Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][CH2:10][CH2:11][N:12]([C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][CH:40]=1)[C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:37])=[C:24]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Cl)[CH:29]=2)[CH:25]=1)=[O:18])[CH3:13]>>[CH3:8][O:9][CH2:10][CH2:11][N:12]([C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][CH:40]=1)[C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:37])=[C:24]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:29]=2)[CH:25]=1)=[O:18])[CH3:13]
Reactant: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(NC(=O)c3cccc(CCl)c3)c2)c1
Reactant: CN1CCNCC1
Product: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(NC(=O)c3cccc(CN4CCN(C)CC4)c3)c2)c1
Temperature: 80 °C

Procedure:
A mixture of N-methylpiperazine (3 ml) and N-(5-{3-[N-(2-methoxyethyl)-N-methylamino]benzamido}-2-methylphenyl)-3-chloromethylbenzamide (0.21 g) was stirred and heated to 80° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was evaporated and the residue was triturated under diethyl ether. There was thus obtained the title compound (0.17 g); NMR Spectrum: (DMSOd6) 2.17 (d, 6H), 2.33 (m, 8H), 2.98 (s, 3H), 3.23 (s, 3H), 3.50 (m, 6H), 6.87 (d, 1H),7.2 (m, 4H), 7.46 (m, 2H), 7.57 (m, 1H), 7.8 (s, 1H), 7.86 (m, 2H), 9.87 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 530.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH3:36].C(=O)([O-])[O-]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][C:27]=3[CH3:36])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: Cc1ccc2ccccc2c1CCl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (308 mg, 974 μmol) in DMF (2.43 ml) was added 1-(chloromethyl)-2-methylnaphthalene (223 mg, 1.17 mmol) and cesiuim carbonate (952 mg, 2.92 mmol). The reaction was stirred at rt for 2 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (364 mg, 80% yield) as an off-white oil. MS m/z 493 (MNa)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:15]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[N+:11]([C:8]1[C:9]2[O:10][CH2:15][O:1][C:2]=2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1O
Reactant: ClCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc([N+](=O)[O-])c2c1OCO2

Procedure:
14.2 g of 2,3-dihydroxy-4-nitrobenzaldehyde in 1000 ml of DMF is stirred with 57.6 ml of bromochloromethane and 50.6 g of cesium carbonate at 100° C. for 7 hours. The batch is added to 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed several times with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. The brown solid that is obtained is purified by column chromatography (silica gel, hexane/ethyl acetate 100:0->60:40). 7.4 g of 7-nitro-benzo[1,3]dioxole-4-carbaldehyde is obtained as a light yellow solid. The latter is mixed in 400 ml of acetone at 10° C. with a solution of 11.8 g of potassium permanganate in 190 ml of acetone/water (1:1). It was stirred for 10 hours, added to 2 N hydrochloric acid and filtered through diatomaceous earth. The acetone is removed in a vacuum, and the aqueous phase is made alkaline with sodium hydroxide solution. It is extracted with ether, and then the aqueous phase is acidified with hydrochloric acid. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 4.36 g of 7-nitro-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brown solid, flash point 230–239° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][N:32]4[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]4)([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:38][C@@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][N:32]5[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]5)([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:41]3[CH2:42][CH2:43][C@@H:39]([F:38])[CH2:40]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: F[C@@H]1CCNC1
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CN2CC[C@H](O)C2)C1
Product: O=S(=O)(c1ccc(N2CC[C@@H](F)C2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CN2CC[C@H](O)C2)C1

Procedure:
The title compound was prepared by the method of Example 20 using (S)-1-[(S)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-ylmethyl]-pyrrolidin-3-ol and (R)-3-fluoropyrrolidine. LCMS (Method G): 597 (M+H)+, Retention time 3.30 minutes.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(N[C:18]1[CH:27]=[C:26]([NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])[C:25]([O:34]C(=O)CCC)=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH3:40])=[N:23]2)(=O)CCC.[OH2:41]>C(O)(=O)C>[C:29]([NH:28][C:26]1[C:25](=[O:34])[C:24]2[N:23]=[C:22]([CH3:40])[CH:21]=[CH:20][C:19]=2[C:18](=[O:41])[CH:27]=1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(=O)Nc1cc(NC(=O)CCC)c2ccc(C)nc2c1OC(=O)CCC
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Yield: 77 %

Procedure:
This compound was prepared by the oxidation of the corresponding acylamido with potassium dichromate in glacial acetic acid. In a 500 ml. round-bottomed flask equipped with a magnetic bar, 5,7-dibutyramido-8-butyroxy-2-methylquinoline (34) (prepared as described in Examples 31-34) (3.29 g., 8.25 mmol) was suspended in 122 ml of glacial acetic acid. A solution of potassium dichromate (8.8 g., 0.03 mol) in 115 ml. of water was added and stirred. The stirred suspension began to dissolve but, after two hours, more solid continued to precipitate. Dichloromethane (70 ml.) was added to promote solution. The resulting two-phase solution mixture was stirred at room temperature overnight. The two-phase solution mixture was extracted with dichloromethane (12×50 ml.). The organic extracts were washed with a 3% sodium bicarbonate solution (200 ml.), dried with magnesium sulfate, and rotoevaporated to yield an orange-yellow solid. After vacuum drying, the solid weighed 1.65 g. (a yield of 77%). The product was recrystallized from ethyl acetate: mp. 188°-189° C.; 1H NMR (CDCl3) δ1.00 (3H, t, J=7.4 Hz, C-7NHCOCH2CH2CH3), 1.69-1.82 (2H, m, C-7NHCOCH2CH2CH3), 2.48 (2H, t, J=7.4 Hz, C-7NHCOCH2CH2CH3), 2.74 (3H, s, C-2CH3), 7.53 (1H, d, J=8.0 Hz, C-3H), 7.90 (1H, s, C-6H), 8.28 (1H, d, J=8.0 Hz, C-4H), 8.36 (1H, br. s, C-7NH); IR (KBr) vmax 3338, 3275, 2964, 2935, 2875, 1711, 1682, 1654, 1644, 1615, 1588, 1502, 1323, 1310, 1133 cm-1 ; EIMS, m/e (relative intensity) 258 (81), 215 (7), 188 (base), 161 (66); HRMS, m/e for C14H14N2O3 calculated 258.100442, found 258.100227; analysis for C14H14N2O3 calculated C, 65.11; H, 5.46; N, 10.85; found C, 65.22; H, 5.51; N 10.01.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35][CH2:36]C(OCC)=O)[CH2:31][CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][C:10]=1[CH3:43])#[N:2].C[Mg]Br.Cl>O1CCCC1>[OH:35][C:32]([CH3:33])([CH3:31])[CH2:36][O:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[C:10]([CH3:43])[CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[C:26]([CH3:28])[N:27]=[C:19]23)[CH2:34][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2nc(C)nn12
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Reaction time: 0.5 h

Procedure:
Ethyl [(trans-4-{6-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (0.71 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.4 M tetrahydrofuran solution, 2.7 mL) was added at 0° C. The reaction mixture was stirred for 30 min, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (0.41 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=1.O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:16](=[O:17])[C:13]2[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
4-Aminobenzonitrile (1.10 g) was dissolved in chloroform (30 ml). After having been cooled to 0° C., the reaction solution was added with 4-dimethylaminopyridine (1.70 g) and p-toluic acid chloride (1.95 g). The reaction solution was warmed back to room temperature and stirred overnight. The reaction solution was added with distilled water and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then purified by recrystallization (hexane/ethanol), thereby obtaining the subject compound (1.26 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: BrCCOc1ccc(OCCCCOc2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCOc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(2-bromoethoxy)-4-(4-phenoxybutoxy)benzene.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[CH:11]=[CH:10]2>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.COCCOC>[Cl:3][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([Cl:6])[CH:8]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cc(Cl)ccc2[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: COCCOC
Product: Clc1ccc2nc(Cl)ccc2c1
Reaction time: 6 h

Procedure:
Phosphorus oxychloride (16.72 Kg) was charged to a vessel containing 6-chloroquinolin-2(1H)-one (12.50 Kg) (Prepared according to method of Johnston K. M. et al., J. Chem. Soc. Perkin Trans. 1, 1972, 1648 and references therein), benzyltrimethylammonium chloride (1.575 Kg) and 1,2-dimethoxyethane (87.8 Kg) at 70° C. 1,2-dimethoxyethane (22.5 Kg) was charged as a line rinse. The reaction was stirred at 70° C. to 75° C. for ca. 6 hours before the batch was concentrated to ca. 44 L by vacuum distillation (<40° C.). The concentrate was diluted with dichloromethane (253.1 Kg), adjusted to 38° C. to 45° C. and quenched by the addition of water (37.5 Kg) whilst maintaining the temperature at 38° C. to 45° C. After 70 minutes the batch was cooled to 25° C. to 30° C. and treated with Celite (1.30 Kg) for 40 minutes. The slurry was pressure filtered via a 1 μm filter membrane and the filtrates diluted with dichloromethane (87.5 Kg). The phases were separated and the aqueous phase extracted twice with dichloromethane (82 Kg). The combined organic extracts were washed sequentially with 5% w/w sodium hydrogen carbonate solution (37 L), water (37 Kg) and then concentrated to ca. 75 L at 25° C. to 40° C. Isopropanol (96.5 Kg) was charged and the batch then concentrated to ca. 75 L at 25° C. to 40° C. Isopropanol (95.4 Kg) was charged and the batch then concentrated to ca. 75 L at 25° C. to 40° C. The resultant slurry was stirred at 16° C. to 18° C. for 2 hours and then filtered. The filter cake was washed with isopropanol (19.7 Kg) at ca. 20° C. and then dried at up to 50° C. in vacuo to provide the subtitle compound as an off white solid (12.04 Kg).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH2:11](Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:3]([O:2][P:1]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: CCOP([O-])OCC
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCc1ccccc1)OCC
Temperature: -15 °C
Yield: 51.6 %

Procedure:
Diethyl phosphite (27.64 g, 200 m mole) was dissolved in DMF (200 ml), and to the solution at nitrogen atmosphere while stirring and -15° C., sodium hydride (60% in oil, 9.6 g, 220 m mole) was added. The mixture was stirred for 1 hour at not more than 0° C. To the solution phenethyl bromide (37.0 g, 200 m mole) was dropwise added and further the mixture was stirred overnight at room temperature. DMF was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated and the thus obtained oily product was distilled under reduced pressure to obtain diethylphenethylphosphonate (25.0 g, yield: 51.6%) of boiling point 136.5~137.5° C./3 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[CH:11]=[C:12]([C:14]([OH:16])=O)[NH:13][C:8]2=[CH:7][CH:6]=1)=[O:4].Cl.Cl.[N:19]1([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[CH:11]=[C:12]([C:14](=[O:16])[NH:25][CH:22]3[CH2:21][CH2:20][N:19]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)[CH2:24][CH2:23]3)[NH:13][C:8]2=[CH:7][CH:6]=1)=[O:4]
Reactant: NC1CCN(c2ccncc2)CC1
Reactant: COC(=O)c1ccc2[nH]c(C(=O)O)cc2n1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(c4ccncc4)CC3)cc2n1
Reaction time: 2 h

Procedure:
To a solution of 450 mg 1H-pyrrolo[3,2-b]pyridine-2,5-dicarboxylic acid 5-methyl ester in 9 mL dichloromethane and 1.13 mL triethylamine, 614 mg 3,4,5,6-tetrahydro-2H-[1,4′]bipyridyl-4-ylamine dihydrochloride and 520 mg bis(2-oxo-3-oxazolidinyl)phophinic chloride were added at room temperature and the mixture was stirred for 2 hours. After treatment of the reaction mixture with 5 mL saturated aqueous solution of potassium carbonate the precipitate was collected by filtration and coevaporated twice with toluene. The residue was directly subjected to the subsequent reaction without further purification.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:30][C:31]1[CH:35]=[CH:34][O:33][C:32]=1[CH3:36]>O>[CH3:36][C:32]1[O:33][CH:34]=[CH:35][C:31]=1[CH2:30][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: Cc1occc1CCl
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccoc2C)CC1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a stirred mixture of 4.6 parts of a sodium hydride dispersion 50% and 450 parts of N,N-dimethylformamide were added portionwise 57.6 parts of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate under nitrogen atmosphere. Upon complete addition, stirring was continued for 30 minutes at room temperature. 27.0 Parts of 3-(chloromethyl)-2-methylfuran were added dropwise while cooling. Upon completion, stirring was continued for 1 hour. Water was added dropwise to the mixture and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was stirred in 1,1'-oxybisethane. The solid product was filtered off and 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 stirred in 1,1'-oxybisethane. The product was filtered off and dried, yielding 37.5 parts (19.0%) of ethyl 4-[[1-[(2-methyl-3-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 150.4° C. (int. 23).
Reaction SMILES: [Na].[C:2]1([CH:8]2[O:13][CH2:12][CH:11]([OH:14])[CH2:10][O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O.ClCCl>[C:2]1([CH:8]2[O:13][CH2:12][CH:11]([O:14][CH3:17])[CH2:10][O:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC1COC(c2ccccc2)OC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
10 g of the sodium salt of 1b, obtained by reaction with sodium hydride in dimethylformamide, was treated with 16 g of methyl iodide. The mixture was stirred at 50° C. for 5 hours, and the dimethylformamide was eliminated in vacuo. The residue was dissolved in dichloromethane, washed and dried. The solvent was evaporated off and the product was chromatographed on silica gel (eluent : dichloromethane) to give 2b.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[C:1]([C:5]1[CH:10]=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccccc1C(C)(C)C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (30 mL) was cooled to 0° C. and solid N-(2-tert-butylphenyl)acetamide (1.0 g, 5.2 mmol) was added in several portions. To the resulting solution was added KNO3 (578 mg, 5.7 mmol). The reaction mixture was allowed to warm to rt over 2 h and then stirred at rt overnight. The reaction mixture was poured over ice and a white precipitate formed. The precipitate was isolated by filtration (1.04 g, 84%). LCMS: (FA) ES+ 237.2 (M+1), ES− 235.1 (M−1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(F)c2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Chloro-3-fluoro-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])=[CH:5][CH:4]=1.COS(OC)(=O)=O.[C-:25]#[N:26].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:25]#[N:26])[CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(C=Cc2cccc[n+]2[O-])cc1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)O
Product: COc1ccc(C=Cc2cccc(C#N)n2)cc1

Procedure:
Following the general method described in example 2b, 2-[2-(4-methoxy-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a yellow crystalline material. Mp. 121-122° C. (isopropanol), MS: m/e=236 (M+)
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:12]=1[C:13]#[N:14].Cl>CO>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[C:12]=1[C:13](=[N:2][OH:3])[NH2:14]
Reactant: NO
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 56.6 %

Procedure:
In 540 ml of methanol was dissolved 58.8 g of hydroxylamine hydrochloride and to the solution was added 160 ml of aqueous solution of sodium carbonate containing 49.4 g thereof. 40 g of 2-fluoro-6-trifluoromethylbenzonitrile was added thereto at room temperature with stirring, and then further stirred 3 hours at 60° C. After removing the solvent methanol by distillation from the solution, the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and it was concentrated under reduced pressure, thereby obtaining crude crystals. The crystals were then added with 200 ml of 3N aqueous solution of hydrochloric acid and thoroughly stirred, then the insoluble substance resulted in the solution was removed by filtration. The filtrate was then neutralized with 10% aqueous solution of sodium hydroxide under cooling and then extracted again with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure to obtain 26.6 g of the objective compound. m.p. 155-157° C.