Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CN=CC=1.[FH:7].N[C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([O:23][CH3:24])[CH:13]=[CH:12]2.[OH-].[K+].N([O-])=O.[Na+]>N1C=CC=CC=1>[F:7][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:23][CH3:24])[C:15]=2[C:19]([F:22])([F:21])[F:20])[C:10]=1[CH3:25]
Reactant: COc1ccc2c(C)c(N)ccc2c1C(F)(F)F
Reactant: F
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc2c(C)c(F)ccc2c1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
A 250 mL nalgene bottle with magnetic stir bar under an N2 atmosphere was charged with HF-pyridine (75 mL) and cooled to -78° C. in a dry ice-isopropanol bath. When the HF-pyridine solution was frozen, a solution of the 6-amino-2-methoxy-5-methyl-1-trifluoromethylnaphthalene (10.07 g, 39.4 mmol) in pyridine (25 mL, previously dried over KOH) was added slowly. Again, when the solution was frozen, solid sodium nitrite (4.55 g, 1.67 eq) was added and the dry ice-isopropanol bath was removed. The reaction mixture was stirred at room temperature for 30 minutes (after 10 minutes the frozen solids had melted). The reaction mixture was then heated in a 65° C. oil bath for 2 hours. During this heating period a foamy precipitate had collected in the reaction vessel. The reaction mixture was cooled to room temperature and added to water (1 L). The aqueous phase was extracted with ether (3×300 mL). The combined ether extracts were washed with saturated aqueous NaCl (200 mL). Silica gel (40 mL) was added to the ether phase and the ether was removed. The silica absorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the white solid product (7.82 g, 77%), m.p. 97°-99° C.
Reaction SMILES: [Cl-].[C:2]([NH+:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18](=[O:30])[N:19]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:14]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:13]=2)[CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3]>CO.CCOC(C)=O.O=[Pt]=O>[C:2]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18](=[O:30])[N:19]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:14]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:13]=2)[CH2:10][CH2:11]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[NH+]1CC=C(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Agent: O=[Pt]=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)N1CCC(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 75 mg of 1-tert-butyl-4-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl]-1,2,3,6-tetrahydropyridinium chloride in 3 mL of MeOH and 1 mL of EtOAc was added 35 mg of PtO2 (Adam's catalyst). The mixture was evacuated and purged with N2, then evacuated and purged with H2, then stirred under an H2 balloon for 1 h. The mixture was filtered through Celite, washing with MeOH, and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH, followed by preparative HPLC (YMC C8 19×50 mm column; 10:90 to 90:10 v/v acetonitrile/water+0.05% TFA over 12 min; 20 mL/minute) to yield the title compound. Mass spectrum (ESI) 542 (M+1). 1H NMR (500 MHz, CD3OD): δ 1.40 (s, 9H); 2.04-2.20 (m, 4H); 3.00-3.12 (m, 3H); 3.68 (br d, J=12.5 Hz, 2H); □6.46 (s, 1H); 6.75 (d, J=10 Hz, 1H); 7.48-7.75 (m, 8H).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:69]=[C:70]([NH:74][CH:75]5[CH2:80][CH2:79][N:78]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:77][CH2:76]5)[CH:71]=[CH:72][CH:73]=4)[CH:66]=3)[N:61](S(C3C=CC(C)=CC=3)(=O)=O)[CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:69]=[C:70]([NH:74][CH:75]5[CH2:80][CH2:79][N:78]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:77][CH2:76]5)[CH:71]=[CH:72][CH:73]=4)[CH:66]=3)[NH:61][CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)c2)CC1
Yield: 68 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-((3-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (150 mg, 0.209 mmol) was hydrolyzed by lithium hydroxide (18 mg, 0.418 mmol) in THF/methanol/water (5/1/1 ml) to yield 80 mg (67.7% yield) of the titled compound after column purification using 2% methanol in DCM as eluent. MS: m/z=562.9 (M+1).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]([CH2:41][O:42][P:43]([O:52]C3C=CC=CC=3)([O:45]C3C=CC=CC=3)=[O:44])([CH2:39][OH:40])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=O)[CH2:28][CH2:29][CH2:30][CH2:31][C:32]4C=CC=[CH:34][CH:33]=4)=[CH:23][CH:22]=3)C3C(=CC=CC=3)C=2C=CC=1.C(=O)=O>>[NH2:17][C:18]([CH2:39][OH:40])([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:25][CH:26]=1)[CH2:41][O:42][P:43](=[O:44])([OH:45])[OH:52]
Reactant: O=C(NC(CO)(CCc1ccc(C(=O)CCCCc2ccccc2)cc1)COP(=O)(Oc1ccccc1)Oc1ccccc1)OCC1c2ccccc2-c2ccccc21
Agent: O=C=O
Product: CCCCCCCCc1ccc(CCC(N)(CO)COP(=O)(O)O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Compound obtained in step b) (0.32 g, 0.4 mmol) is dissolved in ethanovwater (10 ml, 3/2) and, after addition of barium hydroxyde-octahydrate (0,56 mg, 1.8 mmol), is kept at 75° C. for 14 hours. After cooling to RT the slurry is neutralized with solid carbon dioxide and filtered. The residue is dissolved in acetic acid (95%; 5 ml) and then diluted with water to a volume of 50 ml. The resulting precipitate is filtered off and dried over P4O10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.CC(OC(C)=O)=O.[N+:25]([O-])([OH:27])=[O:26].C(O)(=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:25]([O-:27])=[O:26])=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)C1CCCCC1CC2=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1[N+](=O)[O-])C1CCCCC1CC2=O
Reaction time: 3 h
Yield: 34 %

Procedure:
Combine 6-methoxy-2,3,4,4a,10,10a-hexahydro-1H-phenanthren-9-one (0.936 g, 4.06 mmol), Ac2O (5.0 mL), and a solution of 90% HNO3/acetic acid (0.8 mL), and stir under Nitrogen atmosphere at 0° C. After 3 hours, add ethyl acetate. Wash the ethyl acetate with sodium bicarbonate solution and then brine, dry over sodium sulfate, and concentrate in vacuum. Flash chromatograph using dichloromethane (isocratic) to yield the titled compound (0.378 g, 34%) as a solid. TLC Rf=0.25 in dichlormethane. 1H NMR (CDCl3): 8.22 (d, 1H, J=8.8 Hz), 7.04 (d, 1H, J=8.8 Hz), 3.99 (s, 3H), 2.96 (m, 2H), 2.49 (m, 2H), 1.63 (m, 8H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=O)=[CH:15][CH:14]=1)([O-])=O>C1(C)C=CC=CC=1>[NH2:10][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:20])[C:7](=[O:9])[C:4]2[CH:3]=[CH:2][C:1]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C1CCCCC1
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N)cc1
Reaction time: 8 h

Procedure:
4-Cyclohexylcarboxylic acid (5.0 g) and 4-nitrophenylisocyanate (4.0 g) were stirred in toluene (150 ml) for 3 hours and then left to stand overnight. The precipitate was filtered off with suction and washed with diethyl ether. The resulting amide was ethylated by method F and hydrogenated by method B. This resulted in the product with the molecular weight of 308.43 (C20H24N2O); MS (ESI): 309 (M+H+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1C=CC=CC=1>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:20](=[O:21])[O:22][CH2:23][CH3:24])=[CH:11][CH:12]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-[3-(trifluoromethyl)phenoxy]benzenamine (6.0 grams; 0.21 mol) and pyridine (50 ml) were placed in a glass reaction vessel equipped with a mechanical stirrer and placed in an ice bath. Ethyl chloroformate (5 ml) was added dropwise to the reaction mixture with continuous stirring. Stirring was continued overnight and the mixture was then poured into ice water (500 ml). The precipitate was washed with water and dried. It was found to have a melting point of 74°-75.5° C. In fraud analysis confirmed the identity of the desired product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH3:16][N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[CH3:16][NH:17][C:18]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:19]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.5 h

Procedure:
To 6.0 g (0.024 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of dry benzene was added dropwise 1.37 g (0.024 mole) of methylisocyanate, and stirring was continued for 30 minutes. The solid which crystallized in the flask was recrystallized from 95% ethanol to obtain 5.0 g (76%), mp 145°-147°.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1>C(O)C>[CH:18]1([CH2:21][NH:22][C:8]2[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15])=[CH:6][C:7]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]1
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CC1
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCC2CC2)c([N+](=O)[O-])c1

Procedure:
Following general procedure 2B: N,N-diethyl-4-fluoro-3-nitrobenzamide (0.823 g, 3.42 mmol) and cyclopropylmethanamine (0.39 mL, 4.50 mmol) in 80% aqueous ethanol (17 mL) were stirred at 85° C. for 16 h. The crude product (1.00 g), an orange solid, was used in subsequent steps. 1H-NMR (CD3OD): δ 8.23 (d, J=2.0 Hz, 1H), 7.55 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 7.09 (d, J=9.2 Hz, 1H), 3.47 (br s, 3H), 3.31 (q, J=2.0 Hz, 2H), 3.27 (d, J=6.4 Hz, 2H), 1.23 (overlapping t and m, J=7.0 Hz, 7H), 0.68–0.60 (m, 2H), 0.40–0.34 (m, 2H). MS (ESI) (M+H)+=292.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][CH2:14][CH:10]([C:11]([NH2:13])=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:16][CH2:15][CH2:14][C@@H:10]([C:11]([NH2:13])=[O:12])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)[C@@H]1CCCN(Cc2ccccc2)C1
Reaction time: 72 h
Yield: 48 %

Procedure:
Cupriavidus sp. KNK-J915 stain (FERN BP-10739) was inoculated in a medium (glycerol 1.0%, peptone 0.5%, malt extract 0.3%, yeast extract 0.3%, isovaleronitrile 0.1%, pH 7.0) sterilized in a Sakaguchi flask, and stirred and cultivated at 30° C. for 72 hours. After completion of the cultivation, the bacterial cells were collected by centrifugal separation, and suspended in 100 mM phosphate buffer (pH 7.0) to obtain a 20-fold concentrated bacterial cell suspension. To the bacterial cell suspension (100 ml), racemic 1-benzylnipecotamide (5 g) was added. The pH of the solution was adjusted to 7 using NaOH, and then the mixture was shaken at 30° C. for 60 hours. After completion of the reaction, solid substance such as bacterial cells was removed by centrifugal separation from the reaction mixture, and the pH of the mixture was adjusted to 10.0 using NaOH. The mixture was stirred at room temperature for 1 hour, and then precipitated crystal was filtrated to obtain 2.4 g of (R)-1-benzylnipecotamide. The compound was analyzed by the method of Example 1; as a result, the optical purity was 99.8% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[O:13][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:10][CH:11]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2cc(Cl)cc(Cl)c2)o1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cc(Cl)cc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (67) (67 mg, 0.26 mmol) was coupled to ethyl ester (60) (50 mg, 0.26 mmol) using Method C. The crude residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(pyrid-2-yl)benzoic acid(1.01 g, 5.09 mmol) in tetrahydrofuran (15 mL) at 0° C. was added 1.0M lithium aluminum hydride in tetrahydrofuran (5.09 mL, 5.09 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 3 hours, cooled to 0° C., and quenched by dropwise addition of water (0.25 mL), 4N aq. NaOH (0.25 mL), and water (0.75 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 4-8% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][NH:4][C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:4]([C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][C:2]([F:18])([F:19])[F:1])=[O:24]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](NCC(F)(F)F)CC2
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](N(CC(F)(F)F)C(=O)c1ccccc1Cl)CC2
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a cooled (0° C.) solution of (R)-methyl 3-(2,2,2-trifluoroethylamino)-2,3-dihydro-1H-indene-5-carboxylate (A-18) (870 mg, 3.18 mmol, 1.0 eq.) in methylene chloride (12 ml) was added TEA (1.1 ml, 7.95 mmol, 2.5 eq.) and the reaction mixture was allowed to stir for 15 min. 2-Chlorobenzoyl chloride (0.44 ml, 3.50 mmol, 1.1 eq) was added to the reaction mixture and it was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the mixture was diluted with methylene chloride (50 ml) and the organic layer was washed with water (20 ml) and brine (20 ml), and dried over anhydrous Na2SO4. The solvent was evaporated to afford the crude product which was purified by column chromatography (silica gel; 7% ethyl acetate/hexanes) to yield the desired compounds as a colourless gummy solid. Yield: 85% (1.1 g, 2.67 mmol).
Reaction SMILES: [CH:1]1([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[CH:1]1([C:5]2[N:6]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1ccc2[nH]c(C3CCC3)nc2c1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CCC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 90.3 %

Procedure:
Using 2-cyclobutyl-1H-benzo[d]imidazole (72 mg, 0.419 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (150 mg, 0.419 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (170 mg, 90%) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:17]1[C:18]2[C:25]([I:26])=[C:24]([CH:27]=[O:28])[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:19]=2[N:20]=[CH:21][N:22]=1>C(#N)C>[I:26][C:25]1[C:18]2[C:17]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:22][CH:21]=[N:20][C:19]=2[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[C:24]=1[CH:27]=[O:28]
Reactant: C[Si](C)(C)CCOCn1c(C=O)c(I)c2c(Cl)ncnc21
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(C=O)c(I)c2c(N3CCOCC3)ncnc21

Procedure:
Morpholine (1.09 g, 12.5 mmol) and N,N-diisopropylethylamine (2.94 g, 22.7 mmol) were added to a solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (C28) (5.0 g, 11 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at reflux for 16 hours, whereupon it was cooled and concentrated in vacuo; the residue was purified by chromatography on silica gel (Gradient: 0% to 20% ethyl acetate in petroleum ether) to provide the product as a yellow oil. Yield: 4.0 g, 8.2 mmol, 74%. 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.54 (s, 1H), 6.01 (s, 2H), 3.92-3.98 (m, 4H), 3.70-3.75 (m, 4H), 3.58-3.65 (m, 2H), 0.91-0.96 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:37]N1C(=O)CCC1=O.ClCCCl>C(Cl)Cl>[Br:37][CH:2]([Cl:1])[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CCl)c3c2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Cl)Br)c3c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A mixture of 3-[3-(chloromethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00266 mol), azo-bis-isobutyronitrile (0.100 g), N-bromosuccinimide (0.712 g, 0.00400 mol) and 1,2-dichloroethane is stirred one hour at reflux. Additional azo-bis-isobutyronitrile (0.0500 g) and N-bromosuccinimide (0.100 g) are added and the mixture is stirred two hours at reflux, cooled to room temperature, diluted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to an orange gum. Chromatography of the gum on silica gel with methylene chloride:ether gives the title compound as a white foam (0.950 g, 80.2%, mp 93-96° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]([S:23][CH2:24][CH:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CC(N(C)C)=O>[C:15]([S:23][CH2:24][CH:25]([CH3:29])[C:26]([N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)CNC1Cc2ccccc2C1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(CSC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
N-(2-Indanyl)glycine (1.0 g) is suspended in 10 ml of dimethylacetamide, then 2.0 g of 3-benzoylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and thereafter stirring is continued at room temperature for 2 hours. The reaction mixture is poured into 100 ml of water, and extracted with 200 ml of ethyl acetate. The extract is washed with 20 ml of 10% hydrochloric acid and with water, and dried over anhydrous sodium sulfate. After ethyl acetate is distilled off under reduced pressure, the residue is subjected to silica gel column chromatography and eluted with acetone-benzene (1:9). The oil obtained is crystallized from an ethyl ether-petroleum ether mixture, to give 1.4 g of N-(3-benzoylthio-2-methylpropionyl)-N-(2-indanyl)glycine, colorless needles showing a melting point of 113°-115° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[CH3:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:3]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=2)=[CH:23][C:22]=1[CH3:30]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: Cc1cc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1Cl

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 4-chloro-3-methylphenylboronic acid (Step 1) to give 4-(4-chloro-3-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 151.5-152.2° C.; NMR (CDCl3) δ 2.29 (s, 3H), 3.05 (s, 3H), 6.73 (dd, J=2, 8 Hz, 1H), 6.98 (d, J=2 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.19-7.32 (m, 4H), 7.82 (d, J=9 Hz, 2H); MS (FAB) m/z 399 (M+Li)+; HRMS calc'd for M+ 392.0449, found 392.0437. Anal. Calc'd for C20H15ClF2O2S: C, 61.15; H, 3.85; F, 9.67. Found: C, 61.04; H, 3.79; F, 9.55.
Reaction SMILES: CC(=CC)C.B#B.[CH3:8][C:9]([CH3:24])([CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:11]#[CH:12].[Br:25]Br>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[Br:25]/[CH:12]=[CH:11]/[CH:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:9]([CH3:24])([CH3:8])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: BrBr
Reactant: C#CC(OC1CCCCO1)C(C)(C)CCCC
Agent: B#B
Agent: CC=C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC(C)(C)C(/C=C/Br)OC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled solution of 3.5 g. (50 moles) of 2-methyl-2-butene in 25 ml. of tetrahydrofuran under an inert atmosphere is added 25 ml. of 1 M diborane in tetrahydrofuran dropwise over 10 minutes. The mixture is stirred at 0°-5° C. for 2 hours and then the solvent is removed under vacuum. The residue is dissolved in 20 ml. of carbon tetrachloride and to the resulting solution cooled to 0° C. is added a solution of 5.25 g. (22 mole) of 4,4-dimethyl-3-tetrahydropyranyloxy-1-octyne (Example 995) in 10 ml. of carbon tetrachloride over 10 minutes. The cooling bath is removed and the mixture is allowed to stir at ambient temperature for 1.5 hours. The mixture is cooled to 0° C. and a solution of 3.52 g. (22 moles) of bromine in 15 ml. of carbon tetrachloride is added over 10 minutes. The cooling bath is removed and the mixture is refluxed for 6 hours under an inert atmosphere. The mixture is cooled and poured into dilute sodium hydroxide solution. The organic phase is washed with water and saturated brine, dried (Na2SO4), and evaporated. The residue is chromatographed upon silica gel and the title compound is isolated with 5% ethyl acetate in benzene.