Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]([CH:13]([C:15]2[O:19][C:18]([CH3:20])=[C:17]([CH3:21])[CH:16]=2)O)=[CH:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]1=2.[BH4-].[Na+]>C(=S)=S>[S:8]1[C:12]([CH2:13][C:15]2[O:19][C:18]([CH3:20])=[C:17]([CH3:21])[CH:16]=2)=[CH:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]1=2
Reactant: Cc1cc(C(O)c2cc3ccccc3s2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: S=C=S
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cc2cc3ccccc3s2)oc1C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
Trifluoroacetic acid (30 mL) was added dropwise to a rt, stirred suspension of benzo[b]thiophen-2-yl-(2,3-dimethyl-furan-5-yl)-methanol (9.56 g, 40.0 mmol) and sodium borohydride (7.0 g, 200 mL) in carbon disulfide (100 mL) under a try N2 atmosphere over a period of 30 min. After an additional 3 hours, the reaction mixture was carefully quenched and further diluted with aqueous ammonium chloride (250 mL). Aqueous mixture was extracted with ethyl ether (500 mL). The ethyl ether extract was washed with water and brine. Silica gel (100 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent 99:1 petroleum ether:ethyl acetate) to provide the title compound as an oil (3.75 g, 42%): NMR (CDCl3); δ7.74 (d, J=8 Hz, 1H), 7.67 (d, J=8, Hz, 1H), 7.35-7.22 (m, 2H), 7.08 (d, J=1 Hz, 1H), 5.93 (s, 1H), 4.15 (s, 2H), 2.17 (s, 3H), 1.90 (s, 3H); MS (EI): [M+], 242.
Reaction SMILES: [H-].[Na+].N1C=CN=C1.C([NH:27][C@@H:28]([C:31]([OH:33])=[O:32])[CH2:29][OH:30])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34](I)[CH2:35][CH2:36][CH3:37]>O1CCCC1>[CH2:34]([O:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[NH2:27])[CH2:35][CH2:36][CH3:37]
Reactant: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCCCOC[C@@H](N)C(=O)O
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 52.6 %

Procedure:
To a mixed solution of 60% sodium hydride (28.8 g), imidazole (1.08 g, 15.9 mmol), and dry tetrahydrofurane (270 ml), a mixed solution of N-trityl-D-serine (25.0 g, 72.0 mmol) and dry tetrahydrofurane (150 ml) was dripped in 15 minutes at -15° C., and the mixture was stirred for 45 minutes at -15° C. Further, butyl iodide (65.5 ml, 576 mmol) was added, and the mixture was stirred for 2 hours at -15° C. Moreover, at -15° C., adding 60% sodium hydride (12.0 g) and butyl iodide (129 ml, 1.13 mol), the mixture was stirred for 1 day at -20° C. Adding water (1 liter) to the reaction solution, it was extracted with ether (300 ml×2), and the organic layer was washed with 5% aqueous solution of citric acid (200 ml) and saturated brine (100 ml), and dried over magnesium sulfate. The solvent was evaporated in vacuo, and 50% acetic acid-ethanol solution (100 ml) was added to the obtained oily matter, and the mixture was stirred for 15 hours at room temperature. The sediment was filtered, and washed with ethanol and ether, and O-butyl-D-serine (6.11 g, 53%) was obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: FC(F)(F)c1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-trifluoromethylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 370.2 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.58 (br s, 1H); 8.39 (br s, 1H); 7.85 (d, J=8.2 Hz, 1H); 7.69 (s, 1H); 7.61 (d, J=7.6 Hz, 1H); 7.57 (d, J=7.6 Hz, 1H); 7.49 (m, 1H); 6.85 (d, J=5.3 Hz, 1H); 6.38 (br s, 1H); 4.81 (d, J=6.2 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.[ClH:21]>C1COCC1.O1CCOCC1>[ClH:21].[ClH:21].[CH3:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN1CCNCC1c1ccccc1
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 3-phenylpiperazine-1-carboxylate (288 mg, 1.1 mmol), and formaldehyde (185 mg, 6.16 mmol) in methanol (7 mL) was added sodium triacetoxyborohydride (949 mg, 4.48 mmol) at 0° C. After stirring for 3 h at room temperature, the reaction mixture was diluted with 10% sodium bicarbonate solution and ethyl acetate. The aqueous part was extracted with ethyl acetate and the combined organic part was dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by flash chromatography (20/1 dichloromethane/methanol) to provide 4-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (307 mg, 101%). (M+H)+=277 m/e. To a solution of 4-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (307 mg, 1.11 mmol) in THF (3 mL) at 0° C. was added 4M HCl in dioxane (0.9 mL). The reaction mixture was stirred overnight and concentrated in vacuo. The residue was triturated with dichloromethane and filtered to provide 1-methyl-2-phenyl-piperazine dihydrochloride (290 mg), which was used as is for the next step.
Reaction SMILES: [CH2:1]=[N:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([C:25]([CH3:27])=[O:26])[C:20]([O:22]CC)=O>C1(C)C(C)=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20](=[O:22])[N:2]([C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:1][O:26][C:25]=1[CH3:27]
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1OC
Reactant: C=NC(C)(C)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(C)N1COC(C)=C(c2ccccc2OC)C1=O
Reaction time: 3 h
Yield: 117.4 %

Procedure:
A solution of ethyl 2-(N-methyleneamino)-2-methylpropionate (10.3 g) in xylene was added during 1 hour to a solution of ethyl 2-(2-methoxyphenyl)acetoacetate (8.51 g) in xylene whilst heating under reflux. The rate of addition was controlled so as to equal the rate of azeotropic distillation (via a Dean and Stark separator). Additional xylene was then added and distillation continued for 3 hours. The mixture was evaporated in vacuo to give ethyl 2-[2,3-dihydro-5-(2-methoxyphenyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate (14.1 g), NMR 1.25(t,3H), 1.55(s,6H), 1.8(s,3H), 3.75(s,3H), 4.1 5(m,2H), 5.3(s,2H), 6.9-7.3(m,4H).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[C:36]([C:37]([O:39]CC)=[O:38])=[CH:35][N:34]=[C:33]([C:42]([F:45])([F:44])[F:43])[N:32]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[C:31]1[C:36]([C:37]([OH:39])=[O:38])=[CH:35][N:34]=[C:33]([C:42]([F:43])([F:44])[F:45])[N:32]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1cnc(C(F)(F)F)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-2-trifluoromethyl-pyrimidine-5-carboxylate (194 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→7:3) to give 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-2-trifluoromethyl-pyrimidine-5-carboxylic acid (165 mg). MS (m/z): 755 [M+H]+
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[O:18][CH2:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:23]2[CH:22]=[CH:21][C:20]3[O:16][CH2:17][O:18][C:19]=3[CH:24]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCO3)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and benzo[1,3]dioxole-5-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 4 h. 1H NMR (400 MHz, CDCl3) δ 7.27-6.74 (m, 7H), 5.90 (s, 2H), 3.77 (s, 2H), 3.71 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.62 (t, 2H); MS 328 (M+1).
Reaction SMILES: [Na].C(O)C.[CH3:5][O:6][C:7]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]#[N:23].[C:24](=O)([O-:28])[O:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[C:22]([CH:21]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:7]=1[O:6][CH3:5])[C:24]([O:25][CH2:26][CH3:27])=[O:28])#[N:23]
Reactant: CCOC(=O)[O-]
Reactant: COc1c(CC#N)cccc1Sc1ccccc1C
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C#N)c1cccc(Sc2ccccc2C)c1OC
Yield: 96.3 %

Procedure:
Sodium metal (0.7 g), dried ethanol (20 ml), 2-[2-methoxy-3-(o-tolylthio)phenyl]acetonitrile (7.7 g), ethyl carbonate (13 g) and toluene (50 ml) were treated in a similar manner to that of Example 22-(1) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]acetate (9.4 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C(Cl)Cl>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:3](=[O:4])[CH2:2][Br:1])=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: O=C(Br)CBr
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(CBr)NCCc1ccc([N+](=O)[O-])cc1

Procedure:
Bromoacetyl bromide (806 mg, 4.0 mmol) was added dropwise to a solution of p-nitrophenylethylamine (665 mg, 4.0 mmol, freshly prepared from the hydrochloride salt) in 30 mL CH2Cl2 over 6 min at 0° C. with stirring. Then, the reaction mixture was stirred at 0° C. for 1 h. The resulting precipitate was filtered off and washed twice with 10 mL CH2Cl2, which was combined with filtrate and rotoevaporated to dryness. Chromatography over 20 g silica gel and elution with 5:3 ethyl acetate:hexane gave crystalline N-(4-nitrophenylethyl)bromoacetamide (compound 74). Recrystallization from ethyl acetate-hexane gave 290 mg (58% yield) of compound 74 as yellow needles: mp 123°-124° C. IR (nujol) 3276, 1659, 1515, 1343 cm-1 ; NMR 2.99 (t, 2H), 3.60 (q, 2H), 3.88 (s, 2H), 6.54 (m, 1H), 7.38-8.20 (AA'BB', 4H) ppm.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:11])=[N:7][NH:8][C:9]=1[NH2:10])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:14]=[C:15]([CH3:18])[CH:16]=O>C(O)C.C(O)(=O)C>[C:1]([C:5]1[C:6]([NH2:11])=[N:7][N:8]2[CH:16]=[C:15]([CH3:18])[CH:14]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C=O)=CN(C)C
Reactant: CC(C)(C)c1c(N)n[nH]c1N
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cnc2c(C(C)(C)C)c(N)nn2c1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture from Example 105A (1.56 g, 10.1 mmol), 3-dimethylamino-2-methyl-2-propenal (1.63 g, 14.4 mmol) and acetic acid (25 μL, 0.44 mmol) in ethanol (10 mL) was heated by microwave to 150° C. for 30 minutes. The mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (EtOAc, Rf=0.53) afforded 1.66 g (80%) of the title compound. MS (DCI) m/z 205 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[I-].[K+].CC(C)=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OCc1ccccc1
Yield: 98 %

Procedure:
The mixture of 31.62 g (190 mmol) 1-(4-hydroxy-3-methoxy-phenyl)-ethanone, 16.36 g (118 mmol) potassium carbonate, 0.5 g potassium iodide, 400 ml acetone and 33.15 g (190 mmol) ml benzyl bromide were refluxed for 2 days. The solvent was evaporated, the residue was taken up in 400 ml of water. The precipitate was filtered, washed with 100 ml of sodium carbonate saturated aqueous solution and 2×100 ml of water, then dried on air to give 47.8 g of product [A]. Yield 98%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:51])[CH2:7][C@@H:8]([NH:33]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:9]([NH:11][C@H:12]([C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)=[CH:24][N:25]=1)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:10])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:51])[CH2:7][C@@H:8]([NH2:33])[C:9]([NH:11][C@H:12]([C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)=[CH:24][N:25]=1)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)c1ncc(-c2ccc(I)cc2)[nH]1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)CC(=O)OC(C)(C)C)c1ncc(-c2ccc(I)cc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of (R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-N-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-succinamic acid tert-butyl ester (1.5 g, 1.88 mmol) (from step 8-G) in methylene chloride (30 mL) was added piperidine (6 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography over silica gel gradient eluted from 100% methylene chloride to 10% v/v methanol/methylene chloride in 30 minutes to give ((R)-3-amino-N-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-succinamic acid tert-butyl ester (0.93 g, 86%). LC-MS: calcd for C26H31IN4O3 [M+H+] 575. Found 575.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23][CH2:24]I>CCCCCCC.CCOC(C)=O>[Cl:21][CH2:22][CH2:23][CH2:24][N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[O:12][CH2:11][C:10]1=[O:14]
Reactant: CC(C)c1cccc2c1OCC(=O)N2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)c1cccc2c1OCC(=O)N2CCCCl
Yield: 69.7 %

Procedure:
8-Isopropyl-4H-benzo[1,4]oxazin-3-one (95MF83) (0.115 g, 0.60 mmol), Cs2CO3 (0.293 g, 0.90 mmol) and 3-chloro-1-iodopropane (0.135 g, 0.66 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF98) (0.112 g, 70%). 1H NMR (CDCl3) δ 7.03-6.95 (m, 2H), 6.93-6.90 (m, 1H), 4.57 (s, 2H), 4.09 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.33-3.25 (m, 1H), 2.20-2.13 (m, 2H), 1.22 (d, J=7.2 Hz, 6H); 13CNMR (CDCl3) δ 164.9, 142.8, 137.8, 128.5, 122.8, 121.4, 112.5, 67.7, 42.5, 39.3, 30.3, 27.2, 22.7.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][C:2]1[C:1](=[O:10])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1C=Cc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(Br)=Cc2ccccc21

Procedure:
The indenone compound of formula 16 prepared in Step 3 is dissolved in CCl4, N-bromosuccinimide (1 to 1.2 eq) and 2,2′-azobisisobutyronitrile (10 to 15 wt %) are added thereto. The resulting mixture is allowed to reflux for 2 to 3 h with stirring, to obtain the 2-bromoindenone of formula 17.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=2[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18]O>C(O)(=O)C>[CH:1]1([CH2:7][S:8]([C:9]2[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=2[OH:15])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: Cc1cc(O)c(SCC2CCCCC2)c(=O)o1
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)CC2CCCCC2)c(=O)o1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
A solution, consisting of 6.00 g. (0.0236 mole) of 3-cyclohexylmethylthio-4-hydroxy-6-methyl-2-pyrone and 2.67 g. (0.0236 mole) of 30% hydrogen peroxide in 30 ml. of glacial acetic acid, was allowed to stand at room temperature for 26 hours, after which period of time it was poured into ice water, giving a white solid precipitate, which was collected on a filter and dried in vacuo over calcium chloride. The crude product weighed 5.8 g. (91 percent) and melted at 132.5°-133.5°C. Recrystallization from ethanol gave the pure 3-cyclohexylmethylsulfinyl-4-hydroxy-6-methyl-2-pyrone as white needles, m.p. 137°-138°C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CO>[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:3]1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1CCNC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N)C1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
In methanol (30 ml), 3-aminopyrrolidine (0.54 g) was dissolved under ice cooling, followed by the addition of diisopropylethylamine (720 μl) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.84 g). The resulting mixture was gradually heated to room temperature and stirred for 11 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜5% methanol-dichloromethane), whereby the title compound (0.59 g, 94%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].[NH:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:5]([NH:7][CH2:8][C:9]([N:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1)=[O:11])=[O:6]
Reactant: O=C(O)CNC(=O)c1ccc(Cl)c(Cl)c1
Reactant: OC1CCNC1
Product: O=C(NCC(=O)N1CCC(O)C1)c1ccc(Cl)c(Cl)c1

Procedure:
The titled compound was prepared from (3,4-dichloro-benzoylamino)-acetic acid (preparation #14) and pyrrolidin-3-ol according to the general procedure G. m/z: (M+H)+ 317.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4]1=[O:5].C(N(CC)CC)C.Cl[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:20]1([C:19]([NH:2][C@@H:3]2[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4]2=[O:5])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1CCCCNC1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1NCCCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred suspension of 173 g of (R)-α-amino-ε-caprolactam hydrochloride, 266 g of triethylamine and 1,700 ml of chloroform, 293 g of chlorotriphenylmethane was added portionwise under ice-cooling. The resulting mixture was stirred for an hour under the same conditions, and then for two hours at room temperature. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and to the resultant oily residue 600 ml of n-hexane-ethyl acetate (2:1) mixture was added under heating and stirring. The crystalline precipitates obtained were collected by filtration, washed with 1,000 ml of n-hexane-ethyl acetate (10:1) mixture and dried to provide 290 g of (R)-α-triphenylmethylamino-ε-caprolactam, m.p. 189° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:23])[N:10]([CH2:12][C:13]2[NH:14][C:15]3[C:16]([N:22]=2)=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=3)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9](=[O:23])[N:10]([CH2:12][C:13]2[N:22]([CH2:31][O:30][CH2:29][CH2:28][Si:27]([CH3:34])([CH3:33])[CH3:26])[C:16]3=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=[C:15]3[N:14]=2)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(Cc1nc2ncc(Br)cc2[nH]1)C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of phenylmethyl[(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)methyl]methylcarbamate (0.22 g, 0.59 mmol) in N,N-dimethylformamide (3.0 mL) was added 60% sodium hydride in mineral oil (56 mg, 1.48 mmol) and the reaction mixture was stirred for 30 minutes at room temperature, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (0.11 mL, 0.62 mmol). The reaction mixture was stirred at room temperature for 16 hours then it was quenched by the careful addition of saturated aqueous ammonium chloride and partitioned with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and washed with 10% aqueous citric acid (2×20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. Gradient flash chromatography (15% to 35% ethyl acetate in hexane) gave phenylmethyl{[6-bromo-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}methylcarbamate (0.28 g, 93%). MS (EI) for C22H29BrN4O3Si: 506 (MH+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:27][C:28]1[CH:29]=[C:30]([CH3:37])[C:31]2[O:35][CH:34]=[CH:33][C:32]=2[CH:36]=1>C(Cl)(Cl)(Cl)Cl>[Br:27][C:28]1[CH:29]=[C:30]([CH2:37][Br:1])[C:31]2[O:35][CH:34]=[CH:33][C:32]=2[CH:36]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc2ccoc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc2ccoc12
Temperature: 25 °C
Yield: 31.5 %

Procedure:
N-Bromosuccinimide (10.0 g) and di-benzoylperoxide (500 mg) were added in five equal portions to a solution of 5-bromo-7-methylbenzofuran (9.7 g) stirring at reflux in CCl4 (100 ml), whilst being irradiated with an 850 W lamp. After the final addition, the reaction was stirred at reflux for a further 2 hours, then cooled to room temperature. The solution was filtered and the filtrate washed with 2N NaOH--H2O (40 ml), brine (40 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by MPLC (1% ethyl acetateln-hexane) gave 5-bromo-7-bromomethyl benzofuran as a dlear oil (4.2 g). 1H NMR (360 MHz,CDCl3)δ4.86 (2H, s), 6.69 (1H, d, J=3.0 Hz), 7.54 (1H, s), 7.62 (1H, s), 7.86 (1H, d, J=3.0 Hz).