Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[CH3:3][N:4]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([CH3:13])=[N:5]1>S(=O)(=O)(O)O>[I:1][C:7]1[C:6]([CH3:13])=[N:5][N:4]([CH3:3])[C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: II
Reactant: Cc1cc(C(F)(F)F)n(C)n1
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c(C(F)(F)F)c1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Iodine (30 g) was dissolved in 60% sulfuric acid (fuming, 80 g), and 1,3-dimethyl-5-trifluoromethylpyrazole (13.12 g, 80 mmol) was slowly added under ice-cooling. The mixture was stirred at 0° C. for 2 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained crude crystals were washed with hexane to give the desired compound (20 g) as crystals.
Reaction SMILES: C([C:6]1[C:7](=[O:17])[NH:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1[OH:16])(OCC)=O>Cl>[OH:16][C:15]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7](=[O:17])[CH:6]=1
Reactant: CCOC(=O)c1c(O)c2c([nH]c1=O)CCCC2
Agent: Cl
Product: O=c1cc(O)c2c([nH]1)CCCC2

Procedure:
A suspension of 3-carboethoxy-4-hydroxy-5,6,7,8-tetrahydro-carbostyril (19.4g; 0.082 mole) in 2N hydrochloric acid (200 ml) was refluxed 30 hrs. and the clear solution evaporated to dryness. Water was added and the solution brought to pH 4.0 with dilute sodium hydroxide solution. The precipitated white product was filtered off, washed well with water and recrystallised from glacial acetic acid, m.p. >330° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]=[N:8][N:7]=1)(=O)C.[OH-].[Li+].Cl>O.CO.O1CCCC1>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-n2nnnc2CO)cc1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
To a solution of [1-(4-cyanophenyl)-1H-tetrazol-5-yl]methyl acetate (2.48 g, 10.2 mmol, Intermediate 8) in water (15 mL), methanol (15 mL) and tetrahydrofuran (THF) (30 mL), cooled in an ice bath, was added lithium hydroxide (0.244 g, 10.2 mmol). The reaction mixture was stirred at 0-5° C. for 1.5 hours. The reaction mixture was acidified with the addition of 2N HCl (5.5 ml). The majority of the organic solvent was then removed from the reaction mixture under vacuum leading to precipitation of a white solid which was filtered then dried under vacuum at 40° C. for 18 hours to yield the title compound as a white solid (1.43 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]1)=[CH:8][CH:7]=[CH:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1)=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(N3CCN(CC#N)CC3)cccc2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(N3CCN(CCN)CC3)cccc2c1

Procedure:
A solution containing 4.2 g of the compound obtained in Stage C, in 25 ml of tetrahydrofuran is added dropwise at room temperature to a suspension, stirred under a nitrogen atmosphere, of 1.1 g of lithium aluminum hydride in 25 ml of tetrahydrofuran. Stirring is maintained for 20 minutes after the addition is complete, and the reaction medium is then hydrolyzed with the requisite quantity of water saturated with ammonium chloride. The precipitate formed is filtered off and washed with tetrahydrofuran, and the filtrates are concentrated under vacuum to yield an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([F:15])[C:3]=1[C:16]1[N:21]=[C:20]([C:22]([NH:24][C:25]2[C:26]([N:35]3[CH2:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([NH:42]C(=O)OC(C)(C)C)[CH2:36]3)=[C:27]3[CH2:33][CH2:32][CH:31]([OH:34])[C:28]3=[N:29][CH:30]=2)=[O:23])[CH:19]=[CH:18][C:17]=1[F:50].Cl.O1CCOCC1>>[NH2:42][C@H:37]1[CH2:38][C@@H:39]([CH3:41])[CH2:40][N:35]([C:26]2[C:25]([NH:24][C:22]([C:20]3[CH:19]=[CH:18][C:17]([F:50])=[C:16]([C:3]4[C:2]([F:1])=[CH:7][C:6]([O:8][CH:9]5[CH2:14][CH2:13][CH2:12][O:11][CH2:10]5)=[CH:5][C:4]=4[F:15])[N:21]=3)=[O:23])=[CH:30][N:29]=[C:28]3[CH:31]([OH:34])[CH2:32][CH2:33][C:27]=23)[CH2:36]1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(OC5CCCOC5)cc4F)n3)cnc3c2CCC3O)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(OC5CCCOC5)cc4F)n3)cnc3c2CCC3O)C1

Procedure:
The alcohol intermediate made above was treated with 4.0 M HCl in dioxane (1 mL, 5 mmol) at room temperature overnight. The solution was concentrated under reduced pressure and the resulting residue was purified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to give two separated diastereoisomers of the title compound as white powders.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][CH:30]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:29][CH:30]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:31](=[O:36])[C:32]([F:33])([F:34])[F:35])=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: O=C(O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F

Procedure:
To a solution of (5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)acetic acid (title compound in Reference Example 2, 8.57 g, 22.6 mmol) and 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 5.91 g, 27.2 mmol) in DMF (75 mL) were added WSCI hydrochloride (5.20 g, 27.2 mmol) and HOBT (6.10 g, 45.1 mmol). The resulting mixture was stirred at room temperature for 16 h, poured into 0.5N hydrochloric acid (500 mL), and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration of the extract was separated and purified by silica gel column chromatography (chloroform-ethyl acetate, 83:17) to give 11.4 g (87%) of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidyl)-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)-acetamide as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]1[CH3:33])=[O:4].[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[NH:45][C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1>>[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[N:45]([CH2:2][C:3]([N:5]4[CH2:10][CH2:9][N:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:18]([F:19])([F:21])[F:20])[C:22]([F:24])([F:25])[F:23])=[CH:13][C:12]=5[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]4[CH3:33])=[O:4])[C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1
Reactant: CC1(c2ccc3c(c2)CCO3)NC(=O)NC1=O
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@@H](C)C1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)CCO4)C2=O)[C@@H](C)C1

Procedure:
(S)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-(2,3-dihydrobenzofuran-5-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)=[O:12])=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[OH:30][C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1>O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]2[O:12][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[OH:30])=[O:5]
Reactant: CC(C)(CCl)NC(=O)c1c(S(C)(=O)=O)ccc(C(=O)Cl)c1Cl
Reactant: Cn1nccc1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NC(C)(C)CO3)c2Cl)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
At 15° C., 1.65 g (4.3 mmol) of 2-chloro-3-(1-chloro-2,2-dimethyleth-2-ylaminocarbonyl)-4-methylsulfonylbenzoyl chloride in 25 ml of dioxane and 0.45 g (4.5 mmol) of triethylamine in 10 ml of dioxane were added dropwise to a mixture of 0.42 g (4.3 mmol) of 5-hydroxy-1-methylpyrazole in 10 ml of dioxane. The mixture was stirred at room temperature for 4 hours and then filtered off through silica gel, which was rinsed with dioxane. The combined filtrates were concentrated to 60 ml and admixed with 1.24 g (9 mmol) of finely powdered potassium carbonate. The mixture was heated under reflux for 5 hours and cooled, the solvent was removed under reduced pressure, the residue was taken up in water, insoluble components were filtered off and the solution was acidified using 10% strength hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases were subsequently washed with water, dried and concentrated. 1.2 g (68% of theory) of 4-[2-chloro-3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[OH:16])[CH2:2][C:3]([CH3:5])=[CH2:4].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:16][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=1[CH2:1][CH2:2][C:3]([CH3:5])=[CH2:4])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)CCc1cc(OC)c(OC)cc1O
Solvent: c1ccncc1
Product: C=C(C)CCc1cc(OC)c(OC)cc1OC(C)=O

Procedure:
100 mg. of the phenol of Example 1 was combined with 2 ml. of pyridine and 1 ml. of acetic anhydride for one hour. The reaction mixture was extracted with ether and the ether extract washed sequentially with water, 1NHCl, water and saturated salt solution then dried over sodium sulfate. Upon evaporation 0.11 grams of the acetate was recovered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](OC)=[O:17])=[CH:12][C:11]=1[O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(OC2CCCCO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(CO)cc2OC2CCCCO2)c1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To 26.3 (1.61 g, 4.47 mmol) in THF (10 mL) at 0° C., was added LAH (1.0M solution in THF, 6.70 mL, 6.70 mmol). The reaction was stirred for one hour and then carefully diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to provide 26.4 (0.990 g, 66.7% yield).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:31]=[CH:30][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:18][CH:19]=3)=[O:13])=[CH:30][CH:31]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(F)cc3)cc2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)C3CC3)cc2)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A solution of cyclopropanecarbonyl chloride (Aldrich, 448 mg, 4.31 mmol) in 5 mL of methylene chloride was slowly added over 5 minutes to N-(4-(4-aminobenzoyl)phenyl)-4-fluorobenzamide (1.2 g, 3.59 mmol) in 20 mL of methylene chloride containing 3 mL of pyridine. The reaction was stirred at room temperature for 12 h then quenched with 40 mL of water. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were washed with 0.5 N HCl (100 mL), brine (100 mL), dried over sodium sulphate, and filtered. Concentration of the organics provided N-(4-(4-(cyclopropanecarboxamido)benzoyl)phenyl)-4-fluorobenzamide (1.3 g, 3.23 mmol) as a tan solid which was used without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH:17]=[O:18])=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:24])[CH2:10][C:11]([CH3:23])([CH3:22])[O:12]2)(=O)=O.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:7]2[C:16]([CH:17]=[O:18])=[C:15]([CH:19]([CH3:20])[CH3:21])[CH:14]=[C:13]3[C:8]=2[C:9](=[O:24])[CH2:10][C:11]([CH3:22])([CH3:23])[O:12]3)=[CH:30][CH:29]=1
Reactant: CC(C)c1cc2c(c(OS(=O)(=O)C(F)(F)F)c1C=O)C(=O)CC(C)(C)O2
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC(C)(C)O2
Temperature: 25 °C

Procedure:
A solution of 800 mg (2.03 mmol) of 6-formyl-7-isopropyl-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (Example 19A), 369 mg (2.64 mmol) of 4-fluorophenyl-boronic acid, 164 mg (142 μmol) of tetrakis(triphenylphosphine)palladium and 731 mg (3.45 mmol) of potassium carbonate and 10 ml of degassed dioxane is stirred at 100° C. overnight. After cooling to room temperature, ammonium chloride solution is added and the mixture is extracted twice with ethyl acetate. After drying of the combined organic phases over sodium sulfate, the solvent is removed under reduced pressure and the residue is purified by column chromatography (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 20:1).
Reaction SMILES: [Na].[CH2:2]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)[CH3:3].Br[CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>CO>[CH2:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: CCc1ccc(S)cc1
Agent: [Na]
Solvent: CO
Product: CCc1ccc(SCC=C(C)CCC=C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2 g. of sodium in 50 ml. of methanol at about 0° is added 35 g. of p-ethylphenylmercaptan. After about 0.5 hour, 15 g. of 1-bromo-3,7-dimethylocta-2,6-diene is added and then the mixture is refluxed for about two hours. Then the solvent is evaporated and the concentrate taken up in petroleum ether which is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 1-(p-ethylphenyl)thio-3,7-dimethylocta-2,6-diene which can be purified by chromatography. ##STR11##
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si](C=[N+]=[N-])(C)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)Cc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
To a solution of 1.55 g of 4-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetic acid in methanol (20 ml) was added 13.2 ml of trimethylsilyldiazomethane (2 M solution in hexane) and the resulting mixture was reacted at room temperature for 1 hour. After distilling off the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.0 of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][C:6]1([C:13](OCC)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][C:6]1([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1(Cc2cccc(OC)c2OC)CCCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CC2(CO)CCCCCC2)c1OC
Temperature: 25 °C
Yield: 87.6 %

Procedure:
The crude ester (26 g, 82 mmol, from Step B above), was dissolved in 400 mL anhydrous THF to which was added solid LiAlH4 (4.6 g, 123 mmol) in small portions at room temperature. The reaction was stirred at room temperature until TLC indicated completion. The reaction was then quenched with 1M HCl and diluted with ether. The layers were separated, and the organic layer was washed with 1M HCl, water, and brine. The organic layer was dried over MgSO4, filtered and evaporated. The resulting oil was purified by silica gel chromatography to give 20 g of the title product as a colorless oil.
Reaction SMILES: C(NC1SC(S(Cl)(=O)=O)=C(C)N=1)(=O)C.C[O:16][C:17](=[O:78])[C@@H:18]([NH:34][C:35]([CH:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][N:38]1[S:65]([C:68]1[S:72][C:71]([NH:73]C(=O)C)=[N:70][C:69]=1[CH3:77])(=[O:67])=[O:66])=[O:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[NH2:73][C:71]1[S:72][C:68]([S:65]([N:38]2[CH:37]([C:35]([NH:34][C@@H:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)[C:17]([OH:78])=[O:16])=[O:36])[CH2:46][C:45]3[CH:44]=[C:43]4[O:47][CH2:48][C@H:49]([C:51]5[CH:52]=[CH:53][C:54]([O:57][CH2:58][C:59]6[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=6)=[CH:55][CH:56]=5)[O:50][C:42]4=[CH:41][C:40]=3[CH2:39]2)(=[O:67])=[O:66])=[C:69]([CH3:77])[N:70]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccccc2)cc1)CO3
Agent: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: Cc1nc(N)sc1S(=O)(=O)N1Cc2cc3c(cc2CC1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccccc2)cc1)O3
Yield: 29.6 %

Procedure:
(S)-2-{[(S)-3-(4-Benzyloxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino-[2,3g]-isoquinoline-8-carbonyl]-amino}-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride according to General Procedure E. The resulting (S)-2-{[(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-(4-benzyloxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (18 mg) was hydrolyzed according to General Procedures N and B to the title compound (5 mg). LCMS (m/z) 843.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([S:17](Cl)(=[O:19])=[O:18])[CH2:15][CH3:16]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:17]([CH2:14][CH2:15][CH3:16])(=[O:19])=[O:18])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 41, step 41.1, 1-Boc-piperazine replacing piperazine-1-carboxylic acid benzyl ester and 1-propanesulfonyl chloride replacing benzoyl chloride.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH:9]([N:11]2[C:24]3[CH:23]=[C:22]([C:25](=[S:27])[NH2:26])[CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:3]1.[CH2:28](N)[CH2:29][CH3:30].S>C(O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH:9]([N:11]2[C:24]3[CH:23]=[C:22]([C:25](=[S:27])[NH:26][CH2:28][CH2:29][CH3:30])[CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:3]1
Reactant: CC1CCCN(CC(C)N2c3ccccc3Sc3ccc(C(N)=S)cc32)C1
Reactant: CCCN
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC(C)C1)c1ccccc1S2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 10-{(2RS)-1-[(3RS)-3-methyl-1-piperidyl]-2-propyl}-2-phenothiazinecarbothioamide acid fumarate (1 g) and propylamine (2.5 cc) in absolute ethanol (20 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (1.5 g) is purified by chromatography on a column (height: 25 cm; diameter: 2 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (80:20 by volume) (250 cc) of ethyl acetate and cyclohexane and collecting 40-cc fractions. The combined fractions 3 and 4 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.9 g) is dissolved in ethanol (3 cc) at 60° C., and this hot solution is poured, with stirring, into a solution of fumaric acid (0.23 g) in ethanol (3.5 cc) under reflux. After cooling, stirring is continued for 2 hours at a temperature in the region of 5° C. The solid formed is drained, washed with ethanol (2×1 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-{(2RS}-1-[(3RS)-3-Methyl-1-piperidyl]-2-propyl}-N-propyl-2-phenothiazinecarbothioamide neutral fumarate (0.53 g) is thereby obtained in the form of a yellow solid, m.p. 126° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Cc1c([N+](=O)[O-])ccc2c1CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: Cc1c([N+](=O)[O-])ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a suspension of 4-methyl-5-nitroindoline (4.767 g, 0.0268 mol) in 100 mL of methanol was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.697 g, 0.0295 mol) all at once and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then evaporated and the residue was taken up in dichloromethane. This solution was then washed with saturated aqueous NaHCO3 (×4), dried (Na2SO4) and evaporated to give a solid. Crystallization of this material from ethyl acetate-hexane (-20° C.) afforded 4.161 g of the title compound as greenish-gold needles, mp 179°-180° C. Chromatography of the mother liquor (SiO2 /ethyl acetate-hexane, 1:1 ) gave an additional 0.417 g of the pure product. Total yield=4.578 g (97%): IR (KBr) 3318, 1604, 1585 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.72 (br s, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.56 (t, J=2.8 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 6.79 (m, 1H), 2.75 (s, 3H). Anal. Calcd for C9H8N2O2 : C, 61.35; H, 4.58; N, 15.90. Found: C, 61.32; H, 4.40; N, 15.96.