Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1cnc2cc[nH]c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2ccc3ncccc32)cc1
Temperature: 60 °C
Yield: 61.2 %

Procedure:
A solution of 1H-pyrrolo[3,2-b]pyridine (1.30 g, 9.42 mmol) in DMF (15 ml) was treated with sodium hydride (60% in mineral oil, 434 mg, 11.3 mmol) at r.t. until effervescence ceased. After cooling to 0° C. benzyl bromide (1.68 ml, 14.1 mmol) was added and the reaction warmed at 60° C. overnight. The reaction mixture was partitioned between water and EtOAc (50 ml each) and extracted with EtOAc (50 ml). The combined organics were washed with brine (20 ml), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a brown oil (1.20 g, 58%). δH (CDCl3) 8.39 (1H, d, J 4.4 Hz), 7.48 (1H, d, J 8.2 Hz), 7.30 (1H, d, J 3.1 Hz), 7.26-7.18 (3H, m), 7.04-6.69 (3H, m), 6.67 (1H, d, J 4.4 Hz), 5.11 (2H, s). LCMS (ES+) RT 1.56 ml 209 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:6][CH2:5][N:4]([C:7]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)[CH2:3]1.[CH3:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][NH2:21]>C1(C)C=CC=CC=1>[F:1][C:2]1([F:16])[CH2:6][CH2:5][N:4]([C:7]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[N:21][CH2:20][CH2:19][C:18]([CH3:23])([CH3:22])[CH3:17])[CH2:3]1
Reactant: CC(C)(C)CCN
Reactant: O=Cc1cccc(F)c1N1CCC(F)(F)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN=Cc1cccc(F)c1N1CCC(F)(F)C1

Procedure:
2-(3,3-Difluoropyrrolidin-1-yl)-3-fluorobenzaldehyde (400 mg, 1.745 mmol) was taken in toluene (15 mL) and 3,3-dimethylbutan-1-amine (176.6 mg, 234.8 μL, 1.745 mmol) was added. The reaction mixture was refluxed overnight with a Dean Stark trap to remove the water. The reaction mixture was then concentrated and used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Br[CH2:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CBr
Reactant: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 55 °C
Yield: 77.6 %

Procedure:
To a stirred solution of 8-bromo-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.00 g, 3.08 mmol) in DMF (12 mL) at room temperature under argon was added 3-(bromomethyl)-2-methyl-6-(trifluoromethyl)pyridine (861 mg, 3.39 mmol), followed by K2CO3 (1278 mg, 9.24 mmol). The resulting suspension was warmed to 55° C. for 8 h. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. The residue was diluted with water (˜20 mL) and shaken vigorously. A solid formed and was filtered, washed with water and air-dried. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes) to obtain 1.19 g (71% yield) of title compound as a tan amorphous solid. HPLC/MS: retention time=3.90 min, [M+H]+=497.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[O:20]=[C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:23]=2[O:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:25]3[C:24]4[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:23]=4[O:22][C:21]3=[O:20])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: N#Cc1ccc2[nH]c(=O)oc2c1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(C#N)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (190 mg, 0.625 mmol, 1 eq), 2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48) (100 mg, 0.625 mmol, 1 eq), cesium carbonate (400 mg, 1.23 mmol, 2 eq) in DMF (2 ml) was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, washed with water and purified with flash chromatography to give 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (49).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: CCOCC
Product: O=C(CN1CCCC1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 95.3 %

Procedure:
2-bromo-1-(4-bromophenyl)ethanone (5.0 g, 18 mmol) was dissolved in 10 mL diethyl ether and added dropwise over 15 min to a solution of pyrrolidine (3.0 mL, 36 mmol) in 20 mL diethyl ether cooled to 0° C. in an ice bath. The resulting solution was allowed to warm to room temperature and maintained for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in 100 mL of EtOAc and washed with sodium bicarbonate (100 mL) and then brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4.6 g (96%) of the title compound as a yellow/orange solid. MS (ES) m/e 268/270 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:26][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([CH:3]1[CH2:26][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:6]2=[N:7][C:8]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN1CC(CC)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCC1Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N(CCCCCCC(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A (0° C.) cooled solution of ethyl 7-(7-ethyl-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (0.22 g, 0.44 mmol) in THF:H2O (4:1, 5 ml) was treated with LiOH.H2O (0.072 g, 1.76 mmol) and stirred at RT overnight. A further 2 equivalents of LiOH.H2O was added and the reaction mixture was heated to 50° C. for 4 hours. The solvent was removed under reduced pressure and the aqueous layer was acidified to pH 3 and partitioned between water and ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum. The crude material was purified by chromatography on silica eluting with 10% EtOAc in hexane followed by preparative HPLC (MeCN in water eluent) to afford the titled compound;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: COC(=O)C(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)CNc1cc(Br)ccc1[N+](=O)[O-]
Yield: 59.1 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (9.4 g, 42.7 mmol) in tetrahydrofuran (100 mL) were added methyl 3-amino-2-methylpropanoate (5 g, 42.7 mmol) and potassium carbonate (11.8 g, 85.4 mmol). The reaction mixture was stirred with refluxing for 3 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 3-(5-bromo-2-nitrophenylamino)-2-methylpropanoate as a light yellow solid (8 g, 59%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][CH2:14][C:15]1[NH:24][C:23](=O)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[CH2:6]([O:13][CH2:14][C:15]1[N:24]=[C:23]([Cl:3])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2nc(COCc3ccccc3)[nH]c(=O)c2c1
Solvent: CC#N
Product: COc1ccc2nc(COCc3ccccc3)nc(Cl)c2c1
Reaction time: 1 h
Yield: 69 %

Procedure:
30 ml of phosphorus oxychloride was added to a suspension of 1.50 g (5.06 mmol) of 2-benzyloxymethyl-6-methoxyquinazolin-4(3H)-one in 75 ml of acetonitrile. The obtained mixture was heated under reflux. After one hour, the reaction mixture was distilled under a reduced pressure to remove the solvent and the obtained residue was dissolved in chloroform. The obtained solution was washed with a saturated aqueous solution of sodium hydrogen-carbonate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 1.10 g of the title compound as a yellow crystal.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:20])=[CH:4][CH:3]=1.CO.C([O-])(O)=[O:24].[Na+]>Cl.C(Cl)(Cl)Cl>[OH:24][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccncc1N1CCN(c2ccc(F)nc2)C1=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc(O)nc2)C1=O
Temperature: 100 °C
Yield: 98.96 %

Procedure:
1-(6-Fluoro-pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (30A: 0.1 g, 0.00036 mmol) in 5% HCl (10 mL) was added into the reaction flask and the flask was heated to reflux at 100° C. overnight. The reaction was monitored by TLC (10% MeOH in chloroform. The reaction mixture was basified with NaHCO3 solution and extracted with chloroform. The organic layer was washed with water, brine solution, dried and concentrated to afford 72 mg of the product (98.96% yield).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH:1]1([CH2:4][CH2:5][N:6]([CH2:24][C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=2)[C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: FC(F)(F)c1ccc(-c2cccc(NCCC3CC3)c2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(CN(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.5 %

Procedure:
To a solution of N-(2-cyclopropylethyl)-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (100 mg, 0.33 mmol) in anhydrous MeCN (7 mL) under nitrogen at room temperature was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (94 mg, 0.33 mmol) and N,N-diisopropyethylamine (57.5 μl, 0.33 mmol). The resultant solution was heated to reflux and stirred for 2.5 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge) eluted with 1:200–1:100 EtOAc:cyclohexane afforded the title compound as a colourless oil (141 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH:23]=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F:47][C:48]1[CH:53]=[C:52](I)[CH:51]=[CH:50][C:49]=1[C:55]([F:58])([F:57])[F:56].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:52]2[CH:51]=[CH:50][C:49]([C:55]([F:57])([F:58])[F:56])=[C:48]([F:47])[CH:53]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Fc1cc(I)ccc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1cc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Temperature: 80 °C
Yield: 67 %

Procedure:
A vessel containing 3,4-bis(benzyloxy)-6-ethenylpyridazine (Intermediate 78, 1.09 g, 3.42 mmol), tris-(2-methylphenyl)phosphane (0.208 g, 0.685 mmol), 2-fluoro-4-iodo-1-(trifluoromethyl)benzene (1.191 g, 4.11 mmol) and palladium(II) acetate (0.038 g, 0.171 mmol) was evacuated and acetonitrile (10 ml) and triethylamine (9.07 ml, 65.1 mmol) were added in vacuo and then the mixture was flushed with nitrogen. The reaction was then heated in the microwave at 80° C. for 4 hours and, upon cooling, was diluted with dichloromethane and washed with saturated aqueous ammonium chloride solution. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil which was purified by column chromatography (silica, eluting with 30-100% dichloromethane in petrol) to yield 3,4-bis(benzyloxy)-6-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]pyridazine (1.1 g, 2.29 mmol, 67% yield).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1.Cl>CO>[CH3:3][C:4]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(OCC=C(C)CCC=C(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCCC(C)=CCOc1ccc(CC(=O)O)cc1
Yield: 61 %

Procedure:
1N potassium hydroxide (46 ml) was added to a solution of methyl 2-{4-[(3,7-dimethy-2,6-octadienyl)oxy]phenyl}acetate (9.46 g, 31.28 mmol) in methanol (70 ml) and refluxed for 1 hour. The mixture, with 3N hydrochloric acid (50 ml) added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The residue was purified by recrystallization (ethyl acetate/hexane), to give 2-{4-[(3,7-dimethyl-2,6-octadienyl)oxy]phenyl}acetic acid (5.50 g, 61%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH2:16][CH2:15][C@H:14]([NH2:17])[C@H:13]([O:18][CH3:19])[CH2:12]1.[H][H]>C(O)(=O)C>[CH3:19][O:18][C@H:13]1[C@@H:14]([NH2:17])[CH2:15][CH2:16][N:11]([CH2:10][C:2]2[NH:1][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=3[N:3]=2)[CH2:12]1
Reactant: CO[C@@H]1CN(Cc2nc3ccccc3[nH]2)CC[C@@H]1N
Reactant: [H][H]
Solvent: CC(=O)O
Product: CO[C@@H]1CN(Cc2nc3c([nH]2)CCCC3)CC[C@@H]1N

Procedure:
A mixture of 9 parts of cis-1-(1H-benzimidazol-2-ylmethyl)-3-methoxy-4-piperidinamine and 150 parts of acetic acid was hydrogenated at normal pressure and at room temperature with 2 parts of rhodium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) saturated with ammonia, as eluent. The second fraction was collected and the eluent was evaporated, yielding 5 parts of cis-3-methoxy-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-methyl]-4-piperidinamine as a residue (intermediate 113).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](=[O:32])[CH3:31]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH3:22])[C:30](=[O:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cc1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C(C)=O)c1ccccc1C)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (1.58 g, 4.80 mmol) in DMF (24 mL) was added cesium carbonate (1.56 g, 4.80 mmol) and the mixture was stirred at 23° C. for 45 min. 1-(2-Methylphenyl)-propan-2-one (0.783 g, 5.28 mmol) and cesium carbonate (2.35 g, 7.20 mmol) were added and the resulting mixture was stirred for 18 h. The mixture was filtered and water was added to the filtrate. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate→40% ethyl acetate/hexane) gave the title compound. MS: m/z=350.1 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([OH:26])[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([O:26][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(Cc2ccccc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCCN1CCCCC1
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(OCCN4CCCCC4)cc13)Sc1ccc(Br)cc1-2
Yield: 60.2 %

Procedure:
According to Example 34, the compound (200 mg) produced in Example 70 was reacted with 1-(2-chloroethyl)piperidine (158 mg) to obtain the title compound (151 mg; 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)Cc2cccc(Br)c2)cc1

Procedure:
A DMF (30 mL) solution of (3-bromophenyl)acetic acid (2.5 g, 11.6 mmol), cesium carbonate (3.78 g, 11.6 mmol) and 4-methoxybenzyl chloride (1.82 g, 11.6 mmol) was stirred overnight at room temperature. The solution was then partitioned between ethyl acetate and water. The organic phase was washed with water (3×), brine and dried over magnesium sulfate. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.43-7.39 (m, 2H); 7.29-7.24 (m, 2H); 7.20-7.16 (m, 2H); 6.90-6.86 (m, 2H); 5.07 (s, 2H); 3.81 (s, 3H); 3.60 (s, 2H). LC1 3.70 min.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[C:3]#[C:2][CH2:1][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:16]
Reactant: C#CCSc1ccccc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)C#CCSc1ccccc1

Procedure:
The title compound was prepared from prop-2-ynylsulfanyl-benzene and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:16]([O:19][C:20](=O)C)(=O)C>>[F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:3]=1[C:4]([C:6](=[CH:16][O:19][CH3:20])[C:7]#[N:8])=[O:5]
Reactant: N#CCC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(=O)OC(C)=O
Product: COC=C(C#N)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 150 °C
Yield: 95.3 %

Procedure:
A mixture of 16 g of 2,3,4,5-tetrafluorobenzoylacetonitrile, 15.6 g of trimethyl o-formate and 18.8 g of acetic anhydride is heated at 150° C. (bath temperature) for 3 hours. The solvent mixture is distilled off completely under a waterpump vacuum and finally under a high vacuum, at a bath temperature of 120° C. 18.2 g of 2-(2,3,4,5-tetrafluorobenzoyl)-3-methoxy-acrylonitrile are obtained as a dark brown oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[F:6][C:7]1[CH:8]=[C:9]([CH:13]([OH:19])[C:14](=[NH:18])[O:15]CC)[CH:10]=[CH:11][CH:12]=1>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:8]=[C:9]([CH:13]2[O:19][C:1](=[O:2])[NH:15][C:14]2=[O:18])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=N)C(O)c1cccc(F)c1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2cccc(F)c2)O1

Procedure:
By the procedure of Example 3, except that a reaction time of 16 hours at room temperature was employed following the cold perfusion with phosgene and the product was extracted into methylene chloride following quench over crushed ice, ethyl 1-(3-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (16 g., 0.068 mole) was converted to toluene recrystallized 5-(3-fluorophenyl)oxazolidine-2,4-dione (7.51 g., 56%; m.p. 147°-149° C.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:21]#[N:22])([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[C:21]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1)#[N:22]
Reactant: CCOC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C#N)(C(=O)OCC)c2ccc(OC)c(OC)c2)cc1

Procedure:
Reaction of 1c with 2c produced 3q. MS found M+H=497. The oxalate salt of 3q was recrystallized from ethyl acetate; mp 83-84° C.
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][CH2:8][CH:9](Cl)[CH3:10])[CH:3]([CH3:5])[CH3:4].[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[N:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8][CH2:9][CH2:10][S:24]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)CNCCC(C)Cl
Agent: Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCCCN1CC(C)C

Procedure:
4-Aminobutanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydro,1,3-oxazepine. The 1,3-oxazepine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxybutylamine. The 3-hydroxybutylamine was reacted with SOCl2 according to Method B9a, Step 3 to give N-isobutyl-3-chlorobutylamine HCl salt. The 3-chlorobutylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiazepine.