Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+].C(O)(=O)/C=C/C(O)=O.[NH2:31][CH2:32][CH2:33][C:34]#[N:35]>O.C(Cl)(Cl)Cl>[C:32]([CH2:33][CH2:34][NH:35][C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:16])#[N:31]
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: N#CCCN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)NCCC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
4'-methylbiphenyl-2-carboxylic acid (50.00 g, 0.236 mol,), thionyl chloride (87.5 ml, 1.20 mol) and chloroform (500 ml) were mixed and refluxed for 4 hours. The thionyl chloride and solvent were removed in vacuo, and the residue suspended in toluene (300 ml). The mixture was evaporated in vacuo and the residue suspended once more in toluene and evaporated to insure removal of traces of thionyl chloride. The resultant acid chloride was dissolved in tetrahydrofuran (100 ml) and slowly added in five equal portions alternatingly with five equal portions of 1.0N NaOH (236.0 ml, 0.236 mol) to a solution of β-aminopropionitrile fumarate (30.3 g, 0.236 mol) in 1.0 N NaOH (236.0 ml, 0.236 mol) at 0° with stirring. The reaction was allowed to warm slowly to room temperature. After 24 hrs, water (500 ml) was added and the aqueous mixture extracted with ethyl acetate (3×500 ml). The organic layers were combined and dried (MgSO4), and the solvent removed in vacuo to yield a crude solid which, after recrystallization from methylcyclohexane/butyl chloride, yielded 53.5 g of a white solid. M.P.=102.0°-103.5°. NMR (200 MHz, CDCl3) δ: 7.68 (d, 1H, J=7Hz); 7.56-7.19 (m, 7H); 5.65 (bm, 1H); 3.43 (d of t, 2H); 2.39 (t, 2H, J=7Hz). Anal. calcd. for C17H16N2O; C, 77.25; H, 6.10; N, 10.60. Found: C, 77.42; H, 6.40; N, 10.68.
Reaction SMILES: N[C@H:2]([C:7](O)=O)[CH2:3][C:4](=O)O.N[C@H:11]([C:13](O)=O)[CH3:12].[NH2:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20]>>[NH2:16][C@H:17]([C:22]([O:24][CH2:7][C:2]1[CH:13]=[CH:11][CH:12]=[CH:4][CH:3]=1)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1

Procedure:
Anal. for amino acids [6-N HCl, 110° C., hydrolysis for 24 hours; figures in parentheses show theoretical values.]: Asp 2.00(2); Ala 1.06(1); Leu 2.11(2) LSIMS (M+H+)=714, (theoretical value)=714
Reaction SMILES: [CH3:1]C(C=O)=O.C(OC([NH:13][NH:14][C:15]([C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24])=[NH:16])=O)(C)(C)C.[CH2:25](O)[CH3:26]>>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:15]1[N:14]=[N:13][C:25]([CH3:26])=[CH:1][N:16]=1
Reactant: CC(C)(C)OC(=O)NNC(=N)c1c(F)cccc1F
Reactant: CC(=O)C=O
Reactant: CCO
Product: Cc1cnc(-c2c(F)cccc2F)nn1
Reaction time: 16 h

Procedure:
1.89 g of methylglyoxal (40% in water) are added to 2.71 g of N′-[(2,6-difluorophenyl)-iminomethyl]-hydrazinecarboxylic acid tert-butyl ester in 30 ml of ethanol and stirring is carried out at room temperature for 16 h. The reaction mixture is then concentrated, and the residue is taken up in 20 ml of formic acid and stirring is continued at room temperature for 5 h. The reaction mixture is concentrated by evaporation; the residue is again dissolved in 20 ml of ethanol, boiled under reflux for 2 h, then concentrated and purified by means of column chromatography. In this way 3-(2,6-difluorophenyl)-6-methyl-[1,2,4]triazine having a melting point of 90-93° C. is obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.C(O[BH-](O[C:36](=[O:38])[CH3:37])OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:12][C:8]2[N:7]([CH2:6][O:38][CH2:36][CH2:37][Si:2]([CH3:1])([CH3:14])[CH3:3])[CH:11]=[CH:10][N:9]=2)[CH2:12][C:8]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[CH:11]=[CH:10][N:9]=2)=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CN(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde (CAS Registry Number: 101226-42-0, 1.5 g) and {[4-(methyloxy)phenyl]methyl}amine (0.39 mL) in dichloromethane (containing 1% acetic acid) (10 mL), sodium triacetoxyborohydride (1.91 g) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was added by an aqueous 1 N sodium hydroxide solution and then extracted with dichloromethane. The extract thus obtained was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol:triethylamine=1:0:0→10:1:0→10:1:0.1) to obtain the title compound (1.71 g) having the following physical properties.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[OH:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][NH2:25]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][OH:28])[CH2:21][CH2:20][OH:19])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCN(CCO)CCO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1NCCN(CCO)CCO
Temperature: 80 °C
Yield: 41.1 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 30 ml of N-methylpyrrolidinone, 2.29 g of N,N-bis(2-hydroxyethyl)ethylenediamine, and 1.72 g of triethylamine. The reaction medium was heated at 80° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 1.5 g of 2[[2-(4-nitro-2-methylphenylamino)ethyl]-(2-hydroxyethyl)amino]ethanol (17) were obtained.
Reaction SMILES: [CH2:1]([C:3]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[C:17]([CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)#[N:18]>O1CCOCC1>[C:17]([CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:15][CH2:14][C:13]([NH:12][C:3]([CH2:4][CH3:5])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:1][CH3:2])=[O:16])[CH:24]=1)#[N:18]
Reactant: N#CCc1c[nH]cn1
Reactant: C=CC(=O)NC(CC)(CC)c1ccccc1
Solvent: C1COCCO1
Product: CCC(CC)(NC(=O)CCn1cnc(CC#N)c1)c1ccccc1

Procedure:
In a similar manner to Example 24, N-(l-ethyl-1-phenylpropyl)acrylamide (6.1 g) and 4-cyanomethylimidazole (3.0 g, Sigma Chemicals) were reacted in 1,4-dioxane (60 ml) in the presence of Triton B (0.8 ml) to give 3-[4-(cyanomethyl)imidazol-1-yl]-N-(1-ethyl-1-phenylpropyl)propionamide, m.p. 121-122° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Br:24])[CH:17]=2)[C:7]=1[F:25])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([O:15][C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Br:24])[CH:17]=2)[C:7]=1[F:25])[CH3:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(Oc2cc(Br)cc(C#N)c2)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(N)c(Oc2cc(Br)cc(C#N)c2)c1F
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of ester (117a, 4.34 g, 10.26 mmol), Fe powder (2.40 g, 43.07 mmol), and NH4Cl (2.30 g, 43.07 mmol) in EtOH (80 mL) and H2O (40 mL) was heated to reflux for 2 h. The solution was cooled to RT and filtered through CELITE®. The filter cake was washed with EtOAc (200 mL), the aqueous and organic layers were separated, and the organic layer was washed with brine (2×60 mL). The solution was dried with anhydrous MgSO4, and evaporated to provide 3.98 g (98%) of the [4-amino-3-(3-bromo-5-cyano-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (117b).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.[CH2:9]([C:16]1[S:20][C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C@H:29]([NH:34][CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:37]1)[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O>[CH2:9]([C:16]1[S:20][C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C@H:29]([N:34]([CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38]([C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[CH2:37]1)[C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:8])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reactant: O=C(O)[C@@H]1CCCO1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)C(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
The solution of (S)-(−)-2-tetrahydrofuroic acid (50 mg, 0.43 mmol) in thionyl chloride (0.5 mL) was refluxed for 30 min, and the volatile materials were completely concentrated in vacuo. The crude product was then dissolved in dichloromethane (0.3 mL), which was then added to a solution of (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (40 mg, 0.066 mmol) and N,N-diisopropylethylamine (34 μL, 0.197 mmol). After the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the desired (3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (30 mg, 64.6%). LC/MS (uplc): MH+ 706.0, 1.40 min.
Reaction SMILES: C1CC(=C(F)CNC2CCN([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)CC2)CC1.[CH:23]12[CH2:29][CH:26]([CH:27]=[CH:28]1)[CH2:25][CH:24]2[CH2:30][OH:31].[OH-].[K+].[CH2:34](Br)CCCCCCC>O.CS(C)=O>[CH2:30]([O:31][CH2:34][C:18]12[CH2:14][CH:15]([CH2:20][CH2:19]1)[CH:16]=[CH:17]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:23][CH3:29]
Reactant: OCC1CC2C=CC1C2
Reactant: FC(CNC1CCN(Cc2ccccc2)CC1)=C1CCCC1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCOCC12C=CC(CC1)C2
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 9.7g (0.075 mol) of 5-norbornene-2-methanol, and 25 ml of DMSO. Potassium hydroxide (7.3g, 85% in purity; 0.13 mol) was added to the above mixture. After the above mixture was reacted at room temperature for 4 hrs., 15.9 g (0.15 mol) of n-octylbromide was slowly added to the above mixture over 25 min. The reaction was carried out at 80° C. for 3.3. hrs. After the reaction mixture was cooled to room temperature, the reaction mixture was combined with water (100 mL), extracted with chloroform (2×150 mL), washed with water (2×100 mL), and dried with sodium sulfate. The solvent was evaporated and the residue was vacuum distilled to give pure product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:38][C:39]1[C:40]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=2)=[O:46])=[N:41][CH:42]=[CH:43][CH:44]=1>ClCCl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[CH:20][C:16]=2[C:17]([NH:38][C:39]2[C:40]([C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=3)=[O:46])=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:19])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CSc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoic acid (201 mg, 0.55 mmol) was diluted with dichloromethane (5 mL), pyridine (52 μL, 0.64 mmol), and DMF (2 drops). Oxalyl chloride (52 μL, 0.60 mmol) was added and vigorous bubbling occurred. After about 30 minutes, the reaction was concentrated in vacuo. The residue was diluted with dichloromethane (5 mL) and the 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (123 mg, 0.50 mmol) was added, followed by pyridine (72 μL, 0.64 mmol). The reaction was stirred overnight and then diluted with dichloromethane (50 mL) and washed with water (3×5 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (CH2Cl2 through 5% EtOAc/CH2Cl2) to give the desired product as a pale yellow amorphous solid (214 mg, 0.36 mmol, 72%).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][C:14]1[N:15]=[C:16]([CH2:19][C:20]([CH3:22])=O)[S:17][CH:18]=1.[NH2:23]/[C:24](/[CH3:28])=[CH:25]\[C:26]#[N:27]>C(O)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:19]([C:16]3[S:17][CH:18]=[C:14]([CH3:13])[N:15]=3)=[C:20]([CH3:22])[NH:23][C:24]([CH3:28])=[C:25]2[C:26]#[N:27])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: CC(=O)Cc1nc(C)cs1
Reactant: COc1cc(C#N)ccc1C=O
Reactant: C/C(N)=C/C#N
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C)NC(C)=C1c1nc(C)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
800 mg (4.96 mmol) of the compound from example 3A, 770 mg (4.96 mmol) of the compound from example 4A and 407 mg (4.96 mmol) of 3-aminocrotononitrile are dissolved in 12 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is taken up in 20 ml of ethyl acetate. After stirring at the reflux temperature for 60 min, the resulting solid is filtered off hot. The precipitate obtained in this way is washed with a little diethyl ether. 720 mg (40% of theory) of the title compound are obtained.
Reaction SMILES: C1OC2C(C3C4OCOC=4C=CC=3P(C3C=CC=CC=3)C3C=CC=CC=3)=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2O1.O(C(C)(C)C)[Na].C1(C)C=CC=CC=1.[O:58]=[C:59]1[CH2:66][C:63]([CH3:65])([CH3:64])[CH2:62][C:61]([CH3:67])=[CH:60]1>[Cu].CC(O)(C)C>[CH3:64][C:63]1([CH3:65])[CH2:62][CH:61]([CH3:67])[CH2:60][C:59](=[O:58])[CH2:66]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: [Cu]
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccc3c(c2-c2c(P(c4ccccc4)c4ccccc4)ccc4c2OCO4)OCO3)cc1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC1CC(=O)CC(C)(C)C1
Temperature: 50 °C
Reaction time: 17 h
Yield: 18 %

Procedure:
Into a 100-mL stainless-steel autoclave was put 22.6 mmol (0.03 mmol; Cu reduced) of the chiral copper complex [CuBr((S)-SEGPHOS)]n obtained in the same manner as described in Example 1, 18.3 mg (0.03 mmol) of (S)-SEGPHOS and 28.8 mg (0.30 mmol) of NaO-t-Bu, followed by replacing with nitrogen in the autoclave, and then 2 mL of a mixed solvent of toluene and t-BuOH in a ratio of 3:1, and isophorone 1 (0.15 mL, 1 mmol) were added. The reaction was carried out with stirring under a hydrogen pressure of 5.0 MPa at 50° C. for 17 hours. The reaction mixture was analyzed by using GC. The results indicated that the products shown in the scheme A, that is, 3,3,5-trimethylcyclohexanone 2 was obtained in a yield of 18% (optical purity 93% ee), 3,3,5-trimethylcyclohexanol 3 was obtained in a yield of 61% (dr: 93/7, optical purity of main diastereomer: 95% ee), and 3,3,5-trimethyl-2-cyclohexenol 4 was obtained in a trace amount, respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][CH2:7][CH:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:5]2.[H][H]>[Pd].C(O)C>[NH2:12][C:10]1[CH:11]=[CH:2][CH:3]=[C:4]2[C:9]=1[NH:8][CH2:7][CH:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NC1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CNc2c(N)cccc2C1
Yield: 103.3 %

Procedure:
A mixture of t-butyl (6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolinyl)-carbamate (3.72 g, 0.01 mol), absolute ethanol (150 mL) and 10% palladium on carbon (0.60 g) was hydrogenated (50 lb hydrogen pressure) for 18 hours. The mixture was filtered through celite and the solvent removed. The residual foam was partitioned between ethyl acetate and 1 N sodium hydroxide, and the ethyl acetate phase was evaporated under reduced pressure to give 2.72 g of t-butyl (8-amino-1,2,3,4-tetrahydro-3-quinolyl)carbamate (compound XXXII) as an oil.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([O:27]CC)=[O:26])[C:4]=1[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:2].O.[OH-].[Li+].O>O1CCCC1.CO>[C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([OH:27])=[O:26])[C:4]=1[CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]1)#[N:2]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c(C2CCCC2)n1CC(=O)O
Yield: 96.8 %

Procedure:
General procedure I was followed using ethyl 2-(3-cyano-2-cyclopentyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (747 mg, 1.55 mmol) and lithium hydroxide monohydrate (130 mg, 3.09 mmol) in tetrahydrofuran (9.3 mL), methanol (3.1 mL), and water (3.1 mL). The product 2-(3-cyano-2-cyclopentyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid (685 mg, 1.50 mmol, 97% yield) was isolated as a tan solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.99 (dd, 1H), 7.42 (ddd, 1H), 7.31 (dd, 1H), 7.00 (d, 1H), 4.65 (s, 2H), 4.30 (s, 2H), 3.32-3.36 (m, 4H), 2.94 (m, 1H), 1.87-2.04 (m, 13H, composite of multiple shifts), 1.59-1.70 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][C:9]([CH3:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:7]2[N:22]=[CH:23][C:24]([C:25]#[N:26])=[C:6]12)=[O:4].[Cl:27][C:28]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:29]=1[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[ClH:1].[Cl:41][C:37]1[CH:38]=[CH:39][CH:40]=[C:28]([Cl:27])[C:29]=1[CH2:30][N:31]1[CH2:32][CH2:33][N:34]([CH2:2][C:3]([N:5]2[CH2:10][C:9]([CH3:11])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=3)[N:7]3[N:22]=[CH:23][C:24]([C:25]#[N:26])=[C:6]23)=[O:4])[CH2:35][CH2:36]1
Reactant: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Reactant: Clc1cccc(Cl)c1CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3c(Cl)cccc3Cl)CC2)C1
Product: Cl

Procedure:
A mixture of 1 g of 4-(chloroacetyl)-7-[3-(trifluoromethyl)phenyl]-4,5-dihydro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, 1 g of 2,6-dichlorobenzylpiperazine, 600 mg of potassium carbonate and 100 ml of toluene was reacted as described in Example 16, giving the base form of the product, which was converted to the hydrochloride salt by the procedure of Example 97, giving 1.66 g, mp 252°-254° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4]C.Cl.Cl.Cl.[CH2:9]([NH:17][C:18]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[NH:22])=[NH:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)CCC>[C:3]([OH:4])(=[O:2])[CH3:9].[CH2:24]([NH:23][C:21]1[NH:20][C:18]([NH:17][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:19][CH2:1][N:22]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCNC(=N)NC(=N)NCCCCCCCC
Reactant: COCOC
Agent: Cl
Solvent: CCCCO
Product: CC(=O)O
Product: CCCCCCCCNC1=NCN=C(NCCCCCCCC)N1
Yield: 72.4 %

Procedure:
200 ml of butanol, 13 ml (0.15 mol) of methylal and 1.2 ml of concentrated hydrochloric acid were added to 5.8 g (14.6 mmol) of N1,N5-dioctyl-biguanide dihydrochloride, and the mixture was refluxed for 28 hours. The solvent was distilled off under reduced pressure. To the residue were added 50 ml of ethanol, 30 ml of water, and 5.9 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed successively with 10% aqueous sodium acetate andwater, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methyl ethyl ketone to obtain 2.1 g of colorless crystals having a melting point of 117 to 121° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([B-](F)(F)F)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[K+].Cl[C:22]1[C:27]2[O:28][CH:29]([CH3:33])[C:30](=[O:32])[NH:31][C:26]=2[CH:25]=[C:24]([CH:34]=[O:35])[CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O.CC(O)C>[CH2:9]([C:22]1[C:27]2[O:28][CH:29]([CH3:33])[C:30](=[O:32])[NH:31][C:26]=2[CH:25]=[C:24]([CH:34]=[O:35])[CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Reactant: F[B-](F)(F)Cc1ccccc1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC1Oc2c(Cc3ccccc3)cc(C=O)cc2NC1=O
Temperature: 115 °C
Reaction time: 20 h
Yield: 28.2 %

Procedure:
To a suspension of potassium phosphate, tribasic (0.564 g, 2.66 mmol), potassium benzyltrifluoroborate (0.263 g, 1.330 mmol), 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.2 g, 0.886 mmol) in toluene (Ratio: 5.00, 20 mL) and water (Ratio: 1.000, 4.0 mL) was added PdOAc2 (0.015 g, 0.066 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.062 g, 0.133 mmol) at 23° C. The reaction was stirred at 115° C. for 20 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was reconstituted in DCM (1.0 mL) and purified via medium pressure chromatography using a gradient eluant of 1-5% MeOH:DCM. The appropriate fractions were combined and solvent was removed via rotary evaporation. The late eluting fractions were dried in vacuo to provide a yellow solid. The yellow solid was re-suspended in IPA (1.0 mL), heated at reflux to furnish a solution, cooled to room temperature, filtered, rinsed with IPA, and dried in vacuo to provide the title compound as an off-white solid (0.0704 g, 0.250 mmol, 28.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.82 Hz, 3H) 3.98 (s, 2H) 4.75-4.81 (m, 1H) 7.16-7.32 (m, 6H) 7.45 (d, J=2.02 Hz, 1H) 9.80 (s, 1H) 10.93 (s, 1H). ESI-MS: m/z 282.2 (M+H)+. mp=163.2-166.1° C.