Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: CCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid (4.5 g) and 4-nitrophenol (2.75 g) in 35 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (3.4 g) and the mixture was stirred at room temperature for 4 hours. After the normal work up, crystallization of the crude ester from 2-propanol yielded 4.9 g of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 75°-76° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:16][NH:17][CH3:18]>O>[CH3:16][N:17]([CH3:18])[C:2]1[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: CNC
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Solvent: O
Product: COC(=O)c1cnc(N(C)C)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 2.5 g (10.43 mmol) of methyl 6-chloro-4-(trifluoromethyl)nicotinate and 18.4 ml (146 mmol) of a 40% solution of dimethylamine in water is heated at 100° C. for 1 hour. A precipitate is subsequently collected by filtering the cooled mixture and is washed with 150 ml of water. After drying under reduced pressure, 2.3 g of the expected compound are isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:11][CH2:12][CH3:13]
Reactant: COc1ccc(N)cc1
Reactant: CCCC=O
Product: CCCCNc1ccc(OC)cc1
Yield: 96.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4-methoxyaniline (500 mg, 4.06 mmol) and butyraldehyde (360 μL, 4.06 mmol) were converted to the title compound (700 mg, 88%). 1H NMR (CDCl3) δ 6.89-6.73 (m, 2H), 6.69-6.50 (m, 2H), 3.76 (s, 3H), 3.10 (t, J=7.2 Hz, 2H), 1.70-1.28 (m, 4H), 1.02-0.90 (m, 3H); MS(ESI+) m/z 180.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](O)=[N:4][CH:3]=1.N1C=CC=CC=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:5]1[C:6]2[N:7]([CH:8]=[CH:9][N:10]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc(O)c2nccn12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1cnc(Cl)c2nccn12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of 5-Methyl-imidazo[1,2-a]pyrazin-8-ol (1.32 g, 8.86 mmol) in POCl3 (25 mL) is added pyridine (0.53 mL, 6.6 mmol) and the reaction stirred at 120° C. under N2 atmosphere for 4 h 30 min. The reaction is cooled to 60° C. and poured into 80 g of ice and stirred for 1 h. The mixture is neutralized with NaOH (20%), extracted with CHCl3/IPA 9/1, dried with MgSO4 anh., filtered and concentrated to get a crude that is purified by column chromatography using a gradient of (DCM/MeOH:98/2 to 95/5) to give 8-Chloro-5-methyl-imidazo[1,2-a]pyrazine as a pale yellow solid (0.39 g, 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]([CH3:18])[CH2:13][CH2:14][C:15](O)=O)=[O:11].C(OC(=O)C)(=[O:21])C>>[CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:15][CH2:14][C:13](=[O:21])[N:12]([CH3:18])[C:10]1=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Cl)ccc1NC(=O)N(C)CCC(=O)O
Product: Cc1cc(Cl)ccc1N1CCC(=O)N(C)C1=O
Yield: 24.1 %

Procedure:
At first, 8.0 g (0.03 moles) of N-(2-methyl-4-chlorophenylcarbamoyl)-N-methyl-β-alanine was added to 250 ml of acetic anhydride, and the mixture was refluxed with heating for 2.5 hours. Acetic anhydride was removed therefrom by distillation under reduced pressure, and precipitated crystals were recrystallized from 60 ml of ethyl acetate and 150 ml of n-hexane, whereby 1.8 g of the desired compound was obtained as crystals having a melting point of 120° to 127° C. (yield: 24.1%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.[CH3:14][N:15]([CH3:23])[CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>C(Cl)Cl>[Br:8][C:4]1[N:3]=[C:2]([C:19]2([OH:22])[CH2:20][CH2:21][CH:16]([N:15]([CH3:23])[CH3:14])[CH2:17][CH2:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)C1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Product: CN(C)C1CCC(O)(c2cccc(Br)n2)CC1
Temperature: -78 °C
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, dissolve 2,6-dibromopyridine (10 g, 42.4 mmol) in anhydrous DCM (250 mL). Cool to −78° C. Add a solution of n-BuLi (1.6 M in hexanes) (29 mL, 46.2 mmol) very slowly via a syringe. After the addition, stir the reaction at −78° C. for 1 hr. Add a solution of 4-dimethylamino-cyclohexanone (5.4 g, 38.5 mmol) in anhydrous DCM (10 mL) dropwise to the reaction mixture via a syringe. Stir the reaction at −78° C. for 90 min. then allow to slowly warm to room temperature over 4 hr. Quench the reaction with saturated NaHCO3 solution. Dilute with more DCM, wash with more saturated NaHCO3 solution. Separate the organic layer, dry over anhydrous sodium sulfate, then evaporate the solvent under reduced pressure. Purify the residue by chromatography (silica gel, 6% 2M NH3-MeOH in DCM) to yield the desired 1-(6-bromo-pyridin-2-yl)-4-dimethylamino-cyclohexanol as a mixture of diastereomers (7.7 g, 67% yield): MS (ES): m/z=299 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:22]=[CH:23][N:24]=3)[CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:32]1[CH:33]=[C:34]([C:38]2[N:39]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:40]=[CH:41][N:42]=2)[CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1>[C:7]1([N:13]([C:36]2[CH:37]=[CH:32][CH:33]=[C:34]([C:38]3[N:39]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:40]=[CH:41][N:42]=3)[CH:35]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=[CH:23][N:24]=3)[CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(Nc2cccc(-c3nccn3-c3ccccc3)c2)cc1
Reactant: Brc1cccc(-c2nccn2-c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(N(c2cccc(-c3nccn3-c3ccccc3)c2)c2cccc(-c3nccn3-c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
Sodium tert-butoxide (1.082 g, 11.27 mmol), N-phenyl-3-(1-phenyl-1H-imidazol-2-yl)aniline (2.45 g, 7.87 mmol), 2-(3-bromophenyl)-1-phenyl-1H-imidazole (2.1 g, 7.04 mmol), tris(dibenzylideneacetone)palladium(0) (Pd2dba3) (0.161 g, 0.176 mmol) and 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (0.289 g, 0.704 mmol) were charged into the reaction vessel with 100 mL of toluene. This mixture was degassed with nitrogen then was heated to reflux for 24 h. The reaction mixture was cooled to room temperature then was partitioned with 100 mL of water. The toluene layer was separated and the aqueous was extracted with another 100 mL of toluene. The toluene extracts were combined, dried over magnesium sulfate then were filtered and stripped under vacuum. The crude residue was passed through a silica gel column (15-30% acetone/DCM) and was purified if necessary using neutral alumina chromatography (7-10% ethyl acetate/DCM) yielding N-phenyl-3-(1-phenyl-1H-imidazol-2-yl)-N-(3-(1-phenyl-1H-imidazol-2-yl)phenyl)aniline (1.35 g, 2.55 mmol, 36.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16]>C(#N)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N+:3]=1[O-:16]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(Cl)[n+]([O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
Urea hydroperoxid complex (1.19 g, 12.6 mmol) was added to a stirred solution of ethyl 6-chloronicotinate (1.10 g, 6.0 mmol) in acetonitrile (15 mL) at room temperature. This mixture was stirred for 10 min at 0° C. followed by slow addition of an acetonitrile solution (5 mL) of trifluoroacetic anhydride (2.52 g, 12.0 mmol). After the addition the mixture was stirred for 2 h at room temperature. Thereafter, the reaction mixture was diluted with a saturated aqueous NaHCO3 solution and extracted with dichloromethane. The organic phase was dried (Na2SO4) and concentrated to afford 0.98 g (81% yield) of the title compound as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.94 (s, 1H), 7.81 (dd, J=8.4, 1.6 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H); MS (EI) m/z 202 and 204 (M++1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:29][CH3:30])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[CH2:29]([N:9]1[C:8]2[CH:31]=[CH:32][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH3:30]
Reactant: CCn1c(Nc2nc3ccc(Oc4cccnc4)cc3s2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(Nc2nc3ccc(Oc4cccnc4)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 88.6 %

Procedure:
1-Ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylic acid (133.0 mg) was prepared by following General Procedure E starting from 1-ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylic acid methyl ester (155.0 mg) and sodium hydroxide (2.0 N solution, 1.0 mL) MeOH (0.5 mL) and THF (1.0 mL).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)NOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCC(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
N-(benzyloxy)-6-(BOC-amino)hexanamide (5.65 g, 16.8 mmol) was dissolved in methylene chloride (40 mL), and the resulting solution thus obtained was cooled at 0° C. The trifluoroacetic acid (2.5 mL, 34 mmol, 2.0 eq.) was added thereto slowly and stirred at room temperature for 24 hrs. The reaction proceeded until no starting material was detectable by TLC. The resulting reaction mixture thus obtained was distilled under a reduced pressure to remove the solvent and thus obtained the title compound quantitatively.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([CH2:26][C:27]#[N:28])=[CH:20][NH:21]2.[CH3:29][N:30]=[C:31]=[O:32]>O1CCCC1>[CH3:29][NH:30][C:31]([N:21]1[C:22]2[C:18](=[C:17]([Cl:16])[CH:25]=[CH:24][CH:23]=2)[C:19]([CH2:26][C:27]#[N:28])=[CH:20]1)=[O:32]
Reactant: N#CCc1c[nH]c2cccc(Cl)c12
Reactant: CN=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)n1cc(CC#N)c2c(Cl)cccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a solution of 2,2,6,6-tetramethyl piperidine (0.18 ml, 1.05 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) was added butyllithium (2.5M in hexanes; 0.42 ml, 1.05 mmol). The reaction was cooled to −78° C. and a solution of (4-chloro-1H-indol-3-yl)-acetonitrile (200 mg, 1.05 mmol) in anhydrous tetrahydrofuran (5 ml) was added, maintaining the temperature between −78° C. and −72° C. After 5 minutes, methyl isocyanate (0.06 ml, 1.05 mmol) was added. The dry ice bath was removed after 15 minutes and the reaction was allowed to stir overnight. After the solvent was removed under reduced pressure, the residue was partitioned between dichloromethane(100 ml) and saturated sodium chloride solution (5 ml). The organic extract was dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane to give 4-chloro-3-cyanomethyl-indole-1-carboxylic acid methylamide as a white solid (54 mg, 21%). 1H NMR (CDCl3) δ: 3.07 (d, 3H, J=4.7 Hz), 4.17 (s, 2H), 7.24 (m, 2H), 7.50 (s, 1H), 8.14 (m, 1H) M+247.
Reaction SMILES: [CH2:1]1[C:5]2(CCCC[C:6]2=[O:11])[CH2:4]CC1.C1(=O)CCCCC1.C[Mg]Cl.[Cl-].[NH4+].[CH3:24][C:25]1([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31][C:26]21[CH2:30][CH2:29][CH2:28][CH2:27]2>O1CCCC1>[C:6]([O:35][C:25]1([CH3:24])[CH2:34][CH2:33][CH2:32][CH2:31][C:26]21[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:11])[C:5]([CH3:1])=[CH2:4]
Reactant: O=C1CCCCC12CCCC2
Reactant: CC1(O)CCCCC12CCCC2
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O=C1CCCCC1
Product: C=C(C)C(=O)OC1(C)CCCCC12CCCC2
Temperature: 25 °C
Yield: 87 %

Procedure:
With stirring under nitrogen atmosphere at room temperature, a mixture of 100 g of spiro[4.5]decan-6-one (which had been synthesized from cyclohexanone by a method as described in A. P. Krapcho, Synthesis, 1974, p 383 and references cited therein) and 200 ml of tetrahydrofuran was added dropwise to a tetrahydrofuran solution of 1.28 mol methylmagnesium chloride (which had been prepared from 31.1 g of metallic magnesium, 400 ml of tetrahydrofuran and chloromethane), during which time the temperature was kept below 60° C. The reaction mixture was refluxed for 30 minutes, after which a saturated ammonium chloride aqueous solution was added to stop the reaction. Through ordinary work-up of extraction, washing and drying, and subsequent vacuum distillation, there was obtained 93.3 g (yield 87%) of the target compound, 6-methylspiro[4.5]decan-6-ol.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:23])([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:5][CH:4]=1)=[O:2].[Mn]([O-])(=O)(=O)=[O:31].[K+].O>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]([OH:31])=[O:2])=[CH:8][CH:7]=2)=[C:10]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=1)([CH3:23])[CH3:22])[CH3:21]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C(=O)O)cc2)c(OCCCOC)c1
Reaction time: 18 h
Yield: 96 %

Procedure:
Ethyl 3-[4′-formyl-2-(3-methoxypropoxy)biphenyl-4-yl]-3-methylbutanoate (1.0 g, 2.5 mmol) was dissolved in acetone (40 mL) and a solution of potassium permanganate (1.4 g, 8.8 mmol) and water (20 mL) was added at room temperature. The mixture was stirred for 18 hrs and then filtered. Dichloromethane was added and the mixture was then acidified at 0° C. with HCl 1N. The aqueous layer was extracted three times with dichloromethane and the combined organic layers were washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 1.0 g, (96%) of the desired product as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To a solution of the compound (3 g) obtained in Example 321 (1) in ethanol (5 ml) was added dropwise a 4N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the mixture was acidified with a 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.92 g) as foam. (2) N-{3-[2-[(4-Chloro-2-methoxyphenyl)imino]-4-(4-fluorophenyl)thiazol-3 (2H)-yl]propyl}glycine
Reaction SMILES: [F:1][CH:2]([F:12])[C@@:3]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6][S:7][CH3:8])[NH2:4].Cl.C(Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:12][CH:2]([F:1])[C@@:3]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6][S:7][CH2:8][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:4]
Reactant: ClCc1ccccc1
Reactant: CSCC[C@](N)(C(=O)O)C(F)F
Agent: Cl
Product: N[C@@](CCSCc1ccccc1)(C(=O)O)C(F)F

Procedure:
A mixture of α-difluoromethylmethionine (0.2 mole), concentrated hydrochloric acid (0.2 l) and benzylchloride (23 ml) is heated to reflux temperature for 24 hours. The reaction mixture is then concentrated under reduced pressure to a syrup which is dissolved in water. The aqueous solution is extracted with ether, and the aqueous phase is heated with charcoal and filtered. The precipitate is diluted with hot water to a volume of 100 ml and brought to a pH of about 4-5 by addition of aqueous ammonia. On cooling, α-difluoromethyl-S-benzylhomocysteine precipitates and is collected.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)=[O:15])[CH3:12].[Sn](Cl)(Cl)(Cl)Cl.Cl>C1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[C:19]([C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[NH:18][CH:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cc[nH]c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1c[nH]c(C(=O)c2cccnc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A solution of 2-chloronicotinoyl chloride (493 mg, 2.8 mmol) in benzene (1 mL) was added to a mixture of 1H-pyrrole-3-carboxylic acid ethyl ester (390 mg, 2.8 mmol) in benzene (3 mL), followed by a dropwise addition of tin (IV) chloride (0.5 mL). The mixture was stirred at room temperature under nitrogen for overnight. The reaction was treated with 2N HCl and extracted with ethyl acetate. The combined ethyl acetate was washed, dried and concentrated to give 390 mg (50%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [C:1]([CH2:5][OH:6])([F:4])([F:3])[F:2].C(Cl)(Cl)(Cl)Cl.B(F)(F)F>O>[F:2][C:1]([O:6][CH2:5][C:1]([F:4])([F:3])[F:2])([F:4])[F:3]
Reactant: OCC(F)(F)F
Agent: FB(F)F
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)COC(F)(F)F
Temperature: 150 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
Fifty grams (0.50 mol) of CF3CH2OH, 192 g (1.25 mol) of CCl4, 280 g (14 mol) of HF, and 7 g (0.1 mol) of BF3 were charged to a 1.2 liter metal tube and the mixture was agitated at 150° C. and autogeneous pressure for 8 hours. The tube was cooled and 300 mL of water was pumped in. The tube was brought to room temperature and volatiles (108.6 g) were transferred under vacuum to a 1 liter stainless steel cylinder fitted with a needle valve. The contents of the cylinder were held at 25° C. while low boilers were transferred out at 1 atmosphere and distilled from CaCl2 through a low-temperature still. A 2.5 mL foreshot having a boiling point range of -14° to 2.5° C., largely CF2Cl2, was followed by 62.7 g of product, boiling point range of 2.5° to 15° C. (mainly 8° to 9° C.), then 8 mL with a boiling point range of 15° to 23.5° C., largely CFCl3. The main product cut was shown by NMR and GC/MS to be 84% CF3CH2OCF3 with 6% CF2Cl2 and 10% CFCl3 also present, so that 2,2,2-trifluoroethyl trifluoromethyl ether was obtained in 63% yield, 52.7 g.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH:17]=[C:18]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][NH:23][CH2:24]2>COC(O)C>[NH:17]=[C:18]([N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][N:23]([C:2]1[NH:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=1)[CH2:24]2
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: N=C(c1cccc2c1CCNC2)N1CCOCC1
Agent: COC(C)O
Product: COc1cc2nc(N3CCc4c(cccc4C(=N)N4CCOCC4)C3)[nH]c(=O)c2cc1OC
Temperature: 95 °C
Reaction time: 18 h
Yield: 17.9 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b(0.159 g, 0.62 mmol) and 5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline 28a (0.179 g, 0.69 mmol) in methoxyethanol (10 mL) was heated to 95° C. with stirring for 18 h. the volatiles were evaporated and the residue was purified by flash column eluting with 2% methanol in dichloromethane containing 0.2% of ammonium hydroxide to yield 50 mg of 2-[5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinolin-2-yl]-6,7-dimethoxy-3H-quinazolin-4-one 901. The product was converted to the hydrochloric acid salt, mp. 249-251° C., [M+H]+=450.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO[CH:26](OC)[CH2:27][NH2:28].C(O)(C)C>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:26]=[CH:27][N:28]=[C:10]2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(NC(=O)c2ccncc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: COc1ccc(-n2ccnc2-c2ccncc2)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Preparation 87 (N-(4-methoxyphenyl)isonicotinamide, 1 g, 4.39 mmol) was dissolved in phosphorous oxychloride (POCl3) (5 mL) then phosphorous pentachloride (913 mg, 4.39 mmol) was added. The mixture was heated at 120° C. for 4 h. The POCl3 was removed in vacuo, aminoacetaldehyde dimethyl acetal (9.5 mL, 87.8 mmol) and isopropanol (10 mL) were added, and the mixture was stirred at 23° C. for ca. 16 h. The reaction mixture was concentrated in vacuo and concentrated hydrochloric acid (36.5%, 25 mL) in isopropanol (15 mL) was added. The reaction mixture was heated at 90° C. for 24 h. After cooling to 23° C., aqueous sodium hydroxide (1N) and aqueous sodium bicarbonate were added to obtain pH=8. The mixture was extracted with methylene chloride, was dried (MgSO4), and was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/hexanes/methanol (80:20:0 to 76:19:5) to afford 811 mg (74% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 160.069, 149.952, 144.142, 137.853, 131.004, 129.882, 127.414, 124.977, 122.195, 115.114, 55.808; MS (AP/Cl) 252.4 (M+H)+.