Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].CS([C:26]1[N:31]=[CH:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][N:27]=1)(=O)=O.O>C1COCC1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:26]2[N:27]=[CH:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=2)[CH2:18][CH2:17]1)(=[O:15])=[O:14]
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
NaH 60% (0.0217 mol) was added portionwise at room temperature to a solution of 1-(2-naphtalenesulfonyl)-piperazine (0.011 mol) in THF (50 ml) under N2 flow. The mixture was stirred at room temperature for 1 hour, then cooled to 0° C. A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ester (0.014 mol) in THF (30 ml) was added quickly. The mixture was stirred at room temperature for 2 hours, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was taken up in diethyl ether. The precipitate was filtered off and dried, yielding 3.92 g (84%) of 2-[4-(2-naphthalenylsulfonyl)-1-piperazinyl]- 5-pyrimidinecarboxylic acid, ethyl ester (interm. 8), melting point>260° C.
Reaction SMILES: B.C1COCC1.[C:7]([C:10]1[S:11][C:12]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:13][C:14]=1[NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[O:17])(=O)[NH2:8].Cl>C1COCC1>[NH2:8][CH2:7][C:10]1[S:11][C:12]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:13][C:14]=1[NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[O:17]
Reactant: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2C(N)=O)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2CN)cc1
Yield: 85 %

Procedure:
To a solution of BH3THF (1.8 mL, 1M in THF) was added a solution of N-(2-carbamoyl-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea in THF (3 mL) and the resulting mixture was heated under reflux for 48 h. After cooling to room temp., a concentrated hydrochloric acid solution was added, and the resulting mixture was extracted with EtOAc. The organic layer was washed with a saturated Na2CO3 solution, and a saturated NaCl solution, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 0.1% NH4OH/10% MeOH/CH2Cl2 to afford N-(2-aminomethyl-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.18 g, 85%): 1H NMR (CDCl3) δ1.38 (s, 9H), 2.34 (s, 3H), 3.81 (s, 2H), 6.72 (s, 1H), 7.29 (d, J=8.6 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 7.87 (s, 1 h); FAB-LRMS m/z 318 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12.[CH:11](O)=[O:12].C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH:11]([NH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)=[O:12]
Reactant: O=CO
Reactant: NCc1ncn2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CNCc1ncn2ccsc12
Temperature: 0 °C

Procedure:
To the ice-cooled solution of the whole amount of the crude 7-aminomethyl-imidazo[5,1-b]thiazole in 5 ml of dichloromethane was added a mixture of 0.5 ml of formic acid and 0.5 ml of acetic anhydride which had been preliminarily sitrred and reacted at 50° C. for 10 minutes. The resulting mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture were added 10 ml of water, 20 ml of dichloromethane and 5 ml of a 50% aqueous potassium carbonate solution, and the organic layer was separated. The aqueous layer was further extracted thrice with 20 ml of dichloromethane. The combined organic layer was purified by flash column chromatography on silica gel (eluted with chloroform: methanol=15:1) to give the title compound in a yield of 0.088 g (36%). NMR (CDCl3) δ: 4.53 (2H, d, J=5.8 Hz), 6.84 (1H, d, J=4.2 Hz), 6.86 (1H, br), 7.38 (1H, d, J=4.2 Hz), 7.93 (1H, s), 8.26 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24](O)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:28][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]([CH3:26])([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH3:25])[N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)CC=C(c2nc(C(C)(C)N3CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-amide (as prepared in Example 56, step (e)), morpholine, and thionyl chloride in DCM solvent according to the procedure in Example 14, step (e).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([SH:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].I[CH:13]([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]([C:5]1[C:10]([S:11][CH:13]([CH3:15])[CH3:14])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: COC(=O)c1nccnc1S
Product: COC(=O)c1nccnc1SC(C)C
Yield: 61 %

Procedure:
3-Mercapto-pyrazine-2-carboxylic acid methyl ester (0.35 g, 2.0 mmol) obtained in Step A and 2-iodopropane were reacted in the same manner as in Step A of Preparation Example 5 to obtain the title compound (0.267 g, 61%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[N:4]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:3](=[O:21])[N:4]([CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3cccnc3)C2=O)cc1
Temperature: 150 °C
Yield: 40 %

Procedure:
To a solution of 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.50 mmol, 149 mg) in DMF (1 mL) was added 4-methoxyaniline (1.10 mmol, 135 mg) The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 77 mg (40%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=1.8 Hz, 1H), 8.54 (dd, J1=4.7 Hz, J2=1.6 Hz, 1H), 7.80-7.75 (m, 1H), 7.35 (bs, 1H), 7.26 (dd, J1=7.8 Hz, J2=4.7 Hz, 1H), 7.15-7.05 (m, 3H), 6.98-6.94 (m, 2H), 6.62-6.50 (m, 4H), 4.78 (s, 2H), 3.68 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1)=[O:6])[CH3:3].[C:18]([NH:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN=C=NCCCN(C)C.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:2]([O:4][C:5](=[O:6])[NH:7][C:8]1[CH:13]=[N:12][C:11]([C:14](=[O:16])[NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][N:28]3[CH2:27][CH2:26][CH:25]([C:23](=[O:24])[NH:22][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:30][CH2:29]3)[CH:33]=2)=[CH:10][CH:9]=1)([CH3:1])([CH3:3])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)NC(=O)C1CCN(Cc2cccc(N)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(NC(=O)OC(C)(C)C)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
A solution of 5-[[(1,1-dimethylethoxy)carbonyl]amino]-2-pyridinecarboxylic acid (1 g, 4.11 mmol) in DCM (30 mL) is treated successively with 1-(3-amino-benzyl)-piperidine-4-carboxylic acid tert-butylamide (1.309 g, 4.525 mmol), EDC-HCl (1.577 g, 8.227 mmol), DMAP (75 mg, 0.62 mmol). The RM is stirred at RT for 18 h. DCM (10 mL) and aq. sat. NaHCO3 solution (30 mL) are added and the organic phase is extracted twice with DCM (2×20 mL). The combined organic layers are dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel using a gradient of DCM/MeOH from DCM to DCM/MeOH 9:1. After concentration of the product containing fractions, the title compound (1.21 g, 58%) is obtained as a beige powder LC-MS A: tR=0.75 min; [M+H]+=510.23.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1.O>O1CCCC1.C(OCC)(=O)C>[CH3:9][C:8](=[CH:24][C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)=Cc1cccnc1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Sixty percent sodium hydride (in oil) (224 mg, 5.6 mmol) was suspended in tetrahydrofuran (5 mL). To this, triethyl 2-phosphonopropionate (1.2 mL, 5.6 mmol) was added under a nitrogen atmosphere with cooling in an ice bath and the mixture was stirred at the same temperature for 30 minutes. To this, 3-pyridinecarboxaldehyde (300 mg, 2.8 mmol) was added and the mixture was stirred at the same temperature for 1.5 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 2/1) to give ethyl 2-methyl-3-(pyridin-3-yl)acrylate (480 mg, yield: 90%).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([C:18]([OH:20])=O)=[C:4]1[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:5]1=[N:6]2.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].C(N(CC)CC)C>O=S(Cl)Cl.C(Cl)Cl>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][C:18]([C:3]1[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=2)[N:6]=[C:5]2[C:11]3[C:16]([NH:17][C:4]=12)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:20]
Reactant: CN(C)CCN
Reactant: O=C(O)c1c2ccccc2nc2c1[nH]c1ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)CCNC(=O)c1c2ccccc2nc2c1[nH]c1ccccc12
Reaction time: 14 h
Yield: 60.2 %

Procedure:
10H-indolo[3,2-b]quinoline-11-carboxylic acid (0.5 g, 1.9 mmol) was dissolved in 20 ml of refluxing SOCl2, After 6 hours a clear solution was obtained, and all volatiles were removed in vacuo. The crude acid chloride was suspended in 10 ml of CH2Cl2. A solution of N,N-dimethylethylendiamine (0.2 mL, 2.26 mmol) and triethylamine (2.2 ml) in 10 ml of CH2Cl2 was added at room temperature, and the mixture was stirred for 14 hours. The organic phase was washed (NaHCO3, brine) and dried (MgSO4). Removal of the solvent and purification by chromatography on alumina (CH2Cl2/MeOH, 90:10) yielded the desired compound (0.38 g, 61%) as a solid. m. p. 175-176° C. 1H-NMR [MeOD, _, ppm]: 8.16 (d, J=7.8 Hz, 1H), 7.92 (m, 2H), 7.35-7.20 (m, 3H), 7.04 (m, 2H), 3.62 (m, 2H, CH2NO), 2.55 (m, 2H, CH2N(CH3)2), 2.29 (s, 6H, N(CH3)j. MS (EI, m/z) 277 (M++1).
Reaction SMILES: [CH:1]1([C:4]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])([CH3:9])/[C:5](=[N:7]/[OH:8])/[NH2:6])[CH2:3][CH2:2]1.[CH2:17](OC(OCC)OCC)C>CC(O)=O>[CH:1]1([C:4]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])([C:5]2[N:6]=[CH:17][O:8][N:7]=2)[CH3:9])[CH2:3][CH2:2]1
Reactant: CC(N[S@](=O)C(C)(C)C)(/C(N)=N/O)C1CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC(N[S@](=O)C(C)(C)C)(c1ncon1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
(Z)-2-cyclopropyl-2-((R)-1,1-dimethylethylsulfinamido)-N′-hydroxypropanimidamide (321 mg, 1.30 mmol) in triethoxymethane (2.0 ml, 12 mmol) was treated with AcOH (2 ml) at rt. The reaction was allowed to stir at rt for 16 h. LCMS showed a major peak with the expected M+H. The reaction was concentrated to dryness azeotroping with toluene 2×. The resulting yellow oil was purified on silica gel (Biotage, EtOAc/hexanes gradient (Rf ˜0.2 in 70% EtOAc/Hex, visualized with permanganate stain), to give the expected product (first eluting diastereomer, 120 mg, 0.466 mmol, 36% yield) consistent by LCMS and NMR. LC-MS retention time: 1.21 min; m/z M+H: 258. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 5.29 (s, 1H), 1.53-1.49 (m, 1H), 1.47 (s, 3H), 1.10 (s, 9H), 0.49-0.40 (m, 4H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[F:29])[O:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)[CH:13]=1.CN1C(=O)CCC1.[CH3:37][N:38]([CH2:40]/[CH:41]=[CH:42]/[C:43](Cl)=[O:44])[CH3:39]>C1COCC1.CN(C=O)C.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[F:29])[O:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([NH:25][C:43](=[O:44])/[CH:42]=[CH:41]/[CH2:40][N:38]([CH3:39])[CH3:37])[CH:22]=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CN(C)C/C=C/C(=O)Cl
Reactant: Nc1cccc(Nc2cc(Oc3ccc(F)c(Cl)c3)ncn2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Oc3ccc(F)c(Cl)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (155 mg, 1.2 mmol) was added dropwise to a mixture of 4-N,N-dimethyl aminocrotonic acid HCl salt (200 mg, 1.2 mmol) in 5 mL of THF at 0° C. To this mixture was added 3 drops of DMF/THF solution (made from 5 drops of DMF in 1 mL of THF). The reaction mixture was stirred at RT for 2 h, then was cooled to 0° C. ice bath. A solution of N1-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-yl)benzene-1,3-diamine (200 mg, 0.6 mmol) 2 mL of NMP) was added to the dimethylaminocrotonyl chloride solution and the resulting mixture was stirred for 3 h at 0° C. The reaction was quenched with 3 mL of 1N NaOH, and was extracted with EtOAc (2×25 mL). The crude product mixture was purified by flash chromatography on silica gel with MeOH/NH4OH/DCM solvent system to afford (E)-N-(3-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-ylamino)phenyl)-4-(dimethylamino)but-2-enamide (I-92) as a light colored solid. MS (m/z): MH+=442, 444 (3:1), H-NMR (DMSO) δ 10.08 (s, 1H), 9.67 (s, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 7.59 (d, 1H), 7.57 (t, 1H), 7.53-7.24 (m, 4H), 6.29 (b, 1H), 6.23 (s, 1H), 3.51 (d, 2H), 2.21 (s, 6H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](=O)[N:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:13][C:9]=3[C:8]([CH2:21][CH3:22])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]1([N:6]2[C:10]3[CH2:11][N:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:13][C:9]=3[C:8]([CH2:21][CH3:22])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c2c1CN(c1ccccc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCc1nn(C2CCCC2)c2c1CN(c1ccccc1)C2
Temperature: 0 °C
Yield: 61.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-3-ethyl-6-oxo-5-phenyl-4,6-dihydro-1H-pyrazolo[3,4-c]pyrrole (0.17 g, 0.58 mmole) in anhydrous ether (15 ml) was added lithium aluminum hydride (0.17 g, 4.6 mmole). The majority of the ether (12-13 ml) was then removed by distillation, and the remaining mixture diluted with toluene (25 ml) and heated to reflux over 24 hours. The mixture was cooled to 0° C. and cautiously treated with ice. The resulting mixture was filtered through celite, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was chromatographed on a silica column using 1:9 ethyl acetate/hexane as eluent to give 100 mg of a colorless oil. 1H NMR (250 MHz, CDCl3) δ 1.26 (t, J=7.6 Hz, 3H), 1.65-2.25 (m, 8H), 2.67 (q, J=7.6 Hz, 2H), 4.35 (s, 2H), 4.45 (s, 2H), 4.53 (pentet, J=7.5 Hz, 1H), 6.61 (d, J=8.1 Hz, 2H), 6.74 (t, J=7.4 Hz, 1H), 7.29 (dd, J=7.5 and 8.4 Hz, 2H); MS m/z 282.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[C:27]=2[F:36])[CH2:22][CH2:21]1>CN(C=O)C>[F:36][C:27]1[C:28]([F:35])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=[CH:31][C:26]=1[C@H:23]1[CH2:24][CH2:25][C@H:20]([CH2:19][O:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:21][CH2:22]1
Reactant: Oc1cccc(F)c1F
Reactant: CCOc1ccc(C2CCC(CCl)CC2)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([C@H]2CC[C@H](COc3cccc(F)c3F)CC2)c(F)c1F
Temperature: 70 °C
Reaction time: 7 h

Procedure:
2,3-Difluorophenol (46) (13.8 g) and tripotassium phosphate (K3PO4; 73.4 g) were added to DMF (200 ml) under a nitrogen atmosphere, and the mixture was stirred at 70° C. The compound (15) (20.0 g) was added thereto and the stirring was continued at 70° C. for 7 hours. After the reaction mixture obtained had been cooled to 30° C., solids were separated by filtration, and then toluene (100 ml) and water (100 ml) were added to and mixed with the filtrate. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from a mixed solvent of Solmix A-11 and ethyl acetate (Solmix A-11:ethyl acetate=2:1 by volume) and dried, giving 19.8 g of 2,3-difluoro-4-ethoxy-[trans-4-(2,3-difluorophenoxymethyl)cyclohexyl]benzene (47). The yield based on the compound (15) was 74.8%.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:49])[CH2:14][C@@:15]1([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[O:34])[C@H:19]([CH3:20])[CH2:18][N:17]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:32])[CH2:16]1)(C)(C)C>ClCCl>[Cl:32][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:29])([F:31])[F:30])[C:22]=1[CH2:21][N:17]1[CH2:18][C@@H:19]([CH3:20])[C@@:15]([CH2:14][C:13]([OH:49])=[O:12])([C:33](=[O:34])[NH:35][CH:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]2)[CH2:16]1
Reactant: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)O)C(=O)NC1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 117.2 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 5c (82 mg, 0.133 mmol) in dichloromethane (dehydrated) (3 mL) under ice-cooling, followed by stirring at room temperature for 2.5 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (elution solvent: water/methanol) to give the title compound (72 mg, yield: quant.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.C(O)(=O)C>[Zn].O>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=1[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: Brc1ccc2noc(-c3ccccc3)c2c1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 80 °C
Yield: 94 %

Procedure:
5-Bromo-3-phenyl-2,1-benzisoxazole (7.5 g, 28.6 mmol), water (14.6 ml), and zinc dust (9.3 g, 143 mmol) were combined. Acetic acid (8.6 ml, 143 mmol) was added and the mixture was stirred and heated at 80° C. for 90 minutes. After cooling to room temperature, both the liquid and solid portion of the reaction were extracted with methylene chloride. The combined methylene chloride solutions was washed once with sodium hydroxide solution (10%) and several times with water. Drying (sodium sulfate) and evaporation yielded the desired product (7.42 g) of mp. 92°-102° C.
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.OO.[F:16][C:17]([F:47])([C:43]([F:46])([F:45])[F:44])[C:18]([F:42])([F:41])[C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([I:28])([F:27])[F:26]>FC(F)(F)C(O)=O>[F:8][C:7]([F:10])([F:9])[C:6]([O:11][I:28]([O:5][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[C:25]([F:27])([F:26])[C:24]([F:30])([F:29])[C:23]([F:32])([F:31])[C:22]([F:34])([F:33])[C:21]([F:36])([F:35])[C:20]([F:37])([F:38])[C:19]([F:40])([F:39])[C:18]([F:41])([F:42])[C:17]([F:47])([F:16])[C:43]([F:44])([F:45])[F:46])=[O:5]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: O=C(O)C(F)(F)F
Product: O=C(OI(OC(=O)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
To a mixture of 10.6 ml (75.2 mmols) of trifluoroacetic anhydride and 30 ml of trifluoroacetic acid was added dropwise 1.36 ml of a 35% aqueous hydrogen peroxide solution (H2O2, 15.7 mmols and H2O, 55 mmols) in an ice bath. After completion of addition, the mixture was stirred for 1.5 hour and 5.0 g (7.7 mmols) of heneicosafluoro-n-decyl iodide was added thereto, followed by allowing the mixture to react at 0° to 5° C. for 24 hours. The solvent was then distilled off to obtain 6.3 g (94% yield) of di(trifluoroacetoxy)iodoheneicosafluoro-n-decane as white fluffy crystals.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C@H:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH2:7][C:8](OC)=[O:9])[CH3:3]>CO>[CH3:1][CH:2]([N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C@H:5]1[C:12]([O:14][CH3:15])=[O:13])[CH3:3]
Reactant: COC(=O)CC[C@H](NC(C)C)C(=O)OC
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)N1C(C)C
Temperature: 140 °C
Yield: 89.1 %

Procedure:
Dimethyl N-(1-methylethyl)-glutamate (0.200 g) was dissolved in methanol and heated in a sealed tube in a microwave reactor at 140° C. for 20 minutes. Thin-layer chromatography indicated that the starting material remained intact so the solvent was evaporated and replaced with toluene. The mixture was heated at reflux temperature for ˜3 hrs and then evaporated to give methyl 1-(1-methylethyl)-5-oxo-prolinate (0.152 g) as a light yellow oil which was used in the subsequent step without further purification.