Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:29][O:16][C:7]1[N:8]=[C:9]([CH3:15])[C:10]2[C:5]([C:6]=1[CH2:17][C:18]1[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1cc2c(C)nc(O)c(Cc3ccc4ccccc4c3)c2cc1OC
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1cc2c(C)nc(OC)c(Cc3ccc4ccccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6,7-dimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol CCH 29038 free base (58 mg, 161 μmol) in dry DMF (6 mL) at 0° C. in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added LiHMDS (1.0 N in TBME, 175 μL, 175 μmol) and the mixture was stirred for 20 min at RT. Dimethyl sulphate (18 μL, 192 μmol) was then added at 0° C. and the mixture was stirred overnight at RT. The mixture was then concentrated to dryness at 40° C. under vacuum and the residue was taken up in CH2Cl2 (40 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 86:14) provided 23 mg of 3,6,7-trimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinoline. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.50 M HCl solution in MeOH (0.4 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 3,6,7-trimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinoline hydrochloride 18 as a brown solid (25 mg, 38% yield).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=3)[CH:26]=2)(=[O:24])=[O:23])[C:16]1=[O:36].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40].C(=O)([O-])[O-].[K+].[K+]>>[CH3:42][O:41][C:39](=[O:40])[CH2:38][N:21]([S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=2)[CH:26]=1)(=[O:23])=[O:24])[CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:3]2[CH:2]=[CH:7][C:6]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:5][CH:4]=2)[C:16]1=[O:36]
Reactant: O=C1C(NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCCN1c1ccc(-n2ccccc2=O)cc1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CN(C1CCCN(c2ccc(-n3ccccc3=O)cc2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1

Procedure:
The compound of Example 2 was treated with methyl bromoacetate in the presence of potassium carbonate using the procedure described for the preparation of compound 9, Part A. Purification by flash chromatography provided the title compound. MS(ESI+) (M+H)+. 1HNMR (CDCl3) δ 8.48 (s, 1H); 7.85 (m, 4H); 7.53 (m, 2H); 7.37 (m, 3H); 7.27 (m, 2H); 6.85 (m, 1H); 6.45 (m, 1H); 4.60 (m, 1H); 4.30 (m, 1H); 3.80 (m, 1H); 3.74 (m, 3H); 3.60 (m, 1H); 3.40 (m, 1H); 2.55 (m, 1H); 2.15 (m, 3H) ppm. MS m/z 580.0 (M+H)+. HRMS calcd for C29H27N3O6SCl: 580.1309. Found: 580.1310.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.[CH3:18][C:19]1[C:24]([Cl:25])=[C:23](Cl)[N:22]2[N:27]=[CH:28][N:29]=[C:21]2[N:20]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:25][C:24]1[C:19]([CH3:18])=[N:20][C:21]2[N:22]([N:27]=[CH:28][N:29]=2)[C:23]=1[NH:17][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:16]
Reactant: Cc1nc2ncnn2c(Cl)c1Cl
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nc2ncnn2c(N[C@@H](C)c2ccc(F)cc2)c1Cl

Procedure:
0.300 g (3.0 mmol) Triethylamine, a spatula tip of tetrabutylammonium iodide and 0.514 g (3.7 mmol) of (S)-1-(4-fluorophenyl)-ethylamine were added successively to a solution of 0.500 g (2.5 mmol) of 5-methyl-6,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine in 10 ml of toluene under stirring. The reaction mixture was heated at reflux for 5 hours and then stirred for another 12 hours at room temperature. The solvent was evaporated under reduced pressure and dichloromethane was added to the resulting residue. The resulting reaction mixture was washed with 2N hydrochloric acid and with water. The organic phase was separated, dried and the solvent was evaporated under reduced pressure. Treatment of the resulting residue with hexane yielded 0.520 g (1.7 mmol, 68% of theory) of the title compound having a melting point of 103-104° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]1[CH:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>C(Cl)Cl>[Br:1][CH2:21][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:12])[CH:20]=1
Reactant: N#Cc1ccc(CO)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CSC
Product: N#Cc1ccc(CBr)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0° C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to −20° C. then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile, as described in Step C above, (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0° C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified after chromatography (silica gel, 5-10% EtOAc/hexane).
Reaction SMILES: C(OC[CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12][S:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl.[C:33](=O)(O)[O-:34].[Na+]>C(Cl)Cl>[OH:34][CH2:33][SH:11]1[CH2:10][CH2:15][O:14][CH:13]([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12]1
Reactant: O=C([O-])O
Reactant: Nc1ccn(C2CSC(COCc3ccccc3)CO2)c(=O)n1
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccn(C2C[SH](CO)CCO2)c(=O)n1
Temperature: -78 °C

Procedure:
1-(5-benzyloxymethyl-1,4-oxathian-2-yl)cytosine (0.12 g) was dissolved in methylene chloride (10 ml), and the solution was cooled to -78° C. To the solution, 1M boron trichloride solution (3.7 ml) was added dropwise, and the resultant mixture was stirred at the same temperature for 4 hours. Mixed solvent of methanol-methylene chloride (1/1, 8 ml) was added thereto, and sodium bicarbonate was added to neutralize the reaction mixture. Upon raising the temperature of the reaction mixture to room temperature, the solvent was distilled off under reduced pressure to obtain white solid.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][CH:6]1[O:11][CH:10](Br)[CH:9]([O:13][C:14]([CH3:16])=[O:15])[CH:8]([O:17][C:18]([CH3:20])=[O:19])[CH:7]1[O:21][C:22]([CH3:24])=[O:23])=[O:3].[CH3:25][S:26](=[S:29])([O-:28])=[O:27].[Na+]>C1(C)C=CC=CC=1>[CH3:25][S:26](=[S:29])([O:28][C@@H:10]1[O:11][C@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[C@H:7]([O:21][C:22](=[O:23])[CH3:24])[C@H:8]([O:17][C:18](=[O:19])[CH3:20])[C@H:9]1[O:13][C:14](=[O:15])[CH3:16])=[O:27]
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Reactant: CS(=O)([O-])=S
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](OS(C)(=O)=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 66.4 %

Procedure:
Acetobromogalactose 1 (1.1 g, 2.68 mmol) and sodium methanethiosulfonate (0.45 g, 3.35 mmol) in toluene (50 mL) were concentrated in vacuo to approximately 30 mL to remove any water as the azeotrope. The mixture was made up to 50 mL with more toluene and again concentrated to 30 mL. A catalytic amount of tetrabutylammonium iodide was added and the mixture heated at reflux for 75 minutes. After cooling, Celite (to stop the formation of a salt cake on top of the column) was added and the whole mixture loaded directly on to a flash silica column. Elution with 40% ethyl acetate in petroleum ether and recrystallization from petroleum ether/ethyl acetate gave the title compound (787 mg, 67%) as colorless prisms; mp 118-119° C. (petroleum ether/ethyl acetate); [α]23D=+8.5 (c 1.0, CHCl3); IR (KBr) 1753 (C═O), 1325, 1138 (S—SO2) cm−1;1H NMR (400 MHz, CDCl3) δ 1.99 (s, 3H, Ac), 2.50 (s, 3H, Ac), 2.08 (s, 3H, Ac), 2.17 (s, 3H, Ac), 3.43 (s, 3H, CH3SO2—), 4.05 (ddd, J 7.4, 4.2, 0.9 Hz, 1 H), 4.08 (dd, J 18.3, 7.5 Hz, 1H), 4.20 (dd, J 10.8, 4.3 Hz, 1H), 5.13 (dtd, J 10.7, 7.6, 3.4 Hz, 1H), 5.26 (s, 1H), 5.27 (dd, J 14.8, 10.3 Hz, 1H), 5.48 (dd, J 3.4, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.5, 20.6, 20.6, 20.6 (4×CH3CO), 52.7 (CH3SO2—), 61.8 (C-6), 65.8, 67.0, 71.3, 75.3, 87.0 (1J1CH 165 Hz, C-1), 169.7, 169.7, 170.0, 170.2 (4×C═O); HRMS m/z (ES): found 460.0951; C15H26NO11S2 requires 460.0947.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1.[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.O>CN(C)C=O>[CH2:42]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3ccccc3)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Sodium hydride (60%, oily, 28.0 mg) was added to a solution of ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (378 mg) in N,N-dimethylformamide (5 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. Benzyl bromide (0.10 ml) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[3-benzyloxy-5-[2-(2-pyrazinyl)-4-thiazolyl methoxy]benzyl]-4-pheny-3-pyrrolyl]propionate (419 mg, yield: 95%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 126–127° C.
Reaction SMILES: C1(OC)C=CC=CC=1.[N+:9]([C:12]1[CH:28]=[CH:27][C:15]2[O:16][C:17]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:18]=3[O:19][C:14]=2[CH:13]=1)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:24][C:22]1[CH:21]=[CH:20][C:18]2[O:19][C:14]3[CH:13]=[C:12]([NH2:9])[CH:28]=[CH:27][C:15]=3[O:16][C:17]=2[CH:23]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1O2
Agent: [Pd]
Solvent: COc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)Oc1ccc(N)cc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a mixture of 1200 ml of anisole and 800 ml of THF were added 69.7 g (0.254 mole) of 2,7-dinitrodibenzodioxin and 22.2 g of 10% palladium/carbon and hydrogen gas was passed through the mixture with stirring at room temperature for 8 hours. The 10% palladium/carbon was removed by filtration, then a precipitate containing the 10% palladium/carbon was collected by filtration, and the precipitate was rinsed with THF. The rinsings were concentrated and dried under reduced pressure to give 25.0 g (0.117 mole, 46.0% yield) of 2,7-diaminodibenzodioxin. The product showed a purity of 98.1% (HPLC, 254 nm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:26].[K+].[K+].OO.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]=1[C:11]([NH2:12])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(OCc2ccccc2)cncc1OCc1ccccc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1c(OCc2ccccc2)cncc1OCc1ccccc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a mixture of 3,5-bis(benzyloxy)isonicotinonitrile (2.5 g, 7.9 mmol, 1 eq.) and K2CO3 (4.37 g, 31.6 mmol, 4 eq.) in DMSO (10 mL) was added H2O2 (30% in water, 2.0 mL) at rt. The mixture was stirred at rt O/N and added water (50 mL). The solid was collected and dried to give 3,5-bis(benzyloxy)isonicotinamide (2.2 g, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 2H), 7.59-7.33 (m, 10H), 5.83 (s, 2H), 5.25 (s, 4H), 4.81 (s, 2H). LRMS (M+H+) m/z 335.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17](F)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Solvent: CCO
Product: COc1ccc(CNc2cc3c(Nc4cccc(Br)c4)ncnc3cn2)cc1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
A mixture of 4-[(3-bromophenyl)amino]-6-fluoro-pyrido[3,4-d]pyrimidine (0.48 g) and 4-methoxybenzyl-amine (10.3 g) in ethanol (50 mL) was heated to 100° C. for 5 days. The resulting product was chromatographed on silica gel, eluting with CH2Cl2:EtOAc (3:1), to give 4-[(3-bromophenyl)amino]-6-[(4-methoxyphenyl)methyl-amino]pyrido[3,4-d]pyrimidine (0.18 g,) mp (aqueous methanol), 178-179.5° C. A 0.10 g portion of this was dissolved in 5 mL trifluoroacetic acid and heated under reflux for 1 hour, and the mixture was evaporated to dryness. The residue was partitioned between EtOAc and aqueous ammonia, and the crude product was chromatographed on alumina, eluting with CH2Cl2:MeOH (97:3) to give 6-amino-4-[(3-bromophenyl)amino]pyrido-[3,4-d]pyrimidine (0.040 g,), mp (CH2Cl2) 241.5-242° C.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)(Cl)Cl.CO>[C:1]1([CH2:7][S:8]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CSc2nc3cnccc3[nH]2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccccc1)c1nc2cnccc2[nH]1
Reaction time: 0.75 h

Procedure:
To a chilled (0°-5° C.) solution of 3.3 g (0.014 mol) of 2-[[(phenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine in 50 mL of chloroform and 5 mL of methanol was added dropwise a solution containing 2.78 g (0.014 mol) of m- chloroperoxybenzoic acid in 50 mL of chloroform. The reaction mixture was then stirred at room temperture for 45 minutes. Approximately one half of the chloroform was removed in a rotary evaporator and the reaction mixture was then poured into 200 mL of ether. The reaction mixture was cooled in ice. The precipitate that formed was collected and amounted to 1.78 g. The product was suspended in aqueous 10% sodium bicarbonate solution, filtered and was air dried overnight. The product amounted to 1.39 g. An analytical sample (m.p. 190°-193° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CCC(=O)O
Reaction time: 2.5 h
Yield: 100.8 %

Procedure:
4.0 g (11.0 mmol) of 5'-O-(tert-Butyldimethylsilyl)-2'-deoxy-5-fluorouridine was dried by twice dissolving the nucleoside in 25 ml of anhydrous pyridine in a round bottom flask and evaporating the pyridine on a rotary evaporator. To the thus dried protected nucleoside re-dissolved in 20 ml pyridine was added 0.54 g (4.4 mmol) of 4-dimethylaminopyridine all at once and 0.84 g (8.4 mmol) succinic anhydride (Aldrich Chemical Company, Milwaukee, Wis. 53233) in three portions over 90 min. After stirring for 2.5 hrs, another equal portion of 4-dimethylaminopyridine was added. The flask was sealed with a serum stopper and the mixture was allowed to stir overnight. After this time, pyridine was removed on the rotary evaporator by co-evaporation with 4×50 ml toluene to give a tan foam. The foam was dissolved in 100 ml dichloromethane and extracted with 3×100 ml cold aqueous 10% citric acid, followed by 100 ml water. The dichloromethane layer was dried over magnesium sulphate, filtered, and the solvent was removed on a rotary evaporator to give 3.9 g of a tan foam. This foam was dissolved in a minimal amount of dichloromethane and applied to a column (4.5×30 cm) packed with silica gel (350 g, 230-400 mesh) in dichloromethane. Under medium air pressure (9-12 psi) the column was first eluted with 1 L of chloroform followed by elution with 1 L of 1% methanol in chloroform. The percentage of methanol was increased 1% for each successive litre. The product was eluted into fractions between 2% and 10% methanol in chloroform. Product fractions were pooled and the solvent was removed on the rotary evaporator to give 2.0 g (4.3 mmol) of a white solid: m.p. 133.4°-135.3° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.N12CCN(CC1)CC2.[NH2:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][C:17]=1I>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:27]([O:26][C:25]([NH:24][CH2:23][C:19]1[CH:18]=[C:17]2[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[NH:15][C:16]2=[N:21][C:20]=1[CH3:22])=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1nc(N)c(I)cc1CNC(=O)OC(C)(C)C
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1nc2[nH]c(C(=O)O)cc2cc1CNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 92158 %

Procedure:
Under argon, pyruvic acid (6.90 ml, 100.1 mmol) and 1,4-diazabicyclo[2.2.2]octane (843 g, 7.51 mmol) were added to a solution of tert-butyl [(6-amino-5-iodo-2-methylpyridin-3-yl)methyl]carbamate (840 mg, 2.31 mmol) in N,N-dimethylformamide (0.5 ml), and the flask was evacuated and flushed with argon. Then argon was passed through the solution for 5 min and then palladium(II) acetate (25.9 mg, 0.11 mmol) was added and the mixture was heated to 100° C. for 2 h. The cooled solution was filtered through Celite and the dimethylformamide was distilled off. The residue was then taken up in water and acidified with hydrochloric acid, giving a 5-{[(tert-butoxycarbonyl)amino]methyl}-6-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (650 g, 88% of theory). HPLC-MS: log P=0.58; mass (m/z): 306.1 (M+H)+; 1H-NMR (DMSO) 1.37 (s, 9H), 2.33 (s, 3H), 4.17 (d, 2H), 6.57 (s, 1H), 7.68 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C)C=O.O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[N:8]2[CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of E/Z 6-Bromo-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (5.3 g, 16 mmol) prepared in example 157a in N,N-dimethyl-formamide (50 mL) at 0° C. was added NaH (60% in mineral oil) (0.64 g, 16 mmol), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.65 g, 16 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na2SO4. The solvent was removed and the residue was purified by chromatography (hexanes) to give E/Z-6-Bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as a yellow oil (Yield 4.5 g, 60%).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.CS([Cl:35])(=O)=O>ClCCl.N1C=CC=CC=1>[Cl:35][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3ccccc32)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(Cl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.57 g) is dissolved in dichloromethane (30 ml) and pyridine (1.1 ml), and thereto is added dropwise methanesulfonyl chloride (0.9 ml) in small portions at 0° C. Then, the mixture is stirred at room temperature for 3 days. The solvent is distilled off and the resulting residue is poured into ice-water. The precipitated crystal is collected by filtration, washed with water, and dried to give 5-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.10 g) as light yellow powder.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]=[C:26]=[O:27]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:8]([NH:10][C:26]([NH:25][CH3:24])=[O:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN=C=O
Reactant: NC(=O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Yield: 68.8 %

Procedure:
A solution of 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionamide (143 mg, 0.46 mmol) in toluene (10 mL) was treated with methyl isocyanate (0.04 mL, 0.69 mmol). The reaction mixture was heated under reflux for 24 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionyl]-3-methyl-urea (116 mg, 69%) as a white solid: EI-HRMS m/e calcd for C22H26N2O3 (M+) 366.1943, found 366.1946.