Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]([CH:6]1[S:10][CH2:9][CH:8](O)[CH:7]1[N+:12]([O-:14])=[O:13])[CH3:5].S(Cl)(C)(=O)=O.C(N(CC)CC)C.O>ClCCl>[CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]([CH:6]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH2:9][S:10]1)[CH3:5]
Reactant: CC(C)CC(C)C1SCC(O)C1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(C)C1SCC=C1[N+](=O)[O-]
Reaction time: 7.5 h
Yield: 47.7 %

Procedure:
After dissolving 0.50 g of 5-(4-methylpentan-2-yl)-4-nitrotetrahydrothiophen-3-ol in 4 ml of dichloromethane, 0.27 g of mesyl chloride and 0.33 g of triethylamine were gradually dropped thereto at 4° C. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for 7.5 hours. Water was added to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 0.22 g of 2-(4-methylpentan-2-yl)-3-nitro-2,5-dihydrothiophene (yield: 47.7%).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:24][C:25](=[O:40])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:28]([CH3:39])[CH:27]=1)[CH2:19][CH2:20][C:21]([OH:23])=O)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:72][N:73]1[CH2:76][C:75]2([CH2:80][CH2:79][NH:78][CH2:77]2)[CH2:74]1.FC(F)(F)C(O)=O.ClCl>C(#N)C.C(OCC)(=O)C.C(O)C.C(N(CC)CC)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C@@H:18]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[O:33])=[C:28]([CH3:39])[CH:27]=3)[CH2:19][CH2:20][C:21]([N:78]3[CH2:79][CH2:80][C:75]4([CH2:76][N:73]([CH3:72])[CH2:74]4)[CH2:77]3)=[O:23])=[N:10][C:11]=2[CH:16]=1
Reactant: CN1CC2(CCNC2)C1
Reactant: Cc1cc(C(=O)NC(CCC(=O)O)c2nc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCO
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC3(CN(C)C3)C2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 67 %

Procedure:
Prepared analogously to Example 1g from N-[1-(1-tert-butoxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, TBTU, diisopropylethylamine, 2-methyl-2,6-diazaspiro[3.4]octane in acetonitrile, and subsequent reaction with trifluoroacetic acid analogously to Example 17. Yield: 67%; Rf value: 0.05 (silica gel; ethyl acetate/ethanol/triethylamine=70:27:3); C31H37ClN6O3 (577.13); mass spectrum: (M+H)+=577/579 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:11](=[O:27])[NH:12][C:13]2[C:18]([C:19]=1[O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][N:16]=[CH:15][CH:14]=2.C(=O)([O-])[O-].[K+].[K+].CI.[C:36](#N)[CH3:37]>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:11](=[O:27])[N:12]([CH2:36][CH3:37])[C:13]2[C:18]([C:19]=1[O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:17][N:16]=[CH:15][CH:14]=2
Reactant: CC#N
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2ccncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2c(F)ccc(F)c2Cl)c(OC(=O)C(C)(C)C)c2cnccc21
Temperature: 100 °C

Procedure:
To a solution of 2,2-dimethyl-propionic acid 3-(2-chloro-3,6-difluoro-phenyl)-2-oxo-1,2-dihydro-[1,6]naphthyridin-4-yl ester (250 mg) in acetonitrile (1.5 ml) was added potassium carbonate (88 mg) followed by methyl iodide (51 μl). The reaction mixture was heated to 100° C. for 22 minutes in a microwave and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and water. The phases were separated. The organic fraction was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:3 and then 1:1) to give Compound No. B1 of Table B as an orange oil (16 mg). 1H-NMR (400 MHz, CDCl3): 8.84 (s, 1H), 8.71 (d, 1H), 7.32 (d, 1H), 7.18-7.23 (m, 1H), 7.05-7.10 (m, 1H), 4.38 (q, 2H), 1.41 (t, 3H), 1.16 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C:6]1([CH3:12])[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1C(=O)Nc2cc(Cl)ccc21
Reactant: BrCc1ccccc1
Product: CC1(Cc2ccccc2)C(=O)Nc2cc(Cl)ccc21

Procedure:
The title compound was prepared from 6-chloro-3-methyl-1,3-dihydro-indol-2-one (700 mg) following similar methods to those described in Preparation 185 using benzyl bromide instead of iodomethane to give the title compound (641 mg) as a white solid. MS: [M+H]+=272.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(#N)C>[CH2:24]([O:23][C:21]([C:4]1[N:5]=[C:6]2[C:15](=[O:16])[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:7]2[C:3]=1[CH2:2][N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Reactant: CN1CCNCC1
Solvent: CC#N
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CN1CCN(C)CC1
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (630 mg, 1.5 mmol) in acetonitrile (180 ml) was added N-methylpiperazine (200 mg, 2.0 mmol). Stirring of the mixture was continued overnight at 25° C. followed by evaporation in vacuo. The residue was submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanol/ammonium hydroxide (90:10:0.5) to give 450 mg (69%) of the title compound. M.p. 255° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=4)[CH:13]=[C:5]3[C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CC(C)=O.[I-].[Na+]>[CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:37][CH2:38][N:39]5[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:18][CH:19]=4)[CH:13]=[C:5]3[C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(-c3ccc(O)cc3)c3cccc1n32
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCc1c(-c2ccc(OC)cc2)c2cc(-c3ccc(OCCN4CCCCC4)cc3)c3cccc1n32
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
1-Ethyl-4-(4-hydroxyphenyl)-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.368 g, 1.0 mmol), potassium carbonate (2.07 g, 15.9 mmol), sodium iodide (8 mg, 0.05 mmol) and 1-(2-chloroethyl)piperidine hydrochloride was suspended in 70 ml of dry acetone. The mixture was refluxed for 6 hours, and stirred at room temperature for 16 hours. Remaining salts were filtered off, and the solvent was evaporated. The crude product was purified by column chromatography over silica gel 60, using 15% of methanol in dichloromethane as the eluent. Fractions containing the product were combined and the solvent was evaporated. The crude product was crystallised from diethyl ether and petroleum ether to afford 0.326 g (68%) of the title compound. 1H--NMR (CDCl3, 200 MHz) δ: 1.40-1.70 (m,9 H); 2.50-2.60 (m, 4 H); 2.82 (t, 2 H); 3.26 (q, 2 H); 3.91 (s, 3 H); 4.19 (t, 2 H); 7.01-7.13 (m, 4 H); 7.62-7.83 (m, 6 H); 7.92 (d, 1 H); 8.14 (d, 1 H).
Reaction SMILES: [N:1]1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][NH:19][CH2:20][CH2:21][NH:22][CH3:23].C([O-])([O-])=O.[K+].[K+]>O>[CH3:18][N:19]([CH2:20][CH2:21][NH:22][CH3:23])[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNCCN(C)c1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 21.6 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.29 mmol), N,N′-dimethylethylenediamine (Aldrich Chemical Company) (0.15 mL, 1.44 mmol) and K2CO3 (0.40 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by flash chromatography on silica gel with 9:1 CHCl3:MeOH as eluant to give 18.5 mg (22%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOH. 1H NMR (CDCl3; 400 MHz): δ 2.60 (s, 6), 3.04 (t, 2, J=4.5), 3.15 (s, 3), 3.75 (t, 2, J=4.5), 6.76 (s, 1), 7.31-7.42 (m, 3), 7.70 (d, 2, J=7.4). MS m/z: 296 (M+1), 294 (M−1). HRMS: Calcd for M+H: 296.1875. Found: 296.1884.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH2:2].[C:8](Cl)([Cl:10])=[O:9].Cl>>[CH2:4]([O:3][CH:1]=[CH:2][C:8]([Cl:10])=[O:9])[CH:5]([CH3:7])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: C=COCC(C)C
Agent: Cl
Product: CC(C)COC=CC(=O)Cl
Temperature: 52.5 °C

Procedure:
100 g (1 mol) of isobutyl vinyl ether are initially charged in a 2 l stirred apparatus and heated to 50-55° C. 1024 g (10.4 mol) of phosgene are subsequently introduced over a period of 21 h, and 900 g (9 mol) of isobutyl vinyl ether are added dropwise over a period of 19 h. After an extra reaction time of 0.5 hours, the reaction mixture is heated to 80° C. with nitrogen stripping to eliminate hydrogen chloride. The low-boilers are then distilled off via a 15 cm Vigreux column, and the residue is analyzed by is gas chromatography. This gives 1364 g (70%) of crude isobutoxyacryloyl chloride (calc. 100%).
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([O:26][CH2:27][CH3:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:24][CH3:25].[Li+].[OH-]>>[C:20]([C:16]1[O:17][C:18]([CH3:19])=[C:14]([CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:26][CH2:27][CH3:28])[C:3]([OH:29])=[O:2])=[C:7]([O:24][CH3:25])[CH:8]=2)[N:15]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1OC)C(=O)O

Procedure:
In analogy to the procedure described in example 46 d], (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2-methoxy-phenyl]-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2-methoxy-phenyl]-2-ethoxy-propionic acid as colorless liquid.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(O)C>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:14](=[NH:17])[CH2:13][CH2:12][S:11][CH2:10][C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)(=[O:26])=[O:27])=[CH:21][CH:20]=1
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCC(=N)NS(=O)(=O)c2ccc(N)cc2)cs1
Yield: 79.3 %

Procedure:
In 10 ml of ethanol were dissolved 1 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and 0.69 g p-aminobenzenesulfonamide and after causing reaction for 48 hours at room temperature, the solvent was distilled off under reduced pressure. Then, the residue formed was purified by a silica gel column chromatography using a mixture of chloroform and methanol (20:1→10:1) to provide 1.2 g N-(p-aminobenzenesulfonyl)-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine as an amorphous solid. The product shows the following physicochemical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:26][S:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:41])=[O:40])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:11])([F:13])[F:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(c1ccc(OS(=O)(=O)c2ccccc2)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
To a suspension of 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (Example 179, 55 mg) and cesium carbonate (52 mg) in N,N-dimethylacetamide (1 ml) was added benzenesulfonyl chloride (25 mg). After being stirred at room temperature for 2 days, more benzenesulfonyl chloride (14 mg) was added and the mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine and with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane=>cyclohexane/EtOAc 1:1) to give the title compound (29 mg) as an off-white solid. MS (m/e)=522.2 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25]O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:19]([O:18][C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a stirred solution of dimethyl 4-hydroxyisophthalate (1.27 g, 6.04 mmol), (S)-N-Boc-Prolinol (1.22 g, 6.06 mmol), PPh3 (1.90 g, 7.24 mmol) in THF (30 mL) was added DIAD (1.43 mL, 7.26 mmol)at room temp. The resulting stirred mixture was then heated under reflux for 15 hr. After cooling to room temp, the resulting mixture was evaporated and the residue was purified by column chromatography on silica-gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 2.10 g (88%) dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]isophthalate as a yellow oil. 1H-NMR (CDCl3) δ 1.26 (s, 9 H), 1.85–2.16 (m, 3 H), 3.36–3.46 (m, 2 H), 3.90 (s, 6 H), 4.11–4.31 (m, 2 H), 4.95–5.02 (m, 2 H), 7.09 (dd, H, J=9.3, 24.9 Hz), 8.11–8.14 (m, 1 H), 8.46 (d, 1 H, J=9.3 Hz)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[N:15]([CH3:17])[CH3:16].[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[N:15]([CH3:17])[CH3:16])=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CN(C)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N(C)C)nc1Cl
Yield: 69.4 %

Procedure:
The same operation as in Example (196b) was performed using tert-butyl cis(±)-4-amino-3-(dimethylamino)piperidine-1-carboxylate obtained in Example (200c) (93 mg, 0.382 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (80.1 mg, 0.459 mmol), 1-hydroxybenzotriazole hydrate (77.5 mg, 0.573 mmol), WSC hydrochloride (110 mg, 0.573 mmol) and triethylamine (79.9 μL, 0.573 mmol), to obtain 106 mg of the title compound (69%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:17]#[N:18])=[CH:12][N:13]=[C:14]([NH:15][CH3:16])[C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=[O:20].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:17]([NH2:18])=[O:20])=[CH:12][N:13]=[C:14]([NH:15][CH3:16])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CNc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CNc1ncc(C(N)=O)c2[nH]c3ccc(F)cc3c12
Temperature: 50 °C

Procedure:
8-Fluoro-1-(methylamino)-5H-pyrido[4,3-b]indole-4-carbonitrile (36 mg, 0.150 mmol) was combined with K2CO3 (55.9 mg, 0.405 mmol) and dissolved in DMSO (3 ml) followed by the addition of hydrogen peroxide (0.066 ml, 0.749 mmol). The solution was heated at 50° C. for three hr. The solution was cooled to ambient temperature directly purified by HPLC (eluted with MeCN/H2O with 1% TFA).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:30])[N:23]([CH3:31])[CH:22]=2)[C:12]1=[O:32])=[O:5])C.O.[OH-].[Li+].C(O)(=O)C>CO.O>[CH3:31][N:23]1[C:24]2[C:29](=[C:28]([CH3:30])[CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]([C:7]3[CH2:8][CH2:9][CH2:10][C:6]=3[C:4]([OH:5])=[O:3])[C:12]2=[O:32])=[CH:22]1
Reactant: CCOC(=O)C1=C(n2c(=O)n(Cc3cn(C)c4cccc(C)c34)c3ccccc32)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1cccc2c1c(Cn1c(=O)n(C3=C(C(=O)O)CCC3)c3ccccc31)cn2C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
A solution of 120 mg (0.28 mmol) of 2-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclopent-1-enecarboxylic acid ethyl ester and 23 mg (0.56 mmol, 2.0 eq.) of lithium hydroxide monohydrate in 5 mL of methanol and 1 mL of water was stirred at room temperature for 2.5 days. Then the pH of the resulting mixture was adjusted to 3 with acetic acid and diluted with water. The precipitate was collected and washed with water. The isolated light pink solid was pumped overnight to give 94 mg (84%) of 2-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclopent-1-enecarboxylic acid as a light pink solid.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][C:16]([O:18]CC)=[O:17])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][C:16]([OH:18])=[O:17])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)N1CCC(COc2ccc(F)cc2C(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(F)ccc1OCC1CCN(C(=O)CC(=O)O)C1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a stirred solution of ethyl 3-{3-[(2-tert-butyl-4-fluorophenoxy)methyl]pyrrolidin-1-yl}-3-oxopropanoate (434 mg, 1.19 mmol) obtained in Example 214 in THF (5.0 ml) was added lithium hydroxide (1.0M aqueous solution, 5.0 mL, 5.0 mmol) at room temperature. After 3 hr, the reaction mixture was adjusted to about pH 1 with 1.0N hydrochloric acid. The obtained solution was concentrated under reduced pressure, and to the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (392 mg, 98%) as a white solid.
Reaction SMILES: O[C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:3]([CH3:7])[C:4]([OH:6])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)(Cl)Cl.C(#N)C.CS([O-])(=O)=O.[Hg+2].CS([O-])(=O)=O>[CH3:7][C@H:3]1[C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:5][C:4]1=[O:6]
Reactant: C[C@H](C(=O)O)[C@H](O)CCCCc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [Hg+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C[C@@H]1C(=O)O[C@@H]1CCCCc1ccccc1
Temperature: 48 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
(+)-(2S, 3R)-3-Hydroxy-2-methyl-7-phenylheptanoic acid is added to a solution of triphenylphosphine (0.88 g, 3.4 mmol) and 2,2'-dipyridyl disulfide (0.7 g, 3.2 mmol) in chloroform (20 mL) and is stirred for 20 minutes. Mercury(II) methanesulfonate (1.6 g, 4.2 mmol) is suspended in acetonitrile (52 mL), warmed to 48° C. and the activated ester/chloroform solution is added over 5 minutes. This mixture is heated for 1 minute after completion of the addition and then cooled. The mixture is filtered through Celite, the filtrate concentrated in vacuo and the residue is purified by column chromatography (silica, 25% ether in petroleum ether) to yield (3S,4R)-3-methyl-4-(4-phenylbutyl)oxetan-2-one (0.3 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.31-7.26 (m, 2H), 7.21-7.15 (m, 3H), 4.19-4.13 (m, 1H), 3.25-3.16 (m, 1H), 2.64 (t, J=7.6 Hz, 2H), 1.95-1.64 (m, 4H), 1.55-1.40 (m, 5H), 1.37 (d, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([C:28]#[N:27])=[CH:30][CH:31]=3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCc3ccc(C#N)cc3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and p-(aminomethyl)benzonitrile hydrochloride and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:21]O>CO>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:21])=[O:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
In 630 g of methanol was dissolved 203 g of 4-tert-butylcyclohexanecarboxylic acid. The solution was combined with 0.54 g of conc. sulfuric acid and heated under reflux for 72 hours. The reaction solution was allowed to cool to room temperature, 18 g of 2.5 wt % sodium hydroxide/methanol mixture was added, and the solvent was distilled off in vacuum from the reaction solution. The crude oil was purified by vacuum distillation, obtaining 207 g of methyl 4-tert-butylcyclohexanecarboxylate as colorless liquid (yield 95%, isomer ratio 76:24).