Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([OH:4])=[O:3].[C:19](ON1C(=O)CCC1=O)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[C:19]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: NCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(-c2ccc(C(=O)O)cc2)cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
4-(4-Carboxyphenyl)benzylamine hydrochloride (10 g, 0.038 mol) was taken in a mixture of 10% Na2CO3 (100 mL) and dioxane (25 mL). To this a solution of Fmoc-OSu (15.4 g, 0.045 mol) in dioxane (50 mL) was added at 10° C. and the reaction was stirred at RT for 4 h. Solvent was removed under reduced pressure and the residue was acidified with an aqueous solution of HCl (1.5 N), extracted with EtOAc and the crude was recrystallised from EtOAc to give N-Fmoc-4-(4-carboxyphenyl)benzylamine (8.5 g, 45%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[CH:12]=[C:11]([C:13](OC)=[O:14])[N:10]=[CH:9][C:8]=2[N:17]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9][C:8]=2[N:17]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2sc(NC(C)C)nc2cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Nc1nc2cnc(CO)cc2s1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 93.3 %

Procedure:
To a solution of methyl 2-(isopropylamino)thiazolo[4,5-c]pyridine-6-carboxylate (0.1286 g, 0.51 mmol, 1.0 eq.) in THF (1.3 mL) under nitrogen at 0° C. was added LAH (1M, THF; 0.8 mL, 0.8 mmol, 1.6 eq.). After 1.25 h, ice and EtOAc were added, the cold bath was removed, and the solution was stirred to room temperature. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give (2-(isopropylamino)thiazolo[4,5-c]pyridin-6-yl)methanol as a light yellow solid (0.1063 g, 93% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:13][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([F:1])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(O)cc(C(=O)O)cc1F
Solvent: O
Product: COc1c(F)cc(C(=O)O)cc1OC(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The compound of step 2 (169 mg, 913 mmol) was suspended in acetic anhydride (1.75 ml) and heated at 100° C. for 3 h. The solution was cooled, water (2 ml) was added, and the mixture was stirred at 60° C. for 1 h. Upon cooling, crystals formed which were filtered off and dried in vacuo to give 120 mg of the title compound.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]([CH:12]1[NH:24][CH2:23][C:21]2=[C:22]3[C:17](=[C:18]([C:25]4[C:26](=[O:40])[NH:27][C:28](=[O:39])[C:29]=4[C:30]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[NH:32][CH:31]=4)[CH:19]=[CH:20]2)[CH:16]=[CH:15][N:14]3[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C>CO>[CH2:2]([O:9][C:10]([CH:12]1[NH:24][CH2:23][C:21]2=[C:22]3[C:17](=[C:18]([C@H:25]4[C@H:29]([C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[NH:32][CH:31]=5)[C:28](=[O:39])[NH:27][C:26]4=[O:40])[CH:19]=[CH:20]2)[CH:16]=[CH:15][N:14]3[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)C(c2ccc3c4c2ccn4CC(C(=O)OCc2ccccc2)NC3)=C1c1c[nH]c2ccccc12
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)C1Cn2ccc3c([C@@H]4C(=O)NC(=O)[C@H]4c4c[nH]c5ccccc45)ccc(c32)CN1
Temperature: 25 °C

Procedure:
Magnesium turnings (195 mg, 8.0 mmol) were added to a solution of 7-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid benzyl ester (230 mg, 0.44 mmol) in anhydrous methanol (20 ml) and heated to reflux under an atmosphere of nitrogen for 1.5 hours. After cooling to room temperature the mixture was poured into ethyl acetate (200 ml) and washed with 1 M hydrochloric acid (100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was then purified by silica gel chromatography using 50-60% ethyl acetate in hexanes to yield (±)-trans-7-[4-(1H-indol-3-yl)-2,5-dioxo-pyrrolidin-3-yl]-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid benzyl ester as an off white solid (205 mg). 1H NMR (DMSO-d6) 400 MHz δ: 11.56 (s, 1H), 11.03 (d, 1H, J=2 Hz), 7.21-7.43 (m, 10H), 7.09 (t, 1H, J=7.2 Hz), 6.92-7.00 (m, 2H), 6.82-6.89 (m, 3H), 5.04 (s, 2H), 4.87 (d, 2H, J=7.6 Hz), 4.54 (dd, 2H, J=7.6 and 28.8 Hz), 4.30 (m, 2H), 3.92 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][NH:13][CH2:14][CH:15]=[CH2:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:14]([N:13]([CH3:12])[CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:15]=[CH2:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: C=CCNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN(C)Cc1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To solution of 3-nitrobenzaldehyde (1.5 g, 9.92 mmol) in CH2Cl2 (60 mL) was added N-methyl allyl amine (1.19 g, 12.40 mmol), the reaction mixture was stirred for 2 h. Na(OAc)3BH (4.2 g, 19.85 mmol) was then added portionwise over 5 mins. The resulting mixture was stirred at ambient temperature overnight and then quenched with saturated NH4Cl. The product was extracted with CH2Cl2 thrice and the combined organic extracts were washed brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was column purified (EtOAc/Hexane) to furnish 1.1 g of (xA). 1H NMR (400 MHz, CDCl3): δ 8.20 (m, 1H), 8.08-8.12 (m, 1H), 7.65-7.69 (m, 1H), 7.48 (t, 1H), 5.84-5.96 (m, 1H), 5.12-5.26 (m, 2H), 3.58 (s, 2H), 3.02-3.06 (m, 2H), 2.20 (s, 3H). MS (m/z): 207 [MH]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][CH3:21])([CH3:15])([CH3:14])[CH3:13].[H-].[Li+]>C1(C)C=CC=CC=1>[C:12]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH2:23][O:24][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH2:19][CH2:20][CH3:21])([CH3:13])([CH3:14])[CH3:15]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCCN(CCO)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCCN(CCOc1ccc([N+](=O)[O-])c(C)n1)C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
A mixture of 6-chloro-2-methyl-3-nitro-pyridine (1 g, 5.79 mmol), (2-hydroxyethyl)-propyl-carbamic acid tert-butyl ester (1.18 g, 5.79 mmol) and lithium hydride (0.05 g, 6.37 mmol) in toluene (5 ml) was stirred at 90° C. for 4 h. After evaporation of the solvent under reduced pressure the residue was purified by silica gel chromatography with heptane/ethyl acetate (10:0; 8:2; 0:10) as eluent to provide 1.38 g (70.2%) of the product.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C(=O)(O)[O-].[Na+].[CH2:29]([OH:31])[CH3:30]>S(=O)(=O)(O)O>[CH2:29]([O:31][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH3:30]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
2α,3α-Epoxy-5α-pregnan-20-one (180 mg) was dissolved in 20 mL of absolute ethanol and cooled to °C. and added to a cold 1.0 mL ethanol solution containing 3-drops of concentrated sulfuric acid. This reaction mixture was stirred for 30 minutes at this temperature and an additional 30 minutes at room temperature, poured into 20% sodium bicarbonate solution and washed several times with chloroform. The combined organic phase was dried over potassium carbonate and concentrated and purified by preparative TLC silica plate in hexane/ethyl acetate (1:1), to give (80 mg, 40% yield) the title compound as fine white crystals.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)([O-:3])=[O:2].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([O-:3])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:15])=[O:11])=[O:2]
Reactant: O=C(O)CCCCO[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
5-(Nitrooxy)pentanoic acid (489 mg, 3.00 mmol; US Patent 2006/189603) was dissolved in anhydrous DCM (30 mL) under N2, cooled to 0° C., and added in succession anhydrous DMF (1 drop) and oxalyl chloride (262 uL, 3.00 mmol). Allowed to stir at ambient temperature for 12 h. 13CNMR displayed acid chloride (δ171 ppm) with small amount of carboxylic acid (˜δ173 ppm). Evaporated and dried in vacuo to yield 450 mg (80%) of 5-chloro-5-oxopentyl nitrate as light yellow oil, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:46][N:47]([CH3:54])[C:48]1[CH2:49][NH:50][CH2:51][CH2:52][N:53]=1.C(N(C(C)C)CC)(C)C>>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:50]3[CH2:51][CH2:52][N:53]=[C:48]([N:47]([CH3:54])[CH3:46])[CH2:49]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CN(C)C1=NCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN=C(N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 101.8 %

Procedure:
Following a procedure similar to that described in Preparation 1(i), but using 446 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 178 mg of N,N'-carbonyldiimidazole, 289 mg of 3-dimethylamino-1,2,5,6-tetrahydropyrazine bis(trifluoroacetate) and 289 μl of diisopropylethylamine, 460 mg of the title compound were obtained, as a powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH2:26][OH:27]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2=[N:20][C:19](/[C:22](=[N:26]/[OH:27])/[CH3:23])=[CH:18][N:17]=[C:16]2[N:15]=[N:14]1
Reactant: NO
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Agent: Cl
Product: C/C(=N\O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 65 %

Procedure:
The title compound (68.0 mg, 62%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (100.0 mg, 0.31 mmol) and hydroxylamine hydrochloride (43.1 mg, 0.62 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.49 (bs, 1H), 9.31 (s, 1H), 8.92 (d, 1H), 8.40 (d, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.54 (d, 1H), 6.22 (s, 2H), 2.23 (s, 3H). LCMS (method A): [MH]+=338, tR=5.15 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[Br:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[CH:26]=[C:27]([S:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[C:17]4[CH:16]=[CH:15][C:14]5[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=5[C:12]=4[NH:11][C:10](=[O:22])[C:9]3=[O:23])[CH:3]=2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4cccc(Br)c4)c2)c1=O)CCCC3
Yield: 29 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 3-bromobenzenesulfonyl chloride (21 μL, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 15 mg, yield 29%).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.Cl>O1CCCC1>[CH2:15]([N:4]([CH2:1][CH:2]=[CH2:3])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][S:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([Br:24])[CH:26]=1)(=[O:33])=[O:32])(=[O:7])=[O:6])[CH:16]=[CH2:17]
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1N
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)c1cccc(Br)c1
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A mixture of N,N-diallyl-4-aminopyridine-3-sulfonamide (0.25 g, 1.0 mmol) and cesium carbonate (0.82 g, 2.5 mmol) in tetrahydrofuran (10 mL) was stirred for 5 min, 3-bromobenzenesulfonyl chloride (0.17 mL, 1.2 mmol) was added and the reaction was stirred at room temperature over night. Diluted hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was evaporated. Purification by column chromatography, using chloroform/methanol (95:5) as the eluent, gave the title compound in 72% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:8](=[O:24])[C:7]12[CH2:35][O:34][C:26]2[CH:27]=[C:28]3[C:29](=[CH:33][C:25]1=2)[CH2:30][CH2:31][O:32]3
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(Cl)c2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 7′-chloro-1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.45-7.06 (m, 14H), 6.38-6.32 (m, 2H), 4.75 (s, 2H), 4.48 (t, J=8.7 Hz, 2H), 2.94 (t, J=8.7 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH2:26][CH2:27][C:28]#[N:29])[C:10]2=[O:30])=[CH:5][CH:4]=1.[OH-:31].[Na+].OO>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH2:26][CH2:27][C:28]([NH2:29])=[O:31])[C:10]2=[O:30])=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(CCC#N)C2=O)cc1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(CCC(N)=O)C2=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of 3-[-3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-1-yl]-propionitrile (60 mg, 0.15 mmol) (from Example 26 supra) in dimethyl sulfoxide (2 mL) at 0 C was added 1.0 N aqueous sodium hydroxide solution (0.42 mL, 0.42 mmol) followed by 35% aqueous hydrogen peroxide (0.35 mL) (Fisher). The reaction mixture was stirred at 0° C. for 2 hours and then at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with water (3×20 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude solid (71 mg) which was purified by recrystallization from hexanes-ethyl acetate to give 3-[-3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-1-yl]-propionamide as a gray solid. (Yield 28.3 mg, 45.1%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)(=[O:13])=[O:12].[H-].[Na+].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1)#[N:24]>C1COCC1.CN(C=O)C>[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:17]2[CH2:18][CH2:19][N:14]([S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[CH2:15][C:16]2=[O:20])=[CH:27][CH:26]=1)#[N:24]
Reactant: O=C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Reactant: N#Cc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2=O)cc1
Reaction time: 0.33 h
Yield: 54.3 %

Procedure:
In THF (8 ml) and DMF (2 ml) was dissolved 4-(naphthalene-2-sulfonyl)-2-piperazinone (290 mg), and to the mixture was added sodium hydride (60% in oil, 40 mg) at 0° C. The mixture was stirred for 20 minutes, to which was added 4-cyanobenzylchloride (182 mg), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (MgSO4) and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless crystals of the title compound (220 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[Cu](C#N)[C:12]#[N:13].N>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[C:12]#[N:13]
Reactant: N#C[Cu]C#N
Reactant: Fc1cc(Br)cc(F)c1F
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c(F)c(F)c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
To 50 ml of N-methylpyrrolidone were added 10 g of 3,4,5-trifluorobromobenzene and 8.5 g of copper cyanide, and the mixture obtained was stirred at 150° C. for 4 hours. Then, aqueous ammonia was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.0 g of 3,4,5-trifluorobenzonitrile.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>O>[OH:17][CH:15]1[CH2:16][N:6]2[C:2](=[N:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)[NH:1][CH2:13]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1CNc2nc3ccccc3n2C1
Reaction time: 3 h

Procedure:
1.33 g. (0.01 moles) of 2-amino-benzimidazole are dissolved in 100 ml. of alcohol, and 0.4 g. (0.01 moles) of sodium hydroxide dissolved in 5 ml. of water are added to the mixture, followed by the addition of 0.92 g. (0.01 moles) of epichlorohydrine. The reaction mixture is boiled for about 3 hours. The reaction is completed when the inorganic salt ceases to separate. The separated sodium chloride is filtered off, washed with 2 × 5 ml. of alcohol, and the combined filtrate and wash is evaporated to dryness. 1.8 g. (80%) of white, crystalline 1,2,3,4-tetrahydro-3-hydroxy-pyrimido[1,2-a]benzimidazole are obtained; m.p.: 158°-160°C (heating rate: 4°C/min.).
Reaction SMILES: [CH3:1][NH2:2].O.[Br:4][CH:5]([CH2:9][CH2:10][Br:11])[C:6](Br)=[O:7]>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:6](=[O:7])[CH:5]([Br:4])[CH2:9][CH2:10][Br:11]
Reactant: O=C(Br)C(Br)CCBr
Reactant: CN
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNC(=O)C(Br)CCBr
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution mixture consisting of 40% aqueous methylamine solution (7.9 g, 0.10 mol, manufactured by JUNSEI CHEMICAL CO., LTD.) and water (3.3 g) was cooled to not more than 10° C. To the solution mixture, 2,4-dibromobutyric acid bromide (38 g, 0.12 mol) was added dropwise over a period of 15 minutes while keeping the temperature at not more than 10° C. After the completion of the dropwise addition, the mixture was heated to 30° C. and stirred for 30 minutes. The reaction liquid was combined with 50 g of chloroform, and the organic phase was extracted. The organic phase was separated and dried over magnesium sulfate, and the magnesium sulfate was filtered out. The organic phase obtained was concentrated to afford a crude crystal, which was then washed with a 1:1 solution of diethyl ether and hexane to give N-methyl-2,4-dibromobutyric acid amide (21.4 g, 0.083 mol, mp: 54° C., yield: 69%).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1>CS(C)=O.[Cl-].[Na+].O>[CH3:13][O:12][C:9]1[N:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: [C-]#N
Reactant: COc1ccc(CCl)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC#N)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
Sodium cyanide (1.25 g, 25.4 mmol) was added to a solution of 5-(chloromethyl)-2-methoxypyridine (1.00 g, 6.34 mmol) in DMSO (10 ml) and stirred for 18 h at room temperature. After completion of reaction, the reaction mixture was diluted with brine and the compound was extracted with DCM (3×35 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by column chromatography using 100-200 silica gel, 10% ethyl acetate in petroleum ether as eluent to afford 0.6 g (63.8%) of 2-(6-methoxypyridin-3-yl)acetonitrile as white color solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([OH:20])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23].Br[CH2:40][CH2:41][CH3:42]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:40][CH2:41][CH3:42])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23]
Reactant: CCCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CCC2
Product: CCCOc1cc2c(cc1OC)CCCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide with 1-bromopropane.