Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:30]1[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[C:33]([C:40]([O:42][CH3:43])=[O:41])=[CH:32][N:31]=1.C1N2CCN(CC2)C1>>[CH3:43][O:42][C:40]([C:33]1[C:34]([C:36]([F:39])([F:37])[F:38])=[N:35][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:31][CH:32]=1)=[O:41]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1C(F)(F)F

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate and DABCO (17 h, r.t.) to give the title compound as a white solid. MS (m/e)=620.2 [M+H+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[Br:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>O1CCCC1.CCCCCC>[Br:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:37]=[CH:38][CH:39]=1
Reactant: CCCCCBr
Reactant: O=Cc1cccc(Br)c1
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC=Cc1cccc(Br)c1
Reaction time: 0.25 h

Procedure:
To 14.7 gm of the Wittig salt prepared from 1-bromopentane and triphenylphosphine in 80 ml of tetrahydrofuran at 0° C. is added 22.5 ml of n-butyl lithium (1.6M) in hexane. The mixture is stirred for 15 minutes, and 3.8 ml of 3-bromobenzaldehyde is added. This mixture is stirred for 30 minutes; and after concentrating and diluting with ether, the solids are filtered off. Further concentration of the filtrate and chromatography over silica gel eluting with 3:2 hexane:ether yields pure 3-bromo-(1-hexenyl)benzene as a clear oil.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C@@H:12]1[N:17]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:16][CH2:15][C:14]([C:24]2[N:25]=[C:26]([SH:29])[S:27][CH:28]=2)=[CH:13]1.O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:21]([O:20][C:18]([N:17]1[C@@H:12]([CH3:11])[CH:13]=[C:14]([C:24]2[N:25]=[C:26]([S:29][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:27][CH:28]=2)[CH2:15][CH2:16]1)=[O:19])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)N1CCC(c2csc(S)n2)=C[C@@H]1C
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of lithium hexamethyldisilazide in THE (1M, 1.26 ml, 1.26 mmol) was added at 0° C. to a solution of allyl (6S)-6-methyl-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2H)-pyridine carboxylate (373 mg, 1.26 mmol) in THF (15 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 4.80 g, 2.52 mmol) and the solution was allowed to stand in a refrigerator for 60 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate) to give allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (590 mg, 76%).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=S)[NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)[CH3:2].IC.[C:21]1([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]1[N:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8](=[O:10])[C:7]2[C:6](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)[CH3:18]
Reactant: NNC(=O)Cc1ccccc1
Reactant: CCN(CC)C(=S)Nc1ccccc1C(=O)OC
Solvent: CI
Solvent: CO
Product: CCN(CC)c1nc2ccccc2c(=O)n1NC(=O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 13.5 %

Procedure:
Methyl 2-(3,3-diethyl-thioureido)benzoate (0.500 g, 1.88 mmol) was dissolved in methanol (10 mL), followed by addition of iodomethane (234 μL, 3.75 mmol). The reaction mixture was heated at 80° C. for 10 minutes under microwave conditions making sure the temperature did not exceed 80° C. The reaction mixture was evaporated to dryness and then redissolved in ethanol (20 mL), followed by addition of phenylacetic acid hydrazide (0.367 g, 2.44 mmol). The mixture was stirred for 48 h at reflux. After cooling the mixture was filtered and the filtrate was evaporated to dryness. The crude product was purified by column chromatography (EtOAc/Heptane) giving the title compound (0.089 g, 14%). LC-ESI-HRMS of [M+H]+ shows 351,1818 Da. Calc. 351,182101 Da.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:7][CH:6]=1)=[O:4].Cl.[C:15](=N)(OCC)[CH3:16]>N1C=CC=CC=1>[CH3:15][C:16]1[O:11][C:10]([C:8]2[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:12][N:13]=1
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2nnc(C)o2)s1
Temperature: 25 °C

Procedure:
A stirred suspension of 5-methoxycarbonyl-2-thiophenecarboxylic acid hydrazide (548 mg, 2.74 mmoles) and ethyl acetimidate hydrochloride (372 mg, 3.01 mmoles) in 10 ml of pyridine was refluxed for four hours, cooled to room temperature and evaporated in vacuo. The residual oily solid was dissolved in ethyl acetate and washed with water, 1N hydrochloric acid and 5% sodium bicarbonate. The ethyl acetate was dried (magnesium sulfate) and evaporated in vacuo to a pale tan solid (242 mg, 39%), m.p. 142°-5° C. This material was used directly without further purification. Exact Mass: 224.0253, Calculated: 224.0256; EIMS (m/z): 224 (M+, base), 193 (M+ -CH3O, 33%), 169 (C7H7O3S, 83%); 1HNMR (DMSO-d6) delta, 7.88 (1H, d, J=3.9Hz), 7.80 (1H, d, J=3.9Hz), 3.87 (3H, s), 2.58 (3H, s); ir (potassium bromide): 1705, 1571, 1291, 1101, 751 cm-1.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([Cl:32])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH:23]=1)[O:14][C:15]([N+:20]([O-:22])=[O:21])([CH3:19])[C:16](O)=[O:17].CN(C)C=O.C>ClCCCl>[Cl:32][C:24]1[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:6]([Cl:5])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH:23]=1)[O:14][C:15]([N+:20]([O-:22])=[O:21])([CH3:19])[C:16]([Cl:3])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)O)[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)Cl)[N+](=O)[O-]
Yield: 84 %

Procedure:
9.7 g (82 mmol) of thionyl chloride were added dropwise to a solution of 30 g (68 mmol) of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-α-phenoxy-propionic acid and 0.5 ml of dimethylformamide in 100 ml of 1,2-dichloroethane at room temperature. The mixture was heated under reflux for 4 hours. Active charcoal was added, the mixture was filtered and the filtrate was concentrated. After digesting the oily residue with 100 ml of ligroin, 26.2 g (84% of theory) of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-α-phenoxy-propionyl chloride were obtained in the form of yellow crystals of melting point 92° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:16])=O)=[CH:7][N:8]2[CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.ClCCl.[CH3:30][NH:31][CH3:32]>CN(C=O)C>[CH3:30][N:31]([CH3:32])[C:14]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]#[N:13])[CH:7]=1)=[O:16]
Reactant: CNC
Reactant: N#CCn1cc(C(=O)O)c2ccc(Br)cc21
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cn(CC#N)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a reaction tube was added 26 mg (94 micromol) of 6-bromo-1-cyanomethyl-1H-indole-3-carboxylic acid, 138 mg (approximately 186 micromol of carbodiimide functionality) of polystyrene carbodiimide resin (Argonaut Technologies, Foster City Calif., Product No. 800371), 21.3 mg (158 micromol) of HOBT (hydroxybenzotriazole), 1.5 mL dichloromethane, and 3 drops of DMF. The tube was capped, swirled and allowed to shake on a mechanical shaker for 1 hour at room temperature. The cap was removed, and dimethylamine (1 equivalent, 78 micromol) was added to the tube. The tube was re-capped and shaken for 24 hours at room temperature. 200 microliters of DMF was then added to the tube, and the tube was re-capped and shaken for an additional 48 hours, after which 130 mg (230 micromol) of polystyrene isocyanate resin (Argonaut Technologies, Foster City Calif., Product No. 800260) was added, followed by 1 hour of shaking, to remove excess dimethylamine. The content of the tube was filtered through a Varian liquid extraction tube (pre-washed with 20 microliters of saturated sodium bicarbonate solution), and washed 3× with 1 mL dichloromethane. The combined organic fractions were evaporated under reduced pressure to yield 6-Bromo-1-cyanomethyl-1H-indole-3-carboxylic acid dimethylamide as an oil. Step 4
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: CCCCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CCCCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 63.1 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 0.65 g (0.98 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-pentyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 68-(b) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 0.33 g of the title compound was obtained as a white solid. (Yield: 62%)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2)=[O:6].[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][N:2]([CH2:3][CH2:4][C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]2=3)=[O:6])[CH3:1])=[CH:26][CH:25]=1
Reactant: Cc1ccc(CCBr)cc1
Reactant: CNCCC(=O)N1c2ccccc2NC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(CCN(C)CCC(=O)N2c3ccccc3NC(=O)c3ccccc32)cc1

Procedure:
A mixture of 5-(3-methylaminopropionyl)-10,11-dihydrodibenzo [b,e][1,4]diazepin-11-one (0.20 g) (J. Med. Chem., 1963, 6, 255), 4-methylphenethyl bromide (0.14 g) and sodium hydrogen carbonate (60 mg) in acetonitrile (20 ml) was heated under reflux for 16 hours and evaporated. The residue was partitioned between water and dichloromethane and the organic layer washed with brine, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-20% methanol as eluant. Appropriate fractions were combined and evaporated and the residue crystallised from ether to give the title compound as a colourless solid, 60 mg (21%).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20](F)[CH:19]=1>CN(C)C=O>[CH3:9][C:8]([O:7][C:6](=[O:12])[N:5]([CH2:4][CH2:3][CH:2]([O:1][C:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[N+:24]([O-:26])=[O:25])[CH2:14][CH2:15][CH3:16])[CH3:13])([CH3:10])[CH3:11]
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: CN(C)C=O
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxyhexyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2-fluoronitrobenzene in N,N-dimethylformamide.
Reaction SMILES: [C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16]([OH:18])[C@H:15]([N:19]2[C:23]3[N:24]=[C:25]([NH2:29])[NH:26][C:27](=[O:28])[C:22]=3[S:21][C:20]2=[O:30])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:32](=[S:40])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16]([O:18][C:32]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:40])[C@H:15]([N:19]2[C:23]3[N:24]=[C:25]([NH2:29])[NH:26][C:27](=[O:28])[C:22]=3[S:21][C:20]2=[O:30])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](OC(=S)Oc2ccccc2)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Yield: 33.4 %

Procedure:
To a solution of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl benzoate (compound 26d, 4.32 g, 10.0 mmol) in DCM (60 mL) was added DMAP (2.44 g, 20 mmol) and O-phenyl chloromethanethioate (1.6 mL, 12.0 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:10 to 1:1 EtOAc in petroleum ether) to afford 1.9 g of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-phenoxycarbothioyloxy-tetrahydrofuran-2-yl]propyl benzoate (compound 26e). MS obsd. (ESI+) [(M+H)+]: 569.
Reaction SMILES: [Se](=O)=[O:2].[Cl:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[C:16]3[CH3:21])=[CH:7][CH:6]=1>O1CCOCC1.O>[Cl:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[C:16]3[CH:21]=[O:2])=[CH:7][CH:6]=1
Reactant: Cc1ccnc2c(OCc3ccc(Cl)cc3)cccc12
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccnc2c(OCc3ccc(Cl)cc3)cccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
Selenium dioxide (620 mg, 5.6 mmol) was suspended in dioxane (5 mL); a few drops of water was added until a clear solution was obtained. The mixture was heated to 100° C. and 8-(4-chlorobenzyloxy)-4-methyl quinoline (1.6 g, 5.6 mmol) in dioxane (20 mL) was added dropwise during a period of 2 hours. The mixture kept at 100° C. for 4 hours, filtered hot and concentrated. The residue was treated with 1N HCl (200 ml), and filtered. The filtrate was neutralized with 3N NaOH, and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), and concentrated. Recrystallization from toluene provided 1.02 g (62%) yellow needles.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[C:26]([I:29])[N:25]=[C:23]([NH2:24])[C:22]=2[N:21]=[C:20]1Br)(=O)C.[CH3:31][NH2:32]>>[I:29][C:26]1[N:25]=[C:23]([NH2:24])[C:22]2[N:21]=[C:20]([NH:32][CH3:31])[N:19]([C:28]=2[N:27]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CN
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3c(N)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
The reaction was performed with 2′,3′,5′-tri-O-acetyl-2-iodo-8-bromoadenosine (6, 100 mg, 0.17 mmol) and methylamine (16 ml, 40% w/v in water). Yield 54.6 mg (0.13 mmol, 77%), mp 162–164÷C; 1H NMR (DMSO-d6) δ 7.02 (d, 1H, J=5.15 Hz, NH), 6.93 (s, 2H, NH2), 5.77 (d, 1H, J=7.56 Hz, H-1′), 5.66 (t, 1H, J=4.81 Hz, OH-2′), 5.31 (d, 1H, J=6.52 Hz, OH-5′), 5.18 (d, 1H, J=4.46 Hz, OH-3′), 4.56 (q, 1H, J=5.15 Hz, H-2′), 4.09–4.04 (m, 1H, H-3′), 3.98–3.91 (m, 1H, H-4′), 3.68–3.57 (m, 2H, H-5′), 2.86 (d, 3H, J=4.46 Hz, CH3); MS m/z 423 (M+H)+; Anal. (C11H15IN6O4) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5].[CH2:39]([N:41]=[C:42]=[O:43])[CH3:40]>C1COCC1>[C:4]([C:3]1[C:2]([NH:1][C:42]([NH:41][CH2:39][CH3:40])=[O:43])=[N:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:21][CH2:22]3)=[CH:14][CH:15]=2)=[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=1)#[N:5]
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1N
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)c(-c2ccccc2)cc1C#N

Procedure:
The mixture of 2-amino-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (6-3; 0.025 g, 0.05 mmol) and ethylisocyanate (0.007 mg, 0.100mmol) in THF (1 mL) was heated to 100 C for 0.5 h and concentrated. The residue was purified by silica gel chromatography (3-6% MeOH in CH2Cl2) to give the title compound (7-1). LRMS m/z (M+H) Calcd: 572.7, found: 572.2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[CH3:13][O:14][C:15](=[O:18])[CH2:16]Br>>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([C:3]=1[CH2:16][C:15]([O:14][CH3:13])=[O:18])=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2
Reactant: Cc1ccc2c(c1)CC(C)C2=O
Reactant: COC(=O)CBr
Product: COC(=O)CC1=C(C)Cc2cc(C)ccc21

Procedure:
The above reactions of Example 1C are repeated except that the starting materials are 2,5-dimethylindanone and methylbromoacetate. With the same reaction conditions and techniques, methyl 2,6-dimethyl-3-indenylacetate is obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C=O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH:12]=[CH:11]2)=[O:4]
Reactant: O=C(CCl)Nc1cccc2ccc(O)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Reaction time: 16 h

Procedure:
To a solution of the crude alcohol from Step A (50.3 mmol) in 150 mL of DMF at 0° C. was added triethylamine (15.0 mL, 108 mmol), followed by dropwise addition of methanesulfonyl chloride (6.0 mL, 77.5 mmol). After 16 hours, additional portions of triethylamine (7.0 mL, 50 mmol) and methanesulfonyl chloride (3.0 mL, 39 mmol) were added. After 4 hours, the solution was concentrated in vacuo and partitioned between EtOAc and saturated NH4Cl solution. The organic layer was extracted with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide a dark purple solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]#[N:14])=[CH:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:15]N1C(=O)CCC1=O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Cl:15][C:12]1[NH:11][CH:10]=[C:9]([C:13]#[N:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1c[nH]cc1-c1cccc(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c[nH]c(Cl)c1-c1cccc(F)c1
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To a solution of 41.0 g (220 mmol) of 4-(3-fluorophenyl)-1H-pyrrole-3-carbonitrile in 400 ml of tetrahydrofuran are added portionwise 33.0 g (242 mmol) of N-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 24 hours at reflux. After cooling, 200 ml of water containing 5 g of sodium thiosulfate are added and, after stirring for 5 minutes, the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 45.5 g of 5-chloro-4-(3-fluorophenyl)-1H-pyrrole-3-carbonitrile in the form of a whitish powder after triturating in 200 ml of dichloromethane, filtering off and drying.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44]O)=[CH:39][CH:38]=1)#[N:36].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:44][CH2:43][C:40]2[CH:41]=[CH:42][C:37]([C:35]#[N:36])=[CH:38][CH:39]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(OCCc2ccc(C#N)cc2)c1
Yield: 44.3 %

Procedure:
To a solution of t-butyloxycarbonylamino-3-hydroxybenzene (418.5 mg; 2 mmol; from step (i) above), triphenylphosphine (629.5 mg; 2.4 mmol) and 2-(4-cyanophenyl)ethanol (353.2 mg; 2.4 mmol) in THF (50 mL), under an atmosphere of nitrogen, was added diethylazodicarboxylate (518 mg; 3 mmol) and the mixture was stirred for one week. Ice cold water was added and the THF was removed by evaporation. The remaining water phase was extracted three times with EtOAc. The combined organic phase was washed twice with 0.2 M NaOH, once with brine, and then dried (Na2SO4). Evaporation followed by flash chromatography using a stepwise gradient of toluene:EtOAc (100:0, 90:10, 80:20 and 60:40) gave 300 mg (44%) of the sub-title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:11]=1>C(O)C>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH:16][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC#N
Reactant: NCCc1ccc(Cl)cc1
Solvent: CCO
Product: N#CCC(=O)NCCc1ccc(Cl)cc1
Yield: 70.8 %

Procedure:
5.6 g of ethyl cyanoacetate and 7.8 g of 4-chlorophenethylamine are refluxed for 9 h in 50 ml of ethanol to give a solution. After concentration and cooling, this solution gives a residue which crystallizes. This is taken up with ether, filtered off and washed with ether to give 7.8 g of N-2-(4-chlorophenyl)ethylcyanoacetamide in the form of a white solid melting at 122° C. Yield 70%.