Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]=[C:46]=[O:47])[CH:40]=1.C(N(CC)CC)C>CN(C)C=O>[O:28]=[C:26]1[NH:25][C:24](=[O:29])[CH:23]([CH2:22][C:21]2[CH:30]=[CH:31][C:18]([O:17][CH2:16][C:14]3[N:13]([CH3:32])[C:12]4[CH:33]=[C:8]([O:7][C:6]5[CH:5]=[C:4]([NH:3][C:46]([NH:45][C:41]6[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:37])([F:48])[F:49])[CH:40]=6)=[O:47])[CH:36]=[CH:35][CH:34]=5)[CH:9]=[CH:10][C:11]=4[N:15]=3)=[CH:19][CH:20]=2)[S:27]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), α,α,α-trifluoro-m-tolyl isocyanate (149 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→ethyl acetate as the eluant and the product was recrystallized from a mixture of methanol and diisopropyl ether (1:3) to afford the title compound (239 mg, mp 161.8-163.4° C.).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(N(C)C)=O.O>[CH3:11][O:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1ccnc(Cl)c1C#N
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccnc(Oc2ccccc2)c1C#N
Temperature: 75 °C
Yield: 70.4 %

Procedure:
A solution of 2-chloro-4-methoxynicotinonitrile (1.02 g) in dimethylacetamide (30 mL) was treated with cesium carbonate (2.96 g) followed by phenol (0.683 g) at room temperature. The mixture was heated to 75° C. overnight. The mixture was cooled to room temperature, diluted with water (100 mL) and the precipitated solids collected by filtration, to provide the title compound (0.964 g) with the following physical data.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[CH:17][CH:16]=2)[C:5]=1[C:6]([NH2:8])=[O:7].Cl.[CH2:30]([OH:33])[CH2:31][CH3:32]>O>[Cl:13][C:11]1[CH:10]=[C:9]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])=[CH:19][CH:20]=2)[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:33][CH2:30][CH2:31][CH3:32])[N:12]=1
Reactant: CCCO
Reactant: NC(=O)c1c(Nc2ccc(C(=O)N3CCOCC3)cc2)cc(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCOc1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of powdered solid sodium hydroxide (121 mg, 3.04 mmol) in 1-propanol (10 mL) was stirred at rt until the solid material dissolved. Then 2,6-dichloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (600 mg, 1.518 mmol) was added and the mixture was stirred. The resulting suspension was placed in a heating block at 60° C. for 2 hrs. Next, the reaction mixture was cooled to rt and acidified with HCl (4 ml, 1N) and diluted with water. The cloudy precipitate was extracted into CH2Cl2 and concentrated to give 600 mg of light yellow solid. LCMS: (M+H)+=419.20, 421.19 (Cl pattern).
Reaction SMILES: [F:1][C:2]1([F:34])[O:6][C:5]2[CH:7]=[C:8]([OH:33])[C:9]([C:11]3(O)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]3=[O:31])=[CH:10][C:4]=2[O:3]1.FC1(F)OC2C=C(O)C(C3(O)C4C(=CC=CC=4)N(CC4OC(C(F)(F)F)=CC=4)C3=O)=CC=2O1>>[F:34][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]([OH:33])[C:9]([CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]3=[O:31])=[CH:10][C:4]=2[O:3]1
Reactant: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C1(O)c1cc2c(cc1O)OC(F)(F)O2
Agent: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc2c(cc1O)OC(F)(F)O2
Product: O=C1C(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc2N1Cc1ncccc1C(F)(F)F

Procedure:
Following the procedure described in PREPARATION 71B and making non-critical variations using 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-one to replace 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one, 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-one was obtained (91%) as a colorless amorphous solid: MS (ES+) m/z 465.2 (M+1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[C:28](O)(=[O:32])[CH2:29][CH2:30][CH3:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CCCC(=O)O
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (9 mg, 31%), MS (ISP) m/z=402.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and butyric acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1
Product: Cc1cc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c(C)n1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4-chloro-2,6-dimethyl-3-nitropyridine (Tanaka, A.; et al. J. Med. Chem., 1999, 41, 4408.) and 4-aminophenylethyl alcohol.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.O.[C:17]([O:21][C:22]([NH:24][C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C(=O)CCC1=O.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>C(OCC)(=O)C>[CH3:29][CH:27]([CH3:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[C:30]([N:50]1[CH2:51][CH2:52][N:47]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=2)[CH2:48][CH2:49]1)=[O:32]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc(N2CCNCC2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
Under cooling with ice, an ethyl acetate solution (40 ml) of N,N'-dicyclohexylcarbodiimide (10.3 g) was added dropwise to an ethyl acetate solution (150 ml) containing tert-butoxycarbonyl-L-leucine monohydrate (12.5 g) and N-hydroxy succinimide (5.76 g), and the mixture was stirred at room temperature for 3 hours. While cooling again with ice, 1-(2-pyridyl)piperazine (8.16 g) was added, and the mixture was stirred overnight at room temperature. The precipitate was removed by filtration, and the filtrate was washed first with an aqueous sodium carbonate solution and then with a saturated sodium chloride solution, dried over sodium sulfate and distilled under reduced pressure to remove the solvent, whereupon a crude reaction mixture was obtained. The reaction mixture was purified by silica gel column chromatography (developing solvent:methylene chloride:methanol=10:1) to yield 16.1 g of tert-butyl (s)-3-methyl-1-[4-(2-pyridyl)piperazine-1-yl carbonyl]butylcarbamate (yield: 85.6%).
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[C:2]([CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:7]([O:8][CH3:9])[N:6]=[CH:5][N:4]=1
Reactant: COc1ncnc(OC)c1Br
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ncnc1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of 5-bromo-4,6-dimethoxypyrimidine (473 mg; 2.15 mmol) in anh. THF (5 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.50 ml; 2.40 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (503 mg; 2.15 mmol) in anh. THF (2 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 60 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (15 ml), Et2O (30 ml) and water (15 ml). The separated organic layer was then washed with brine (15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 5-(4,6-dimethoxypyrimidin-5-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate as a yellow solid. LC-MS (conditions A): tR=0.66 min.; [M+H]+: 374.06 g/mol.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:13])[CH:7]([C:11]#[N:12])[CH:8]1[CH2:10][CH2:9]1)C>C1COCC1>[C:11]([CH:7]([CH:8]1[CH2:10][CH2:9]1)[C:6]([OH:13])=[O:5])#[N:12]
Reactant: CCOC(=O)C(C#N)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#CC(C(=O)O)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
IN NaOH (3.26 ml, 3.26 mmol) was added to a solution of cyano-cyclopropyl-acetic acid ethyl ester (0.5 g, 3.26 mmol) in THF (15 ml). After 4 hours stirring at 25° C., the reaction mixture was evaporated in vacuo, re-dissolved in water (20 ml) and neutralized by the addition of IN IICl solution (3.26 ml). This mixture was then extracted with EtOAc (3×20 ml) and the combined, dried (Na2SO4) organics evaporated in vacuo to give impure cyano-cyclopropyl-acetic acid as a clear oil. This material was used without any further purification in the preparation of Example 4B.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.[C:16]([O:19][CH2:20][CH3:21])(=O)C.[CH3:22][N:23](C)[CH:24]=[O:25]>>[OH:12][C:9]1[CH:8]=[CH:7][C:22]2[N:23]([CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=3)[C:24](=[O:25])[CH2:16][O:19][C:20]=2[CH:21]=1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: COc1ccc(CCBr)cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CCN2C(=O)COc3cc(O)ccc32)cc1OC

Procedure:
A solution of the amide (0.50 mmol) was added to a mixture of sodium hydride (2.3 mmol) and dimethyl formamide (2.0 ml). After stirring for 30 min a solution of 1-bromo-2-(3,4-dimethoxyphenyl)ethane (0.50 mmol) in dimethyl formamide (1.0 ml) was added at 0° C. After 2 h an aqueous workup with ethyl acetate was performed. The organic layers were dried with magnesium sulfate and concentrated. Purification by flash chromatography provided the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].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.[CH3:66][N:67]([CH3:71])[CH2:68][CH2:69][NH2:70]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:70][CH2:69][CH2:68][N:67]([CH3:71])[CH3:66])=[O:20])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 34.4 %

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7)(90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.110 mL, 0.632 mmol). After stirring for 5 min, the mixture was treated with N1,N1-dimethylethane-1,2-diamine (37.1 mg, 0.421 mmol). After stirring for 3 min, the solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 (×3), then dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was subsequently dissolved in MeOH and dried (hydrophobic frit). The solvent was removed and the residue triturated in Et2O to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)nicotinamide (36 mg, 0.072 mmol, 34.4% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[F:21])=[CH:10][C:9]([C:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]=1)=[C:8]([O:35][CH3:36])[CH:7]=2)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:35][CH3:36])=[C:9]([C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]=3)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:1]#[N:2]
Reactant: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCNCC1
Yield: 63 %

Procedure:
A solution of tert-butyl 4-(3-cyano-4-(2-fluoro-4-methylphenylamino)-7-methoxycinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Method 85, 600 mg, 1.23 mmol) in CH2Cl2 (4.9 mL) and trifluoroacetic acid (4.9 mL, 63.6 mmol) was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with chloroform to remove trifluoroacetic acid, and the residue purified with reverse phase HPLC (MeCN/water) to give 302 mg (63%) product. m/z 390.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[OH:8][C:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][CH2:22][NH:23]S(C3C=CC(C)=CC=3)(=O)=O)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11].[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[OH:8][C:9]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N+:15]([CH2:21][CH2:22][NH:23][C:53]([NH:52][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:54])([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NCC[N+]23CCC(CC2)[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C3)cc1
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])C(F)(F)F
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)Nc1ccccc1

Procedure:
This compound is made analogously to (R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 49) by replacing p-toluenesulfonyl chloride with phenyl isocyanate.
Reaction SMILES: ClCCl.[CH2:4]([C@H:6]1[O:8][CH2:7]1)[Cl:5].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OC)(C)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Cl:5][CH2:4][C@@H:6]([OH:8])[CH2:7][O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC[C@@H]1CO1
Reactant: Oc1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O[C@H](CCl)COc1ccccc1
Reaction time: 1 h
Yield: 115.8 %

Procedure:
To a mixture of N′,N′-disalicylidene ethylenediaminatocobalt(II) (173 mg, 0.532 mmol) and dichloromethane (13 ml) was added (±) camphorsulfonic acid (148 mg, 0.638 mmol) and the reaction system was stirred for 1 hour while being filled with air. The reaction solution was evaporated to dryness under reduced pressure to give a crude blackish (dark) brown cobalt (III) complex. Thereto was added tert-butylmethyl ether (5 ml) to disperse the crude cobalt (III) complex and then thereto were added (S)-epichlorohydrin (2.50 ml, 31.9 mmol, optical purity 99% e.e.) and phenol (2.50 g, 26.6 mmol) in order. The mixture was stirred for 24 hours under nitrogen atmosphere at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (20 ml), the solution was washed with a 6% aqueous sodium hydroxide solution (10 ml) and a saturated sodium chloride solution (10 ml) in order, and the organic layer was condensed under reduced pressure to give crude (S)-1-chloro-3-phenoxy-2-propanol (5.75 g). This crude compound (5.75 g) was dissolved in isopropanol (10 ml) and thereto was added a 24% aqueous sodium hydroxide solution (6.64 g, 39.8 mmol) under ice-cooling. The mixture was stirred for 1 hour at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (50 ml) and the solution was washed with water (20 ml), a saturated aqueous ammonium solution (20 ml) and a saturated aqueous sodium chloride solution (20 mm) in order. The organic layer was condensed under reduced pressure to give (R)-glycidylphenyl ether (3.96 g). Quantitative analysis by gas chromatography and optical purity measurement by HLPC were conducted on the compound. As a result the subject compound, (R)-glycidylphenyl ether (3.80 g, 95.4%) was produced with optical purity at 99% e.e.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([O-:28])=[O:27].O>C(Cl)Cl>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([S:35]([O:1][CH2:2][C@H:3]2[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)(=[O:37])=[O:36])=[CH:33][CH:34]=1)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)OC(C)(C)O1
Reaction time: 22 h
Yield: 110.5 %

Procedure:
To a stirring 20°-25° C. solution of the (4R-cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2-dimethyl-1,3- dioxane-4-acetate (European Patent Application 0319,847) (10 g, 0.038 mol) in methylene chloride (250 mL) containing triethylamine (7 mL, 0.05 mol) is added 4-nitrobenzenesulfonyl chloride (10.5 g, 43 mmol). Stirring is continued at 20°-25° C. for 22 hours, the solution is poured onto 200 mL of water and the layers separated. The upper aqueous layer is extracted with 250 mL of methylene chloride and the combined organic layers are washed with 100 mL each of saturated sodium bicarbonate solution to ensure complete removal of 4-nitrobenzenesulfonyl chloride and then saturated sodium chloride solution. Drying the solution with magnesium sulfate and concentration in vacuo gives 18.7 g of the product as a brown oil which solidifies immediately.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH2:22])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:24])([F:25])[F:26])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH:22][C:30](=[O:31])[CH2:29][C:28]([F:34])([F:33])[F:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: O=C(O)CC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(F)(F)F)NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-amine (0.1 g, 0.247 mmol) in CH2Cl2 (10.0 ml) was added 3,3,3-trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIPEA (0.047 g, 0.370 mmol) and the reaction was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, and the separated CH2Cl2 layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400 MHz, CDCl3) δ 7.32, (d, J=6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J=8.0, 1H), 7.14 (d, J=8.8, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z 514.86 ([M+H]+); IR (thin film) 3428, 1112, 857 cm−1.