Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[C:5]([CH3:18])[CH:4]=1.[C:19]([N:22]1[CH2:26][CH:25]=[N:24][C:23]1=O)(=[O:21])[CH3:20]>>[C:19]([N:22]1[CH2:26][CH2:25][N:24]=[C:23]1[NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[C:5]([CH3:18])[CH:4]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CC=NC1=O
Reactant: Cc1cc(N)n(-c2cccc(C(F)(F)F)c2)n1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1cccc(C(F)(F)F)c1

Procedure:
5-Amino-1-(3-trifluoromethylphenyl)-3-methyl pyrazole HCl (20.0 g.) and 1-acetyl-3-imidazolinone (11.1 g.) were reacted as described in Example I to give 15.0 g. product. mp 173°-175°
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]2[C:39]([CH3:41])([CH3:40])[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:42]([OH:44])=[O:43])[CH:36]=3)[NH:31]2)[CH:27]=[CH:28][CH:29]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:23][C:24]1[CH:25]=[C:26]([CH:30]2[C:39]([CH3:40])([CH3:41])[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:42]([OH:44])=[O:43])[CH:36]=3)[NH:31]2)[CH:27]=[CH:28][CH:29]=1)=[O:6]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: O=C(O)c1cccc(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2cccc(F)c2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
A solution of 3-fluoro-benzoic acid (119 mg, 0.85 mmol) and 1,1′-carbonyldiimidazole (179 mg, 1.1 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h. Then a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.68 mmol) in N,N-dimethylformamide (1.5 mL) was added and the mixture was allowed to stir at 50° C. for 3 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(3-fluoro-benzoylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (40 mg, 14%) as a white solid: LC/MS m/e calcd for C25H23FN2O3 (M+H)+: 419.47, observed: 419.1.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[O:25][CH:26]([CH3:27])[CH3:28])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(F)cc3C2)c1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
The mixture of 5-fluoro-2-(2-isopropoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (96) (544 mg, 1.36 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (97) as white solid (460 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:36])[C:8]4[CH:20]=[C:19]([C:21]#[C:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:18]([O:27][CH2:28][C@H:29]5[CH2:33][O:32]C(C)(C)[O:30]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl>CO>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:36])[C:8]4[CH:20]=[C:19]([C:21]#[C:22][C:23]([OH:26])([CH3:24])[CH3:25])[C:18]([O:27][CH2:28][C@H:29]([OH:30])[CH2:33][OH:32])=[CH:17][C:9]=4[C:10]([CH3:15])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1OC[C@H]1COC(C)(C)O1)C(C)(C)c1[nH]c3cc(Cl)ccc3c1C2=O
Agent: Cl
Solvent: CO
Product: CC(C)(O)C#Cc1cc2c(cc1OC[C@H](O)CO)C(C)(C)c1[nH]c3cc(Cl)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.8 %

Procedure:
The resulting 3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (20 mg, 0.04 mmol) was dissolved in methanol (3 mL), added with 1 N hydrochloric acid (1 ml), and stirred at room temperature for 12 hr. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residues were washed with methylene chloride to obtain the title compound (pale yellow powder, 5.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13]C(=O)C)[CH:5]=[CH:6][C:7]=1[S:8](=[O:12])(=[O:11])[NH:9][CH3:10].[OH-].[Na+]>Cl>[NH2:13][C:4]1[CH:5]=[CH:6][C:7]([S:8]([NH:9][CH3:10])(=[O:12])=[O:11])=[C:2]([F:1])[CH:3]=1
Reactant: CNS(=O)(=O)c1ccc(NC(C)=O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNS(=O)(=O)c1ccc(N)cc1F
Yield: 83.2 %

Procedure:
The above prepared N-(3-fluoro-4-methylsulfamoylphenyl)acetamide (1.55 g, 6.3 mmol) was suspended in 40 mL of 6M HCl and heated to reflux for 1 hr. The reaction was cooled in an ice bath and an NaOH solution was added to adjust the mixture to pH 5. The resulting white precipitate was isolated by filtration and was washed with water and dried to yield 1.07 g (83%) of the title compound. MS (m/z, ES+): 205.0 (M+1, 100%); 1H NMR (500 MHz, ppm, DMSO-d6): 7.35 (m, 1H), 7.12 (m, 1H), 6.40 (m, 2H), 6.23 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:28])[NH:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][NH:24][CH2:25]3)=[CH:20][CH:19]=2)[CH:11]=1)=[O:7].Br[CH2:35][CH:36]([F:38])[F:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:37][CH:36]([F:38])[CH2:35][N:24]1[CH2:23][CH2:22][C:21]2[C:26](=[CH:27][C:18]([NH:17][C:16]([C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=3)[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:28])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: FC(F)CBr
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(CC(F)F)CC4)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 3,4-dimethoxy-N-[3-(1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide (50.0 mg, 0.12 mmol) in 1 mL of DMF. Added 2-bromo-1,1-difluoro-ethane and (0.02 mL, 0.20 mmol) K2CO3 (50.0 mg, 0.36 mmol). The mixture was stirred at room temperature overnight. LC-MS indicated low conversion to alkylated product. Heated the mixture to 60° C. for 8 h with continued low conversion, thereafter it was heated to 75° C. for 48 h. LC-MS indicated the desired product. Dissolved in 5 mL of DMF and purified via prep HPLC (5%-95% CH3CN/H2O) to give 28.1 mg of N-{3-[2-(2,2-difluoro-ethyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-benzyl}-3,4-dimethoxy-benzamide. MS, electrospray 510.4 (M+H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CN(CCN(C)C)C.[Li]CCCC.[Cl:40]N1C(=O)CCC1=O>C1COCC1.C(OCC)C.O>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[C:21]([F:26])[C:22]([Cl:40])=[C:23]([F:25])[CH:24]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC[C@H]1CC[C@H](CCc2c(F)cccc2-c2cc(F)cc(F)c2)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](CCc2c(F)cccc2-c2cc(F)c(Cl)c(F)c2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 0.1 m of 1-(trans-4-n-propylcyclo-hexyl)-2-(3,3′, 5′-trifluorobiphenylyl)ethane and 0.1 m of TMEDA in 300 ml of THF is treated dropwise at about -65° with 0.1 m of n-BuLi (1.5 M in hexane). The mixture is stirred at this temperature for a further 30 minutes, and 0.2 m of N-chlorosuccinimide in 70 ml of THF is then slowly added. When the addition is complete, the mixture is allowed to warm to −20° and is hydrolyzed using H2O. The product is dissolved completely by adding diethyl ether. Extractive work-up and purification by chromatography and crystallization give l-(trans-4-n-propylcyclohexyl)-2-(4′-chloro-3,3′, 5′-trifluorobiphenylyl)ethane.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[C:20]([F:22])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:23])[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[Br:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:37][CH:34]4[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH2:32][CH2:33]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:20]([F:22])[CH:21]=1
Reactant: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 40.8 %

Procedure:
Using an analogous procedure to that described in the preparation of the starting material in Example 8, 4-(4-bromo-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (1 g, 2.62 mmol) was reacted with 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (845 mg, 3.93 mmol), (prepared as described for the starting material in Example 1), to give 4-(4-bromo-2,6-difluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (620 mg, 41%).
Reaction SMILES: [I:1]I.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C=CC=CC=1>[I-:1].[I-:1].[C:16]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: [I-]

Procedure:
The 3α-iodo derivative of 4,4-nor-methyl glycyrrhetinic acid, methyl ester is prepared by a method similar to that used by Greenhouse and Muchowski [Greenhouse, R., Muchowski, J. M., Can. J. Chem. 59 (1981) 1025-1027] (see Example 1). To a solution of 12.69 g (0.05 mole) of iodine in anhydrous benzene (35 mL) is added a solution of triphenylphosphine (13.12 g, 0.05 mole) in dry benzene (50 mL). After the solution becomes pale, an abundant yellow precipitate of triphenylphosphine diiodide is produced. To this solution is added directly 4,4-nor-methylglycyrrhetinic acid, methyl ester (9a) (4.56 g, 0.01 mole) and this suspension is heated to reflux with stirring for 22 hours. After cooling, the reaction mixture is mixed with ice-water (60 mL) and extracted. The benzene layer is further extracted with water (2×100 mL), dried over anhydrous sodium sulfate, evaporated and dried in vacuo to an off white solid. This residue is triturated with n-pentane (200 ml) and the insoluble triphenylphosphine oxide filtered. After rotary evaporation of the pentane solvent, the product is recrystallized from toluene:acetone.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:23])[CH:15]=[CH:16]C2C=CC=CC=2)[CH:10]=[CH:11][CH:12]=1>ClC1C=CC=CC=1>[OH:6][C:7]1[CH:8]=[C:9]2[C:10]([CH:16]=[CH:15][C:14](=[O:23])[NH:13]2)=[CH:11][CH:12]=1
Reactant: COc1cccc(NC(=O)C=Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=c1ccc2ccc(O)cc2[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
AlCl3 (11.5 g, 86.3 mmol) was added portion-wise to a suspension of intermediate 13 (4.2 g, 16.6 mmol) in chlorobenzene (90 mL) at 0° C. The reaction mixture was gradually warmed to 120° C. and stirred for 3 h. The mixture was poured into ice water and the resulting precipitate was collected by filtration, washed with water, and purified by flash chromatography on silica gel column (elution with DCM/MeOH=60:1) to give 7-hydroxyquinolin-2(1H)-one (intermediate 14) (1.41 g, 53%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([NH:9][C@@H:10]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[S:22][C:23](Br)=[CH:24][N:25]=3)=[CH:16][CH:15]=2)=[O:12])=[O:8])[N:3]=[CH:2]1.C([O-])=O.[NH4+]>[Pd].CO>[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([NH:9][C@@H:10]([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:18][CH:19]=2)=[O:12])=[O:8])[N:3]=[CH:2]1
Reactant: O=C(Cc1c[nH]cn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ncc(Br)s2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(Cc1c[nH]cn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2nccs2)cc1
Temperature: 70 °C
Yield: 49.3 %

Procedure:
A flask was charged with (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(4-(5-bromothiazol-2-yloxy)phenyl)propanamide (25 mg, 0.045 mmol), prepared as in Example 1, methanol (20 mL), ammonium formate (300 mg, 4.84 mmol), and palladium on carbon (10%, 100 mg) and the mixture was heated at 70° C. for 30 minutes. The mixture then was cooled to ambient temperature and filtered. Product was purified from the residue by chromatography (EtOAc to EtOAc/MeOH (9:1)) and then further purified by reverse phase HPLC to provide Compound 206, (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(4-(thiazol-2-yloxy)phenyl)propanamide (10.6 mg, 51%), as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.35 (s, 1H), 8.43 (d, J=6.4 Hz, 1H), 7.68 (d, J=11.2 Hz, 2H), 7.60 (s, 1H), 7.31-7.23 (m, 8H), 6.95 (s, 1H), 4.70-4.64 (m, 1H), 4.49 (s, 2H), 4.14-4.09 (m, 2H), 3.69-3.63 (m, 2H). MS (EI) for C24H23N5O4S. found 478.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[N:36]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4Cc4ccccc4)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 3.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (R)-4-benzyloxazolidin-2-one (354 mg), the title compound (38 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:18]([CH3:25])([CH3:24])[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C@H:13]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH2:12][C@@H:11]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:62].N1C=CC=CC=1>CCOCC.CCCCCC.C(#N)C>[CH3:1][O:2][C:3](=[O:41])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:18]([CH3:25])([CH3:24])[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C@H:13]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH2:12][C@H:11]1[Cl:62]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](OC2CCCCO2)C(C)(C)CC=C(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](OC2CCCCO2)C(C)(C)CC=C(C)C)[C@H](OC2CCCCO2)C[C@H]1Cl
Reaction time: 0.17 h

Procedure:
A solution of 1.15 g of (5Z,13E)-(8R,9S,11R,12R,15R)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16,16,19-trimethyl-5,13,18-prostatrienoic acid methyl ester, 780 mg of triphenylphosphine, and 15 ml of a solution of 0.97 ml of carbon tetrachloride, 0.79 ml of pyridine, and 48 ml of acetonitrile was stirred for 55 hours under argon at room temperature. The mixture was then diluted with 15 ml of ether and 30 ml of hexane, further stirred for 10 minutes, and filtered. The residue from the evaporation was extracted with a mixture of 5 ml of ether and 95 ml of hexane, filtered, and concentrated to dryness under vacuum. The residue was purified by column chromatography on silica gel with hexane/20-50% ethyl acetate as the eluent, thus obtaining 1.07 g of the desired compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][OH:7].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>O1CCCC1.C(OCC)(=O)C>[Si:8]([O:3][CH2:4][CH2:5][CH2:6][OH:7])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCO
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a suspension of sodium hydride (0.1 mole) in anhydrous tetrahydrofuran (200 ml) cooled to 0° C. with stirring under an atmosphere of nitrogen is added a solution of 1,3-dihydroxypropane (0.1 mole) in tetrahydrofuran (150 ml) slowly over a period of 1 hour. Then a solution of tert-butyldimethylsilyl chloride (0.1 mole) in tetrahydrofuran (150 ml) is added slowly over a period of 1 hour. Stirring is continued for 6 hours. The mixture is then diluted with ethyl acetate (400 ml), washed with water (100 ml), brine (75 ml), dried and concentrated to afford the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[C:7](=[O:13])[CH2:6]2>O>[C:1]([C:7]1([OH:13])[CH:8]2[CH2:11][CH2:12][N:5]([CH2:10][CH2:9]2)[CH2:6]1)#[N:2]
Reactant: O=C1CN2CCC1CC2
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(O)CN2CCC1CC2
Reaction time: 3 h

Procedure:
A solution of potassium cyanide (10.15 g, 0.156 mol) in water (31.25 ml) was added dropwise to a solution of 1-azabicyclo[2.2.2]-octan-3-one hydrochloride (25.0 g, 0.155 mol) in water (31.25 ml) at 0°-5°. Following the addition, the reaction mixture was stirred for 3 h and then filtered. The solid was washed with ice-cold water (2×15 ml) and was then dried over phosphorus pentoxide overnight, m.p. 155°-156°. Recrystallisation of a 1 g sample from dioxane gave pure 3-cyano-3-hydroxy-1-azabicyclo[2.2.2]octane, m.p. 172°-173°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>ClCCl>[Cl:32][CH2:8][C:6]1[O:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:7]=1
Reactant: OCc1cc(C(F)(F)F)no1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(CCl)on1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 3-trifluoromethyl-5-hydroxymethylisoxazole [(700 mg, 4.2 mmol) See K. Tanaka et al, Bull. Chem. Soc. Jpn., 57, 2184 (1984)] and triphenylphosphine (1.43 g, 5.4 mmol) in carbontetrachloride (50 ml) and dichloromethane (20 ml) is heated at reflux for 6 hours. The reaction mixture is then cooled to room temperature, and passed through a silica gel plug. Concentration affords in 82% yield the desired 5-chloromethyl-3-trifluoromethylisoxazole of sufficient purity for the following step (Example 24).
Reaction SMILES: C1(CNC([NH:11][CH:12]([CH2:16][C:17]([NH2:19])=[O:18])[C:13]([NH2:15])=[O:14])=O)C=CC=CC=1.C(O)C.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([O-:35])=O>[Pd].ClCCl>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([NH:11][CH:12]([CH2:16][C:17]([NH2:19])=[O:18])[C:13]([NH2:15])=[O:14])=[O:35]
Reactant: NC(=O)CC(NC(=O)NCc1ccccc1)C(N)=O
Reactant: O=C([O-])c1ccc2ccccc2n1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)CC(NC(=O)c1ccc2ccccc2n1)C(N)=O

Procedure:
A solution of[1S-[1R*(R*), 2S*]]- N1[3-[[[(1,1-dimethylethyl)amino]carbonyl]n-butyl)amino]-2-hydroxy-1-(phenylmethy)propyl]-2-[(phenylmethylcarbamoyl)amino]-butanediamide (1.03 g, 1.77 mmol) in 40 mL of abs. ethanol ws then deprotected by hydrogenolysis in the presence of 10% palladium on carbon catalyst to give, after filtration and concentration, the free amine (428 mg) which was coupled with N-hydroxysuccinimide ester of 2-quinoline carboxylate (270 mg, 1.0 mmol) in dichloromethane for 16 h to give 380 mg, 63% of [1S-[1R*(R*), 2S*]]-N1[3-[[[1,1-dimethylethyl)amino]carbonyl](n-butyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide, mp 102.1°-103° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([NH:16][C:17]2[N:22]=[C:21]([CH2:23]O)[CH:20]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[N:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+].C(=O)=O>ClCCl>[C:10]1([NH:16][C:17]2[N:22]=[C:21]([CH2:23][F:7])[CH:20]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[N:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1cc(C2CC2)nc(Nc2ccccc2)n1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 0 °C

Procedure:
6.1 g (37.8 mmol) of diethylaminosulfur trifluoride in 15 ml of dichloromethane are slowly added dropwise within a period of one hour, with stirring, to a suspension of 9.1 g (37.8 mmol) of 2-phenylamino-4-hydroxymethyl-6-cyclopropylpyrimidine in 80 ml of dichloromethane. After the addition of 50 ml of ice-water, 50 ml of 10% aqueous sodium hydrogen carbonate solution are added dropwise. When the evolution of carbon dioxide has ceased, the organic phase is separated off and the aqueous phase is extracted twice with 20 ml of dichloromethane each time. The combined dichloromethane solutions are washed with 15 ml of water, dried over sodium sulfate and filtered, and the solvent is evaporated. The black oil which remains is purified by column chromatography over silica gel (toluene/chloroform/diethyl ether/petroleum ether (b.p. 50°-70° ); 5/3/1/1). After the eluant mixture has been evaporated off, the yellow oil is diluted with 20 ml of petroleum ether (b.p. 50°-70° C.) and crystallised at reduced temperature. The yellowish crystals melt at 50°-52° C. Yield: 4.9 g (20.1 mmol; 53% of the theoretical yield).