Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.O[C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:37]([C:36]1[CH:39]=[CH:40][C:33]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:34][CH:35]=1)=[O:38]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
0.61 ml (3.07 mmol) of diisopropyl diazene-1,2-dicarboxylate is added drop by dr op at 0° C. under argon to 0.5 g (2.05 mmol) of tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate, 0.3 g (2.46 mmol) of 4-hydroxybenzaldehyde and 1 g (3.07 mmol) of supported triphenylphosphine (3 mmol/g of resin) diluted in 14.5 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at room temperature for 20 hours, and then the solid is filtered and rinsed with dichloromethane. The filtrate is concentrated and diluted in sodium hydroxide solution (1 M), the product is extracted several times with ethyl acetate, and then the organic phases are combined, dried on magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (eluent: 4:6 cyclohexane/ethyl acetate to 100% ethyl acetate) to yield 0.58 g of tert-butyl 4-(3-(4-formylphenoxy)propyl)piperazine-1-carboxylate in the form of a colorless oil.
Reaction SMILES: [O:1]=[C:2]([O-:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[C:2]([OH:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)CO
Reaction time: 144 h

Procedure:
H3494 produced extracellularly 2.7 g xylonate I−1 after 144 h at pH 5.5 (Table 1, FIG. 10). Xylonate began to accumulate in the culture supernatant after the initial glucose supply had been either consumed or converted to ethanol. The xylonate production rate (33 mg xylonate I−1 h−1 or 10 mg xylonate [g biomass]−1 h−1) decreased after the ethanol had been consumed (13 mg xylonate I−1 h−1 or 3 mg xylonate [g biomass]−1 h−1; FIG. 10). The yield of xylonate on xylose was approximately 0.47 g xylonate [g xylose]−1. In addition to xylonate, xylitol, glycerol and acetate were also produced. Glycerol and acetate were subsequently consumed, but the xylitol was not.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CCCCCCS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CCCCCCS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(hexylsulfonyl)benzene MS (ESI): mass calcd. for C22H24FN3O2S, 413.16; m/z found, 414.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.31 (s, 1H), 8.21-8.13 (m, 2H), 7.81 (m, 1H), 7.72 (m, 1H), 7.49 (dd, J=7.6, 1.2, 1H), 7.43 (dd, J=3.6, 1.4, 1H), 7.40 (s, 1H), 2.89-2.80 (m, 2H), 1.50 (m, 2H), 1.31-1.11 (m, 6H), 0.85 (t, J=7.1, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12]C(=O)C)(=O)C.Cl>CO>[NH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)NCCCCCCCOC(C)=O
Agent: Cl
Solvent: CO
Product: NCCCCCCCO

Procedure:
1-Acetoxy-7-acetamidoheptane (11.8 g, 54.3 mmol) was dissolved in 20 mL of methanol in a 200 mL round bottom flask. To this was added 50 mL of 40% aqueous hydrochloric acid and the mixture was heated at reflux for 60 hours. All volatiles were removed under reduced pressure. The desired 7-amino-1-heptanol was obtained as the crystalline hydrochloride salt, m.p. 74°-81° C., MS: 131 (MH+).
Reaction SMILES: [N:1]1([C:10]2[C:11](=[O:26])O[C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si](C)(C)[NH:29][Si](C)(C)C.CO>C1(C)C=CC=CC=1>[N:1]1([C:10]2[C:11](=[O:26])[NH:29][C:13](=[O:25])[C:14]=2[C:15]2[C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]([CH3:24])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cn1cc(C2=C(n3ccc4ccccc43)C(=O)OC2=O)c2ccccc21
Solvent: CO
Solvent: Cc1ccccc1
Product: Cn1cc(C2=C(n3ccc4ccccc43)C(=O)NC2=O)c2ccccc21
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A mixture, 163 mg of 3-(1-indolyl)-4-(1-methyl-3-indolyl)furan-2,5-dione, 2.6 g of hexamethyldisilazane, 0.6 g of methanol and 50 ml of toluene was stirred at 40° C. for 1 hour and then at 110° C. for 1 hour. The mixture was evaporated and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 75 mg of 3-(1-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 235°-236° C.
Reaction SMILES: [C:1](=[C:3]1N=C2C=CC=CC2=N1)=O.[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:17])=[O:16])([CH3:14])[CH3:13].C([Li])C>CO>[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([OH:34])[CH2:1][CH3:3])[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:16])=[O:17])([CH3:14])[CH3:13]
Reactant: O=C=C1N=c2ccccc2=N1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: [Li]CC
Solvent: CO
Product: CCC(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1

Procedure:
Specifically the carbonyl benzimidazole, 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole, is reacted with ethyl lithium to form the desired carbinol, 1-isopropylsulfonyl-2-amino-6-(1-phenyl-1-hydroxy-1-propyl)benzimidazole.
Reaction SMILES: [CH:1]1([C:6]2[C:15]([C:16]#[N:17])=[C:14](O)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:12]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:24]>CN(C=O)C>[Br:24][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[N:7]=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1O
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1Br
Reaction time: 20 h
Yield: 76.8 %

Procedure:
To a solution of 2-cyclopentyl-4-hydroxy-6-trifluoromethyl-quinoline-3-carbonitrile (200 mg, 490 μmol) in DMF (2.00 ml) was added phosphorus tribromide (1.47 ml, 1.47 mmol) dropwise at 0° C. The reaction mixture was allowed to reach room temperature and stirring was continued for 20 h. The mixture was concentrated in vacuo and the remaining residue was poured on water. The mixture was extracted with EtOAc and the combined extracts were dried with Na2SO4 and evaporated. The resulting yellow solid was purified by column chromatography (silica gel, dichloromethane) to afford the title compound (139 mg, 77%) as white solid. MS (ESI): 369.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(Cl)CCCCCBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)CCCCCBr)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
To a stirred mixture of 1-(2-methoxyphenyl)piperazine (21.34 mmol) and pyridine (25.6 mmol) in 60 mL of dry dichloromethane was added dropwise a solution of 6-bromohexanoyl chloride (23.52 mmol) in 20 mL of dichloromethane at 0° C. under nitrogen. After addition, the mixture was allowed to warm to room temperature and stirred for 1-2 hours. The mixture was quenched with 10% potassium carbonate in water, and extracted with dichloromethane. The organic phase was washed with brine and water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 5% methanol, 0.5% ammonium hydroxide in ethyl acetate to give 1-(2-methoxyphenyl)-4-(6-bromohexanoyl)piperazine (6.00 g, 76%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([N:14]([CH2:17][CH2:18][O:19][C:20]([N:22]1[N:27]=[C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[NH:34][CH2:33][CH2:32][CH2:31]3)[CH:25]([CH3:38])[S:24][C:23]1=[O:39])=[O:21])[CH2:15][CH3:16])[CH3:13].O>ClCCl>[CH2:12]([N:14]([CH2:17][CH2:18][O:19][C:20]([N:22]1[N:27]=[C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]([C:8](=[O:10])[CH3:9])[CH2:33][CH2:32][CH2:31]3)[CH:25]([CH3:38])[S:24][C:23]1=[O:39])=[O:21])[CH2:15][CH3:16])[CH3:13]
Reactant: CC(=O)Cl
Reactant: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3)C(C)SC1=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3C(C)=O)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
5 ml of triethylamine and then, dropwise with stirring, 4 ml of acetyl chloride are added to a solution of 12 g of 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-(1,2,3,4-tetrahydro-6-quinolyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one [obtainable in analogy to Example 1 by reacting 5-(1,2,3,4-tetrahydro-6-quinolyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one with 2-(N,N-diethylamino)ethyl chloroformate] in 100 ml of dichloromethane. The mixture is subsequently stirred at 20° C. for one hour and decomposed with water and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-(1-acetyl-1,2,3,4-tetrahydro-6-quinolyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][C:9]([NH2:12])=[CH:8][N:7]=1
Reactant: COCCNc1cnc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCNc1cnc(N)cn1
Reaction time: 4 h
Yield: 80.6 %

Procedure:
A solution of (2-methoxy-ethyl)-(5-nitro-pyrazin-2-yl)-amine (290 mg, 1.46 mmol) in ethyl acetate (25 mL) was treated with 10% palladium on activated carbon (40 mg). The reaction mixture was then placed on a Parr shaker under a hydrogen atomsphere of 50 psi for 4 h. The catalyst was then filtered off through a pad of celite, and the celite pad was then washed well with ethyl acetate. The filtrate was then concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 98/2 to 95/5 methylene chloride/methanol) afforded N-(2-methoxy-ethyl)-pyrazine-2,5-diamine (198 mg, 80%) as an orange solid: EI-HRMS m/e calcd for C7H12N4O (M+) 168.1011, found 168.1018.
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[F:30][C:31]1([F:45])[CH2:33][CH:32]1[CH2:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1>>[F:30][C:31]1([F:45])[CH2:33][CH:32]1[CH2:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:41])=[CH:38][CH:37]=1
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(OCC2CC2(F)F)cc1
Product: C[C@@H](COc1ncc(NC(=O)c2ccc(OCC3CC3(F)F)cc2)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 4-((2,2-difluorocyclopropyl)methoxy)benzoic acid, and in the same manner as in Step A of Example 4 and Step D of Example 83, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH2:20][NH:21][C:22](OCCC)=O)([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)CCC>[CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH2:20][NH:21][CH3:22])([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCOC(=O)NCCCC1(O)c2ccccc2C=Cc2c(C)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CNCCCC1(O)c2ccccc2C=Cc2c(C)cccc21

Procedure:
13.5 g. of 1-methyl-5-(3-methylcarbethoxyaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene, 120 ml. of n-butanol and 14.5 g. of potassium hydroxide are boiled at reflux under an atmosphere of nitrogen for 20 hours. The solution is then evaporated to dryness and the residue taken up in ether. The ethereal solution is shaken out with dilute hydrochloric acid. The aqueous, acidic solution is again made alkaline with potassium carbonate. The oil which separates out is extracted with ether. The ethereal solution is washed with water, dried over sodium sulfate and evaporated. The 1-methyl-5-(3-methylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene obtained is a thick oil which is immediately utilized as a reactant.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]1[O:17][CH2:16][C:15](C(O)=O)=[CH:14][C:13]2=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:34])C=CC=CC=1.Cl>ClCCl.C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]1[O:17][CH2:16][C:15](=[O:34])[CH2:14][C:13]2=1
Reactant: COc1ccc2ncc3c(c2c1)C=C(C(=O)O)CO3
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2c1)CC(=O)CO3
Temperature: 90 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
Triethylamine (13 μL, 0.09 mmol, 1.2 eq) is added at room temperature to a stirred solution of 6-methoxy-2H-1-oxa-9-aza-phenanthrene-3-carboxylic acid (20 mg, 0.08 mmol, 1.0 eq) in dichloromethane (1 mL), followed by a solution of diphenylphosphoryl azide (23 mg, 0.08 mmol, 1.0 eq) in toluene (1.5 mL). After 1 h 30 stirring at 80° C., 6M hydrochloric acid aqueous solution (0.5 mL) is added and the resulting mixture is heated at 90° C. for 2 hours. The reaction mixture is then cooled down to room temperature and extracted with ethyl acetate (3×10 mL) and saturated sodium hydrogen carbonate aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate) to afford 6-methoxy-4H-1-oxa-9-aza-phenanthrene-3-one as a yellow semisolid (5 mg, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.CCOCC>C1COCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCc2ccc(C=CCCCN3CCN(c4ccc(F)cc4Cl)CC3)nc2N1
Agent: [Ni]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCc2ccc(CCCCCN3CCN(c4ccc(F)cc4Cl)CC3)nc2N1
Yield: 79.7 %

Procedure:
7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.268 g, 0.623 mmol) was hydrogenated using Ra—Ni (0.2 g) in THF for 13 hours. The reaction was filtered and concentrated to give an oil. Et2O was added and the product crashed out. The mixture was filtered and dried to give the title compound as a white solid (0.214 g, 80%). MS: APCI: M+1: 431.3 (Exact Mass: 430.19).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:23]([C:25]2[N:29](COCC[Si](C)(C)C)[C:28]3[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:27]=3[N:26]=2)=[CH2:24])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2].C(C1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2)C>Cl.CO.C(Cl)Cl>[CH2:1]([C:3]1[C:4]([C:23]([C:25]2[NH:29][C:28]3[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:27]=3[N:26]=2)=[CH2:24])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2]
Reactant: C=C(c1c(CC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: C=C(c1c(CC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C=C(c1nc2cc(C#N)ccc2[nH]1)c1c(CC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A solution of a mixture of 2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.164 mmol) in 1M HCl in MeOH (10 mL) was stirred at 60° C. for 5 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with CH2Cl2. The layers were separated and the organic phase was successively washed with 5% aq. NaHCO3, H2O and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the title compound, without need of any further purification. MS (ESI+) m/z 481.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>CN(C=O)C>[N:21]1([C:2]2[N:7]=[C:6]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[N:5]=[C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:3]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cn(-c2nc(N3CCOCC3)nc(-n3ccnc3)n2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 32.5 %

Procedure:
The obtained 2,4-dichloro-6-morpholino-1,3,5-triazine (1.17 g, 4.98 mmol) was dissolved in DMF (30 ml), added with anhydrous potassium carbonate (2.91 g, 21.1 mmol) and imidazole (1.43 g, 21.0 mmol) and stirred at room temperature for 17 hours. The reaction mixture was evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography, using dichloromethane and methanol (95:5) as eluant, to obtain 483 mg (yield: 32.6%) of the titled compound as colorless crystals.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[C:12]([CH3:19])[CH:11]=1)(C(C)(C)C)(C)C.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24](O)=O.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[F:20][C:21]1[CH:22]=[C:23]([C:24]2[O:18][N:17]=[C:15]([C:13]3[S:14][C:10]([CH2:9][OH:8])=[CH:11][C:12]=3[CH3:19])[N:16]=2)[CH:27]=[CH:28][C:29]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)c(F)c1
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxy-3-methylthiophene-2-carboximidamide (0.18 g, 0.60 mmol) that was obtained in Example 11 (11d), 3-fluoro-4-phenoxybenzoic acid (0.15 g, 0.66 mmol) that was obtained in Example 11 (11e), N,N′-dicyclohexylcarbodiimide (0.14 g, 0.66 mmol), and 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.90 mL, 0.90 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (0.21 g) in a yield of 93% as a white crystalline solid.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[NH2:19][C:20]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:23][NH:22][N:21]=1>>[F:1][CH:2]([F:18])[C:3]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[C:20]2[N:19]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH:4]=1
Reactant: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(-c3ccncc3)cnn12
Yield: 66.6 %

Procedure:
Reaction of 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (133 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (130 mg, 67%). MS (ISP) 391.2 [(M+H)+]; mp 222° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[NH4+].O[N:12]1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[O:6]=[C:5]1[NH:1][C@H:2]([C:7]([NH2:12])=[O:9])[CH2:3][CH2:4]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of L-pyroglutamic acid (II) (75 gm, 0.580 mol, commercially available) in dimethylformamide (750 ml) was added 1-hydroxy benzotriazole ammonium salt (106 gm, 0.696 mol, prepared according the literature procedure described in WO 2006100119) in one lot at 25° C. To this reaction mass, DCC was added in small portions over a period of 30 minutes at 0-5° C. The reaction mixture was allowed to warm to room temperature and stiffing continued further for 2 hours. The precipitates were removed by filtration and the filtrate concentrated under reduced pressure. The residue was treated with ethyl acetate (1000 ml) and stirred for 1 hour. The precipitate formed was filtered under suction and washed with additional ethyl acetate (2×75 ml). The combined filtrate was concentrated under reduced pressure to obtain 73 gm of (S)-5-oxopyrrolidine-2-carboxamide (III) as a white solid in 98% yield. The solid thus obtained was used without further purification in the next step.