrahydrofuran. The batch is kept at the boiling point for a further 2 hours. After careful addition of water, the mixture is filtered and the filtrate evaporated. The remaining oil is further worked up as in Example 4. 12.4 g (82 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-methyl-piperazine are obtained in the form of the dihydrochloride. m.p. = 192° C. (ethanol).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:9][C:8]([F:34])([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[C:28]([Cl:32])=[C:27]([Cl:33])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:7]1)=[O:5])C.[OH-].[Li+]>CCO.O>[F:34][C:8]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:33])[C:28]([Cl:32])=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:22])([F:23])[F:24])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:9]1
Reactant: CCOC(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid ethyl ester (polar spot of Preparation 5, 1.2 g, 2.23 mmol) in EtOH:H2O (1:1, 80 mL) was added lithium hydroxide (0.469 g, 11.17 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material, reaction mixture was concentrated in vacuo, diluted with water (50 mL) and acidified using 1M HCl up to pH=2 at 0° C., solid was precipitated out. Resulting solid was filtered on Whatmann filter paper. Solid was dissolved in EtOAc (50 mL), dried over sodium sulphate, filtered and evaporated to afford solid, which was washed with n-pentane (3×3 mL) to afford white solid (0.820 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ: 2.75-2.84 (m, 5H), 4.30-4.42 (m, 2H), 7.65 (d, J=8.20 Hz, 2H), 7.77 (d, J=8.16 Hz, 2H), 7.85 (s, 2H), 12.52 (bs, 1H); LC-MS (m/z): 507.90 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:32][OH:33])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH3:36]I.[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:32][O:33][CH3:36])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CI
Reactant: COc1cc(-c2nnc3n2CCCC3(CO)c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCC1(c2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a mixture of {8-(3,4-difluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanol (260 mg) in DMF (2.9 mL) was added sodium hydride (60%, 27.6 mg) at 0° C., and the mixture was stirred for 30 min. Methyl iodide (0.0716 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (69.1 mg).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][S:16][C:10]=2[S:9][CH2:8][CH2:7]1)C.Cl.O>O1CCCC1>[O:13]=[C:12]1[C:11]2[CH:14]=[CH:15][S:16][C:10]=2[S:9][CH2:8][CH2:7][N:6]1[CH2:5][CH:4]=[O:3]
Reactant: CCOC(CN1CCSc2sccc2C1=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=CCN1CCSc2sccc2C1=O
Reaction time: 20 h
Yield: 87.1 %

Procedure:
To a solution of 8.0 g of 2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 160 ml of N,N-dimethylformamide was added 6.3 g of potassium t-butoxide with stirring under ice-cooling and the mixture was stirred for an hour at room temperature. Then to the mixture was added 8.4 ml of bromoacetaldehyde diethyl acetal under ice-cooling. The mixture was stirred for 5 hours at room temperature and water was added thereto and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel using and chloroform and methanol (98.8:0.2) as an eluent to give 6,9 g of 4-(2,2-diethoxyethyl)-2,3-dihydrothieno[3,2-f]1,4-thiazepin-5(4H)-one as a pale yellow oil. To the solution of thus obtained 6.7 g of 4-(2,2-diethoxyethyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 150 ml of tetrahydrofuran was added 20 ml of 10% hydrochloric acid and the mixture was allowed to stand for 20 hours at room temperature, and then poured into water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off to give 4.4 g of 2,3,4,5-tetrahydro-5-oxothieno[3,2-f]-1,4-thiazepin-4-acetaldehyde as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[C:18]([OH:23])=[N:19][CH:20]=[CH:21][CH:22]=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[C:18]([OH:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1cccnc1O
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O)c2c1C

Procedure:
Prepared analogously to example 1.1 from 0.2 g 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 0.1 g 3-amino-pyridin-2-ol in dioxan.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]3[CH:17]=[C:18]([C:21](=[O:33])[NH:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)[CH:19]=[CH:20][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[NH:22][C:21]([C:18]1[CH:19]=[CH:20][C:14]2[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:7][CH:8]=3)[NH:16][C:15]=2[CH:17]=1)=[O:33]
Reactant: COC(=O)CCc1ccc(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above 3-{4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-propionic acid methyl ester was taken up in MeOH (5 mL) then 1N NaOH (5 mL) was added. The solution was stirred at ambient temperature for 3 h then the solution was carefully acidified to pH 3-4 with 1N HCl. The suspension was filtered, washed with water, and dried under reduced pressure to give 3-{4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-propionic acid. 1H NMR (MeOD, 400 MHz): δ 8.45-8.43 (d, J=8.97 Hz, 1H), 8.38-8.36 (d, J=8.97 Hz, 2H), 8.04-8.01 (dd, J=1.77 Hz, 8.59 Hz, 1H), 7.92-7.90 (d, J=8.34 Hz, 2H), 7.77-7.71 (m, 2H), 7.54-7.51 (t, J=7.83 Hz, 1H), 7.1 (s, 2H), 2.96-2.92 (t, J=7.45 Hz, 2H), 2.65-2.62 (t, J=7.71 Hz, 2H), 2.16 (s, 6H). MS (ESI) m/z 465.1 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:17][C:16]=2[Cl:26])[C:6]=1[CH3:27].COC(=O)CC1C2C(=NC=CC=2)NC=1C.[H-].[Na+].BrCC1C=CC(S(CC)(=O)=O)=CC=1Cl.[I-].[Na+]>CN(C=O)C>[Cl:26][C:16]1[CH:17]=[C:18]([S:21]([CH2:24][CH3:25])(=[O:22])=[O:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[C:6]1[CH3:27]
Reactant: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)c(Cl)c1
Agent: CCS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
[1-(2-Chloro-4-ethanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To an ice cooled (0° C.) stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((2.68 g, 13.1 mmol) in dry DMF (95 ml) is added sodium hydride (577 mg of a 60% dispersion in mineral oil, 14.41 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture is re-cooled to 0° C. and treated with 1-bromomethyl-2-chloro-4-ethanesulfonyl-benzene (6.6 g, 22.2 mmol) and sodium iodide (3.3 g, 22.2 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is poured onto water (600 ml) and extracted with 1:1 ethyl acetate/diethyl ether (4×300 ml). The organic portions are washed with brine, dried (MgS04) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:2) to yield the titled product. (MH+421)