Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C([CH2:10][CH3:11])(CC)C([O-])([O-])[O-])C.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].[N-:27]=[N+:28]=[N-:29].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:11][C:10]1[N:12]([C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[N:29]=[N:28][N:27]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(-n2nnnc2C)cc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
Triethylorthoacetate (2.57 ml, 14 mmol) was added to a stirred, heated (75° C.) solution of methyl 3-amino-5-(trifluoromethyl)benzoate (the product of Description 1, step ii) (2.19 g, 10 mmol) in acetic acid (15 ml). The mixture was stirred at 75° C. for 45 minutes, then sodium azide (1.95 g, 30 mmol) was added in portions over 45 minutes. The mixture was stirred at 75° C. for 4 hours, cooled and poured into water (50 ml). The pH was adjusted to 7.0 with aqueous sodium hydroxide (4M) and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (2×50 ml) and brine (50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (30:70 increasing to 60:40) to give methyl 3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)benzoate as a yellow oil (1.62 g, 57%), 1H (CDCl3) δ 8.51 (1H, s), 8.36 (1H, s), 8.02 (1H, s), 4.03 (3H, s), and 2.71 (3H, s). m/z 287 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].Cl[C:38]1N=C(N2CCOC[C@@H]2C)C2CCN(C)CC=2N=1.CC1C=C(C=CC=1B1OC(C)(C)C(C)(C)O1)N>>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][C:16]=3[N:17]=2)=[C:10]([CH3:38])[CH:11]=1)=[O:36])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C)C2
Agent: Cc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)c(C)c1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 13) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by triturating with a (9:1) mixture of petrol ether (40-60)/ethyl acetate, yielding the title compound after filtration and drying of the solid obtained (85 mg, 0.24 mmol, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2].[C:32](Cl)(=[O:34])[CH3:33].CCN(CC)CC>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([C:32](=[O:34])[CH3:33])[CH2:29][CH2:30]1)=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)=O)CC1
Reaction time: 8 h

Procedure:
To a solution of 70 mg of 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester in 4 mL dichloromethane was added 0.026 ml of acetyl chloride followed by addition of 0.13 mL Et3N. This mixture was stirred overnight. The mixture was concentrated and chromatographed on silica with 7 N NH3 in MeOH/dichloromethane to give 76 mg of 2-{[1-(1-acetyl-piperidin-4-ylmethoxy)-4-chloro-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].[C:30](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:43][N:44](C)[OH:45].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([N:44]([O:45][CH3:30])[CH3:43])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: CN(C)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reaction time: 3 h
Yield: 25.6 %

Procedure:
To a solution of 3-[5-bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid from Step C (307 mg, 0.66 mmol) in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol). After stifling at ambient temperature for three hours, N,N-dimethylhydroxylamine HCl (97 mg, 1.0 mmol) and triethylamine (0.18 mL, 1.32 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, 5% citric acid and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as an oil (86 mg, 26%). MS (M, M+2): 508, 510
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:6][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[CH2:4][CH3:5]>CC(C)=O>[I-:2].[CH2:3]([O:6][C:7]1[C:8]([C:12]2[CH:13]=[N+:14]([CH3:1])[CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[CH2:4][CH3:5]
Reactant: CI
Reactant: CCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.37 ml, 6 mmol) and 3-(4-propoxy-1,2,5-thiadiazole-3-yl)pyridine (700 mg, 3.1 mmol) in acetone (10 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.98 g (88%)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C@H:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:33](=[O:34])C1>ClCCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C@@H:12]([C:13]([CH3:16])([CH3:14])[CH3:15])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:33]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1)C(C)(C)C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of the product of Example 111-4 in 1,2-dichloroethane (1325 mL) was treated with triethylamine (37.5 mL, 269 mmol, 1.25 equivalents) and N,N-disuccinimidyl carbonate (68.9 g, 269 mmol, 1.25 eq). The reaction mixture was stirred at 20° C. overnight, washed with 10% Na2CO3 (2×1.5 L). The aqueous was back-extracted with dichloromethane (600 mL). The organics were combined and washed with 1.5 L of brine. The organic layer was concentrated to yield 76.8 gm of crude material. 1H NMR (CDCl3): δ 7.15-7.3(m, 5H), 4.25-4.4(m, 3H), 3.75(m, 1H), 3.67(residual dichloroethane), 3.48(m, 1H), 3.1(m, 2H), 1.4(s, 9H), 1.0(s, 9H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(O)=O.C([O-])(=O)C.[Cu+2:16].C([O-])(=O)C>CO>[Cu:16].[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5]
Reactant: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=CO
Solvent: CO
Product: [Cu]

Procedure:
0.58 g of fumaric acid was dissolved in a mixture solvent having 40 cm3 of methanol and 12 cm3 of formic acid. Then, under stirring at the normal temperature, into the above solution, a further solution in which 1.0 g of copper acetate was dissolved in 80 cm3 of methanol was dripped. After this solution was left still for a few days, the precipitation product was suction-filtered and dried for 110° C./4 hours, whereby 0.3 g of fumaric acid copper was obtained.
Reaction SMILES: [F:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C@H:5]1[CH2:8][C@H:7]([CH2:9][NH:10][CH3:11])[CH2:6]1.C(N(CC)CC)C.[CH3:29][C:30]1[C:34]([C:35]([Cl:37])=[O:36])=[C:33]([CH3:38])[O:32][N:31]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[ClH:37].[F:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C@H:5]1[CH2:8][C@H:7]([CH2:9][N:10]([CH3:11])[C:35]([C:34]2[C:30]([CH3:29])=[N:31][O:32][C:33]=2[CH3:38])=[O:36])[CH2:6]1
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: CNC[C@H]1C[C@H](Oc2cccc(CN3CCCC3)c2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1C(=O)N(C)C[C@H]1C[C@H](Oc2cccc(CN3CCCC3)c2F)C1
Product: Cl

Procedure:
Example 391, ({trans-3-[2-fluoro-3-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylamine (200 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) were dissolved in CH2Cl2 (2 mL). 3,5-Dimethylisoxazole-4-carbonyl chloride (109 mg, 0.7 mmol) was added dropwise under stirring. The mixture was stirred at RT for 3 h and sat. K2CO3 was added. The mixture was stirred at RT for 20 h, dried with Na2SO4, and evaporated. The residue was purified chromatographically (silica gel 40-63 μm, 3 g, hexane/CHCl3 20:80→0:100, then CHCl3/MeOH 100:0→95:5). The residue was dissolved in ether (1 mL). 4N HCl/dioxane (0.20 mL) was added, and the reaction mixture was evaporated to dryness. The obtained crystals were washed with ether and dried in vacuo to give the title compound (160 mg, 52%) as yellow crystals. LC/MS data: 416.2 (M+H) (calculated for C23H30FN3O3 415.51). 1H NMR-data (DMSO-d6): 10.64 (br.s, 1H, NH+); 7.13-7.29 (m, 2H, Ar—H); 6.87-7.12 (m, 1H, Ar—H); 4.53-5.07 (m, 1H), 4.38 (br.s, 2H); 3.57-3.67 (m, 1H); 3.37-3.52 (m, 3H); 2.97-3.13 (m, 2H); 2.91 (s, 3H); 2.61-2.78 (m, 1H); 2.28-2.41 (m, 4H); 2.11-2.23 (m, 6H); 1.94-2.06 (m, 2H); 1.79-1.94 (m, 2H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[C:8](=O)([O:12]CC)[O:9][CH2:10][CH3:11].CN(C)P(=O)(N(C)C)N(C)C.C(O)C>C1C=CC=CC=1>[CH2:10]([O:9][C:8](=[O:12])[CH2:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:11]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)C(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)(C)C
Reaction time: 9 h
Yield: 54 %

Procedure:
A solution of 100 g of pinacolone in 500 cc of benzene was added dropwise over a period of 4 hours at 50° C/150 Torr to a solution of 500 cc of benzene, 900 cc of diethyl carbonate, 125 g of potassium-tert.-butylate and 200 cc of hexamethyl phosphoric acid triamide, and benzene and ethanol slowly distilled off. After the ketone had been added, another 500 cc of benzene were added dropwise. The total reaction time was 9 hours. The reaction mixture was then treated and distilled in the same way as described in 1 above. The yield was 54% of pivaloyl acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][C:32]1([CH2:36][OH:37])[CH2:35][CH2:34]C1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:37][CH2:36][C:32]1([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:28])[CH2:35][CH2:34]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCC1(CO)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC2(CO)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 10.9 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with (1-aminomethyl-cyclobutyl)-methanol (34.5 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyl)-amide (11.2 mg, 10.6%).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Cc1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--see Preparation 8), 4-methylphenethyl bromide (0.44 g), anhydrous potassium carbonate (0.6 g) and acetonitrile (20 ml) was heated under reflux for 1.25 hours. The mixture was partitioned between 10% aqueous potassium carbonate (10 ml) and dichloromethane (20 ml), the layers were separated, and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.32 g.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[Al+3].[Cl-].[Cl-].[Cl-].C[Si]([C:22]#[N:23])(C)C>ClCCl>[C:1]([N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:5][CH:6]1[C:22]#[N:23])(=[O:3])[CH3:2]
Reactant: c1ccc2scnc2c1
Reactant: CC(=O)Cl
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2SC1C#N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Acetylchloride (4.00 g, 51.0 mmol) was added dropwise to a stirring solution of benzothiazole (6.75 g, 50.0 mmol) in dichloromethane (40 mL) under argon atmosphere. A catalytic amount of AlCl3 and trimethylsilylcyanide (5.1 g, 52.0 mmol) were than added into the reaction mixture. After being stirred for 17 h at room temperature, the reaction mixture was evaporated to dryness in vacuo and the residue was triturated with ether to give 3-acetyl-2,3-dihydrobenzo[d]thiazole-2-carbonitrile, 8.2 g (80%); mp 92-93° C. 1H NMR (DMSO-d6) δ 2.39 (3H, s, Me), 7.05 (1H, s, ArH), 7.16-7.26 (2H, m, 2×ArH), 7.49-7.51 (1H, m, ArH), 7.65 (1H, brs, C2-H). Anal. Calcd. for (C10H8N2OS): C, 58.80; H, 3.95; N, 13.72; S, 15.70. Found: C, 58.85; H, 3.95; N, 13.78; S, 15.76.
Reaction SMILES: [OH-:1].C[N+:3]([CH3:6])(C)C.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]#N.C=O>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:15][OH:1])[C:6]#[N:3]
Reactant: N#CCc1ccccc1Cl
Reactant: C[N+](C)(C)C
Reactant: [OH-]
Agent: C=O
Solvent: C1CCOC1
Product: N#CC(CO)c1ccccc1Cl
Yield: 69 %

Procedure:
A 330 μL sample of tetramethylammonium hydroxide (40% in water) was added with stirring to a solution of 750 mg (4.95 mmol) of 2-chlorophenylacetonitrile and 1.86 mL of 37% formaldehyde in 9 mL of tetrahydrofuran. The reaction was quenched at 12 min by acidification with 3 N HCl and diluted with ethyl acetate and water. The organic phase was washed with water, saturated salt solution, then stripped to an oil. This was flash chromatographed on 15 g of silica gel eluting with 5→90% ethanol in hexane. Fractions containing product were stripped to yield 622 mg (69%) of the alcohol as a colorless oil, Rf 0.14 (silica gel, ethyl acetate:hexane=1:4).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[F:25][C:26]1([F:34])[CH2:30][NH:29][C@H:28]([C:31]([NH2:33])=[O:32])[CH2:27]1.CCN(C(C)C)C(C)C.C(#N)C>O>[F:25][C:26]1([F:34])[CH2:30][N:29]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:28]([C:31]([NH2:33])=[O:32])[CH2:27]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC(F)(F)C[C@H]3C(N)=O)cc1OCC2
Yield: 11 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 4,4-difluoro-L-prolinamide hydrochloride with added DIPEA (2.2 eq.) were reacted and the crude product subjected to RPHPLC (C18 column, gradient 5 to 95% acetonitrile in water+0.1% HCO2H) then recrystallisation from IMS to give 381 as a white solid (24 mg, 11%). LCMS: RT=3.21 min, [M+H]+=445. 1H NMR 400 MHz (DMSO-d6) δ: 9.11 (1H, s), 7.90 (1H, d, J=0.64 Hz), 7.87 (1H, s), 7.53 (1H, br), 7.14 (1H, br), 6.08 (1H, s), 5.99-5.91 (1H, m), 4.61 (1H, dd, J=9.53, 4.24 Hz), 4.58-4.49 (4H, m), 4.00-3.98 (2H, m), 2.91-2.90 (1H, m), 2.45 (1H, dd, J=13.51, 4.18 Hz), 1.49 (6H, dd, J=6.59, 3.35 Hz)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.[C:10](=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]([CH:19]=O)[CH3:18]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:19][N:17]([CH3:18])[CH3:16])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(I)cc1
Agent: Cl
Agent: [K+]
Product: CN(C)CCOc1ccc(I)cc1

Procedure:
4-Iodophenol was reacted with 2-chlorodimethylamioethane hydrochloride in DMF under heating in the presence of potassium carbonate to obtain [2-(4-iodophenoxy)ethyl]dimethylamine. The obtained compound was reacted in toluene under heating in the presence of t-butyl piperazine-1-carboxylate, sodium t-butoxide, tri(2-methylphenyl)phosphine and a catalytic amount of tris(dibenzylideneacetone)dipalladium(0) to obtain an objective compound.
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:24])[CH3:23])#[CH:14].[CH2:25]([O:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N+:34]([O-])=[O:35])[CH3:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:24])[CH3:23])[O:35][N:34]=1)[CH3:26]
Reactant: C#Cc1ccccc1NC(C)=O
Reactant: CCOC(=O)CCCCC[N+](=O)[O-]
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCc1cc(-c2ccccc2NC(C)=O)on1
Yield: 116.6 %

Procedure:
Add 1,4-phenylenediisocyanate (5.15 g, 32.2 mmol) to a stirred solution of N-(2-ethynyl-phenyl)-acetamide (2.56 g, 16.1 mmol) and 6-nitro-hexanoic acid ethyl ester (4.56 g, 24.1 mmol) in toluene (200 mL, anhydrous) and stir under N2. Add triethylamine (4.5 mL, 32.2 mmol) and heat to reflux under N2 overnight. Filter mixture through a pad of Celite® and rinse with toluene. Concentrate to get 6.2 g yellow oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-60% EtOAc/hexanes to afford the title compound (4.02 g, 76%). Correct regioisomer is confirmed by NOESY. MS (IS) 331 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:28])([C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:3][CH2:4][CH:5]([CH2:11]CCCCC=C)[C:6]([O:8]CC)=[O:7].C(OCC)(=O)CC(OCC)=O.ICCCCCC=C.ICCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F.[CH2:64]([C:66]1([C:103]2[CH:108]=[CH:107][C:106]([OH:109])=[CH:105][CH:104]=2)[CH:75]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82]CCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:74]2[C:69](=[CH:70][C:71]([OH:102])=[CH:72][CH:73]=2)[O:68][CH2:67]1)[CH3:65]>>[CH2:64]([C:66]1([C:103]2[CH:104]=[CH:105][C:106]([OH:109])=[CH:107][CH:108]=2)[CH:75]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:11][CH:5]([CH2:4][CH2:3][C:2]([F:1])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:22])([F:21])[F:23])[C:6]([OH:8])=[O:7])[C:74]2[C:69](=[CH:70][C:71]([OH:102])=[CH:72][CH:73]=2)[O:68][CH2:67]1)[CH3:65]
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Agent: C=CCCCCCI
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Solvent: CCOC(=O)CC(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared from diethyl malonate, 7-iodo-1-heptene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane as in Example 9 and the allyl compound prepared in Example 21, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]=[CH:19][CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>O.C(Cl)(Cl)Cl>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]4[O:29][CH:19]4[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccccc1)N1CC2CC=Cc3cccc1c32
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CC2CC3OC3c3cccc1c32
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution was prepared from 2.71 g. of 1-benzoyl-1,2,2a,3-tetrahydrobenz[cd]indole in 100 ml. of chloroform. A second solution containing 2.1 g. of 85% m-chloroperbenzoic acid in 100 ml. of chloroform was added. The reaction mixture was stirred at ambient temperature for 41/4 hours. TLC of an aliquot of the solution indicated that most of the starting material had been comsumed. The reaction mixture was diluted with water and the organic layer washed with 1N aqueous sodium hydroxide, with water and with saturated aqueous sodium chloride. The organic layer was dried and the solvent removed therefrom by evaporation in vacuo. The resulting residue containing 1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole formed in the above reaction was dissolved in chloroform and the chloroform solution filtered through florisil. The chloroform was evaporated from the filtrate and the resulting residue crystallized from a mixture of ether and hexane, yielding 1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole melting in the range 103°-115° C. (the above procedure is based upon that of Kornfeld et al., J. Am. Chem. Soc., 78, 3101 (1956))