Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BH4-].[Na+].Cl>C(O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]([OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(O)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxy-5-(1-oxooctadecyl)benzoic acid (1.0 g) was added to 5 ml absolute ethanol, followed by 94 mg of NaBH4. The mixture was stirred at room temperature for 2 hours, then added to 10 ml of 0.1N HCl to give a solid. The solid was filtered, washed with 10 ml of water, dried in air and then at a pressure of 0.5 mm Hg at room temperature for about 65 hours to give the title compound, m.p. ca. 102° C. ##STR10##
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[N:5]=[C:6]([NH:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)(=O)C.O>[CH3:16][S:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]2[S:7][C:6]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[N:5][C:4]=2[CH3:3])=[CH:10][CH:11]=1)=[O:1]
Reactant: CSc1ccc(-c2sc(Nc3cnccn3)nc2C)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(C)=O)cc1
Yield: 32.4 %

Procedure:
Hydrogen peroxide solution (27% in water) (35 ml, 0.28 mmol) is added to a stirred suspension of [4-methyl-5-(4-methylsulfanyl-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine (27c) (0.090 g, 0.28 mmol) in acetic acid (5 ml). After 30 minutes the reaction is diluted with water and brought to pH 10 by addition of aqueous sodium hydroxide. The product is extracted with ethyl acetate (3×50 ml), the combined organic extracts are washed with brine (50 ml), dried (MgSO4) and the solvent removed to give the title compound as an orange solid (0.03 g).
Reaction SMILES: [C:1]([C:4]1([NH:10][S:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=O)=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[Na+].O>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[S:11][NH:10][C:4]3([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[C:1]=2[CH3:2])=[CH:16][CH:17]=1
Reactant: CC(=O)C1(NS(=O)(=O)Cc2ccc(Cl)cc2)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=C(c2ccc(Cl)cc2)SNC12CCCCC2
Temperature: 120 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To N-(1-acetylcyclohexyl)-(4-chlorophenyl)methane-sulfonamide (612 mg, 1.86 mmol), from Example 1, in dry DMF (6 mL) was added NaH (60%, 2.2 eq.) under Ar. The mixture was stirred overnight at 120° C., water was added and the solution was extracted with ethyl acetate. The organic layer was washed with NaCl solution and water, dried (Na2SO4) and concentrated. Recrystallization from ethyl acetate yielded 0.37 g (64%) of 3-(4-chlorophenyl)-4-methyl-2-thia-1-azaspiro[4.5]dec-3-ene, 2,2-dioxide, shown below as a solid. MS (IS): 312 [MH]+
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:16])[S:12][CH:13]=1)[C:6]([OH:8])=O)[CH3:2].[NH2:17][CH:18]1[C:39](=[O:40])[N:20]2[C:21]([C:36]([OH:38])=[O:37])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH2:32][C:33]([OH:35])=[O:34])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12>>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:16])[S:12][CH:13]=1)[C:6]([NH:17][CH:18]1[C:39](=[O:40])[N:20]2[C:21]([C:36]([OH:38])=[O:37])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH2:32][C:33]([OH:35])=[O:34])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12)=[O:8])[CH3:2]
Reactant: CCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Yield: 54.4 %

Procedure:
2-Ethoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (3.0 g.) and 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.12 g.) were reacted according to similar manners to those of Examples 1(b), 2(b), 3(b) and 6(b) to give 7-[2-ethoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.6 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1)(=[O:32])[CH3:31]
Reactant: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Temperature: 25 °C
Yield: 61 %

Procedure:
(E)-5-Amino-1-(2-pyridyl)-2-styryl-1H-benzimidazole (199 mg, 0.64 mmol) was dissolved in acetic anhydride (2 ml) and the solution was allowed to maintain at room temperature for 30 mm. Then the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 ml) and the aqueous mixture was extracted with ethyl acetate (100 ml). The organic extract was washed consecutively with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residual solids were purified by column chromatography (silica gel, 50 g; n-hexane/ethyl acetate (1/2)) and then recrystallized from ethyl acetate to afford 139 mg (61%) of the titled compound as yellow solids.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](=[O:18])[N:9]([CH2:14][CH2:15][CH2:16][OH:17])[N:10]=[CH:11][C:12]=1[OH:13].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:8](=[O:18])[N:9]([CH2:14][CH2:15][CH2:16][OH:17])[N:10]=[CH:11][C:12]=1[O:13][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: O=c1c(Cl)c(O)cnn1CCCO
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1CCCO
Yield: 74.7 %

Procedure:
To 150 ml of N,N-dimethylformamide were added 10.2 g of 4-chloro-5-hydroxy-2-(3'-hydroxypropyl)-3(2H)-pyridazinone (0.05 mol), 8.4 g of 4-chlorobenzyl chloride (0.052 mol) and 10.4 g of anhydrous potassium carbonate (0.075 mol) and heated for about 3 hours at 100° C. to 120° C. After reaction, the mixture solution was poured into water and extracted with ethyl acetate. The resulting solution was washed with water and then with aqueous solution of 5% sodium hydroxide and further with saturated saline. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The solid product thus obtained was washed with n-hexane and dried to obtain 12.3 g of 4-chloro-5-(4'-chlorobenzyloxy)-2-(3'-hydroxypropyl)-3(2H)-pyridazinone.
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1>C(O)C.[Pd]>[CH3:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1
Reactant: Cc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1C
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(Oc2ccc(N)cn2)c1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
In a 50 mL round-bottomed flask 2-[(2,3-dimethylphenyl)oxy]-5-nitropyridine (Intermediate 37, 640 mg) was dissolved in ethanol (10 mL) to give a pale yellow solution. Hydrazine hydrate (0.463 mL, 4.72 mmol) and palladium on carbon (25.10 mg, 0.236 mmol) were added. The reaction mixture was stirred at 90° C. After 1 hour, the reaction was complete. The reaction mixture was filtered and the organic phase was evaporated in vacuo affording the title compound as a pale yellow oil (573 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:19])=[N:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([O:34][CH3:35])=[CH:29][C:28]=1[O:36][CH3:37])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:19])=[N:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:23][C:24](=[O:25])[NH:26][C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([O:34][CH3:35])=[CH:29][C:28]=2[O:36][CH3:37])[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccnc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3c(Cl)nccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vial is charged with (5-Chloro-2,4-dioxo-1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl)-acetic acid tert-butyl ester (53.1 mg, 0.17 mmol), 2-Bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (58.1 mg, 0.187 mmol), and Cs2CO3 (124.3 mg, 0.34 mmol). The mixture is treated with DMF (3 ml) and the solution stirred at RT overnight. The reaction mixture is treated with water and the product extracted with EtOAc (3×10 ml). The organic extracts are combined and washed with water (2×10 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude material is purified using flash column chromatography with an eluent system of isohexane:EtOAc to give the title compound; [M+H]+ 539.
Reaction SMILES: [BH4-].[Na+].[CH:3]([CH2:5][CH2:6][C:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)([C:10]#[N:11])[C:8]#[N:9])=[O:4].O>C(O)C>[OH:4][CH2:3][CH2:5][CH2:6][C:7]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=1)([C:10]#[N:11])[C:8]#[N:9]
Reactant: N#CC(C#N)(CCC=O)Cc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)(CCCO)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.9 %

Procedure:
First, 0.01 g of sodium borohydride was added to the solution of 0.30 g of 2-(2-formylethyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the intermediate (19)) in ethanol at 0° C., followed by stirring for 5 hours at room temperature. Then, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of 2-(3-hydroxypropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the intermediate (20)).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]1[C:8](=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:9]([O:11]C)=O)=[O:4].[O-:17][C:18]#[N:19].[K+]>C(O)(=O)C>[O:17]=[C:18]1[NH:19][C:9](=[O:11])[C:8]2[C:7](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]1[CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)CNc1ccccc1C(=O)OC
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)Cn1c(=O)[nH]c(=O)c2ccccc21

Procedure:
Monatsh. Chem. (1987) 118; pages 71-79 describes the reaction of methyl N-(methoxycarbonylmethyl)anthranilate with potassium cyanate in glacial acetic acid to give methyl 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetate. Although 10 equivalents of potassium cyanate are employed, the yield is only 19%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>>[CH3:3][N:2]([CH2:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:22][N:21]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Reactant: CN(C)Cc1ccc(CSCCN)cc1
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)cc1

Procedure:
Reaction of 2-[4-(dimethylaminomethyl)benzylthio]-ethylamine (1.7 g) with 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (1.7 g) in a similar manner to Example 7(iv) gave 2-[2-(4-(dimethylaminomethyl)benzylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 127°-130°. A sample recrystallised a further time from acetonitrile had m.p. 124°-126°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3cnccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4cnccn4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 92.3 %

Procedure:
With 300 mg of 5-chloro-3-(2-methoxyphenyl)-3-[2-oxo-2-(4-pyrazine-2-ylpiperazin-1-yl)ethyl]-1,3-dihydro-2H-indol-2-one, which is the compound described in Composes IV.1 of the brochure Publication No. WO03/008407, and 201 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 424 mg of the title compound (pale yellow amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[NH2:16]>CN1CCCC1=O>[CH3:11][N:10]1[C:3]2[C:2]([NH:16][C:15]3[CH:17]=[CH:18][C:19]([O:20][C:21]4[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=4)=[C:13]([CH3:12])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1
Reactant: Cn1ccc2ncnc(Cl)c21
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(C)c34)cc2C)cn1
Yield: 51.4 %

Procedure:
To a solution of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in 1-methyl-2-pyrrolidone (1.0 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (192 mg). The title compound (106 mg) was obtained as white powder crystals by the reaction in the same manner as in Example 39 (ii).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]3)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=c1[nH]ccc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)C1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 29.2 %

Procedure:
6-Hydroxy-2H-isoquinolin-1-one (2 g, 12.41 mmol) and potassium carbonate (3.43 g, 2 mol) were mixed with N, N-dimethylformamide (40 ml) at 100° C. A solution of (R)-3- methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester (5.2 g, 1.5 mol) in dimethylformamide (50 ml) was added dropwise over 15 minutes. The mixture was stirred at 100° C. for 3.5 hours and allowed to cool. The crude material was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with sodium hydroxide (2M) then brine and dried over magnesium sulphate. The residue was purified by flash chromatography on silica (eluent: 0-100% Heptane/Ethyl acetate followed by 5% 2M ammonia in methanol/ethyl acetate) to give (S)-3-(Oxo-1,2-dihydroisoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.25g, 29%), El-MS: m/z=345.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[F:12][C:13]1[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.Cl>CN(C)C=O.O>[F:12][C:13]1[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:17][C:18]=1[NH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: N#Cc1ccccc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Nc1ccc([N+](=O)[O-])cc1F
Temperature: 80 °C

Procedure:
21.8 g (0.5 mol) of sodium hydride were added in portions to a solution of 59 g (0.5 mol) of 2-aminobenzonitrile and 53.2 ml (0.5 mol) of 3-fluoronitrobenzene in absolute dimethylformamide, whereby the reaction mixture warmed up to 80° C., with a change in colour from dark green to dark red. After the mixture had been cooled to room temperature, it was diluted with water and acidified with 2N hydrochloric acid, and the precipitate formed was filtered off. The precipitate was purified by chromatography over silica gel using dichloromethane, and the residue from evaporation of the product-containing fractions was thoroughly stirred with ether/petroleum ether 1:2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])([CH3:26])([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([NH:31][CH2:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Agent: Cl
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCCC(=O)OC(C)(C)C)c2nc1OC
Reaction time: 2.5 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and β-alanine tert-butyl ester hydrochloride 153 mg (0.80 mmol). Reaction was continued for 2.5 hours, and the crude product was eluted through a flash column (3:2 hexanes:ethyl acetate), 230 mg (68%), mp 140-142° C., Rf 0.47 (1:1 hexanes:ethyl acetate); 1H NMR (CDCl3): δ 8.31 (s, 1H), 6.37 (br s, 1H), 4.08 (s, 3H), 3.97 (s, 3H), 3.74 (q, 2H, methylene protons, J=6.1 Hz), 2.57 (t, 2H, J=6.3 Hz, J=6.1 Hz), 2.55 (s, 3H), 1.42 (s, 9H); MS (APCI): m/z 421 (M+H). Anal. Calcd. for C19H24N4O7: C, 54.28; H, 5.75; N, 13.33. Found: C, 54.25; H, 5.69; N, 13.00.
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.C1CCN2C(=NCCC2)CC1.[OH:42][CH2:43][CH2:44][O:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH:48]=O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:48]/[C:47]2[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=2[O:45][CH2:44][CH2:43][OH:42])=[N:3]1
Reactant: O=Cc1ccccc1OCCO
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: OCCOc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a solution of (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.10 g, 0.21 mmol) in methanol (0.60 mL), DBU (0.079 mL, 0.53 mmol) was added and 2-(2-hydroxyethoxybenzaldehyde (0.039 g, 0.23 mmol) was further added, followed by stirring at room temperature for 2.0 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5). The obtained compound was added with 2.0 mol/L hydrogen chloride-ethyl acetate solution (2.0 mL) and washed, then the precipitated solid was collected by filtration. The obtained solid was added with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution to separate the mixture into organic layer and aqueous layer. The organic layer was concentrated under reduced pressure and the residue was dried under reduced pressure to obtain Compound 134 (0.024 g, 9%).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[C@@H:3]([CH3:5])[OH:4].[NH:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([N:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[O:8])[C@@H:3]([CH3:5])[OH:4]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 64 %

Procedure:
In the way described in B(1), 0.33 mol Z-Thr-OH and 0.35 mol H-Pro-OtBu are coupled with the aid of HOBt and DCCI in DMF. Yield 64%; melting point 65°-67° C. The Z-Thr-Pro-OtBu obtained in this way is hydrogenated in the way described above (see B.3.b.).
Reaction SMILES: C([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:11]([C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.[CH3:25]O>[Pd]>[CH3:25][O:23][C:21]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH:12]1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:22]
Reactant: O=C(O)C1=C(c2ccc(F)cc2)CN(Cc2ccccc2)CC1
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: COC(=O)C1CCNCC1c1ccc(F)cc1
Yield: 94 %

Procedure:
A mixture of 3.6 g (1.03 mmol) 1-Benzyl-5-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid (Bioorganic & Medicinal Chemistry Letters 2003, 2513-2518); hydrochloride, 16.6 mL HCl in methanol (1.25 N) in 250 mL methanol was stirred at room temperature over night. Further 16.6 mL HCl in methanol (1.25 N) was added and the mixture was stirred at 70° C. and subsequently hydrogenated with H2 over 360 mg Pd/C (10%) for 44 h at room temperature. The mixture was filtered off and evaporated to dryness to yield 2.3 g (94%) of the title compound as colorless oil. MS (m/e): 238.1 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([NH:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH:36]([CH3:38])[CH3:37])[C:20]1=[O:39])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH:36]([CH3:38])[CH3:37])[C:20]2=[O:39])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)N1C(=O)C(NC(=O)[C@H](C)N)N=C(c2ccccc2)c2ccccc21
Product: CC(C)N1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)amino-2,3-dihydro-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-L), the title compound was prepared as a solid (mp.=208–209° C.). The product was purified by slurrying in ether/hexanes (1:1).