Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:4].Br[C:12]1[S:16][CH:15]=[C:14]([C:17]([N:19]2[CH:28]3[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:22][CH2:21][CH2:20]2)=[O:18])[CH:13]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:3]([O:5][C:6](=[O:10])[CH:7]([C:8]#[N:9])[C:12]1[S:16][CH:15]=[C:14]([C:17]([N:19]2[C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:22][CH2:21][CH2:20]2)=[O:18])[CH:13]=1)[CH3:4]
Reactant: CCOC(=O)CC#N
Reactant: O=C(c1csc(Br)c1)N1CCCC2CCCCC21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1cc(C(=O)N2CCC[C@@H]3CCCC[C@@H]32)cs1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 400 mg) was added to a solution of ethylcyanoacetate (0.450 g) in THF (10 mL) and the mixture stirred for 10 minutes. A solution of (5-bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.326 g) and PdCl2(PPh3)2 (0.035 g) in THF (2 mL) was then added dropwise and the mixture heated to 60° C. overnight. The solvent was evaporated and the residue purified by flash chromatography on silica, washing with cyclohexane and ethyl acetate. The fractions containing the desired product were concentrated under vacuum to give the title compound as a clear oil (0.198 g). LCMS m/z 361.27 [M+H]+ RT=3.80 min (Analytical Method 3).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:19]=2[O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Cl:25][C:20]1[C:19]([O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[C:18]([CH:23]=[C:22]([Cl:24])[CH:21]=1)[C:17]([NH:16][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:31]
Reactant: CCOC(=O)C1(NC(=O)c2cc(Cl)cc(Cl)c2OC2CCC2)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccc(F)cc2C1)c1cc(Cl)cc(Cl)c1OC1CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.3 %

Procedure:
The mixture of 2-(3,5-dichloro-2-cyclobutoxy-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester (20) (300 mg, 0.64 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 6 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. The precipitate is filtered to give a pure product (21) as white solid (200 mg, 71%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:13]=[C:12]2[N:14]=[CH:15][NH:16][C:11]2=[C:10]([Cl:17])[CH:9]=1.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[Cl:7][C:8]1[N:13]=[C:12]2[N:14]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH:15]=[N:16][C:11]2=[C:10]([Cl:17])[CH:9]=1
Reactant: Clc1cc(Cl)c2[nH]cnc2n1
Reactant: BrCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c2ncn(Cc3cccc4ccccc34)c2n1
Reaction time: 0.42 h
Yield: 26.2 %

Procedure:
Potassium carbonate (798 mg, 5.77 mmol) was added to a solution of 5,7-dichloro-1H-imidazo[4,5-b]pyridine (350 mg, 1.862 mmol) (5,7-dichloro-3H-imidazo[4,5-b]pyridine, obtained as described in example 1) in N,N-Dimethylformamide (DMF) (6.5 mL) and the mixture was stirred for 25 min. 1-(bromomethyl)naphthalene (576 mg, 2.61 mmol) was then added and the reaction mixture was stirred at rt overnight. The mixture was poured onto water and the precipitate formed was collected by filtration. The residue was purified on silica gel (15 to 30% EtOAc in hexanes) to give 5,7-dichloro-3-(1-naphthalenylmethyl)-3H-imidazo[4,5-b]pyridine (160 mg, 0.488 mmol, 26.2% yield) as a light yellow powder. MS (ES+) m/e 328 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1H), 8.25 (d, J=8.08 Hz, 1H), 7.97-8.03 (m, 1H), 7.92 (d, J=8.34 Hz, 1H), 7.66-7.70 (m, 1H), 7.56-7.66 (m, 2H), 7.41-7.49 (m, 1H), 7.11 (d, J=6.32 Hz, 1H), 6.00 (s, 2H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].C(=O)([O-])[O-:22].[K+].[K+].CC(C)=O.NC(N)=O.OO>O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:22]
Reactant: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: NC(N)=O
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Temperature: 22.5 °C

Procedure:
A mixture of 3-cyano-5-[(dipropylamino)carbonyl]benzoic acid (IX/XXXII, PREPARATION 7, 0.602 g, 2.19 mmol), potassium carbonate (0.212 g, 1.53 mmol), and acetone (2.5 mL) is stirred at 20-25 degrees C. Water (2.5 mL) and urea-hydrogen peroxide adduct (0.825 g, 8.78 mmol) are added and the mixture is stirred for 15 hours at 20-25 degrees C., at which time additional urea-hydrogen peroxide adduct (0.204 g) is added; after stirring for another 3 hours, an additional 0.205 g of urea-hydrogen peroxide is added. After a total of 39 hours has elapsed, the acetone is removed under reduced pressure and the residue is acidified with hydrochloric acid (3N) to pH=2-4. The mixture is extracted with dichloromethane, the organic layer is separated and washed with hydrochloric acid (0.5 N), and the organic phase is dried with anhydrous magnesium sulfate to a solid. The solid is crystallized from dichloromethane/hexane/methanol to give the title compound, MS (ESI+) for C15H20N2O4 m/z (M+H)+=293.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=O.C(OCC)C>C1COCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1ccc(-c2csc(C3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (2.47 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.47 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The volume was reduced to 5 mL and diethylether (5 mL) was added. The mixture was then cooled to −20° C. and filtered. The solid was washed with a small amount of diethylether and dried. m/z=289.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Methyl 3-nitro-5-(trifluoromethyl)benzoate (9.0 g, 36.1 mmol) in methanol (30 mL) was flushed with nitrogen, and treated with palladium (10% on charcoal, 0.90 g). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Flash chromatography on silica gel (30% ethyl acetate/hexanes) afforded 6.8 g (86%). 1H-NMR (CDCl3, 500 MHz) δ 7.64 (s, H), 7.49 (s, 1H), 7.05 (s, 1H), 3.91 (s, 3H). Mass spec.: 220.05 (MH)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][N:31]([C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3]
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester, hydrochloride and benzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]2[NH:8][C:7]3[C:14]4[C:19]([CH2:20][C:6]=3[C:5]=2[C:4]=1[CH3:21])=[CH:18][CH:17]=[CH:16][CH:15]=4.O1CCN(B)CC1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]2[NH:8][C@@H:7]3[C:14]4[C:19]([CH2:20][C@@H:6]3[C:5]=2[C:4]=1[CH3:21])=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: COc1c(C)c(C)c2[nH]c3c(c2c1C)Cc1ccccc1-3
Agent: BN1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1c(C)c(C)c2c(c1C)[C@H]1Cc3ccccc3[C@H]1N2
Temperature: 25 °C

Procedure:
To a solution of 0.65 g (0.00234 mol) of 5,10-dihydro-8-methoxy-6,7,9-trimethylindeno[1,2-b]indole and 0.95 g (0.00957 mol) of morpholino borane in 4 ml of dioxane was added dropwise 1 ml of concentrated hydrochloric acid. The mixture was refluxed for 30 minutes, cooled to room temperature whereupon 3 ml of 6N hydrochloric acid was added. The mixture was then refluxed for another 30 minutes. After cooling to room temperature, the crude mixture was partitioned between ether and aqueous sodium hydroxide. The organic phase was separated and washed with aqueous sodium hydroxide and with water. Drying (MgSO4) and evaporation gave the crude product which was recrystallized from ethyl acetate/light petroleum. Yield 0.46 g (70%). 1H NMR (CDCl3): 2.0 (3H,s), 2.14 (3H,s), 2.28 (3H,s), 3.17 (1H,dd), 3.55 (1H,dd), 3.64 (1H,s), 4.28 (1H,ddd), 5.38 (1H,d), 7.20-7.27 (3H,m), 7.39 (1H,d).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C=O)C>[Si:12]([O:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: Oc1cn[nH]c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cn[nH]c1
Reaction time: 17 h
Yield: 94.3 %

Procedure:
4-Hydroxypyrazole (1.16 g, 13.8 mmol) and imidazole (1.13 g, 16.6 mmol) were suspended in DMF (50 ml) under nitrogen and t-butyldimethylsilylchloride (2.3 g, 15.2 mmol) was added. After stirring 17 hours, the solvent was removed in vacuo and the residue treated with water containing 4.5 g of potassium carbonate. The mixture was extracted with two portions of chloroform and the organic layer dried over sodium sulfate. The solvent was removed in vacuo to yield product (2.58 g, 94%). NMR
Reaction SMILES: [C:1]1([N:10]=[C:11]=[S:12])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[S:9])=[CH:3][CH:2]=1.[CH:13]([NH:16][CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C(#N)C>[C:4]1([NH:7][C:8]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[S:9])[CH:3]=[CH:2][C:1]([NH:10][C:11]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[S:12])=[CH:6][CH:5]=1
Reactant: S=C=Nc1ccc(N=C=S)cc1
Reactant: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)N(C(=S)Nc1ccc(NC(=S)N(C(C)C)C(C)C)cc1)C(C)C

Procedure:
To a solution of 1.92 g. of 1,4-phenylenediisothiocyanate in 100 ml. of acetonitrile is added 2.5 g. of diisopropylamine. On standing, a precipitate forms which is filtered off and crystallized from acetone-cyclohexane to yield 2.7 g. of the title compound, melting point 185° C.
Reaction SMILES: [NH2:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O.O>ClCCl>[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9]/[CH:10]=[N:1]/[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)CC=O
Reactant: C[Si](C)(C)CN
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C/C=N/C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of (aminomethyl)trimethylsilane (Fluka) (1.03 g, 10 mmol) in dichloromethane (20 mL) was added 3,3-dimethyl-butyraldehyde (Aldrich) (1.0 g, 10 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give [3,3-dimethyl-but-(E)-ylidene]-trimethylsilanylmethyl-amine as a colorless oil (1.8 g, 97%).
Reaction SMILES: C(OC(N(C)[C@H](C(O)=O)CCOC)=O)(C)(C)C.ClC1C(F)=C(NC2C3C(=CC(OC)=C([CH2:36][N:37](C)[C@H:38]([C:43]([NH2:45])=[O:44])[CH2:39][CH2:40][O:41][CH3:42])C=3)N=CN=2)C=CC=1>>[CH3:36][NH:37][C@H:38]([C:43]([NH2:45])=[O:44])[CH2:39][CH2:40][O:41][CH3:42]
Reactant: COCC[C@@H](C(N)=O)N(C)Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Agent: COCC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Product: CN[C@@H](CCOC)C(N)=O

Procedure:
N-(tert-butoxycarbonyl)-N,O-dimethyl-L-homoserine was converted to the corresponding amide, followed by removal of the nitrogen protecting group using an analogous as process to that described in Example 7 for the preparation of N2,O-dimethyl-L-serinamide, to give N2,O-dimethyl-L-homoserinamide; 1H NMR spectrum: (DMSO d6) 1.58 (m, 1H), 1.69 (m, 1H), 1.80 (brs, 1H), 2.17 (s, 3H), 2.84 (dd, 1H), 3.20 (s, 3H), 3.34 (m, 2H), 6.93 (brs, 1H), 7.27 (brs, 1H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8](OC(C)(C)C)=O)[CH2:4]1)=[O:2].FC(F)(F)C(O)=O.BrC[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:1]([CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:4]1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CN2CCC(C=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-Butyl 3-formylpyrrolidine-1-carboxylate (4.75 g, 23.84 mmol) was dissolved in dichloromethane (DCM) (20 mL). Trifluoroacetic acid (15 mL, 195 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. After concentrating acetonitrile (100 mL) was added followed by methyl 4-(bromomethyl)benzoate (6.55 g, 28.6 mmol) and potassium carbonate (16.47 g, 119 mmol). The reaction was heated to reflux for 16 hours. The mixture was filtered and concentrated. Dichloromethane (75 ml) was added and the solution was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified via silica gel chromotography (0% to 100% EtOAc:Hex; 50 g-HP-silica gel column). Obtained 2.00 g 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.99-2.23 (m, 2H), 2.46-2.57 (m, 1H), 2.60-2.79 (m, 2H), 2.88-2.99 (m, 2H), 3.68 (d, J=4.29 Hz, 2H), 3.92 (s, 3H), 7.40 (d, J=8.59 Hz, 2H), 7.93-8.09 (m, 2H), 9.66 (d, J=2.02 Hz, 1H);
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([N:14]1[C:18](=[O:19])[C:17]2([CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][CH2:20]2)[N:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[O:19]=[C:18]1[C:17]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[N:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15][N:14]1[C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:41]
Reactant: CC(C)(C)OC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A solution of (S)-benzyl 3-(2-tert-butoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.88 g, 3.39 mmol, 1 equiv) in a mixture of ethyl acetate and ethanol was charged with 10% palladium on carbon (1 g, 20%/wt) and the resulting mixture was hydrogenated at atmospheric pressure for 2 h. The reaction was filtered over Celite and the filtrate was concentrated and dried in vacuo to afford the title compound as a dark grey foam (1.24 g, 93%); MS for C25H31N3O3 m/z 422.24 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH2:12][CH3:13])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=C(C)C2C(=[N:34][OH:35])CC(C3C=CC(F)=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH2:12][CH3:13])[C:9]2[C:8](=[N:34][OH:35])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: CCc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1)C2
Product: CCc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1)C2

Procedure:
The title compound was prepared from 2-amino-4-ethyl-7-(4-fluoro-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 3, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 3/a stage 4).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.Br[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCc1cc2ccccc2s1

Procedure:
2-n-Butylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 97 mmoles, 5.7 ml), 1-bromobutane (9.7 mmoles, 1.0 ml) and THF (20 ml). 0.65 g (46%) of a yellow liquid was isolated.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:19]([O:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)[CH3:20]>CN(C=O)C>[CH2:19]([O:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]1=[O:18])[CH3:20]
Reactant: CCOC(=O)CCCCCCCl
Reactant: O=c1[nH]c2ccccc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 1.9 g. of NaH (80% suspension in mineral oil), 13.2 g. of 1-phenylbenzimidazolin-2-one (produced in usual manner by subjecting N-phenyl-o-phenylenediamine to reaction with phosgene), 120 cc. of DMF, 12.1 g. of 7-chloroenanthic acid ethyl ester and 1.9 g. of NaJ. Eluant in chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [CH2:1]([C:4]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)([CH2:7][CH:8]=[CH2:9])[CH2:5][OH:6])[CH:2]=[CH2:3].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH2:1]([C:4]([C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)([CH2:7][CH:8]=[CH2:9])[CH2:5][O:6][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:32])[F:33])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[CH:2]=[CH2:3]
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: C=CCC(CO)(CC=C)c1ccc(Br)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCC(CC=C)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 2-allyl-2-(4-bromo-phenyl)-pent-4-en-1-ol (from Preparation 3, Step B)(0.206 g, 0.734 mmol), 4′-trifluoromethyl-biphenyl-4-ol (0.184 g, 0.772 mmol), and triphenylphosphine (0.286 g, 1.09 mmol) in toluene (7.0 mL) is treated with 1,1′-(azodicarbonyl)-dipiperidine (0.272 g, 1.08 mmol) and stirred overnight at room temperature. The reaction is then warmed to 80° C. for 6 h, cooled to room temperature, diluted with MeOH, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% EtOAc to 50% EtOAc to provide 0.226 g, (61%) of the title compound as a yellow syrup. 1H NMR (CDCl3): δ 7.66-7.61 (m, 4H), 7.52-7.50 (m, 2H), 7.46-7.44 (m, 2H), 7.24-7.22 (m, 2H), 7.00-6.98 (m, 2H), 5.56 (ddt, J=17.1, 10.3, 7.2 Hz, 2H), 5.05-4.99 (m, 4H), 4.12 (s, 2H), 2.61 (d, J=7.4 Hz, 4H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzoic acid (16.0 g, 0.0864 mol) in dry DMF (100 mL) was added with stirring potassium carbonate (59.0 g, 0.43 mol) followed by methyl iodide (24.5 g, 0.173 mol) and the mixture was stirred for 3 h at ambient temperature. The reaction mixture was diluted with ice water (500 mL), extracted with EtOAc (3×100 mL) and the combined organic phases were washed with water (3×100 mL) and saturated brine solution (100 mL). The organic phase was dried (Na2SO4) and the solvent evaporated affording 17.0 g (99%) of 4-fluoro-3-nitro-benzoic acid methyl ester.
Reaction SMILES: C(OC(=O)CN1C2C=CC=CC=2N(CC2N(CCC(C)C)C3C=CC(C(=N)N)=CC=3N=2)C1=O)(C)(C)C.O[NH:38][C:39]([C:41]1[CH:68]=[CH:67][C:44]2=[N:45][N:46]([CH2:48][C:49]3[N:53]([CH2:54][CH2:55][CH:56]([CH3:58])[CH3:57])[C:52]4[CH:59]=[CH:60][C:61]([C:63](=[NH:66])[NH:64]O)=[CH:62][C:51]=4[N:50]=3)[N:47]=[C:43]2[CH:42]=1)=[NH:40]>>[C:63]([C:61]1[CH:60]=[CH:59][C:52]2[N:53]([CH2:54][CH2:55][CH:56]([CH3:57])[CH3:58])[C:49]([CH2:48][N:46]3[N:45]=[C:44]4[CH:67]=[CH:68][C:41]([C:39]([NH2:40])=[NH:38])=[CH:42][C:43]4=[N:47]3)=[N:50][C:51]=2[CH:62]=1)(=[NH:64])[NH2:66]
Reactant: CC(C)CCn1c(Cn2nc3ccc(C(=N)NO)cc3n2)nc2cc(C(=N)NO)ccc21
Agent: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C(=N)N)ccc21
Product: CC(C)CCn1c(Cn2nc3ccc(C(=N)N)cc3n2)nc2cc(C(=N)N)ccc21

Procedure:
2-[5-Carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2H-benzotriazole-5-carboxamidine was prepared as described for {3-[5-carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester using N-Hydroxy-2-[5-(N-hydroxycarbamimidoyl)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2H-benzotriazole-5-carboxamidine.