Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[NH:19][NH2:20]>>[NH2:9][C:8]1[N:19]([C:12]2[C:11]([Cl:10])=[CH:16][C:15]([Cl:17])=[CH:14][C:13]=2[Cl:18])[N:20]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC=C(C#N)C#N
Product: N#Cc1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N

Procedure:
The title compound was prepared as an orange solid, m.p. 208.5-209.5° C. by the procedure of Preparation A starting with ethoxymethylenemalononitrile and 2,4,6-trichlorophenylhydrazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH2:14].[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1>ClC(Cl)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH:14][C:24](=[O:25])[CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[CH:18]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: O=C(Cl)Cc1cccc(Br)c1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1cccc(Br)c1
Reaction time: 18 h

Procedure:
To a suspension of 2-amino-4-chloro-5-nitrobenzoic acid methyl ester (Example 9, 780 mg in 10 mL dichloroethane) was added a solution of (3-bromophenyl)acetyl chloride (prepared essentially as described in Example 9, 866 mg in 5 mL dichloroethane) and the mixture heated to reflux on an oil bath. After 18 hours, the reaction mixture was concentrated in vacuo and the title compound obtained by crystallization from methanol (1.18 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:14]([F:17])([F:16])[F:15])[N:8]([CH3:13])[C:9]=1[C:10]([OH:12])=O)=[O:4].Cl.Cl.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[C:22]1[CH2:32][CH2:33][NH2:34]>>[CH3:13][N:8]1[C:9]([C:10](=[O:12])[NH:34][CH2:33][CH2:32][C:22]2[N:21]([CH3:20])[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=2)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=[C:7]1[C:14]([F:17])([F:16])[F:15]
Reactant: COC(=O)c1nc(C(F)(F)F)n(C)c1C(=O)O
Reactant: Cn1cc(-c2ccccc2)nc1CCN
Agent: Cl
Product: COC(=O)c1nc(C(F)(F)F)n(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C

Procedure:
The product was obtained starting from 4-(methoxycarbonyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (200 mg, 793 μmol) and 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine hydrochloride (226 mg, 952 μmol, example 7, step 4) according to the method described in example 7, step 5 after aqueous work-up and purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white foam (128 mg, 294 μmol, 37.1%).
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@H:3]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH2:4][OH:5].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:21]([O:5][CH2:4][C@@H:3]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH:2]([CH3:20])[CH3:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)[C@@H](CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 56 °C
Reaction time: 48 h
Yield: 97.3 %

Procedure:
(2S)-3-Methyl-2-[(3-nitroquinolin-4-yl)amino]butan-1-ol (3.97 g, 14.4 mmol) was dissolved in 15 mL of dry pyridine and treated with tert-butyldimethylsilyl chloride (2.40 g, 15.9 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) (176 mg, 1.44 mmol). The reaction mixture was stirred under N2 and heated to 56° C. After 2 days, the reaction mixture was concentrated under reduced pressure. The resulting solid was partitioned between 100 mL of H2O and 100 mL of ethyl acetate. The layers were separated and the organic portion was washed with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 20% ethyl acetate/hexanes) gave N-[(1S)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-3-nitroquinolin-4-amine (5.46 g) as a yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][C:19]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[Cl:13][C:14]1[N:15]=[N:16][C:17]([NH:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([CH3:12])[CH3:11])=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: CC(C)(CN)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cc(NCC(C)(C)c2ccc(F)cc2)nnc1Cl
Yield: 15.1 %

Procedure:
A solution of (2-(4-fluorophenyl)-2-methylpropan-1-amine (5.5 g, 33 mmol, 1.8 equiv), 3,6-dichloro-4-methylpyridazine (3.0 g, 18 mmol, 1.0 equiv) and K2CO3 (5.1 g, 37 mmol, 2.0 equiv) in isopropanol (7.5 mL) was stirred at 100° C. under a blanket of nitrogen for 18 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was concentrated in vacuo. Purification over silica gel using a 20-35% gradient of EtOAc/hexanes gave the desired product (0.80 g, 15%) of a yellow oil which was determined by HPLC to be a 5:1 mixture of regioisomers by HPLC.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C1C=CN=CC=1.[FH:16].N([O-])=O.[Na+]>>[F:16][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: F
Reactant: N#Cc1ccc(N)cn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1ccc(F)cn1
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a 100 mL round bottom flask charged with 5-aminopicolinonitrile (285 mg, 2.44 mmol) at 0° C. was added HF-pyridine (5 mL) under N2. A pale brown solution was formed. In 4 aliquots, NaNO2 (250 mg, 3.62 mmol) was added with stirring. The solution turned green and a brown gas was liberated. After 20 min at 0° C., the solution was allowed to reach rt and stirred for an additional 20 min. A reflux condenser was attached and the reaction mixture was heated at 65° C. for 20 min then allowed to cool to rt. The orange slurry was quenched by the addition of crushed ice and the aqueous layer was extracted with DCM (3×10 mL). The combined organic portions were dried over Na2SO4, decanted and concentrated under reduced pressure to yield 5-fluoropicolinonitrile (152 mg, 52% yield) as a pale orange powder. LCMS: RT=0.63 min [M+H] 122.9 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=0.99 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 96%); NMR: 400 MHz 1H (CDCl3) ppm 8.52 (d, J=2.64 Hz, 1H), 7.70 (dd, J=4.4 and J=8.36 Hz, 1H), 7.50 (m, 1 H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[N+:2]=[N-:3].[C:11](O)(=[O:15])[C:12]([CH3:14])=[CH2:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: [N-]=[N+]=NCCCCCCO
Reactant: C=C(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a 500 mL round bottom flask, a solution of 1-azido-6-hydroxyhexane (14.3 g, 100 mmol), methacrylic acid (7.74 g, 90 mmol), and 4-dimethylaminopyridine (DMAP) (3.67 g, 30 mmol) in 100 mL of methylene chloride was cooled to 0° C. Dicyclohexylcarbodiimide (DCC) (20.63 g, 100 mmol) was dissolved in 50 mL methylene chloride and added slowly to the solution. The resulting mixture was warmed to room temperature and stirred overnight. The precipitate was removed by filtration. After removal of the solvent and silica gel column chromatography (10:1 mixture of hexane and ethyl acetate), the product was obtained as a colorless liquid (yield: 16.1 g, 85%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 60 h
Yield: 94.1 %

Procedure:
A solution of allyl bromide (5.94 mL, 68.78 mmol) in acetone (20 mL) was added, over a period of 20 min, to a mixture of 4-hydroxybenzaldehyde (8.00 g, 65.50 mmol) and K2CO3 (9.96 g, 72.06 mmol) in acetone (100 mL) cooled at 0° C. The mixture was allowed to reach room temperature and stirred for 60 h. After removal of the solvent, the crude residue was dissolved in EtOAc (100 mL) and washed twice with a mixture of water (100 mL) and NaOH (10% aqueous solution, 10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, 10.00 g of 4-(allyloxy)benzaldehyde were obtained [Rf=0.5 (10% EtOAc/Hexanes), pale brown oil, 94% yield]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=O)[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:37]([F:40])([F:39])[F:38])([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[S:50])[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:37]([F:40])([F:39])[F:38])([O-:3])=[O:2]
Reactant: O=C(CCN1CCC(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=[N+]([O-])c1ccc(NC2CCN(C(=S)CCN3CCC(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F

Procedure:
1-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-3-[4-(4-trifluoromethyl-phenyl)-piperidin-1-yl]-propan-1-one (20 mg; 0.035 mmol, prepared in accordance with Example 14) is reacted with Lawesson's reagent (7 mg; 0.018 mmol according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (6 mg; 0.010 mmol). The structure was confirmed using Protocol 1-B. Calculated mass=589; observed mass=589; HPLC retention time=4.74 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:25])[N:9]=1.[CH2:26]([N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][C:30]1=[O:39])[C:27]#[CH:28].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[C:27][CH2:26][N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][C:30]3=[O:39])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:25])[N:9]=1
Reactant: COC1N=C(c2ccccc2F)c2cc(I)ccc2-n2c(C)nnc21
Reactant: C#CCN1C(=O)CCc2ccccc21
Solvent: CCO
Solvent: ClCCl
Product: COC1N=C(c2ccccc2F)c2cc(C#CCN3C(=O)CCc4ccccc43)ccc2-n2c(C)nnc21

Procedure:
The title compound was prepared by coupling rac-6-(2-fluorophenyl)-8-iodo-4-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with 3,4-dihydro-1-(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate/ether to give colorless crystals of rac-1-{3-[6-(2-fluorophenyl)-4-methoxy-1-methyl-4H[1,2,4]triazolo[4,3-a][1,4] benzodiazepin-8-yl]-2-propynyl}-3,4-dihydro-2(1H)-quinolinone with m.p. 155°-160°. These crystals contained 0.33 molar equivalents of water.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1N
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3ccc(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J13) (240 mg, 0.78 mmol) and 3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K10) (293 mg, 0.89 mmol) according to the general procedure M. Obtained as a red foam (288 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C(N(C(C)C)CC)(C)C.Cl.Cl.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][C:30]=2[C:38]([F:41])([F:40])[F:39])[CH2:24][CH2:23]1>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH:8][C:6]3[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([NH2:1])[CH:7]=3)=[O:34])=[CH:31][C:30]=2[C:38]([F:41])([F:39])[F:40])[CH2:26][CH2:27]1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1N
Yield: 74 %

Procedure:
1.04 g of 2,4-diaminotoluene, 104 mg of 4-(dimethylamino)pyridine and 4.9 ml of N,N-diisopropyl-N-ethylamine were dissolved in 40 ml of acetonitrile. Under ice-cool stirring, 3.70 g of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 2) was added by four portions. After stirring for 1 hour, the solvent was distilled off under reduced pressure and diluted with water. The reaction solution was alkalified with an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate twice, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.56 g of the objective compound as a pale brown amorphous.
Reaction SMILES: [CH2:1]([N:8]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH2:45][OH:46])([CH3:44])[C:12]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:58]1[CH:63]=[CH:62][CH2:61][CH2:60][CH2:59]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(Cl)Cl>[CH2:1]([N:8]([C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:42])[CH3:43])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:44])([CH2:45][O:46][CH:59]2[CH2:60][CH2:61][CH2:62][CH2:63][O:58]2)[C:12]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(CO)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COC1CCCCO1)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate in methylene chloride (4.0 ml) were added 3,4-dihydro-2H-pyran (86 μl) and pyridinium p-toluenesulfonate (6.3 mg), and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added water (3 ml), and the mixture was extracted with methylene chloride (5 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure to give the title compound (440 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N([CH2:27][CH3:28])CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([O:14][CH2:15][CH2:16][O:17][C:28]3[CH:27]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[Cl:8])=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)OCCOc1ccc(Cl)cc1Cl

Procedure:
The 2-[4-(3,5-dichloropyridin-2-yloxy)phenoxy]propanoic acid chloride (3.12 grams; 0.009 mol); triethylamine (5 ml): 2,4-dichlorophenoxyethethanol (1.94 grams; 0.0094 mol) and toluene (100 ml) were stirred in a glass reaction flask until thin layer chromatographic analysis showed completion of the reaction. This mixture was transferred to a separatory funnel and washed three times with water (70 ml). The washed material was dried and stripped to a yellow/brown gum (4.8 grams) that solidified on standing and was recrystallized from a mixture of methylene chloride and hexane. The first crop (1.5 grams) analyzed by elemental analysis as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Cc1ccc(O)c(Cl)c1

Procedure:
A mixture of 67 g (0.38 moles) of 3-chloro-4-hydroxyphenylacetic acid, 1.5 g of p-toluenesulfonic acid, and 250 ml of methanol was refluxed overnight, i.e., about 18 hours. The excess methanol was removed by vacuum to give a thick tawny oil. This oil was dissolved in ether, twice washed with water, and dried over anhydrous sodium sulphate. The ethereal solution was filtered, the ether removed and a tawny oil remained. Using as solvent 2.5% v/v methanol in chloroform and a silica gel matrix, thin-layer chromotography showed that the oil was essentially homogeneous, there being only a trace impurity present at the origin, which is believed to be unreacted acid. This oil was satisfactory for use as the starting material for forming the ether of Example 1B.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH:14]([C:25]([O:27][CH3:28])=[O:26])[CH2:13]2)=[N:4][N:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH:14]([C:25]([O:27][CH3:28])=[O:26])[CH2:13]2)=[N:4][N:3]=1
Reactant: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-tert-butyl 2-methyl 4-(4-chlorophthalazin-1-yl)piperazine-1,2-dicarboxylate (754 mg, 1.85 mmol) was partially dissolved in dichloromethane (20 mL). Trifluoroacetic acid (3.50 mL) was added and the reaction stirred at rt for 4 hours. Saturated sodium bicarbonate (50 mL) was added and stirred for 15 minutes. The layers were separated and the aqueous phase was extracted two more times with dichloromethane. The combined extracts were dried (MgSO4) and evaporated to give a foamy yellow solid. MS (M+H)+=307.1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[N:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C(=NCCc1ccccc1)c1ccccc1OCCCN1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CCNCc2ccccc2OCCCN2CCCCC2)cc1
Yield: 80.2 %

Procedure:
N-[[2-[3-(1-Piperidinyl)propoxy]phenyl]methylene]benzeneethanamine (61.5g) is reduced with 20g of sodium borohydride in 320ml of methanol following the procedure described in Example 1B to yield 49.6g of product as an oil, boiling point 216°-221° C at 0.3-0.4mm of Hg.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:10][C:11]1[C:16](C)=[CH:15][N+:14]([O-])=[C:13](C)[C:12]=1[CH3:20])[CH3:9]>C(Cl)(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[C:16]([CH3:15])=[C:11]([O:10][CH2:8][CH3:9])[C:12]([CH3:20])=[CH:13][N:14]=1)(=[O:7])[CH3:6]
Reactant: CCOc1c(C)c[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOc1c(C)cnc(COC(C)=O)c1C

Procedure:
75 ml of acetic anhydride were added dropwise at room temperature to a solution of 31.3 g of 4-ethoxy-2,3,5-trimethylpyridine 1-oxide in 100 ml of chloroform. After boiling under reflux for 16 hours the solution was evaporated, the residue was dissolved in 100 ml of toluene and again evaporated. The residue was taken up in 250 ml of ethyl acetate, whereupon it was extracted three times with 100 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The product was chromatographed on 170 g of silica gel with ether. There was obtained (4-ethoxy-3,5-dimethyl-2-pyridyl)methyl acetate in the form of an oil.
Reaction SMILES: BrC1C=C(Cl)C=CC=1N1[C:13]2=[N:14][C:15]3[C:20](Cl)=[CH:19][CH:18]=[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]=3[N:12]2CC1.C([Li])CCC.CN(C)C=[O:35]>O1CCCC1>[CH2:23]([CH:22]([C:17]1[C:16]2[NH:12][C:13](=[O:35])[NH:14][C:15]=2[CH:20]=[CH:19][CH:18]=1)[CH2:25][CH3:26])[CH3:24]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cccc2[nH]c(=O)[nH]c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of 1-(2-bromo-4-chlorophenyl)-8-Chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (140 mg, 0.309 mmol) in tetrahydrofuran was cooled to −78° C. under nitrogen atmosphere and n-butyllithium (1.6 M solution in n-hexane, 0.213 mL, 0.340 mmol) was added dropwise. After the mixture was stirred at −78° C. for 1 hr, N,N-dimethylformamide (0.120 mL, 1.545 mmol) was added. The mixture was allowed to warm to room temperature for 1 hr. The reaction was quenched by an addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-40% ethyl acetate/n-hexane gradient mixture. The desired fractions for 5-chloro-2-[8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl]benzaldehyde were concentrated in vacuo, and the resulting solid was recrystallized from methanol to give the title compound of example 6 (41 mg, 0.102 mmol, 33%) as a colorless crystal. The desired fractions for 8-chloro-1-(4-chlorophenyl)-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole were concentrated in vacuo, and the resulting solid was recrystallized from methanol to give the title compound of example 7 (17 mg, 0.04542 mmol, 15%) as a colorless crystal.