Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]([CH3:33])[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[OH:15][C:13]1[CH:12]=[C:11]([CH:23]([CH3:33])[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=[C:9]([OH:8])[CH:14]=1
Reactant: CC(CCOc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(CCOc1ccccc1)c1cc(O)cc(O)c1
Reaction time: 2 h

Procedure:
A solution of 3-(3,5-dibenzyloxyphenyl)-1-phenoxybutane (14.7 g., 133.5 mM) in a mixture of ethyl acetate (110 ml.), ethanol (110 ml.) and concentrated hydrochloric acid (0.7 ml.) is hydrogenated for 2 hours under 60 p.s.i. hydrogen in the preseence of 10% palladium-on-carbon (1.5 g.). Removal of the catalyst by filtration and concentration of the filtrate gives an oil. The oil is purified by chromatography on silica gel (100 g.) and eluting with benzene-ethyl acetate consisting of 0-10% ethyl acetate. The middle fractions are combined and concentrated to give the title product: 7.8 g. (80%), as an oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)CC1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 168) (598 mg, 1.18 mmol) and N-methylpiperazine (120 mg, 1.18 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=O)=[C:11]([CH:16]=2)[C:12](OC)=[O:13])=[CH:4][C:3]=1[O:23][CH3:24].[NH2:25][C@@H:26]1[C@@H:31]([OH:32])[CH2:30][CH2:29][O:28][CH2:27]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[CH:16]=[C:11]3[C:10]([CH2:17][N:25]([C@@H:26]4[C@@H:31]([OH:32])[CH2:30][CH2:29][O:28][CH2:27]4)[C:12]3=[O:13])=[C:9]([CH3:19])[C:8]=2[CH3:20])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(F)c(OC)c2)c(C)c(C)c1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1cc(Cc2cc3c(c(C)c2C)CN([C@H]2COCC[C@@H]2O)C3=O)ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
To a solution of methyl 5-(4-fluoro-3-methoxybenzyl)-2-formyl-3,4-dimethylbenzoate (0.35 g) in THF (4.00 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.12 g) and anhydrous magnesium sulfate (0.26 g), and the mixture was stirred at room temperature for 5 hr under nitrogen atmosphere. The insoluble substance was removed by filtration, the filtrate was concentrated, and the residue was diluted with methanol (2.00 mL)-THF (4.00 mL). Sodium triacetoxyborohydride (0.45 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.13 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-ol, sodium hydride and DMF was stirred for 5 minutes at room temperature, then 2-chloro-N,N-dimethylethylamine was added to the resultant and further stirred for 30 minutes at room temperature to give 2-[(1-tert-butoxycarbonylpiperidine-4-yl)oxy]-N,N-dimethylethylamine. A mixture of the obtained 2-[(1-tert-butoxycarbonylpiperidine-4-yl)oxy]-N,N-dimethylethylamine and 4M HCl-dioxane solution was stirred for 7 hours at room temperature to give N,N-dimethyl-2-(piperidine-4-yloxy)ethylamine dihydrochloride.
Reaction SMILES: [C:1]1(O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([O-:12])([O-])([O:9][CH3:10])[CH3:8]>>[CH2:3]([C:1]1[C@@H:5]([CH2:8][C:7]([O:9][CH3:10])=[O:12])[CH2:4][CH2:3][CH:2]=1)[CH2:2][CH2:1][CH2:5][CH3:4]
Reactant: OC1=CCCC1
Reactant: COC(C)([O-])[O-]
Product: CCCCCC1=CCC[C@@H]1CC(=O)OC

Procedure:
Process according to claim 8, wherein said cyclopentenol is reacted with methyl orthoacetate in the presence of pyvalic acid to provide (+)-methyl (1R)-2-pentyl-2-cyclopentene-1-acetate.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][CH2:21]OS(C)(=O)=O)[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].O1CCOCC1>C1COCC1>[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:21][CH2:20][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[O:12]1)[CH3:28]
Reactant: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCN(CC)CCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A solution of methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester (50 mg, 0.135 mmol) and diethylamine (279 μl, 2.7 mmol) in THF (0.8 ml) was heated at 60° C. After 3 hours, dioxane (0.3 ml) was added to give a solution and the reaction continued at 60° C. for 24 h. The reaction was partitioned between EtOAc and water. The EtOAc layer was washed with water, brine, dried with anhydrous Na2SO4 and rotary evaporated to give brown oil. The brown oil was chromatographed (CHCl3 to 2% MeOH/CHCl3 gradient) to yield 3-[3-(2-diethylamino-ethyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow-green solid (33 mg, 71%).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:11])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[OH:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][O:20]2)=[CH:15][CH:14]=1>>[CH3:11][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][O:20]2)=[CH:15][CH:14]=1
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: CC(C)=CCCC(C)=CCBr
Product: CC(C)=CCCC(C)=CCOc1ccc2c(c1)OCCC2

Procedure:
Following the procedure of Example 1, 1-bromo-3,7-dimethyl-2,6-octadiene and 7-hydroxy-chromane are reacted to form 7-(3,7-dimethyl-2,6-octadienyloxy)-chromane; nD20 = 1.5359.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:21])[N:13]=[C:14](S(C)(=O)=O)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:21])[N:13]=[C:14]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(-c3ccc(F)cc3)nc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 60 °C
Yield: 66.4 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-methylsulfonyl-thiazolo[5,4-d]pyrimidin-5-amine (0.40 g, 1.23 mmol) and triethylamine (0.26 ml, 1.85 mmol) in dioxane (6 ml) was added piperazine (0.16 g, 1.85 mmol). The reaction mixture was heated at 60° C. for 5 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 15:1), furnishing the title compound as a light yellow solid (0.27 g, 67%).
Reaction SMILES: [Cl:1][C:2]12[C:15]([Cl:17])([Cl:16])[C:5]([Cl:18])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[C:8]([Cl:13])[C:7]3=[O:14])[C:4]([Cl:19])=[C:3]2[Cl:20].CO>N1C=CC=CC=1>[Cl:1][C:2]12[C:15]([Cl:16])([Cl:17])[C:5]([Cl:18])([C:6]3[C:7]([OH:14])=[C:8]([Cl:13])[CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:19])=[C:3]2[Cl:20]
Reactant: O=C1C=C(Cl)C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: Oc1cc(Cl)c(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
A mixture of 256 grams (0.62 mol.) of 1,2,3,4,6,9,9-heptachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared according to Example 24, and 500 ml. of methanol in a 2 liter reaction flask was stirred at room temperature while air in the reaction vessel was swept out with nitrogen. Six ml. of pyridine was then added to the liquid-solid mixture. The resulting reaction mixture was continuously stirred, and refluxed vigorously for 8.5 hours. After cooling the mixture to 0° C., it was filtered, and the crude solid was washed with cold Skellysolve. Yield 121 grams. The product was recrystallized from a mixture of 1000 ml. of Skellysolve and 250 ml. of acetone. M.P. 120.5°-122° C. The product has the following ##STR58##
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:22](=[O:23])[CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1)N1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzylpiperazine (8g, 45.4 mmol), 3-fluorophenyl acetic acid (7.7 g, 50 mmol), triethylamine (7 ml, 50.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.6 g, 50 mmol) were stirred together in dry dichloromethane (150 ml) for 24 hours. The volatiles were evaporated then the residue was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried then evaporated. The residue was purified by column chromatography on silica using 2% methanol in dichloromethane→10% methanol in dichloromethane. The title compound was obtained as a yellow oil (11.1 g, 77%). δ (250 MHz, CDCl3) 2.28 (2H, t, J=5 Hz), 2.42 (2H, t, J=5 Hz), 3.43 (2H, t, J=5 Hz), 3.44 (2H, s), 3.65 (2H, t, J=5 Hz), 3.71 (2H, s), 6.90-7.37 (9H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[S:14])[NH:12][N:13]=1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[C:11]([S:14][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:10]=1
Reactant: BrCc1ccccn1
Reactant: Cc1ccc(-c2n[nH]c(=S)[nH]2)c(C)c1
Agent: Br
Product: Cc1ccc(-c2nc(SCc3ccccn3)n[nH]2)c(C)c1
Yield: 64 %

Procedure:
Prepared in a similar manner to example 1 using 5-(2,4 dimethylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 3a) and 2-(bromomethyl)pyridine hydrobromide. Yield 64%. 1H NMR (500 MHz, CDCl3): δ 2.34 (s, 3H), 2.57 (s, 3H), 4.37 (s, 2H), 4.51 (s, 2H), 7.04-7.08 (m, 2H), 7.28-7.31 (m, 1H), 7.41-7.43 (d, 1H), 7.74-7.77 (m, 2H), 8.63-8.64 (d, 1H). MS (M+H, 297); mp=112-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH2:13].[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[Cl:12][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11])[NH:1][C:15](=[O:16])[C:14](=[O:20])[NH:13]2
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2[nH]c1=O
Reaction time: 5 h
Yield: 86 %

Procedure:
A mixture of 1,2-diamino-4-chloro-5-trifluoromethylbenzene (13.4 g, 63.6 mmol) and diethyl oxalate (100 ml) was heated at reflux under nitrogen with stirring for 5 h. After being cooled, the solid which formed was filtered off and washed well with ether to afford a pale orange solid (14.5 g, 86%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:18])[C:5](=[N:10][NH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:19]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: COCC(=O)C(=NNc1ccncc1)C(=O)OC
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1nn(-c2ccncc2)cc(OC)c1=O
Yield: 44.8 %

Procedure:
A mixture of methyl 4-methoxy-3-oxo-2-(pyridin-4-ylhydrazono)butanoate (18 g, 70 mmol) and N,N-dimethylformamide dimethyl acetal (28 mL, 210 mmol) in toluene (210 mL) was refluxed for 4 h. The mixture was concentrated under reduced pressure to give black crystals. The crystals were washed with 2-propanol/AcOEt (1:4) to give the title compound (8.2 g, 45% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.99 (3H, s), 4.00 (3H, s), 7.62 (2H, dd, J=4.5, 1.5 Hz), 8.01 (1H, s), 8.79 (2H, dd, J=4.5, 1.5 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(Br)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1,3-dibromo-benzene.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1.[H][H]>C1COCC1.CO.[Pd]>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:18][CH:17]=1)=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2
Reactant: [H][H]
Reactant: Cc1ccc2ncc([N+](=O)[O-])c(Nc3ccc(C(C)(C)C#N)cc3)c2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2ncc(N)c(Nc3ccc(C(C)(C)C#N)cc3)c2c1

Procedure:
2-(4-(6-Methyl-3-nitroquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation 1,600 mg, 1.73 mmol) and 10% Pd—C (90 mg) were shaken in 15 mL of THF-MeOH (1:1) under 25 psi of hydrogen for 3 hours at RT. After completion of reaction, the catalyst was filtered-off and the filtrate was evaporated to dryness to obtain the title compound. Yield: 250 mg (46%); 1H NMR (DMSO-d6, 300 MHz): δ 8.507 (s, 1H), 7.819 (s, 1H), 7.698-7.726 (d, 1H, J=8.4 Hz), 7.641 (s, 1H), 7.211-7.239 (d, 2H, J=8.4 Hz), 7.164-7.198 (dd, 1H, J=8.4 Hz, 1.5 Hz), 6.503-6.532 (d, 2H, J=8.7 Hz), 5.178 (s, 2H), 2.358 (s, 3 Hs), 1.593 (s, 6H); MS: m/z 317 (M+).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:16]O>>[I:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1I
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)ccc1I

Procedure:
To a solution of 2,5-diiodobenzoic acid (1.00 g, 2.67 mmol) in anhydrous MeOH (15 mL) cooled in an ice-bath, SOCl2 (0.50 mL, 6.85 mmol) was cautiously added (exothermal reaction). After the addition, the solution was heated at reflux overnight. It was then concentrated in vacuo to give methyl 2,5-diiodobenzoate (1.04 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:6]2[CH:7]=[N:8][N:9]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:10]=2[CH:11]=1)#[N:2]>C(O)(=O)C.CO>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:6]2[CH:7]=[N:8][N:9]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:10]=2[CH:11]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C#N)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(CN)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 40 °C

Procedure:
6-cyano-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.10 g, 0.257 mmol) was suspended in acetic acid (8 mL). The contents were placed heated at 40° C. under an atmosphere of hydrogen (50 psi; H-cube reactor) at a flow rate of 1 mL/min with recirculation 2 h. Then contents were diluted with MeOH, concentrated in vacuo, and dried under hi vacuum for 18 h. The crude product was dissolved in DCM and purified by silica gel chromatography (eluent: 10-100% gradient of chloroform (containing 10% 2M ammonia in methanol) and dichloromethane. The product was concentrated from MTBE and dried in a vacuum oven at 45° C. for 4 h. The title compound was collected as 68 mg (66%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.75 (m, 2H), 1.82-1.93 (m, 2H), 1.94-2.04 (m, 2H), 2.06-2.17 (m, 6H), 2.21 (s, 3H), 3.85 (s, 2H), 4.35 (d, J=5.05 Hz, 2H), 5.14 (t, J=7.07 Hz, 1H), 5.89 (s, 1H), 7.54 (s, 1H), 7.76 (s, 1H), 8.27 (s, 1H), 8.32 (t, J=5.05 Hz, 1H); LC-MS (ES) m/z=394.0 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][OH:13].B.[K].O>C(O)(=O)C>[O:13]=[C:12]1[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=2)[CH2:8][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CO
Agent: B
Agent: [K]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
1.64 g of o-phthalaldehydic acid methyl ester and 1.5 g of p-aminophenylacetic acid were added to 30 ml of methanol to form a mixture which was agitated at room temperature for one hour and incorporated with 0.54 g of potassium boron hydride in several portions. The whole was reacted at room temperature for 15 hours and freed from the solvent by distillation at a reduced pressure to obtain a residue. The thus obtained residue was incorporated with 50 ml of water and then with a small amount of acetic acid to form an acidic solution, after which crystals precipitated from said solution were filtered off, dried and recrystallized from ethanol thereby to obtain 2.4 g of 1-oxo-2-{p-(carboxymethyl)-phenyl}-isoindoline having the following properties:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C([O:12][CH2:13][C:14]([N:16]([CH2:39][C:40]([OH:42])=[O:41])[C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[NH:26][C:27]([C:29]1[NH:33][C:32]2[C:34]([Cl:38])=[C:35]([Cl:37])[S:36][C:31]=2[CH:30]=1)=[O:28])=[O:15])(=O)C>C1COCC1>[C:40]([CH2:39][N:16]([C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[NH:26][C:27]([C:29]1[NH:33][C:32]2[C:34]([Cl:38])=[C:35]([Cl:37])[S:36][C:31]=2[CH:30]=1)=[O:28])[C:14](=[O:15])[CH2:13][OH:12])([OH:42])=[O:41]
Reactant: CC(=O)OCC(=O)N(CC(=O)O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CN(C(=O)CO)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
Potassium carbonate (20 mg) and MeOH (1 mL) were added to a solution of [[(acetyloxy)acetyl]((1R,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)amino]acetic acid (Method 19, 120 mg, 0.23 mmol) in THF (5 mL) and the reaction was stirred at ambient temperature for 24 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in water and acidified to pH 2.0 and then extracted into EtOAc (3×10 mL). The volatiles were removed by evaporation under reduced pressure to afford the title compound (110 mg, 100%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C1=O)(=[O:3])C.[CH3:27][N:28]([CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35]/[C:16](=[C:6]2\[C:1](=[O:3])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH2:8]([CH:10]1[O:12]C1)[Cl:9].Cl>>[ClH:9].[CH3:1][O:2][C:3]([CH2:4][C:5](=[NH:6])[O:12][CH2:10][CH2:8][Cl:9])=[O:7]
Reactant: ClCC1CO1
Reactant: COC(=O)CC#N
Agent: Cl
Product: COC(=O)CC(=N)OCCCl
Yield: 92 %

Procedure:
A mixture of 9.9 parts of methylcyanoacetate and 8.05 parts of epichlorohydrin was saturated with dry hydrogen chloride gas under ice-cooling and further cooled with icewater for one hour, followed by keeping in a refrigerator overnight. The resulting solid was washed with ethylether and dried to give 19.9 parts of 2-chloroethyl methoxycarbonylacetimidate hydrochloride. Yield 92% Melting point: 103 to 107°C (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: CCS(=O)(=O)Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) was added ethanesulfonyl chloride (25 mg, 0.19 mmol) and the reaction mixture was stirred at room temperature for about 3 hours. Additional sulfonyl chloride (25 mg, 0.19 mmol) was added and the reaction mixture was stirred for about 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in dichloromethane (10 mL) and washed with 1 N aqueous hydrochloric acid (10 mL). The organic portion was separated, dried under reduced pressure, and treated with hydrochloric acid (4 N in dioxane, 5 mL) and stirred at room temperature for about 12 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.29-7.48 (m, 5H), 5.64 (s, 2H), 3.29 (d, J=9.2 Hz, 2H), 1.31 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 383 (M+H)+.