Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH3:17][O:18][C:19]1[C:20]([CH3:33])=[C:21]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH:22]=[O:23].[Cl-].[NH4+]>O1CCCC1>[CH3:17][O:18][C:19]1[C:20]([CH3:33])=[C:21]([CH:22]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:23])[C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C)c(C(O)c2ccccc2OCc2ccccc2)c(OC)c(OC)c1OC
Reaction time: 2 h
Yield: 100 %

Procedure:
Under ice-cooling, into a Grignard reagent (35 ml, a tetrahydrofuran solution) prepared from 2-(benzyloxy)bromobenzene (11.50 g, 0.044 mol) and magnesium (1.16 g, 0.048 mol) was dropped a solution of 3,4,5,6-tetramethoxy-2-methylbenzaldehyde (5.00 g, 0.021 mol) in anhydrous tetrahydrofuran (30 ml) and the mixture was stirred for 2 hours more. The reaction solution was poured into a saturated aqueous solution of ammonium chloride followed by extracting with ether. The extract was washed with a saturated saline and dried. The reaction solution was filtered and the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (8.80 g, 0.021 mol, 99%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[N:16]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=2)=[C:8]([CH3:25])[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:6]1=O.O.FC(F)(F)C(O)=O.[OH-].[Na+]>O1CCCC1>[CH3:25][C:8]1[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:6][N:5]([CH2:4][CH:3]=[O:2])[C:10](=[O:11])[C:9]=1[C:12]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)[N:15]=[CH:14][CH:13]=1
Reactant: COC(Cn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1=C(c2ccnn2-c2ccc(C#N)cc2)C(=O)N(CC=O)CN1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
To a solution of 4-[5-[3-(2,2-dimethoxyethyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 7) (10.0 mg) in tetrahydrofuran (0.5 ml)/water (0.1 mL) was added trifluoroacetic acid (40 μl) and the resulting mixture was stirred at 100° C. for three hours. The reaction mixture was neutralized with aqueous sodium hydroxide solution, and thereto was added water and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford 4-[5-[6-methyl-4-oxo-3-(2-oxoethyl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (9.1 mg).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[C:4]([C:24]([F:25])([F:27])[F:26])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C=O)c2-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CO)c2-c2ccccc2)cc1
Reaction time: 2.5 h
Yield: 22.1 %

Procedure:
To a solution of the aldehyde prepared in Step 2 (165 mg, 0.41 mmol) in methanol (3.5 mL) at 0° C. was added sodium borohydride (16 mg, 0.41 mmol). The reaction solution was kept at 0° C. for 2.5 hours. The reaction was quenched with the addition of an aqueous 1M KHSO4 solution (3 mL). The mixture was extracted with dichloromethane and the organic solution dried and concentrated. The residue was chromatographed on silica (1:1 hexane:ethyl acetate) to give the desired product (36 mg, 46%): m.p. 179-180° C.; 1H NMR d 7.91 (m, 2H), 7.53-7.40 (m, 5H), 6.75 (s, 2H), 4.53 (d, 2h, J=5.0 Hz), 4.30 (t, 1H, J=5.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:12]([Cl:14])=[O:13])[CH2:11][CH2:10][CH2:9]1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([OH:23])[CH2:16]2>>[ClH:14].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:12]([O:23][CH:17]2[CH:18]3[CH2:21][CH2:22][N:15]([CH2:20][CH2:19]3)[CH2:16]2)=[O:13])[CH2:11][CH2:10][CH2:9]1
Reactant: OC1CN2CCC1CC2
Reactant: O=C(Cl)C1(c2ccccc2Br)CCC1
Product: Cl
Product: O=C(OC1CN2CCC1CC2)C1(c2ccccc2Br)CCC1

Procedure:
The title compound was prepared in an analogous manner to that in Example 36. 1-(2-Bromophenyl)cyclobutanecarbonyl chloride, prepared from the compound prepared in Example 9, was reacted with 3-quinuclidinol at 75° C. overnight. The crude was chromatographed on silica gel using EtOAc-Et3N 90:10 as eluent. The yield was 0.2 g (6%); mp 194-200° C.; 1H NMR (CD3OD) δ 1.47-1.74 (m, 2H), 1.82-2.50 (m, 3H), 2.18-2.35 (m, 2H), 2.54-2.71 (m, 2H), 2.79-2.97 (m, 3H), 3.11-3.27 (m, 4H), 3.67-3.75 (m, 1H), 5.10 (m, 1H), 7.16-7.22 (m, 1H), 7.37-7.49 (m, 2H), 7.57 (dd, 1H). Anal. (C18H22BrNO2.HCl) C, H, N.
Reaction SMILES: N1[CH:5]=[CH:4]N=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[C:14]1(/[CH:42]=[CH:43]/[C:44]2[CH:49]=[CH:48][C:47]([CH2:50][CH:51]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([Br:63])=[CH:59][CH:58]=3)[C:52]([CH3:55])([OH:54])[CH3:53])=[CH:46][CH:45]=2)[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=3)[C:30]([CH3:33])([OH:32])[CH3:31])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:63][C:60]1[CH:59]=[CH:58][C:57]([CH2:56][CH:51]([C:52]([CH3:53])([O:54][Si:8]([CH2:4][CH3:5])([CH2:9][CH3:10])[CH2:6][CH3:7])[CH3:55])[CH2:50][C:47]2[CH:46]=[CH:45][C:44](/[CH:43]=[CH:42]/[C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]4[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=5)[C:30]([O:32][Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][CH3:7])([CH3:33])[CH3:31])=[CH:26][CH:27]=4)=[CH:16][CH:15]=3)=[CH:49][CH:48]=2)=[CH:62][CH:61]=1
Reactant: c1c[nH]cn1
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)(O)C(Cc1ccc(Br)cc1)Cc1ccc(/C=C/c2ccc(/C=C/c3ccc(CC(Cc4ccc(Br)cc4)C(C)(C)O)cc3)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C)(C)C(Cc1ccc(Br)cc1)Cc1ccc(/C=C/c2ccc(/C=C/c3ccc(CC(Cc4ccc(Br)cc4)C(C)(C)O[Si](CC)(CC)CC)cc3)cc2)cc1
Yield: 86 %

Procedure:
Imidazole (136 mg, 2.0 mmol), triethylsilyl chloride (0.25 mL, 3.0 mmol) and N,N-dimethylformamide (2.50 mL) were added at 0° C. to 4,4′-((1E,1′E)-1,4-phenylenebis(ethen-2,1-diyl)bis(4,1-phenylene))bis(3-(4-bromobenzyl)-2-methylbutan-2-ol) (396 mg, 0.50 mmol). Following stirring of the resulting mixed liquid at room temperature for 12 hours, a saturated aqueous solution of ammonium chloride was added to halt the reaction. The organic layer was separated from the mixed liquid, and the water layer was extracted with ether. The resulting organic layer was washed with water, dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane), yielding the title compound (10b) (444 mg, 0.43 mmol) as a yellow viscous solid in a yield of 87%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]#[N:20])[CH:15]=2)[CH:10]=1.[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)=[O:25].C1(C)C=CC=CC=1.C(O)C>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:21]([O-:23])=[O:22])=[CH:3][C:2]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:24]=[O:25])[CH:18]=[CH:17]2)#[N:20]
Reactant: N#Cc1ccc2cc(Oc3ccc([N+](=O)[O-])cc3Br)ccc2c1
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc2cc(Oc3ccc([N+](=O)[O-])cc3-c3ccccc3C=O)ccc2c1
Temperature: 25 °C

Procedure:
The compound (3-bromo-4-(6-cyano-2-naphthyloxy)nitrobenzene) (1 g) obtained in a previous production example, 2-formylphenyl boronic acid (610 mg) and tetrakis(triphenylphosphine)palladium (0) (150 mg) were heated to reflux and reacted for 6 hours in a mixture of 2 M sodium carbonate aqueous solution (10 ml), toluene (10 ml) and ethanol (10 ml). After cooling to room temperature, water was added and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (200 g, hexane:ethyl acetate=4:1) to obtain 880 mg of 4-(6-cyano-2-naphthyloxy)-3-(2-formylphenyl)nitrobenzene.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[NH:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([N:34]2[C@H:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37][N:33]2[C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 14.2 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (11.37 g, 37 mmol) in 50 mL of DMF was added into the solution of 1-(benzyloxy carbonyl)pyrazolidine-3-carboxylic acid (12.04 g, 48.1 mmol) and Hunig's base (25.8 ml, 148 mmol) in 70 ml of DMF. The reaction was stirred at 25° C. for 5 hrs. The reaction was diluted with ethyl acetate, and the resulting solution was washed with aqueous NH4Cl (2×200 ml). The aqueous solution was extracted with ethyl acetate (5×100 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica Gel chromatography and then recrystallization from ethyl acetate and hexane to yield (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (2.834 g, 5.27 mmol, 14% yield). MS (ES+) m/z 538.1 (MH+).
Reaction SMILES: [Cl-].[C:2]([CH2:5][CH2:6][CH2:7][NH+:8]([CH3:10])[CH3:9])([OH:4])=[O:3].S(Cl)([Cl:13])=O.[CH3:15]O>>[Cl-:13].[CH3:15][O:3][C:2](=[O:4])[CH2:5][CH2:6][CH2:7][NH+:8]([CH3:10])[CH3:9]
Reactant: CO
Reactant: C[NH+](C)CCCC(=O)O
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Product: COC(=O)CCC[NH+](C)C
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 3-carboxy-N,N-dimethyl-1-propanaminium chloride (2) (45.93 g, 0.27 mol) in anh. methanol (300 ml) at (−10)-0° C. slowly thionyl chloride (55 ml, 0.76 mol) was added and the reaction mixture was stirred for an hour at ambient temperature. The reaction mixture thereafter was stirred at 40-50° C. for 3 hours and evaporated. The residue was dissolved in acetone (110 ml) and precipitated by adding ether (400 ml). The solid was filtered, washed with ether, and once more dissolved in acetone (110 ml) followed by the precipitation with ether (400 ml). The precipitate was filtered, washed with ether, and dried to give 38.4 g (77%) of 4-methoxy-N,N-dimethyl-4-oxo-1-butanaminium chloride.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:18]([CH2:17][CH2:16][CH2:15][Cl:14])(=[O:20])=[O:19])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Yield: 95.8 %

Procedure:
Amine preparation: A mixture of 1-BOC-piperazine (3.26 g), 3-chloropropanesulfonyl chloride (2.63 g) and triethylamine (2.68 mL) was stirred at room temperature in DCM (25 mL). After 2 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g). A mixture of 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g), potassium iodide (1.1 g),potassium carbonate and morpholine (1.6 mL) was heated to reflux in MeCN (100 ml). After 16 h, the reaction mixture was cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-morpholin-4-yl-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.8 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].[Cl:22]CC(O)COC1C=C[C:30]([C:33]2[CH2:34]CC(=O)N[N:38]=2)=CC=1[N+]([O-])=O.C(N)(C)C>CO>[OH:1][CH:2]([CH2:21][NH:38][CH:33]([CH3:34])[CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].[ClH:22]
Reactant: O=C1CCC(c2ccc(OCC(O)CCl)c([N+](=O)[O-])c2)=NN1
Reactant: O=C1CCC(c2ccc(OCC3CO3)c([N+](=O)[O-])c2)=NN1
Solvent: CC(C)N
Solvent: CO
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]
Product: Cl

Procedure:
A mixture of 6-[4-(2,3-epoxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone and 6-[4-(3-chloro-2-hydroxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone (0.9 g) was stirred with methanol (9 ml) and isopropylamine (1.6 ml) and heated under reflux for 60 minutes. Evaporation under reduced pressure gave a glassy solid, 0.96 g, from which 6-[4-(2-hydroxy-3-isopropylaminopropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone was isolated as its hydrochloride (m.p. 210°-215°C) by column chromatography (silica, chloroformmethanol mixtures).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH:20]=O)[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30]>CO.[Pd]>[NH2:30][CH2:20][C:18]1[N:19]=[C:15]2[N:14]([CH2:22][CH3:23])[C:13](=[O:24])[C:12]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:10][C:11]=3[N:16]2[N:17]=1
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(C=O)nc12
Reactant: N
Agent: [Pd]
Solvent: CO
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CN)nc12
Yield: 32.4 %

Procedure:
2 g of 6-benzyl-7-cyclopentyl-4-ethyl-2-formyl-imidazo[4.5-e]-s-triazolo[1.5-a]pyrimidin-5-one (for preparation see synthesis example II) are hydrogenated together with 1 g of ammonia in 30 ml of methanol on 0.2 g of 10% palladium on charcoal (5 bar, 20° C., 2.3 hours). For working up, the catalyst is filtered off and the solvent is distilled off in vacuo. The crude product is purified by chromatography on silica gel (dichloromethane:methanol 95:5) and yields 0.65 g of the title compound in the form of a colourless amorphous solid.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8](N)=[C:7]([NH2:12])[CH:6]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14].[N+:22]([C:25]1C=CC=CC=1C=O)([O-])=O.Cl>[OH-].[Na+].CCOCC>[CH3:3][O:4][C:5]1[C:6]2[NH:22][C:25]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N+:13]([O-:15])=[O:14])=[N:12][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Temperature: 25 °C
Yield: 48 %

Procedure:
This compound was prepared via Scheme 6 in a multistep synthesis as follows: 4-methoxy-l,2-phenylene diamine dihydrochloride (4.2 g, 30.43 mmol) was dissolved in NaOH (3N) and extracted with CH2Cl2. The organic layer was dried over MgSO4 and the solvent removed in vacuo to yield an oil. 1H NMR showed the free base to be pure. To this was added nitrobenzene (100 mL), orthonitrobenzaldehyde (1.09 g, 7.24 mmol) and the reaction was heated overnight. The reaction mixture was cooled to RT and poured onto ethanolic HCl (7.2M). Et2O was added and a red solid precipitated. The precipitate was collected and dissolved in methanol, charcoal was added and the mixture was filtered. The methanol was concentrated on a steam bath and the product was allowed to precipitate as a beige solid. 1H NMR (DMSO-d6) confirmed this to be 4-methoxy-2-(2-nitrophenyl) benzimidazole (3.89 g, 48% yield). This material (2.90 g, 12.1 mmol), along with PtO 2 (0.1 g) was suspended in EtOH (150 mL) and charged with H2 (60 psi). The mixture was shaken for 1 h on a Parr hydrogenation apparatus; the mixture was filtered through a pad of celite and the solvent concentrated in vacuo to a yellow solid shown to be 4-methoxy-2-(2-aminophenyl)benzimidazole. This was acetylated according to General Procedure A and purified by recrystallization from methanol, m.p. 212°-213° C. 1H NMR (300 MHz, DMSO-d6) δ mixture of conformational isomers, 8.66 (d, J=9 Hz, 1H), 8.05 (d, J=9 Hz, 1H), 7.61 (d, J=9 Hz, 0.5H), 7.44 (m, 1.5H), 7.28 (bs, 0.5H), 7.20 (t, J=7 Hz, 1H), 7.01 (d, J=1.5 Hz, 0.5H), 6.86 (m, 1H), 3.81 (s, 3H), 2.22 and 2.25 (s 3H); δ13C NMR (75 MHz, DMSO-d6) δ (mixture of conformational isomers), 168.43, 156.69, 155.81, 150.90, 149.95, 142.90, 138.23, 138.01, 136.55, 134.22, 130.35, 130.14, 127.81, 126.88, 122.64, 119.69, 119.25, 115.30, 113.46, 111.80, 100.87, 94.32, 55.48, 25.20; IR (KBr) 3300-2600, 2750, 1635, 1545, 1270, 815 cm-1 ; MS (DCI) m/e MH+ =281; Analysis calc'd for C16H14N3O2 : C, 68.56; H, 5.03; N, 14.99; found: C, 68.23; H, 5.42; N, 14.8.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[C:5](CC(OCC)=O)#[N:6].[CH2:13]([NH:16][C:17]([NH2:19])=[O:18])[CH2:14][CH3:15]>C(O)C>[NH2:6][C:5]1[N:16]([CH2:13][CH2:14][CH3:15])[C:17](=[O:18])[NH:19][C:2](=[O:1])[CH:3]=1
Reactant: CC[O-]
Reactant: CCCNC(N)=O
Reactant: CCOC(=O)CC#N
Agent: [Na+]
Solvent: CCO
Product: CCCn1c(N)cc(=O)[nH]c1=O
Yield: 95.9 %

Procedure:
Sodium ethoxide (19.99 g, 293.72 mmol, 2 eq) was dissolved in anhydrous ethanol (210 ml) at 50° C. To the solution was added ethyl 2-cyanoacetate (15.67 ml, 146.86 mmol, 1 eq) then 1-propylurea (15 g, 146.86 mmol, 1 eq), and the mixture was stirred at reflux for 24 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in water (70 ml). The pH of the solution was adjusted to ˜7 by using concentrated HCl. The light yellow solid formed was collected by filtration, washed with water, and dried under vacuum to afford 23.82 g of the desired product (96% yield): The desired isomer was determined via 2D-NMR; 1H NMR (400 MHz, DMSO-d6) δ 10.3 (1H), 6.79 (2H), 4.52 (1H), 3.68-3.70 (2H), 1.50 (2H), 0.85 (3H); m/z (ES+) 170.18
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][CH2:11][C@H:12]([CH2:16][N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:13]([OH:15])[CH3:14])=[CH:5][CH:4]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:61]([N:64]([CH:78]([CH3:80])[CH3:79])[P:65](N(C(C)C)C(C)C)[O:66][CH2:67][CH2:68][C:69]#[N:70])([CH3:63])[CH3:62]>ClCCl>[CH:78]([N:64]([CH:61]([CH3:63])[CH3:62])[P:65]([O:66][CH2:67][CH2:68][C:69]#[N:70])[O:15][C@H:13]([CH3:14])[C@@H:12]([CH2:16][N:17]1[CH:25]=[N:24][C:23]2[C:18]1=[N:19][CH:20]=[N:21][C:22]=2[NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:11][O:10][C:9]([C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=1)([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([CH3:80])[CH3:79]
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: COc1ccc(C(OC[C@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.7 %

Procedure:
To a stirred solution of 53 (0.7 g, 1.08 mmol) in 20 ml of anhydrous dichloromethane was added diisopropylammonium tetrazolide (0.18 g) followed b) 0.52 g (1.72 mmol) of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite. After being stirred at room temperature for 20 hrs the reaction was concentrated, and the residue portioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude phosphoramidite was p twice by re-dissolving in small (˜10 ml) amount of ethyl acetate, diluting with hexane (100 ml), allowing precipitate as an oil and decanting the liquid. Drying in vacuo afforded 0.9 g (99%) of 54 as an amorphous white solid. 31P NMR (DMSO-d6): δ 145.96, 145.03.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([NH2:18])=O)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[OH-].[Na+]>C(N(CC)CC)C>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)N1Cc2ccccc2-c2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#CN1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.19 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboxamide (see Example 10), 12 ml of chloroform, 2.7 ml of 50% sodium hydroxide solution and 50 mg of triethylamine is stirred at room temperature for 1 hour. The reaction mixture is then poured onto ice/water and the whole is extracted with methylene chloride. The extracts are washed with water, dried over anhydrous sodium sulphate and evaporated, and the residue is purified by flash chromatography on silica gel [eluent: n-hexane/ethyl acetate (9:1)]. There is obtained 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile, m.p. 118°-121° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)=[O:4].[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][C@@H:19]([CH3:23])[NH:18]1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:16][C@H:17]1[NH:18][C@@H:19]([CH3:23])[CH2:20][N:21]([CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][CH:10]=[N:11]3)=[O:4])[CH2:22]1
Reactant: O=C(CCl)Nc1cccc2ncccc12
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)C[C@H](C)N1

Procedure:
A mixture of 2-chloro-N-(quinolin-5-yl)acetamide (7.76 g) (J. Indian Chem Soc, 1940, 17, 619-621), cis-2,6-dimethylpiperazine (4.42 g), sodium bicarbonate (8.9 g) in ethanol (100 ml) was heated at reflux for 4 h. The solvent was removed under reduced pressure. The residue was partitioned between chloroform and brine. The organic phase collected and the aqeuous phase further extracted (×6) with chloroform. The combined extracts dried (MgSO4) and solvent removed under reduced pressure. Yield: 6.8 g