Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH2:38]([NH2:42])[CH2:39][CH2:40][CH3:41].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:38]([NH:42][C:30]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])=[O:36])[CH2:39][CH2:40][CH3:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: CCCCN
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (50 mg) was dissolved in chloroform (10 ml) and triethylamine (0.2 ml), and a solution of triphosgene (43 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, butylamine (22 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 15 mg (yield 23%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:5]=2[NH:4][CH2:3]1>C1COCC1.[O-2].[Mn+4].[O-2].[O-2].[Mn+2]>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:5]=2[N:4]=[CH:3]1
Reactant: COC(=O)c1cc2c(s1)NCC(=O)N2
Agent: [Mn+2]
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]c(=O)cnc2s1
Yield: 94.7 %

Procedure:
To a suspension of methyl 2-oxo-1,2,3,4-tetrahydrothieno[3,2-b]pyrazine-6-carboxylate 20 (515 mg, 2.427 mmol) in THF (30 mL) was added manganese(IV) oxide (2.11 g, 24.27 mmol). The reaction was stirred at rt for 30 min. manganese oxide was filtrated and washed with EtOAc. The filtrate was evaporated to give crude methyl 2-oxo-1,2-dihydrothieno[3,2-b]pyrazine-6-carboxylate 21 (483 mg, 95%). NMR (400 MHz, DMSO-d6) 3.90 (s, 3H), 7.62 (br s, 1H), 8.13 (s, 1H), 12.80 (br s, 1H). (m/z)=211 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[OH:12].[Br:13]N1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[Br:13][C:4]1[C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(C)c(Br)c1O
Yield: 72.8 %

Procedure:
Into a magnetically stirred suspension of 2,5-dimethyl-4-nitrophenol (12.70 grams, 75.98 mmol) in CH2Cl2 (150 milliliters) at room temperature was added portionwise N-bromosuccinimide (14.88 grams, 83.58 mmol). The mixture rapidly became homogeneous and after one hour thin layer chromatography (3:1 hexane:ethyl acetate) indicated complete consumption of the starting material and formation of a single major product. Saturated Na2SO3 solution (15 milliliters) was added and the solvent was removed under reduced pressure. Ethyl acetate was then added and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford 2-bromo-3,6-dimethyl-4-nitrophenol (13.6 grams, 55.3 mmol, 73%) as a rust colored solid. H'-NMR (CDCl3) 9.26 (brS, 1H), 7.71 (S, 1H), 2.60 (S, 3H), 2.31 (S, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([C:44](=[O:46])[CH3:45])[CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.N>CO.C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][N:13]([C:44](=[O:46])[CH3:45])[CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCNC1

Procedure:
(±)-3-(Acetyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (30 mg, 0.056 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of the solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is extracted with EtOAc (3×). The combined organic layers are washed with water and brine and the organic layer is dried with Na2SO4, filtered, and condensed. The residue is then separated by FCC (0-10%, 2 mol NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 538.9 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.O[N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43]>ClCCl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(ON1C(=O)CCC1=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
201 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in dehydrated dichloromethane (3.6 mL), and 162 mg of N-methylmorpholin was added, followed by cooling to 0° C. 198.8 mg of isobutyl chloroformate was added to the mixture, followed by stirring for 10 minutes, and subsequently 167 mg of N-hydroxysuccinimide was added, followed by further stirring for 0.5 hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=1/2) to afford 161 mg of the title compound as a colorless solid (yield 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[N:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[N:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1cnnc2c1C(=O)CC(c1cc(Cl)ccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1Cl)C2
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 134.3 %

Procedure:
To a mixture of 7-(2,5-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (246 mg) and aminoguanidine hydrochloride (98 mg) were added ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath temperature) for 1.5 hours. The reaction solution was cooled to room temperature, and the crystals were filtered and dried to give 7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 161) (215 mg) as gray white crystals.
Reaction SMILES: [Br-].O([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].CC(C)([O-])C.[K+].[F:32][C:33]1[CH:34]=[C:35]([C@H:39]2[CH2:44][CH2:43][C@H:42]([CH:45]=O)[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1.O>C1COCC1.C1(C)C=CC=CC=1>[F:32][C:33]1[CH:34]=[C:35]([C@H:39]2[CH2:44][CH2:43][C@H:42]([CH:45]=[CH:3][CH2:4][CH2:5][CH3:6])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: CCCCO[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@H]1CC[C@H](c2cccc(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC=C[C@H]1CC[C@H](c2cccc(F)c2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Well-dried butoxyltriphenylphosphonium bromide (58.1 g) and THF (200 ml) were mixed under a nitrogen atmosphere and cooled to −30° C. Then, potassium t-butoxide (t-BuOK; 16.3 g) was put in thereto in twice in the temperature range of −30° C. to 20° C. After the mixture had been stirred at −20° C. for 30 minutes, the compound (37) (20.0 g) dissolved in THF (100 ml) was added dropwise thereto in the temperature range of −30° C. to −20° C. After the reaction mixture had been stirred at −10° C. for 30 minutes, it was poured into a mixture of water (400 ml) and toluene (400 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure. The residue was mixed with sodium benzenesulfonate dihydrate (31.0 g) and Solmix A-11 (100 ml), and heated under reflux for 8 hours. The reaction mixture was cooled to 30° C., and then water (200 ml) and toluene (200 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and heptane (volume ratio; toluene: heptane=1:1) as the eluent and silica gel as the stationary phase powder. The residue was further purified by means of recrystallization from Solmix A-11, and dried, giving 15.8 g of 1-(3-fluorophenyl)-trans-4-(1-pentenyl)cyclohexane (40). The yield based on the compound (37) was 66.2%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[OH-].[Na+].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.[CH3:21]C(C)=O>O>[Cl:13][C:14]1[N:15]=[C:16]([O:9][C:5]2[C:4]([CH3:10])=[CH:3][C:2]([NH2:1])=[C:7]([CH3:8])[CH:6]=2)[CH:17]=[C:18]([CH3:21])[N:19]=1
Reactant: CC(C)=O
Reactant: Cc1cc(O)c(C)cc1N
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Oc2cc(C)c(N)cc2C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4.53 g (33 mmol) 4-amino-2,5-dimethylphenol and 1.44 g NaOH (2M) in 30 ml water were added dropwise to a solution of 4.89 g (30.0 mmol) of 2,4-dichloropyrimidine in 50 ml of acetone. The reaction mixture was stirred for 20 h at ambient temperature.
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:12])=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O/[C:17](/[C:26]([O-:28])=[O:27])=[C:18](/[O:22]C(=O)C)\[C:19]([O-:21])=O)(=O)C.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>C(O)(C)C>[CH3:29][O:28][C:26]([C:17]1[N:12]=[C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][NH:10][N:9]2[C:19](=[O:21])[C:18]=1[OH:22])=[O:27]
Reactant: CC(=O)O/C(C(=O)[O-])=C(/OC(C)=O)C(=O)[O-]
Reactant: Nc1n[nH]cc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCO
Product: COC(=O)c1nc2c(-c3ccccc3)c[nH]n2c(=O)c1O
Temperature: 25 °C
Yield: 567.5 %

Procedure:
Phenyl pyrazole amine (100 mg, 0.63 mmol), diacetoxyfumarate (180 mg, 0.69 mmol) and p-toluenesulphonic acid (5 mg) were heated at 100° C. for 20 minutes before being cooled to room temperature and sonicated with ethanol: i-propanol for 10 min. The resulting precipitate was collected and washed with ethanol. The product was isolated as a yellow solid (47 mg, 26%).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH2:16]([N:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17].C([O-])(=O)C.[Na+]>ClC1C=CC=CC=1Cl>[CH2:16]([N:18]1[C:19]2[CH:20]=[CH:21][C:22]([CH:9]=[O:10])=[CH:23][C:24]=2[S:25][C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:17]
Reactant: CN(C=O)c1ccccc1
Reactant: CCN1c2ccccc2Sc2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1c2ccccc2Sc2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
N-Methylformanilide (5.35 ml, 43.6 mmol) and phosphorus oxychloride (4.06 ml, 43.6 mmol) were added at room temperature to a mixture of 10-ethylphenothiazine (7.62 g, 33.5 mmol) and 1,2-dichlorobenzene (34 ml), and the mixture was stirred at 100° C. for 24 hours. At room temperature, a sodium acetate aqueous solution (45 wt. %, 85 g) was added to the reaction mixture, which was subsequently concentrated under a reduced pressure. Ethyl acetate and water (each 300 ml) were added to the resulting residue in that order and then the reaction product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to give the title compound (5.91 g, 23.1 mmol, 69%) as yellow crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:8]2[O:12][C:11]([CH2:14]OS(C)(=O)=O)([CH3:13])[CH2:10][C:9]=2[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:3])[CH3:2].[I-:29].[Na+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:8]2[O:12][C:11]([CH2:14][I:29])([CH3:13])[CH2:10][C:9]=2[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COS(C)(=O)=O)O2
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CI)O2
Yield: 67.5 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.55 g of 5-acetoxy-4,6-di-t-butyl-2-methanesulfonyloxymethyl-2-methyl-2,3-dihydrobenzofuran and combined with 3.0 g of sodium iodide, and the mixture was heated under reflux for 24 hours. After cooling, water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 10% ethyl acetate to give 0.4 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a colorless oil (yield 68%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[SH:7].Cl.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:24]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]2[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]=[C:20]2[NH:19][CH:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][S:7][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:18][CH2:17]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Reactant: Sc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(Cn2c(NC3CCN(CCSc4ncccn4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.8 %

Procedure:
A mixture of 1.12 parts of 2-pyrimidinethiol, 4.6 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride, 4 parts of potassium carbonate and 80 parts of 2-propanone was stirred for 3 days at room temperature. The reaction mixture was filtered and the filtraate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'oxybispropane, yielding 1.7 parts (35.8%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyrimidinylthio)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 146.1°-147.7° C. (compound 91).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:2].[CH2:14]([C:17](=[CH2:21])[C:18](O)=[O:19])[CH2:15][CH3:16]>>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:18](=[O:19])[C:17]([CH2:14][CH2:15][CH3:16])=[CH2:21])=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13])#[N:2]
Reactant: C=C(CCC)C(=O)O
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Product: C=C(CCC)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Following the procedure described in Example 1, starting from 4-cyano-3-trifluoromethyl-aniline and 2-propyl-acrylic acid, the title compound was prepared as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>CO>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([NH2:14])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Yield: 102.8 %

Procedure:
The compound (29.3 g, 123 mmol) of step A was dissolved in methanol (500 ml), ferric chloride (FeCl3) (1.73 g, 10.7 mmol) and activated carbon (4.5 g) were added and the mixture was stirred at room temperature. Then, hydrazine monohydrate (20 ml, 412 mmol) was added, and the mixture was heated under reflux for 45 min. The reaction mixture was cooled, filtered through celite, and the solution was concentrated under reduced pressure. The obtained oil was diluted with an ethyl acetate-hexane=1:1 mixed solvent (300 ml), washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (26.2 g) as a pale-yellow oil.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([O:16][C:17]1[N:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([N+:30]([O-])=O)[CH:24]=3)=[CH:19][CH:18]=1)[CH2:9]2.CC#N.O>CO.[OH-].[OH-].[Pd+2]>[NH:29]1[C:26]2[CH:27]=[CH:28][C:23]([C:20]3[N:21]=[N:22][C:17]([O:16][C@@H:10]4[CH:11]5[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]5)[CH2:9]4)=[CH:18][CH:19]=3)=[CH:24][C:25]=2[N:30]=[CH:2]1
Reactant: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: c1nc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The product of Example 29B (29 mg, 0.064 mmol) was dissolved in 2.0 mL of methanol and 6 mg of Pd(OH)2/C (Aldrich, 10 wt %) was added. The mixture was stirred under 50 psi of H2 for 30 min. The solution was filtered through a nylon membrane and concentrated. The residue was dissolved in DMF (0.25 mL) and treated with excess triethylorthoformate (0.1 mL). The solution was heated at 80° C. for 2 h, then cooled down to ambient temperature and stirred for 4 h. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 40/60 to 70/30 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (13 mg, 0.04 mmol, 63%). 1H NMR (300 MHz, CD3OD) δ 1.57 (m, 1H), 1.73-1.94 (m, 2H), 2.08 (m, 1H), 2.34 (td, J=6.4, 3.6 Hz, 1H), 2.80-3.03 (m, 6H), 3.50 (ddd, J=14.5, 8.1, 1.5 Hz, 1H), 5.32 (m, 1H), 7.28 (d, J=9.2 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 8.11 (d, J=9.2 Hz, 1H), 8.22 (s, 1H), 8.25 (s, 1H) ppm; MS (DCI/NH3): m/z 322 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].C(N(CC)CC)C.[C:15]([OH:25])(=[O:24])[C:16]1[C:17](=[CH:19][CH:20]=[C:21]([CH:23]=1)[OH:22])[OH:18].C(OCC)(=O)C>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:22][C:21]1[CH:20]=[CH:19][C:17]([OH:18])=[C:16]([CH:23]=1)[C:15]([OH:25])=[O:24])=[O:6]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: O=C(Cl)CCCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCBr)Oc1ccc(O)c(C(=O)O)c1

Procedure:
In a solution of 4-bromobutyrylchloride (3 g, 16.17 mmoles) in tetrahydrofuran (50 ml), cooled at 0° C., triethylamine (4.5 ml, 32.34 mmoles) and then gentisic acid (2.4 g, 16.16 mmol) are dropped under stirring. It is allowed to react at 0° C. for 4 hours, under stirring, then it is evaporated at reduced pressure. The obtained crude product is treated with ethyl acetate, the organic phase is washed with HCl 1% and then brine. The organic phase is anhydrified with sodium sulphate and dried. The obtained residue is purified by chromatography on silica gel column, eluting with methylene chloride/methanol 95/5, obtaining the 5-(4-bromobutyryloxy)-2-hydroxy-benzoic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:33]1[CH2:32][CH2:31][N:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:35][CH2:34]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: O=CCCCOc1nc2c(cc1F)CCC(=O)N2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: Cl
Product: O=C1CCc2cc(F)c(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1

Procedure:
The title compound was prepared by reductive amination of 4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-naphthalen-1-yl-piperazine hydrochloride according to the above procedure. MS: APCI: M+1: 449.1 (Exact Mass: 448.23).
Reaction SMILES: [C:1]([N:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]([NH:19][C@@H:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[O:22])=[O:18])[C:6](=[O:30])[CH:5]1[CH:31]([CH3:33])[CH3:32])(=[O:3])[CH3:2].S([O-])(O)=O.[Na+].C(OCC)(=O)C.[C-:45]#[N:46].[K+]>O>[C:1]([N:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([CH2:16][C:17]([NH:19][C@@H:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]([OH:22])[C:45]#[N:46])=[O:18])[C:6](=[O:30])[CH:5]1[CH:31]([CH3:33])[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@H](C=O)Cc2ccccc2)C(=O)C1C(C)C
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(O)C#N)C(=O)C1C(C)C
Reaction time: 0.5 h

Procedure:
(2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal (630 mg, Compound No. 7-1) is suspended in water (6 ml). Sodium hydrogensulfite (160 mg), water (6 ml) and ethyl acetate (18 ml) are added to the suspension, and the mixture is stirred for 30 minutes. Potassium cyanide (105 mg) is added to the mixture, and the whole is stirred for one day. Water is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (624 mg).