Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(C(F)(F)F)C(F)(F)C(S(O[CH2:41][C:42]([F:56])([F:55])[O:43][C:44]([F:54])([F:53])[C:45]([O:48][C:49]([F:52])([F:51])[F:50])([F:47])[F:46])(=O)=O)(F)F.O>CS(C)=O.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:41][C:42]([F:55])([F:56])[O:43][C:44]([F:53])([F:54])[C:45]([O:48][C:49]([F:50])([F:51])[F:52])([F:47])[F:46])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(OCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
0.5 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 10 mL of dimethylsulfoxide, and 0.28 g of potassium carbonate and 1.0 g of 2,2-difluoro-2-{2-trifluoromethoxy-(1,1,2,2-tetrafluoroethoxy)}ethyl nonafluorobutylsulfonate were added, followed by stirring at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water, extraction with ethyl acetate was carried out, and after washing with a saturated salt solution, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:4) to obtain 0.67 g of 5-acetylamino-3-[2,2-difluoro-2-{2-trifluoromethoxy-(1,1,2,2-tetrafluoroethoxy)}ethoxy]-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:13]([CH3:18])[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:13]([CH3:18])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of methyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]propionate (1.05 g, 2.89 mmol) in tetrahydrofuran (60 mL) at room temperature is added 1N aqueous sodium hydroxide (8.6 mL, 8.67 mmol). The reaction mixture is stirred for 19 hours at room temperature. The tetrohydrofuran is then evaporated. The remaining residue is acidified with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated to give 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]propionic acid.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Cl[CH:22](Cl)[C:23]([OH:25])=[O:24].[CH:27]1([C:33]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)([OH:46])[C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH:44]=[CH:43][CH:42]=[CH:41]3)=[CH:36][C:35]=2[OH:45])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCOCC1>[CH:47]1([C:33]2([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH:44]=[CH:43][CH:42]=[CH:41]4)=[CH:36][C:35]=3[O:45][CH:22]([C:23]([OH:25])=[O:24])[O:46]2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(O)C(Cl)Cl
Reactant: Oc1cc(-n2cccc2)ccc1C(O)(C1CCCCC1)C1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1Oc2cc(-n3cccc3)ccc2C(C2CCCCC2)(C2CCCCC2)O1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a suspension of 228 mg of NaH (60% dispersion in mineral oil) and 18 mg of 18-crown-6 ether in 8 ml of anhydrous dioxane, a solution of 2.3 ml of a solution of dichloroacetic acid (1 M) in anhydrous dioxane was slowly added at room temperature. The reaction mixture was heated to 60° C. and a solution of 504 mg of 2-(Dicyclohexyl-hydroxy-methyl)-5-pyrrol-1-yl-phenol in 6 mL anhydrous dioxane was added and stirred at 95° C. for 6 h. After cooling to 0° C., the reaction mixture was quenched with 2 ml of isopropanol and poured on ice. The aqueous phase was extracted with ether, then acidified with HCl (2 M, to pH 1), and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 118 mg.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].[OH-].[Na+].S([O-])([O-])(=O)=O.[NH4+:26].[NH4+:27].Cl.S1C=CC=CC1.[OH:35][C:36]([CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H]2[C@@H](NC(N2)=O)CS1)=[O:37]>[Pt]>[NH2:26][C@H:38]([C:36]([OH:35])=[O:37])[CH2:39][CH2:40][CH2:41][CH2:42][NH2:27]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: [NH4+]
Agent: [Pt]
Agent: C1=CCSC=C1
Agent: Cl
Product: NCCCC[C@H](N)C(=O)O
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A medium containing 45 g/L of glucose, 15 g/L of molasses, 2 g/L (as nitrogen) of soybean protein hydrolysate, 2 g/L of KH2PO4, 5.6 g/L of NaOH, 10 g/L of ammonium sulfate, 0.8 g/L of MgSO4.7H2O, 20 mg/L of FeSO4.7H2O, 20 mg/L of MnSO4.4H2O, 0.8 mg/L of thiamin hydrochloride and 0.2 mg/L of biotin (pH 6.0) was introduced into 1-L volume small glass fermentation tank in a volume of 300 mL and sterilized by heating at 120° C. for 20 minutes. After the fermentation tank was cooled to 31.5° C, 5 platinum loops of Brevibacterium lactofermentum ATCC 31269 (refer to U.S. Pat. No. 4,066,501) preliminarily grown on an LB plate for 24 hours was inoculated to the medium and cultured at 31.5° C. and pH 7.0 for 30 hours with sufficient aeration and stirring.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[C:6]#[N:7]>C(OCC)(=O)C.[Pd]>[NH2:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To the suspension of 3-methoxy-4-nitrobenzonitrile (11.4 g, 64 mmol) in ethyl acetate (60 mL) was added 10% Pd/C (1 g). The reaction mixture was vigorously shaken in a Parr under an atmosphere of hydrogen (50 psi) at room temperature for 45 min. The mixture was filtered through a short pad of celite, and the filtrate was concentrated to give 4-amino-3-methoxy-benzonitrile as a yellow oil, which solidified at stand (9.5 g, 95%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH2:3]1.[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C(=O)C.ClCCl.O.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][CH:2]2[CH2:7][CH2:6][C:5]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH2:3]2)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1cccc(C2=CCC(N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc(C2=CCC(NC(=O)c3nc(Cl)c(CC)[nH]3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Ethyl 3-(4-aminocyclohex-1-enyl)benzoate obtained in Example (951c) (120 mg, 0.49 mmol) was dissolved in a mixed solution of N,N-dimethylacetamide/dichloromethane=1/1 (10 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 86 mg, 0.49 mmol), 1-hydroxybenzotriazole (100 mg, 0.735 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (141 mg, 0.735 mmol) and triethylamine (102 μL, 0.735 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 150 mg of the title compound as a white solid (76%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][N:12]=[N+]=[N-])=[N+]=[N-]>C1COCC1.[Pt]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH2:12]
Reactant: [N-]=[N+]=NCCOCCOCCN=[N+]=[N-]
Agent: [Pt]
Solvent: C1CCOC1
Product: NCCOCCOCCN
Reaction time: 12 h

Procedure:
To a solution of diazide 19 (14.67 g, 0.073 mol) in THF (100 ml) 1.5 g of 5% Pt on charcoal is added. The mixture is stirred for 12 h under hydrogen. Filtration through Celite™ and evaporation of solvents at reduced pressure gives 1,8-diamino-3,6-dioxa-octane 20.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[CH:15]([C:21]([OH:23])=[O:22])[C:16]([CH3:20])(Br)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.ClCCl.S(Cl)(Cl)=O>ClC(Cl)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH3:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(Br)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
A solution of 7-(2-phenoxyacetamido)-3-methyl-3-bromocepham-4-carboxylic acid (860 mg.) in dry dichloroethane (20 cc) was cooled at -40°--50° C. and pyridine and a 10% dichloromethane solution (4.7 g.) of thionyl chloride were respectively added thereto. The mixture was stirred at -40°--50° C. for one hour and then at room temperature overnight, an poured into ice water and stirred for 30 minutes. The dichloroethane layer was extracted with an aqueous sodium bicarbonate solution and the aqueous layer was acidified with phosphoric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, treated with carbon powder and then concentrated to yield crystals (80 mg.) of 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylic acid, m.p. 172°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[C:13](=[O:33])[CH2:12]1)(=[O:10])=[O:9].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH:13]([OH:33])[CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1CN(S(=O)(=O)c2ccccc2Cl)CCC12CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of rac-8-(2-chloro-benzenesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,6-dione (34 mg, 67.6 μmol) in methanol was added sodium borohydride (2.81 mg, 74.4 μmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with 1N NaOH and diluted with further 1N NaOH and ethyl acetate. The organic layer was separated washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography to give the title compound as an off white solid (5 mg, 15%) MS (ESI): 505.1 (MH+)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][C:5]=1[NH2:6])([O-])=O>C(O)C.[Pd]>[F:11][C:9]1[C:8]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1
Reactant: Nc1cc(N2CCNCC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(N2CCNCC2)cc1N
Yield: 97.2 %

Procedure:
The nitroaniline derivative (5.6 g, 0.023 mol) (obtained in step 1 above) was hydrogenated using 10% Pd-C (1.0 g) in ethanol (25 mL), using a procedure analogous to that described in preparation 1 (step 4) to yield 4-fluoro-5-(piperazin-1-yl)-1,2-phenylenediamine (4.7 g, 98%) as a brown viscous oil. IR (Neat) 3283 cm-1 ; 1H NMR (CDCl3) δ 2.80 (brs, 5H, NH), 2.94 (m, 4H, N(CH2)2), 3.06 (m, 4H, N(CH2)2), 6.42 (d, J=7.8 Hz, 1H), 6.47 (d, J=12.4 Hz, 1H); Mass (m/z) 210 (M+.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26](=[O:43])[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:28]([CH2:27][C:26]([NH:25][CH3:24])=[O:43])[CH:29]=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CNC(=O)Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CNC(=O)Cc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (Stage 228.1.1) to give the title compound as an off-white foam. (HPLC: tR 1.97 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.55-8.53 (m, 1H), 8.45-8.43 (m, 1H), 8.16-8.12 (m, 2H), 8.07-8.01 (m, 1H), 7.95-7.90 (m, 1H), 7.77-7.74 (m, 1H), 7.59-7.57 (m, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.51 (s, 2H), 2.60 (d, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=O)=[C:9]([C:21]#[N:22])[C:8]([CH2:23][CH3:24])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:25](C)[Na].OO>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:22][C:21](=[O:25])[C:9]3=[C:8]([CH2:23][CH3:24])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[Na]
Reactant: CCc1nn(C2CCCC2)c(NC(=O)Cc2ccncc2)c1C#N
Agent: OO
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-4-cyano-5-[(4-pyridinylmethyl)carbonylamino]-1H-pyrazole (2.8 g, 8.6 mmol), ethanol (50 ml), NaOCH3 (1.0 g, 18 mmol) and 30% H2O2 (4.5 ml) was stirred at room temperature for 20 minutes, then was heated at reflux for 3.5 hours. Additional 30% H2O2 (3 ml) was added and the reaction mixture was heated at reflux for 2 more hours. The reaction mixture was concentrated in vacuo, the residue was partitioned between CHCl3 (100 ml) and 10% aqueous NaHCO (50 ml), and the organic layer was separated. The organic layer was concentrated in vacuo, and the residue was crystallized from cyclohexane and a solid was collected by filtration. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ether to 10% methanol/ether, followed by recrystallization from ether, to afford 420 mg of 1-cyclopentyl-3-ethyl-6-(4-pyridinylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 162-164° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 4-fluorobenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80°-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-fluoro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3cccc(C)c3C)c2O1

Procedure:
The title compound was prepared (0.046 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.23 mmol) and methylamine (0.072 g, 2.3 mmol). mp 197-199° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[O:22]1[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23]1>>[OH:22][CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: CC(C)C1CO1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Product: CC(C)C(O)COc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 24 with 1,2-epoxy-3-methylbutane gave 2-(2-(3-(2-hydroxy-3-methylbutoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.0 g, 76%): 1H NMR (400 MHz, CDCl3) δ 8.01-8.03 (m, 1H), 7.47-7.55 (m, 3H), 7.13-7.17 (m, 1H), 6.49-6.54 (m, 3H), 4.12 (t, J=5.6 Hz, 2H), 3.98-4.02 (m, 1H), 3.82-3.88 (m, 3H), 3.68-3.73 (m, 1H), 1.82-1.88 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](=[O:20])C)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[O-].[Na+].[OH-].[Na+].S([O-])([O-])=[O:27].[Na+].[Na+].S(=O)(=O)(O)O>O.O1CCOCC1>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=[O:27])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(C(C)=O)cc2C1
Reactant: O=S([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCC1Cc2ccc(C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
In a 3 liter-reaction vessel, 50 g (1.84×10-1M) of the above-prepared 2-octyl-5-acetylindan and 500 ml of 1,4-dioxane were placed and warmed to 25° C. To the mixture, a mixture solution of 482 g of 10% -sodium hypochlorite aqueous solution and 178 g of 25%-sodium hydroxide aqueous solution was added dropwise in 30 minutes at about 30° C., followed by stirring for 6 hours at 60° C. After the reaction, the reaction mixture was cooled to 40° C. and then a solution of 22 g of sodium sulfite in 750 ml of water was added thereto, followed by stirring for 30 minutes. To the resultant mixture, 380 ml of concentrated sulfuric acid was added to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by drying and recrystallization from ethanol to obtain 37.0 g of 2-octylindan-5-carboxylic acid.
Reaction SMILES: [BrH:1].[NH:2]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:3].[CH:9]([C@@H:11]1[C@:19]2([CH3:20])[C@@:14]([OH:27])([CH2:15][C@@H:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:18]2)[CH2:13][CH2:12]1)=O>O.O1CCOCC1>[BrH:1].[NH:8]1[CH2:7][CH2:6][N:5]=[C:4]1[NH:2]/[N:3]=[CH:9]/[C@@H:11]1[C@:19]2([CH3:20])[C@@:14]([OH:27])([CH2:15][C@@H:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)[CH2:13][CH2:12]1
Reactant: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2C=O
Reactant: NNC1=NCCN1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2/C=N/NC1=NCCN1
Reaction time: 2 h
Yield: 53.7 %

Procedure:
To a solution of 0.93 g of 2-hydrazino-2-imidazoline hydrobromide in 45 ml of water and 30 ml of dioxane a solution of 0.89 g of (1S,3aS,5S,7aR)-1-formyl-5-phenyl-7a-methylperhydroinden-3a-ol in 30 ml of dioxane was added dropwise at room temperature and the mixture was stirred for 2 hrs. The solution was evaporated to dryness under reduced pressure and the residue was ground with ethanol/water then with ethanol to give 0.78 g of the title compound (I-al) as a white solid.
Reaction SMILES: [C:1]([N:3]1[C@H:17]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[C:18]=3[C:15]([CH2:16]2)=[C:14]([CH:19]=[O:20])[NH:13]4)[CH2:6][C@@H:5]([C:21]([O:23][CH3:24])=[O:22])[CH2:4]1)#[N:2].[BH4-].[Na+]>C(#N)C>[CH3:24][O:23][C:21]([C@@H:5]1[CH2:6][C@H:7]2[C@@H:17]([CH2:16][C:15]3[C:18]4[C:12](=[CH:11][CH:10]=[CH:9][C:8]2=4)[NH:13][C:14]=3[CH2:19][OH:20])[N:3]([C:1]#[N:2])[CH2:4]1)=[O:22]
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C#N)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(CO)c(c34)C[C@H]2N(C#N)C1
Yield: 83 %

Procedure:
161 mg of 6-cyano-8beta-methoxycarbonyl-2-ergoline-carbaldehyde (5 mmol) is dissolved in 10 ml of acetonitrile and reduced with 30 ml of sodium borohydride at room temperature in 1 hour. The solvent is largely evaporated, acidified with 2N hydrochloric acid and with addition of aqueous sodium bicarbonate solution the substance is obtained, yield 83%.