Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.FC1C=C2C(=CC=1)NC(=O)C=N2.[H-].[Na+].CS(O[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:35]1)(=O)=O>CN(C=O)C.O.C(OCC)C>[C:44]([O:43][C:41](=[O:42])[NH:40][CH:37]1[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[N:6]=[CH:7][C:8]2=[O:12])[CH2:35][CH2:36]1)([CH3:47])([CH3:46])[CH3:45]
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: O=c1cnc2cc(F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of a 1:1 mixture of 7-fluoroquinoxalin-2(1H)-one (Intermediate 143) and 6-fluoroquinoxalin-2(1H)-one (Intermediate 144) (1.5 g total, 9.1 mmol) was treated with sodium hydride (60% in oil, 0.44 g, 11.0 mmol) at 0° C. The reaction was allowed to stir at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6, 1.33 mmol/mL, 11.0 mmol), dissolved in dry DMF (5 mL) was added and it was stirred at room temperature overnight. The reaction mixture was diluted with water and with diethyl ether (5×50 mL). The combined organic phases were dried over sodium sulfate and concentrated to dryness under reduced pressure. Chromatography with hexanes/acetone (5:1 to 3:1). The higher Rf material was isolated as a mixture of Intermediate 141 with an O-alkylated isomer, which was rechromatographed on silica gel with hexanes/ethyl acetate (1:3) to give pure Intermediate 141 as a colorless solid, 0.24 g, 14%. Isolation of the lower Rf material from the first column gave 0.38 g (21%) of pure Intermediate 142 as a colorless solid.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:16])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCCCc1cccnc1)[C@@H]1CCCN1
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCc1cccnc1)[C@@H]1CCCN1C(=O)NC1CCCCC1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
A mixture of cyclohexylisocyanate (100 mg; 0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 120 mg (36%) of the compound of Example 4 (4, Table I), 1H NMR (CDCl3, 300 MHz): δ1.10-1.27 (m, 6H); 1.69-1.75 (m, 4H); 1.94-2.03 (m, 4H); 2.67-2.73 (t, 2H); 3.31-3.44 (m, 3H); 4.12-4.16 (m, 2H); 4.39-4.42 (m, 1H); 7.25-7.34 (m, 1H); 7.25-7.55 (dd, 1H); 8.45 (s, 2H). Anal. Calcd. for C20H29N3O3—0.6 H2O: C, 64.88; H, 8.22; N, 11.35. Found: C, 64.60; H, 8.18; N, 11.21.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15](=O)[CH3:16])=[N:9]2)=[CH:4][CH:3]=1.C(OP([CH2:26]/[C:27](=[N:32]\[O:33][CH3:34])/[C:28]([O:30][CH3:31])=[O:29])(OCC)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[C:15](/[CH3:16])=[CH:26]\[C:27](=[N:32]/[O:33][CH3:34])\[C:28]([O:30][CH3:31])=[O:29])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOP(=O)(C/C(=N\OC)C(=O)OC)OCC
Reactant: CC(=O)COc1ccn(-c2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Product: CO/N=C(\C=C(\C)COc1ccn(-c2ccc(Cl)cc2)n1)C(=O)OC

Procedure:
To 5.26 g (21.0 mmol) 1-[1-(4-chlorophenyl)pyrazol-3-yl]oxypropan-2-one and 7.20 g (26.9 mmol) methyl (2Z)-3-diethoxyphosphoryl-2-methoxyimino-propanoate (which can be prepared as described for the dimethoxy derivative [(Tetrahedron Let 29, 3361-3364 (1988)] in 100 ml THF have been added at ambient temperature with stirring 2.59 g (23.1 mmol) potassium tert.-butylate. Stirring was continued over night. After removal of the solvent in vacuo the mixture was purified by chromatography on silica with heptane/ethyl acetate. 1.07 g of a 80:20 E:Z-mixture have been collected. This has been used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(O[O:14][C:15]([CH3:18])(C)C)(C)(C)C.[C]=O.[CH2:21]([OH:23])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:21]([O:14][CH2:15][CH3:18])=[O:23])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1ccc(Cl)cc1
Agent: [C]=O
Product: CCOC(=O)Cc1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
p-Chlorotoluene (1.89 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 89 mg ethyl p-chlorophenylacetate was obtained by column chromatography, in a yield of 90%. 1HNMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 3.57 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.19-7.23 (m, 2H), 7.27-7.30 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 14.2, 40.7, 61.0, 128.7, 130.7, 132.6, 133.0, 171.2; HRMS (ESI) calcd. for C10H11ClNaO2 [M+Na]: 221.0340. found: 221.0342. The ethyl p-chlorophenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 75 mg product p-chlorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 98%.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][CH:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])=[O:9])=[CH:4][CH:3]=1.C[O-].[Na+].C(Cl)Cl.Cl>CO>[OH:13][CH2:14][CH2:15][CH:11]1[NH:10][C:8](=[O:9])[N:7]([CH2:6][C:5]2[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:12]1=[O:16]
Reactant: Cc1ccc(CNC(=O)NC2CCOC2=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(CN2C(=O)NC(CCO)C2=O)cc1
Yield: 72.7 %

Procedure:
A solution of crude 1-(4-methyl-benzyl)-3-(2-oxo-tetrahydro-furan-3-yl)-urea (48.5 g, assume 0.137 mol) in MeOH (1.5 L) was treated with sodium methoxide (21.1 g, 0.391 mol) and heated to reflux under N2 for 2 h until done by thin layer chromatography (9:1 CH2Cl2:MeOH). The reaction was cooled and the solvent removed in vacuo to give a residue that was combined with aqueous 1 N HCl (640 mL) and extracted with EtOAc. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 24.72 g (73%) of crude 5-(2-hydroxy-ethyl)-3-(4-methyl-benzyl)-imidazolidine-2,4-dione as a yellow solid which was carried on in the next step without purification. MS (ES+) Calc'd for C13H17N2O3 (M+1) 249. Found m/z 249 (100%). 1H NMR.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].[CH3:24][O:25][CH2:26]CCl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:24][O:25][CH3:26])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Reactant: COCCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
2.37 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide is treated at 20°-25° C under nitrogen, with 0.38 g. of sodium borohydride. After one hour 1.6 ml. of chloroethyl methyl ether is added, and the mixture kept at 20°-30° C for a further three hours. Water is then added and the product filtered off. Recrystallization from cyclohexane gives 1-acetamido-2-nitro-4-methoxyethylthiobenzene.
Reaction SMILES: Cl.[F:2][C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:13]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:6]2[CH2:5][CH2:4][C:3]([F:2])([C:9]3[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=4)[N:13]=3)[CH2:8][CH2:7]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3(F)CCNCC3)n2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(F)(c3nc(COc4ccc(S(C)(=O)=O)cc4)cs3)CC2)nc1

Procedure:
A solution of 4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (4.0 g, 9.01 mmol), 2-chloro-5-ethyl-pyrimidine (1.55 g, 1.2 eq.) and DIPEA (4.7 g, 4 eq.) in 2-propanol (30 mL) in a sealed pressure vessel was stirred at 160° C. (oil bath temperature) overnight. After cooling, the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 8.19 (2H, s), 7.87 (2H, d, J=9.2 Hz), 7.36 (1H, s), 7.10 (2H, d, J=9.2 Hz), 5.23 (2H, s), 4.69 (2H, m), 3.44 (2H, m), 3.03 (3H, s), 2.48 (2H, q, J=7.6 Hz), 2.15˜2.39 (4H, m), 1.21 (3H, t, J=7.6 Hz).
Reaction SMILES: C([OH:3])C.[OH-].[Na+].[CH3:6][C:7]1[C:8]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:9]=2[C:10]2[C:11](=[O:24])N(C3C=CC(C)=CC=3)[C:13](=[O:16])[C:14]=2[CH:15]=1.Cl>O.C(OCC)(=O)C>[CH3:6][C:7]1[CH:15]=[C:14]2[C:13](=[O:3])[O:16][C:11](=[O:24])[C:10]2=[C:9]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[O:27][C:8]=12
Reactant: Cc1ccc(N2C(=O)c3cc(C)c4oc5ccccc5c4c3C2=O)cc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2c(c3c1oc1ccccc13)C(=O)OC2=O
Temperature: 25 °C
Yield: 91 %

Procedure:
5 ml of ethanol and 1.2 ml of a 5 N aqueous sodium hydroxide solution were added to 200 mg of 5-methyl-2-(4-methylphenyl)-1H-benzofuro[3,2-e]isoindole-1,3(2H)-dione. The mixture was refluxed for 30 minutes. Thereto was added 1.2 ml of concentrated hydrochloric acid. The resulting mixture was refluxed for 1 hour and then cooled to room temperature. Then, thereto were added 20 ml of ethyl acetate and 10 ml of water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with 2.0 ml of acetic anhydride. The mixture was refluxed for 30 minutes, and then concentrated to dryness under reduced pressure. The residue was washed with diethyl ether and dried to obtain 140 mg (yield: 91%) of 4-methyldibenzofuran-1,2-dicarboxylic anhydride as light yellow crystals.
Reaction SMILES: [OH-:1].[K+].Cl[C:4](Cl)(Cl)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:15]1([O:23]CCCC)C=CC=C[CH:16]1[CH:17]=[CH2:18]>C(O)CCC>[C:6]1([CH2:5][C:4]([O:23][CH2:15][CH2:16][CH2:17][CH3:18])=[O:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CC1C=CC=CC1(Cl)OCCCC
Reactant: [OH-]
Reactant: ClC(Cl)(Cl)Cc1ccccc1
Agent: [K+]
Solvent: CCCCO
Product: CCCCOC(=O)Cc1ccccc1

Procedure:
The process of Example 4 was followed, using 45 ml. of butanol, 12.5 g. of potassium hydroxide, and 4.6 g. of 1,1,1-trichloro-2-phenylethane. The reflux was carried on for 8 hours, at 110°. The product was 3.85 g. of rather impure oil, apparently containing some of the 2-chloro-2-butoxystyrene impurity, which was converted to desired product by adding 8 ml. of butanol and 40 ml. of 1 N hydrochloric acid and stirring the mixture for 20 minutes. The layers were separated, and the aqueous was extracted with two 30 ml. portions of diethyl ether. The organics were combined and washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum to obtain 4.2 g. of partially purified product, 77% pure by vapor phase chromatography.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[S:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>CC(C)=O>[Br-:1].[O:6]=[C:3]([CH2:4][CH3:5])[CH2:2][S+:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCSC1
Reactant: CCC(=O)CBr
Solvent: CC(C)=O
Product: CCC(=O)C[S+]1CCCC1
Product: [Br-]
Yield: 72.3 %

Procedure:
In a 100 ml three-necked flask, 3.5 g of tetrahydrothiophene was dissolved in 40 ml of acetone. To the solution, 6 g of 1-bromo-2-butanone was added dropwise while stirring. After leaving for 24 hours, the deposited white crystal was collected by filtration. The white crystal was ground to a powder, which was washed with ether. The powder was dried by a vacuum drier at 30° C. for six hours to obtain 6.86 g of 2-oxobutyl-thiacyclopentanium bromide (yield: 72.2%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:10][CH2:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[NH2:29][OH:30]>CO.C(Cl)Cl>[C:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:10][CH2:9][C:8]2=[N:29][OH:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: Cc1ccccc1C1CCC(=O)C(c2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccccc1C1CCC(=NO)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
2-Phenyl-4-(2-methylphenyl)cyclohexanone, 13.1 grams (49.5 mmol), was dissolved in 200 mL methanol/methylene chloride, followed by 11.1 mL (79.3 mmol) triethylamine and 5.5 grams (79.3 mmol) hydroxylamine hydrochloride. The solution was stirred at room temperature for 48 hours, the solvent evaporated, and the resulting solid washed with methanol and dried to afford 8.2 grams (59%) of a yellow solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11](O)[CH2:12][CH:13](O)[CH3:14].[CH2:17](O)[CH2:18][CH2:19][CH3:20]>[OH-].[OH-].[OH-].[OH-].[Ti+4].C1(C)C=CC=CC=1>[C:1]([O:10][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:11][CH2:12][CH2:13][CH3:14])=[O:7]
Reactant: CCCCO
Reactant: CC(O)CCO
Reactant: O=C(O)CCCCC(=O)O
Agent: [Ti+4]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCOC(=O)CCCCC(=O)OCCCC
Reaction time: 14 h
Yield: 50.3 %

Procedure:
To a (2:1:2 mol) mixture of one mol (146 g) of adipic acid, 0.5 mol (45 g) of 1,3-butanediol and 1 mol (72 g) of n-butanol, were added 0.5 g of titanium tetrahydroxide and 60 ml of toluene, and dehydrating esterification was carried out. When acid value was decreased to 6 after 14 hours, 72 g (1 mol) of butanol was added and dehydrating esterification reaction was carried out until an acid value becomes 0.3. After a treatment for catalyst removal, distillation was carried out under reduced pressure to produce 65 g (about 25 mol%) of dibutyl adipate. Further 36 g (13 mol%) of ester-alcohol distillate fraction (160° C.-180° C./0.5 mmHg) was obtained. The yield of high boiling products was 128 g, 55% of the theoretical amount. Liquid chromatographic analysis results of these products showed that n=1 compound is less than the half and they are a mixture of total of 6 kinds of compounds including those with n=2 or greater. The bis-compound which distilled at 235° to 245° C./0.5 mmHg reduced pressure was 56 g which is only 24% of the calculated amount and the oligomer product was 72 g (produced in greater amount than bis-compound). By the addition of an excess amount of butanol, dehydrating esterification reaction is completed swiftly. However, ester interchange reaction occurred concurrently, and the terminals of the diol do not react and and an ester alcohol distillate fraction is formed. The diol is azeotropically distilled too. Although the composition of higher boiling products varies depending on reaction time, temperature, molar ratio, and the like, it was noted that the weight % of the bis compound never exceeded the half amount.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:29]([O:31]CC)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:29]([OH:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A mixture of compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo pentane carboxylate (100 mg, 0.21 mmol) and lithium hydroxide monohydrate (96 mg, 2.1 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml5/ml) was stirred for 3 h at room temperature. After completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylic acid (0.05 g). 1H-NMR (CDCl3, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.68 (m, 2H); 1.94 (m, 2H); 1.78 (m, 4H).
Reaction SMILES: [C:1]([N:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][C:19]=3F)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].Cl.Cl.[NH:28]1[C:32]2=[N:33][C:34]([CH2:37][NH2:38])=[CH:35][CH:36]=[C:31]2[CH:30]=[CH:29]1>>[C:1]([N:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][C:19]=3[NH:38][CH2:37][C:34]3[N:33]=[C:32]4[NH:28][CH:29]=[CH:30][C:31]4=[CH:36][CH:35]=3)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NCc1ccc2cc[nH]c2n1
Reactant: CC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Agent: Cl
Product: CC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccc4cc[nH]c4n3)ccc2C(C)(C)C1

Procedure:
The titled compound was prepared from N-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-6-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 469 (M+H). Calc'd. for C27H28N6O2—468.56.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.CN(C=O)C.[NH2:29][C:30]1[S:31][C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[C:33]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]([NH:29][C:30]2[S:31][C:32]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[C:33]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)=[O:19])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 100 %

Procedure:
1-Benzyloxycarbonylpiperidine-4-carboxylic acid (5.00 g, 19.0 mmol) was dissolved in dichloromethane (80 mL), and thionyl chloride (6.93 mL, 95.0 mmol) and DMF (0.15 mL, 1.90 mmol) were added thereto, followed by 178, stirring under heating and reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (2 mL). The resulting solution was added to a solution of 2-amino-4-(2-furyl)-5-morpholinothiazole (2.01 g, 8.00 mmol) in pyridine (32 mL) obtained in Step 1 of Example 29, and then N,N-dimethylaminopyridine (97.6 mg, 0.800 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:3) to afford the entitled Compound 43 (4.96 g, 100%).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]2=[NH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15]OS(F)(=O)=O>C(Cl)Cl>[C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]2=[N:14][CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1C(=N)N(c2ccccc2)CC1=O
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: CN=C1N(C)C(=O)CN1c1ccccc1

Procedure:
3.78 g. of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, 40 ml. dry methylene chloride and 6 ml. of methylfluorosulfonate are mixed and stirred in a flash equipped with a drying tube at room temperature. After 20 hours the solid was filtered and the filtrate was stripped to dryness. The residue was treated with 30 ml. of water and extracted once with ether. The aqueous layer was separated and added slowly to 12 ml. of 5N NaOH with cooling and stirring. The white precipitate was filtered, washed with water and dried. Thin-layer chromatography showed a single spot (Rf 0.6, 5% EtOH. CH2Cl2). The yield was 2.75 g. (68%), m.p. 116°-118° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[CH:17][C:18]([F:19])=[C:12]([Cl:11])[CH:13]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)cc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-chloro-4-fluoroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 306-307° C.). MS(ES+) m/z 262 ([M+1]+, 100).