Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][N:5]([CH2:43][C:44]([O:46]C)=[O:45])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[CH:9]=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:7]=1.[OH-].[Na+]>CO>[C:44]([CH2:43][N:5]([C:6]1[CH:7]=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:9]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[CH:11]=1)[CH2:4][C:3]([OH:48])=[O:2])([OH:46])=[O:45]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCOCCOCCOCC)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCOCCOCCOCC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 96 %

Procedure:
A solution of 1.76 g (2.58 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-octadecyloxy-5-(3,6,9-trioxaundec-1-yloxy)phenyl]glycine methyl ester and 2.2 ml (12.9 mmol) of 6 N NaOH in 75 ml of methanol was kept at room temperature for 70 hours. The solvent was removed at reduced pressure and the residue was acidified to pH 2. The product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 1.62 g (96% yield, mp 76°-78°) of N-[(Carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: C[O-].[Na+].[Cl-].[NH2:5][C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20]>CO>[Br:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:13][CH2:12][N:7]1[CH:8]=[CH:9][CH:10]=[N:11][C:6]1=[NH:5]
Reactant: Nc1nccc[n+]1CSc1ccccc1Br
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N=c1ncccn1CSc1ccccc1Br

Procedure:
To a solution of 5.4 g of sodium methoxide in 400 ml of methanol is added 33.4 g of 2-amino-1-[[(o-bromophenyl)thio]methyl]pyrimidinium chloride (from Example 3), and the mixture is stirred and heated under reflux for about 5 hours, and filtered while hot. The filtrate is concentrated in vacuo to dryness to give 1-[(o-bromophenylthio)methyl]-2-iminopyrimidine as a pale yellow crystalline solid after recrystallization from cyclohexane.
Reaction SMILES: C([O:8][C@@H:9]1[C@@:13]2([CH2:20][O:21][C@H:10]1[C@H:11]([N:22]1[CH:29]=[C:28]([CH3:30])[C:26](=[O:27])[NH:25][C:23]1=[O:24])[O:12]2)[CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])C1C=CC=CC=1.C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[S:16]([O:15][CH2:14][C@@:13]12[CH2:20][O:21][C@@H:10]([C@H:11]([N:22]3[CH:29]=[C:28]([CH3:30])[C:26](=[O:27])[NH:25][C:23]3=[O:24])[O:12]1)[C@@H:9]2[OH:8])([CH3:19])(=[O:17])=[O:18]
Reactant: Cc1cn([C@@H]2O[C@@]3(COS(C)(=O)=O)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1cn([C@@H]2O[C@@]3(COS(C)(=O)=O)CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O

Procedure:
An ethanol solution of Compound 2 (35 mg, 0.080 mmol) and cyclohexene (0.3 ml, 3.0 mmols) were added to an ethanol suspension of 30 mg of 20% Pd(OH)2/C, and the mixture was heated under reflux for 2 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. Then, the resulting 5′-O-mesyl-5-methyl-2′-O,4′-C-methyleneuridine (Compound 3) obtained as a white solid (27 mg) was used for the next reaction without being purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].[CH2:13]=[O:14].CO>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:13][OH:14])=[C:7]2[OH:12]
Reactant: Oc1ccnc2c(Cl)cccc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cnc2c(Cl)cccc2c1O

Procedure:
8-Chloro-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 8-chloro-4-hydroxy-3-hydroxymethylquinoline, m.p.>300° (from methanol).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH2:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: Cn1c(CN)cc2ccccc21
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc2ccccc2n1C

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (1-methyl-1H-indol-2-yl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.78 min.; [M+H]+: 379.31 g/mol.
Reaction SMILES: O[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[NH4+].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1nc2ccccc2[nH]1
Temperature: 0 °C

Procedure:
2-Hydroxy-1H-benzimidazole (62 g, 0.46 mole) was added to phosphorous oxychloride (200 mL) and the mixture was refluxed for 4.5 hours. The resulting solution was poured over 4 L of ice and the mixture was made strongly basic with ammonium hydroxide. The resulting solid was isolated by filtration, washed with water and dried to provide crude 2-chloro-1H-benzimidazole.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]2[C:33](=[O:42])[C:34]2[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[CH:18][CH:17]=1.[C:43]1(=O)[CH2:47][CH2:46][CH2:45][CH2:44]1>ClC(Cl)C>[CH:43]1([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[C@@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]3[C:33](=[O:42])[C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])=[CH:18][CH:17]=2)[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: O=C1CCCC1
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2c(C)cccc2F)[C@H]1c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2c(C)cccc2F)[C@H]1c1ccc(NC2CCCC2)cc1
Temperature: 45 °C
Yield: 90.2 %

Procedure:
Step c) NaBH(OAc)3 (14.12 g, 66.60 mmol) was added to a solution of ethyl (2R,3S)-2-(4-aminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate (16 g, 41.65 mmol), and cyclopentanone (10.51 g, 125 mmol) in dry dichloroethane (200 mL) at rt. The reaction mixture was heated to 45° C. for 3 h, cooled to rt, quenched with saturated aqueous NaHCO3 solution, extracted with dichloromethane, dried and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, ethyl acetate/hexanes 15-40%) to afford ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate as white solid (17 g, 90%). MS: (ES) m/z 453 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:7]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:6]=3[N:5]2[CH:23]=1.[Cl-].CC(=[NH2+])C.[CH3:29][N:30]([CH3:33])[CH:31]=O>>[CH3:29][N:30]([CH2:33][C:23]1[N:5]2[C:6]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:7]=3[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:9][CH2:10][C:4]2=[N:3][C:2]=1[CH3:1])[CH3:31]
Reactant: Cc1cn2c(n1)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: CN(C)C=O
Agent: CC(C)=[NH2+]
Agent: [Cl-]
Product: Cc1nc2n(c1CN(C)C)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 6.844 (20 mmol) of 2-methyl-8-chloro-6-(o-chlorophenyl)-4H-imidazo[1,2-a]-[1,4]benzodiazepine is treated with 40.0 mmol of dimethylmethylene ammonium chloride in dimethylformamide during 2 hours at 100° C. The reaction mixture is quenched on ice, neutralized with 10% aqueous sodium hydroxide and chromatographed over silica gel with 1 l. fractions of 3% methanol/97% chloroform solutions to give 1-(dimethylamino)methyl-2-methyl-8-chloro-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine of melting point 191°-194° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([CH2:28][N+:29]([O-])=O)[CH2:22][C:23](OCC)=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]2[CH2:28][NH:29][C:23](=[O:24])[CH2:22]2)([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C[N+](=O)[O-])C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCOC(=O)C1(C2CNC(=O)C2)CC(OCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A 11.45 g (25.26 mmol) portion of crude ethyl 3-[1-benzyloxy-3-(isoamyloxycarbonyl)cyclobutan-3-yl]-4-nitrobutanoate was dissolved in 200 ml of ethanol to which was subsequently added 10 ml of Raney nickel under an atmosphere of nitrogen. After replacing nitrogen with hydrogen, this was stirred at 50° C. for 5 hours under an atmosphere of hydrogen. After cooling in an ice bath, the reaction solution was filtered through celite and then the solvent was evaporated under a reduced pressure to give 6.51 g (19.5 mmol) of the title compound. The thus obtained compound was used in the following reaction without purification.
Reaction SMILES: CO[C:3](=[O:50])[C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C@H:24]([NH:42]C(OC(C)(C)C)=O)[C@H:25]([OH:41])[CH2:26][NH:27][C:28]3([C:31]4[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[CH:33][N:32]=4)[CH2:30][CH2:29]3)[CH:18]=2)[CH:5]=1.[OH-].[Na+].Cl.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>O>[C:37]([C:35]1[CH:34]=[CH:33][N:32]=[C:31]([C:28]2([NH:27][CH2:26][C@H:25]([C@@H:24]3[CH2:23][C:19]4[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=4)[O:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:6]4[CH:5]=[C:4]([CH:9]=[C:8]([CH3:10])[N:7]=4)[C:3](=[O:50])[NH:42]3)[OH:41])[CH2:29][CH2:30]2)[CH:36]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: COC(=O)c1cc(C)nc(OCCCCOc2cccc(C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CNC3(c4cc(C(C)(C)C)ccn4)CC3)c2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc2cc(n1)OCCCCOc1cccc(c1)C[C@@H]([C@H](O)CNC1(c3cc(C(C)(C)C)ccn3)CC1)NC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 60 mg (0.0868 mmol) 2-[4-(3-{(2S,3R)-2-tert-butoxycarbonylamino-4-[1-(4-tert-butyl-pyridin-2-yl)-cyclopropylamino]-3-hydroxy-butyl}-phenoxy)-butoxy]-6-methyl-isonicotinic acid methyl ester is treated with 0.17 ml 1N aq sodium hydroxide and stirred for 18 h. The mixture is acidified with 0.17 ml 1N aq hydrochloric acid and evaporated. The residue is taken up into 3 ml 4N hydrochloric acid in dioxan, stirred for 2 h and evaporated. The product is taken up in 20 ml DCM. To the stirred mixture at +4° C. is added subsequently 22.3 mg (0.13 mmol) HOBt, 25 mg (1.5 mmol) EDC and 0.048 ml N-methylmorpholine. The mixture is slowly warmed to rt and stirred 18 h. Water is added and the organic phase is washed with 5% aq sodium bicarbonate and brine, dried over sodium sulfate and chromatographed on silica gel using a gradient of DCM and MeOH/25% aq NH3 2-10%. The title compound is obtained as a colorless resin.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](OC)=O>>[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1ccncc1S(N)(=O)=O
Product: COC(=O)CC1=NS(=O)(=O)c2cnccc2N1
Temperature: 180 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
4-amino-pyridine-3-sulfonic acid amide (0.25 g, 1.44 mmol) was suspended in malonic acid dimethyl ester (5 mL, 43.75 mmol). The flask was purged with nitrogen and the mixture was stirred at 180° C. for 60 min. Upon cooling, the mixture was diluted with ethyl acetate (5 mL) causing immediate precipitation of an undesired side product. The solid was removed by vacuum filtration and rinsed with ethyl acetate (2 mL). The filtrate was passed through a plug of silica gel, eluting with ethyl acetate followed by 5% methanol in ethyl acetate. The fractions containing the 5% methanol in ethyl acetate were combined and concentrated in vacuo to afford the desired product, (1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-acetic acid methyl ester (0.135 g, 0.529 mmol, 37%) as a yellow oil. LC-MS (ESI) calculated for C9H9N3O4S 255.03. found 256.0 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+]([O-])=O)[CH:10]=2)[N:5]=[CH:4][N:3]=1.NC1C=C(F)C=CC=1C(O)=[O:20].C(N)=N.C(O)(=O)C>COCCO>[F:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[O:20])[NH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2cc(F)ccc12

Procedure:
4-Chloro-7-fluoro-6-nitroquinazoline (7) can be prepared by methods similar to those described in J. Med. Chem. 1996, 39, 918-928. Generally, 2-amino-4-fluoro-benzoic acid (1) can be reacted with formamidine (2) and acetic acid (3) in the presence of 2-methoxyethanol to provide 7-Fluoro-3H-quinazolin-4-one (4). The 7-fluoro-3H-quinazolin-4-one (4) can then be nitrated to 7-fluoro-6-nitro-3H-quinazolin-4-one (5), which can be treated with thionyl chloride to yield 4-chloro-6-nitro-7-fluoro-3H-quinazoline (6). The 4-chloro-quinazoline compound (6) can be combined with a desirably substituted aniline, represented above by 4-fluoro-3-chloro-aniline, in the presence of a tertiary amine and isopropanol to provide the 4-anilino-6-nitro-7-fluoro-quinazoline (7).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccccn1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6 g, 28.8 mmol) in toluene (150 ml) at 0° C., trimethylaluminum (2M solution in toluene, 21.6 ml, 43.2 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 2-cyanopyridine (6 g, 57.6 mmol) in toluene (150 ml) was added over 10 minutes and the reaction mixture was heated to 85-90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1500 ml) and filtered. The pale yellow solid (5.2 g, 66%) was used in the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16].C([N:22]([CH2:26][CH3:27])[CH:23]([CH3:25])C)(C)C.N1CCCC1>O1CCCC1>[N:22]1([S:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])(=[O:17])=[O:16])[CH2:23][CH2:25][CH2:27][CH2:26]1
Reactant: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)N1CCCC1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
A solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propane-1-sulfonyl chloride (0.288 g) in dry tetrahydrofuran (5 ml) was treated with N,N-diisopropylethylamine (0.350 ml) and pyrrolidine (0.10 ml) at 22° C. under nitrogen, and the mixture was stirred at 22° C. for 1 h. After standing overnight at room temperature, the mixture was partitioned between saturated aqueous sodium bicarbonate (10 ml) and ethyl acetate (2×10 ml). The organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo to give a white solid (0.145 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([O-:8])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][C:24]([CH2:27][NH2:28])=[CH:25][CH:26]=2)[N:21]=1>C(Cl)(Cl)Cl>[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][C:24]([CH2:27][NH:28][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:25][CH:26]=2)[N:21]=1
Reactant: COc1cc(C(=O)[O-])cc(OC)c1OC
Reactant: NCc1ccc(-c2csc(N)n2)s1
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)NCc2ccc(-c3csc(N)n3)s2)cc(OC)c1OC
Reaction time: 4 h

Procedure:
To a solution of 5.4 g of 3,4,5-trimethoxybenzoate in 100 ml of chloroform is added 4.0 g of 2-amino-4-(5-aminomethyl-2-thienyl)thiazole under cooling with ice at -5° C. to 0° C., and stirred at 15° C. to 25° C. for 4 hours. After the resulting mixture is cooled with ice, the precipitated crystals are collected by filtration and recrystallized from methanol to give 2-amino-4-[5-(3,4,5-trimethoxybenzoylaminomethyl)-2-thienyl]thiazole, melting at 217° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)\[C:17]#[N:18]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(F)cc2F)cc1OC
Yield: 31.2 %

Procedure:
2,4-Difluorobenzaldehyde (142 mg) and 3,4-dimethoxybenzyl cyanide (177 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (94 mg, yield: 31%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]([NH:7][O:8][C@H:9]1[C@H:14]([O:15][CH3:16])[C@H:13]([O:17][CH3:18])[C@@H:12]([O:19][CH3:20])[C@H:11]([CH3:21])[O:10]1)=[O:6].[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[N:34]=2)=[CH:29][CH:28]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]([N:7]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:47])([F:46])[F:48])=[CH:40][CH:39]=3)[N:34]=2)=[CH:29][CH:28]=1)[O:8][C@H:9]1[C@H:14]([O:15][CH3:16])[C@H:13]([O:17][CH3:18])[C@@H:12]([O:19][CH3:20])[C@H:11]([CH3:21])[O:10]1)=[O:6]
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CBr)cc3)n2)cc1
Reactant: COC(=O)CC(=O)NO[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)N(Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)O[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of N-((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yloxy)-malonamic acid methyl ester (P-5; 108 mg, 0.34 mmol) in dry THF (3 mL) was added 60% NaH (14.4 mg, 0.36 mmol) giving gas evolution. To this mixture was added 3-(4-bromomethylphenyl)-1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazole (P-7; 106 mg, 0.26 mmol), and the resulting mixture was heated to 50° C. for 21 h. The mixture was then allowed to cool to room temperature and diluted with EtOAc and washed with H2O. The aqueous fraction was extracted with EtOAc. The organic fractions were combined, washed with brine, dried with anhydrous Na2SO4 and evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 100% Hexane going to 50% EtOAc in Hexane over 15 min and then going to 100% EtOAc over an additional 20 min). The title product (56 mg, 34%) was isolated as a colorless glass: 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.17 (d, J=8.4 Hz, 2H), 7.90-7.70 (m, 2H), 7.41 (dd, J=9.9, 8.4 Hz, 4H), 5.42-5.09 (m, 2H), 4.76 (d, J=15.9 Hz, 1H), 3.83-3.05 (m, 18H), 1,41-1.20 (m, 3H); 13C NMR (151 MHz, CDCl3) δ 167.80, 148.87, 141.93, 137.72, 135.95, 130.20, 128.71, 127.19, 122.81, 121.66, 119.95, 105.05, 82.11, 81.97, 79.79, 76.81, 70.28, 70.04, 60.48, 59.63, 59.20, 58.37, 52.76, 41.66, 30.10, 18.58; ESIMS m/z 639 (M+H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:33]Br>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:33][C:32]3[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc(F)c(F)c2)cc1

Procedure:
The title compound was prepared in two steps in a manner similar to that described in Example 27 step D from methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 3,4-difluorobenzyl bromide, and was isolated as white solid after reverse phase chromatography (46%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.98 (s, 9H), 2.43 (s, 3H), 3.66 (s, 3H), 5.45 (s, 1H), 5.68-5.86 (m, 2H), 6.06 (d, J=2.8 Hz, 1H), 6.97-7.05 (m, 2H), 7.05-7.15 (m, 2H), 7.25-7.31 (m, 2H), 7.31-7.38 (m, 1H), 7.49-7.59 (m, 1H); LCMS (m/z) ES+=495 (M+1).
Reaction SMILES: CO[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.S(=O)(=O)(O)O.F[C:30](F)(F)C(O)=O>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH:8]2[C:3]3[C:4](=[C:20]([CH3:30])[CH:21]=[CH:22][CH:23]=3)[CH2:5][NH:6][CH2:7]2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccccc1CNCC(O)c1ccc(OC)c(OC)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: COc1ccc(C2CNCc3c(C)cccc32)cc1OC

Procedure:
900 mg of α-[[(2-methoxybenzylamino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 7 ml of trifluoroacetic acid, and after adding thereto 0.21 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 60 minutes. The reaction solution was concentrated, and subjected to zzeotropic distillation 3 times, and after adding chloroform, the mixture was basified by addtion of 28% aqueous ammonia. By a separating procedure, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue obtained was recrystallized from ethyl acetate-n-hexane, giving 440 mg of 4-(3,4-dimethoxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline, m.p. 86°-88° C.