Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].Cl[CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[N:28][C:29]([Cl:35])=[CH:30][CH:31]=2)[N:26]=1>>[Cl:35][C:29]1[N:28]=[C:27]2[C:32]([CH:33]=[CH:34][C:25]([N:16]3[C:17](=[O:24])[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]3[CH:4]([C:3](=[O:10])[CH:2]([CH3:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N:26]2)=[CH:31][CH:30]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)C(C)C)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 77.5 %

Procedure:
Ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-4-methyl-3-oxopentanoate may be prepared by working in a manner similar to that described in Example 23, but starting with ethyl 4-methyl-3-oxopentanoate (4.7 g), an oily suspension (50% by weight; 1.2 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.6 g). After recrystallization in diisopropyl ether, ethyl 2-[2-(7-chloro-1, 8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-4-methyl-3-oxopentanoate (7 g), m.p. 146° C., is thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CCOCC>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:11][CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:13])[CH3:12])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
To a stirred suspension of 2-tert-butoxycarbonylamino-2-methyl-1-propanol (5.7 g, 30.11 mmol) and powdered NaOH (6.7 g, 0.151 mol) in Et2O (200 mL) was added p-toluenesulfonyl chloride (6.9 g, 36.14 mmol) at room temp. The stirred resulting mixture was heated under reflux for 8 hr. After cooling, ice-water (100 mL) was added to the solution. Separated Et2O layer was washed with brine, dried over Na2SO4, and evaporated. To the residue was added n-hexane and triturated. The solid was collected to afford 8.5 g (82.2%) 2-tert-butoxycarbonylamino-2-methyl-1-propyl p-toluenesulfonate as a crystalline material. 1H-NMR (CDCl3) δ1.26 (s, 6H), 1.38 (s, 9 H), 2.37 (s, 3H), 4.05 (s, 2H), 4.49 (br, 1H), 7.34 (d, J=7.8 Hz, 2H), 7.78 (d, J=7.8 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[N:29]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: c1ccc2c(c1)CCN2
Product: O=S(=O)(Nc1nccnc1-c1ccc(CN2CCc3ccccc32)cc1)c1ccccc1C(F)(F)F
Yield: 66 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2,3-dihydro-1H-indole, the title compound was isolated as a yellow solid in 66% yield (94% purity by HPLC).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:14])[CH2:12][NH2:13])=[C:6]([O:15][CH3:16])[CH:5]=1)[CH:2]=[CH2:3].[CH:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:14])[CH2:12][NH:13][C:23]([C:19]2[CH:20]=[N:21][CH:22]=[CH:17][CH:18]=2)=[O:24])=[C:6]([O:15][CH3:16])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OC(=O)CN)c(OC)c1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCc1ccc(OC(=O)CNC(=O)c2cccnc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To a solution of Amino-acetic acid 4-allyl-2-methoxy-phenyl ester (510 mg, 1.7 mmol), in DCM (20 mL) were added niacin (0.23 g, 1.9 mmol), N-methyl morpholine (0.96 mL, 8.8 mmol), EDC.HCl (0.67 g, 3.5 mmol) at ice temperature (0° C.). The mixture was allowed to stir at room temperature (25° C.) over a period of 2 hrs. The resulting mixture was diluted with DCM (200 mL) washed with water (2×100 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was purified by silica gel column chromatography to obtain product as off-white solid (210 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][O-:12].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Cl)c1C#N
Yield: 98.5 %

Procedure:
2-Chloro-6-fluorobenzonitrile (Aldrich, 5.0 g, 32.1 mmol) was dissolved in MeOH (100 mL), NaOMe (7.4 mL of 25% wt. solution, 32.1 mmol) and refluxed 18 h. The mixture was concentrated poured into EtOAc/H2O and extracted with EtOAc to give the title compound (5.3 g, 59%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:37]3[C@H:33]2[CH2:34][NH:35][CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@@H:37]3[C@H:33]2[CH2:34][N:35]([C:22](=[O:24])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O[C@@]1(c2ccccc2)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
0.28 g of carbonyldiimidazole is added to a solution of 0.28 g of (2-methoxyphenyl)-acetic acid in 20 cm3 of dry methylene chloride. The mixture is stirred at room temperature for I hour and a suspension of 0.7 g of (3aS,4S,7aS)-4,7,7-triphenyl-perhydroisoindol-4-ol hydrochloride in 20 cm3 of dry methylene chloride and then 0.48 cm3 of triethylamine are subsequently added in succession. The reaction mixture is stirred at room temperature for 24 hours, diluted with 100 cm3 of methylene chloride, washed with 100 cm3 of water (twice) and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 16 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 7 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised in 16 cm3 of acetonitrile. The crystals are filtered off and dried. 0.3 g of (3aS,4S,7aS)-4,7,7-triphenyl-2-[(2-methoxyphenyl)-acetyl]-perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 236° C.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][N+:18]([O-])=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][N:18]=[C:19]([Cl:24])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1c2cc[n+]([O-])cc2OCCN1Cc1ccccc1
Solvent: O
Product: O=C1c2ccnc(Cl)c2OCCN1Cc1ccccc1
Yield: 94 %

Procedure:
A solution of the compound (0.23 g) obtained in step 4 in phosphorus oxychloride (1.0 mL) was stirred at 80° C. for 30 min. The reaction mixture was poured into water, and the resultant product was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane) to give 4-benzyl-9-chloro-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (0.23 g, 94%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[Cl:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:14])([F:15])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a solution of 6-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (31 mg, 0.12 mmol) in concentrated H2SO4 (0.3 mL) at 0° C. was added KNO3 (14 mg, 0.14 1 mmol, Baker). The mixture was stirred at 0° C. for 0.5 h and then at room temperature for 20 h and it was poured into ice water (2 g). The precipitate was collected by filtration, giving 31 mg of crude title compound. The sample was dissolved in 1N KOH (1 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl to give a yellow precipitate which was collected by filtration and then dried in air at 50° C. for 4 h to give the title compound (29 mg, 80%) as a yellow powder. Crystallization from DMSO/H2O gave pure compound (18 mg) as yellow microcrystals. mp: 342°-5° C., IR (KBr, cm-1): 3394, 3301, 3248, 3209, 1761, 1701, 1628, 1542. 1H NMR (DMSO-d6): δ7.618 (s, 1H), 12.351 (s, 1H), 12.552 (s, 1H). HRMS: calcd for C9H3ClF3N3O4 (M+) m/z: 308.9763, found: 308.9759.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=[CH:18][CH:17]=3)[N:12]=[CH:11][N:10]=2)[C@H:5]([OH:26])[C@@H:4]1[OH:27].CO[C:30](OC)([CH3:32])[CH3:31].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH3:31][C:30]1([CH3:32])[O:26][C@H:5]2[C@H:6]([NH:8][C:9]3[CH:14]=[C:13]([NH:15][C:16]4[C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[CH:19]=[CH:18][CH:17]=4)[N:12]=[CH:11][N:10]=3)[CH2:7][C@H:3]([CH2:2][OH:1])[C@H:4]2[O:27]1
Reactant: COC(C)(C)OC
Reactant: OC[C@H]1C[C@@H](Nc2cc(Nc3cccc4c3CCCC4)ncn2)[C@H](O)[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(Nc4cccc5c4CCCC5)ncn3)[C@@H]2O1
Reaction time: 55 h
Yield: 92.3 %

Procedure:
To a stirred solution of (1S,2R,3R,5R)-3-(hydroxymethyl)-5-{[6-(5,6,7,8-tetrahydronaphthalen-1-ylamino)pyrimidin-4-yl]amino}cyclopentane-1,2-diol (70.0 mg, 0.19 mmol) in acetone (5.00 mL) was added 2,2-dimethoxypropane (0.21 mL, 1.70 mmol) and pyridinium p-toluenesulfonate (57.0 mg, 0.23 mmol), and the mixture was stirred for 55 h. The reaction mixture was quenched by addition of saturated NaHCO3 solution (50.0 mL) and then extracted with ethyl acetate (3×50.0 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by flash chromatography (2 to 10% Methanol/DCM) to afford the title compound (72.0 mg, 85%) as a light yellow amorphous solid. LC/MS: Rt=1.59 min, ES+ 411.3 (AA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[CH:13][N:14](C)[C:10]=2[C:9]=1[C:18]#[N:19].Cl.[N:21]([O-])=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[N:21][N:14]([CH3:13])[C:10]=2[C:9]=1[C:18]#[N:19]
Reactant: O=N[O-]
Reactant: Cn1cnc2ccc(-c3ccccc3Cl)c(C#N)c21
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc2ccc(-c3ccccc3Cl)c(C#N)c21
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
The intermediate of Example 8B (126 mg, 0.49 mmol) was stirred in THF (3 mL) with water (2 mL) and 1N HCl (1 mL) at 0° C. Sodium nitrite (37 mg, 0.54 mmol) in water (0.5 mL) was added dropwise, and the reaction stirred for 30 min. The solution was quenched with sat. NaHCO3 solution and extracted with EtOAc. Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc/hexanes) gave 102 mg (78%) of the title compound as a pale orange solid. 1H NMR (400 MHz, CDCl3): δ 8.31 (d, 1H, J=8.4 Hz), 7.39-7.58 (m, 5H), 4.61 (s, 3H). MS (ES) [m+H] calc'd for C14H9N4Cl, 269, 271; found 269, 271.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.CC(C)=[O:22]>>[F:1][C:2]([F:18])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:22])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CC(C)=O
Product: O=C(O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 77 %

Procedure:
To a cold solution of 4′-trifluoromethoxy-biphenyl-4-carbaldehyde (0.9 g, 3.38 mmol) in acetone (10 mL) the Jone's reagent was added slowly at 0° C. drop wise until reaction completes. Acetone was removed completely and the residue was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated to obtain the title compound (0.7 g, 77%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br>CCOCC>[Br:17][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
4-Nitroacetophenone (25 g) in ether (250 ml) was treated with aluminium chloride (catalytic amount) followed by bromine (7.77 ml) for 10 minutes and the reaction was stirred for 30 minutes. The reaction was quenched with aqueous NaHCO3, the ether layer was separated, dried using Na2SO4 and concentrated. The residue was dissolved in EtOAc, dried using Na2SO4, and concentrated to get off white solid which was crystallized in EtOAc/Pet ether to yield 25.5 gm (69%) of the title compound. 1HNMR (CDCl3, 300 MHz): δ 8.19 (d, 2H), 8.36 (d, 2H), 4.47 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([O:14]CC)=O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[Na+].Cl.[OH:21][CH:22]1[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>CO.ClCCl.O>[OH:21][CH:22]1[CH2:25][N:24]([C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)=[O:14])[CH2:23]1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: OC1CNC1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(O)C1
Yield: 89.1 %

Procedure:
To a clear solution of ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.40 g, 1.83 mmol) in dry methanol (5 mL) was added sodium cyanide (18 mg, 0.37 mmol). A solution of 3-hydroxyazetidine hydrochloride (0.45 g, 2.84 mmol) and triethylamine (0.40 mL, 2.84 mmol) in methanol (5 mL) was added at ambient temperature. After stirring for 20 min water (20 mL) and dichloromethane (30 mL) were added. The layers were separated and the aqueous phase was extracted twice with dichloromethane (30 mL). The combined organic layers were evaporated. The crude product was then treated with toluene (5 mL), filtered, washed with toluene (5 mL) and dried in vacuo. There was obtained 0.40 g (90%) of 53A as a solid. 1H NMR (400 MHz, DMSO-d6): δ 3.84 (dd, 1H), 4.31 (m, 2H), 4.56 (m, 1H), 4.79 (dd, 1H), 5.87 (d, 1H), 7.64 (m, 3H), 8.05 (d, 2H), MS (APCI+) m/z 246 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([NH:28][CH2:29][C:30]4[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=4)[C:33]([O:35]C)=[O:34])=[O:27])[CH2:21]3)[CH:17]=[CH:16][N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([NH:28][CH2:29][C:30]4[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=4)[C:33]([OH:35])=[O:34])=[O:27])[CH2:21]3)[CH:17]=[CH:16][N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1cccc(CNC(=O)[C@H]2CCCN(c3ccnc(Nc4cc(OC)c(OC)c(OC)c4)n3)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nccc(N3CCC[C@H](C(=O)NCc4cccc(C(=O)O)c4)C3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 6 (353.7 mg, 0.660 mmol) in a mixture of dioxane (3302 μL) and water (3302 μL) was added lithium hydroxide monohydrate (27.7 mg, 0.660 mmol). The reaction was stirred at room temperature for 72 hours. The reaction mixture was then extracted with DCM. The aqueous layer was diluted with 1N HCl. A precipitate was formed and separated by filtration to give 7 as a light purple solid. 1H NMR (400 MHz, CDCl3 with 1% TFA) δ ppm 1.50-1.70 (m, 1H) 1.83-2.00 (m, 2H) 2.00-2.13 (m, 1H) 2.43-2.56 (m, 1H) 3.23-3.30 (m, 1H) 3.50-3.61 (m, 1H) 3.78-3.92 (m, 10H) 4.01 (d, J=14.08 Hz, 1H) 4.45 (d, J=10.76 Hz, 2H) 6.25-6.37 (m, 1H) 6.86 (s, 2H) 7.38-7.51 (m, 2H) 7.69 (d, J=7.43 Hz, 1H) 7.89-7.99 (m, 2H); M+H 522.23432.
Reaction SMILES: [CH:1]1([CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][NH:5]2)C[CH2:2]1.C(Cl)(=O)CC.C1(C(Cl)=O)CC1>>[CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1)[CH3:2]
Reactant: COc1cc2c(cc1OC)C(C1CC1)NCC2
Agent: CCC(=O)Cl
Agent: O=C(Cl)C1CC1
Product: CCC1NCCc2cc(OC)c(OC)cc21

Procedure:
1,2,3,4-Tetrahydro-1-ethyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1,2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxyisoquinoline but substituting in the first step propionyl chloride for cyclopropyl-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([N:20]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:21][C:22]([O:24]CC)=O)=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[OH-].[Na+].Cl.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CO.O.CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([N:20]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:21][C:22]([N:42]([CH2:43][CH3:44])[CH2:40][CH3:41])=[O:24])=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: CCNCC
Reactant: CCOC(=O)CN(c1ccc(OC)cc1)c1cccc2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)CN(c1ccc(OC)cc1)c1cccc2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl N-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl]-N-(4-methoxyphenyl)glycinate (20 mg, 0.039 mmol) in methanol (0.5 ml) was added 1N sodium hydroxide (0.5 ml). The mixture was stirred at room temperature for 1.5 h, then neutralized with 1N hydrochloric acid (0.5 ml) and concentrated to dryness. To a mixture of the residue, diethylamine (0.0081 ml, 0.079 mmol) and N,N-dimethylformamide (3 ml) were added triethylamine (0.011 ml, 0.079 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (22.4 mg, 0.079 mmol). The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed eluting with a 20% acetone/hexanes) to give the crude product. The crude product was purified by reverse phase HPLC (acetonitrile containing 0.1 trifluoroacetic acid/water containing 0.1% trifluoroacetic acid). The eluent was concentrated in vacuo and the residue was dissolved in methanol (2 ml) before 2M hydrogen chloride in diethylether (2 ml) was added. The mixture was concentrated in vacuo to give 9.6 mg (46%) of the title as a powder.
Reaction SMILES: [O:1]=[C:2]1[CH:10](SC)[C:9]2[C:4](=[C:5]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1>[Ni].O1CCOCC1>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CSC1C(=O)Nc2c(Oc3cccc4ccccc34)cccc21
Agent: [Ni]
Solvent: C1COCCO1
Product: O=C1Cc2cccc(Oc3cccc4ccccc34)c2N1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 68.1 %

Procedure:
A mixture of 2-oxo-3-methylthio-7-(α-naphthoxy)indoline (5.4 g) and Raney nickel (12 ml) in dioxane (70 ml) was stirred at 50° C. for 1.5 hrs. The reaction mixture was allowed to stand and the supernatant was separated by decantation. To the residue was added dioxane and the supernatant was separated again. The dioxane solutions were combined and filtered. The filtrate was evaporated in vacuo, and the oily residue (5.2 g) was crystallized by treating with ethanol to give 2-oxo-7-(α-naphtoxy)indoline (3.15 g). mp 158°-160° C.
Reaction SMILES: CN(C)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)=O.[CH3:18][S:19][C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1.C([O-])(=O)C.[Na+]>ClCCCl.O>[CH3:18][S:19][C:20]1[NH:21][C:22]([C:3](=[O:11])[C:4]2[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=2)=[CH:23][CH:24]=1
Reactant: CSc1ccc[nH]1
Reactant: CN(C)C(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: CSc1ccc(C(=O)c2ccc(F)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
A solution of N,N-dimethyl-4-fluorobenzamide (8.4 g, 0.05 moles) in anhydrous 1,2-dichloroethane (170 ml) containing phosphorous oxychloride (7.7 g, 0.05 moles) was heated at reflux temperature for 1 hour. At the end of this time 2-methylthiopyrrole (2.82 g, 0.025 moles) was added and heating was continued for an additional 0.5 hour. The solution was cooled to room temperature, and to the cooled solution was cautiously added, with good agitation, a solution of sodium acetate (12.3 g, 0.15 moles) in water (50 ml) and the mixture was then boiled under reflux for 1 hour. The organic phase was separated, washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel using ethyl acetate-hexane (1:9) as the eluting solvent. A yellow colored solid 2-(methylthio)-5-(4-fluorobenzoyl)pyrrole (3.2 g, 54%) was obtained which after crystallization from ether-hexane had m.p. 112°-113° C.