Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([CH3:9])=[N:8][C:4]=2[C:3]=1[CH3:19].C1C=C(O[C:27](OC2N=CC=CC=2)=[S:28])N=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:13]([O:12][C:10]([N:6]1[C:5]2[CH:17]=[CH:18][C:2]([N:1]=[C:27]=[S:28])=[C:3]([CH3:19])[C:4]=2[N:8]=[C:7]1[CH3:9])=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-amino-1-t-butoxycarbonyl-2,4-dimethylbenzimidazole (1.1 g, 4.2 mmol) in methylene chloride (60 mL) is added dropwise over 30 minutes to a solution of di-2-pyridyl thionocarbonate (1.9 g, 8.2 mmol) and 4-dimethylaminopyridine (0.1 g) in methylene chloride (150 mL). The mixture is stirred for 2 hours at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1-t-butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzimidazole as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[OH:11])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C)C=O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[O:2])[C:7]#[N:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1ccc(C=O)c(O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Formyl-3-hydroxybenzonitrile (4.0 g) and potassium carbonate (3.76 g) were suspended in N,N-dimethylformamide (20 mL). To the reaction mixture was added benzylbromide (3.6 mL), and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give the title compound (3.0 g).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:18])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CN(C)CCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and N1,N1-dimethylpropane-1,3-diamine according to general procedure 1 providing the intermediate (160 mg, 84%) as a clear oil: Rf=0.16 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.54 (d, J=9.5 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.5 Hz, 1H), 3.40 (t, J=7.1 Hz, 2H), 2.48-2.45 (m, 2H), 2.27 (s, 6H), 1.93-1.88 (m, 2H); ES-MS: (M+H)=298, 300 m/z.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[C:29]([C:36]2[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:43])=[N:30][O:31][C:32]=1[CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:42][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:43])[C:36]=1[C:29]1[C:28]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[N:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:32]([CH:33]([CH3:35])[CH3:34])[O:31][N:30]=1
Reactant: COC(=O)c1cc(C(=O)OC)c2ccc(-c3ccc(O)cc3)cc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)c2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2n1
Yield: 46.5 %

Procedure:
A solution of 75 mg (0.22 mmol) of dimethyl 7-(4-hydroxyphenyl)-2,4-quinolinedicarboxylate, 135 mg (0.44 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 125 mg (0.89 mmol) of K2CO3 in 2 mL DMF was stirred at ambient temperature for 60 hr. EtOAc was added and the mixture washed with three portions of H2O then brine. The solution was concentrated and the residue purified by silica gel chromatography (12 g of silica gel eluting with 0-50% EtOAc in hexanes over 45 minutes) to give 62 mg (46%) of dimethyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2,4-quinolinedicarboxylate as a clear glass. 1H NMR (400 MHz, CDCl3): δ 8.88 (d, J=9.0 Hz, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 7.98 (d, J=9 Hz, 1H), 7.65 (d, J=9 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 7.35-7.31 (m, 1H), 6.91 (d, J=9 Hz, 2H), 4.79 (s, 2H), 4.11 (s, 3H), 4.07 (s, 3H), 3.36 (septet, J=7 Hz, 1H), 1.44 (d, J=7 Hz, 6H). ESI-LCMS m/z 606 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19]S(C2C=CC=CC=2)(=O)=O)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH3:29])[CH:6]=1)#[N:4].CC1CCCO1.[F:36][C:37]([F:53])([F:52])[C:38]1[CH:39]=[C:40]([NH:44][C:45]2[CH2:50][CH2:49][CH2:48][C:47](=[O:51])[CH:46]=2)[CH:41]=[CH:42][CH:43]=1>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19][C:46]2[C:47](=[O:51])[CH2:48][CH2:49][CH2:50][C:45]=2[NH:44][C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:37]([F:36])([F:53])[F:52])[CH:39]=2)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:7]([CH3:29])[CH:6]=1)#[N:4]
Reactant: Cc1cc(C#N)ccc1N(CS(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: Cc1cc(C#N)ccc1N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 150 mg, 3.75 mmol) is added in portions to a mixture of tert-butyl (4-cyano-2-methylphenyl)(phenylsulfonyl)methylcarbamate (step 1, 1.88 g, 3.41 mmol) and 2-methyltetrahydrofuran (10 mL), and the mixture is stirred at room temperature for 30 min 3-(3-(Trifluoromethyl)phenylamino)cyclohex-2-enone (869 mg, 3.41 mmol) is added, and the mixture is stirred for 2 h. Water is added, and the mixture is extracted with dichloromethane. The phases are separated, and the organic layer is concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 1.57 g; ESI mass spectrum [M+H]+=500; Retention time HPLC: 0.79 min (X012_S01).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:49]3[CH2:50][CH2:51][N:46]([CH2:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:47][CH2:48]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(SCC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(SCC)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-ethylsulfanyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C36H45N4O4S2Cl2 [(M+H)+] 731.2254, observed 731.2259.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2.C([Sn](CCCC)(CCCC)[C:26]1[N:27]=[CH:28][N:29](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=1)CCC>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:9]1[CH:10]=[C:2]([C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(-c3c[nH]cn3)cc2CN1Cc1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
A mixture of 5-Bromo-7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (127 mg, 0.343 mmol), 4-Tributylstannanyl-1-trityl-1H-imidazole (300 mg, 0.514 mmol), and Pd(PPh3)4 (79 mg, 0.0514 mmol) in toluene (15 mL) stirred overnight at 110° C. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue (7-Chloro-2-(4-chloro-benzyl)-5-(1-trityl-1H-imidazol-4-yl)-2,3-dihydro-isoindol-1-one) was dissolved in formic acid (5 mL) and stirred at room temperature for 18 hrs. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organics were washed with 3N HCl (2×30 ml) and the aqueous washes were combined, neutralized with 1N NaOH, and extracted with ethyl acetate. The organics were washed with brine, and dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (100% Ethyl acetate—5% 2M NH3 in MeOH/CH2Cl2) provided the title compound (22 mg, 18%). 1H NMR (300 MHz, CDCl3): δ 7.80 (s, 2H), 7.7.75 (s, 1H), 7.46 (s, 1H), 7.35-7.30 (m, 4H), 4.77 (s, 2H), 4.27 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[S:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([Li])(CC)C.C(O[B:38]1[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]1)(C)C>C1COCC1.C1CCCCC1>[CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[S:21][C:22]5[C:27]([B:38]6[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]6)=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3sc3ccccc34)cc21
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3sc3c(B5OC(C)(C)C(C)(C)O5)cccc34)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Into a solution of 4-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]thiophene (10.637 g, 28.3 mmol) in THF (200 ml), a solution of sec-butyllithium 1.4 M (27.2 ml, 38.1 mmol) in cyclohexane at −78° C. was added slowly. The resulting mixture was stirred at −78° C. for 2 hours before quenching with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.65 ml, 42.4 mmol) added at one portion. The mixture was gradually warmed to room temperature, stirred overnight, and then quenched with methanol. The solvent was evaporated. The residue was purified by column chromatography on silica gel with a heptane/DCM (4/1 to 1/1) eluent and then precipitation in MeOH to yield 2-(6-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]thiophen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.3 g, 65.5% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:37])[C:20]4[C:21]([O:29][C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:22]3[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[CH:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:41]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19](=[O:37])[C:20]4[C:21]([O:29][C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:22]3[C:26](=[CH:27][CH:28]=4)[N:25]([CH3:41])[N:24]=[CH:23]3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c3oc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(=O)c3ccc21
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
To a solution of {1-[4-(4-oxo-2-phenyl-4,7-dihydro-pyrano[2,3-e]indazol-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (65 mg, 0.13 mmol) in DMF (3 mL) at 0° C. under an atmosphere of N2 was added sodium hydride (60% in mineral oil, 6 mg, 0.15 mmol). After 5 min, methyl iodide (10 μL, 0.16 mmol) was added and the mixture stirred for a further 2 hours. The reaction was quenched with H2O, partitioned between EtOAc and H2O and the phases separated. The organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 70% ethyl acetate in cyclohexane) to afford the title compound as an oil (41 mg, 60%). LCMS (Method B): RT=4.42 min, [M+H]+=522. Also obtained was {1-[4-(8-Methyl-4-oxo-2-phenyl-4,8-dihydro-pyrano[2,3-e]indazol-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester as a white solid (22 mg, 32%). LCMS (Method B): RT=4.26 min, [M+H]+=522.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Yield: 75.3 %

Procedure:
A stirred solution of 5-chloroindole (455 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (752 mg, 75%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][C:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH:10]=3)[N:5]([CH3:6])[CH2:4]1.C[Si](C)(C)[Cl:22].C[Si](C)(C)Br>>[Cl:22][C:10]1[NH:11][C:12]2[C:19]3[C:9]=1[CH2:8][C@@H:7]1[C:17]([C:16]=3[CH:15]=[CH:14][CH:13]=2)=[CH:18][C@@H:3]([CH2:2][OH:1])[CH2:4][N:5]1[CH3:6]
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)Br
Product: CN1C[C@H](CO)C=C2c3cccc4[nH]c(Cl)c(c34)C[C@H]21

Procedure:
1 g of lysergol is halogenated according to the process of Example 1, except that 1.7 g of trimethylchlorosilane are used instead of trimethylbromosilane. The product is isolated as described in Example 1. The yield of the title compound is 0.73 g (0.0025347 mole, 64.4%), m.p.: 207° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1.[C:20]1([CH3:46])[CH:25]=[CH:24][C:23]([C:26]([O:28][C@@H:29]2[C@@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[O:37])[O:32][C@H:31](Cl)[CH2:30]2)=[O:27])=[CH:22][CH:21]=1>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:31]2[O:32][C@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[O:37])[C@@H:29]([O:28][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:46])=[CH:25][CH:24]=3)=[O:27])[CH2:30]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1
Reactant: CCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Yield: 94.7 %

Procedure:
This reaction was repeated on a larger scale with the sodium salt of 2-chloro-6-(2-propylimidazol-1-yl)purine (1.54 g, 5.87 mmol) in dried CH3CN (100 mL) treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (3.74 g, 9.62 mmol) in CH2Cl2 (100 mL) by general method 2 for 5 h (reaction complete, TLC). Sampling at different reaction times showed no α-nucleoside by 1H NMR (500 MHz). Volatiles were evaporated, and the residue was dissolved in CH2Cl2. The solution was washed (H2O) and dried (Na2SO4), and volatiles were evaporated in vacuo. The residue was chromatographed (EtOAc/hexanes, 1:1→7:3) to give 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-propylimidazol-1-yl)purine (3.42 g, 95%). Recrystallization from EtOAc gave the β-anomer (2.75 g, 76%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].CCOCC>C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH3:14][O:13][C:11](=[O:12])[C:10]([C:9]([O:16][CH3:17])=[O:15])=[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:4]
Reactant: CCOC(=O)C(C)=O
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C)=C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of ZnCl2 (53 g, 388 mmol) in acetic anhydride (120 mL) was stirred at r.t. for 2 h. The resulting solution was decanted, and to this solution was added ethyl pyruvate (25 g, 215 mmol) and dimethyl malonate (25 mL, 215 mmol). The resulting mixture was heated at 100° C. for 1 h, then left standing at r.t. for 16 h. Ether (300 mL) was added and the mixture was washed with ice water (5×300 mL) and saturated NaHCO3 (2×300 mL). The organic layer was dried over MgSO4 and concentrated to give a dark brown oil, which was distilled under reduced pressure to give 34.1 g of the title compound as an orange oil. 1H NMR (CDCl3, 200 MHz): δ=4.26 (q, 2H, J=7.0 Hz), 3.82 (s, 3H), 3.79 (s, 3H), 2.22 (s, 3H), 1.32 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][NH:23][C:22]=2[N:21]=1>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][NH:23][C:22]=2[N:21]=1)(=[O:7])[O:5][CH3:6]
Reactant: COC(=O)CCCCc1ccc2c(n1)NCCC2
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCCC2)OC
Reaction time: 0.75 h

Procedure:
A solution of dimethyl methylphosphonate (13.20 g, 106.5 mmol) in anhydrous THF (165 mL) was cooled to −78° and treated dropwise with 2.5 M n-BuLi (42.3 mL). After stirring at −78° for 45 min, a solution of ester 1-5 (6.6 g, 26.6 mmol) in THF (35 mL) was added dropwise and the resulting solution stirred for 30 min at −78°, quenched with sat. NH4Cl (100 mL), then extracted with ethyl acetate (3×150 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to afford a yellow oil. Chromatography on silica gel (5% MeOH/CH2Cl2) afforded 1-6 as a yellow oil.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24](OC)=[CH:23][CH:22]=1>CS(C)=O>[CH2:20]([O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccccc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 2-hydroxyisoindoline-1,3-dione (1.0 g, 6.13 mmol) in DMSO (10 mL) was added Cs2CO3 (1.997 g, 6.13 mmol). The resulting mixture was stirred at it for 30 min. 1-bromomethyl 4-methoxy-benzene (0.88 mL, 6.13 mmol) was then added dropwise. After stirring at 50° C. overnight, the reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, washed with NH4Cl (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column with gradient hexanes:EtOAc to give 2-(benzyloxy)isoindoline-1,3-dione as a white solid (0.9 g, 49%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.85 (s, 4H), 7.42 (d, 2H), 6.94 (d, 2H), 5.08 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:10]=2[N:9]([CH2:30][O:31][CH3:32])[C:8]1=[O:33])=[O:6].[CH2:34](Br)[CH:35]=[CH2:36].[H-]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1([CH2:36][CH:35]=[CH2:34])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:10]=2[N:9]([CH2:30][O:31][CH3:32])[C:8]1=[O:33])=[O:6]
Reactant: C=CCBr
Reactant: COCN1C(=O)C(C(=O)OC)C(c2ccccc2OC)Cc2cc(C(F)(F)F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)OC)C(=O)N(COC)c2ccc(C(F)(F)F)cc2CC1c1ccccc1OC

Procedure:
To a suspension of sodium hydride (384 mg; 8 mmole; 50% oil dispersion) in dry dimethylformamide (35 ml), cooled in an ice water bath, was added a solution of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-1-(methoxymethyl)-4-(methoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one (917 mg; 21 mmole) in dimethylformamide (8 ml) with stirring. After stirring at 0°-5° C. for 30 minutes, allyl bromide (1.5 ml) was added in one portion, the mixture was allowed to stand at 0°-5° C. for three additional hours, whereupon excess hydride was destroyed by the addition of water. The mixture was diluted with ether and washed with water. The aqueous layer was extracted with ether (three times), and the combined ether extracts were dried (magnesium sulfate) and concentrated. The crude residue was flash chromatographed (silica gel/5-20% ethyl acetate:hexane) to obtain 905 mg of the title compound in crystalline form.
Reaction SMILES: [Na].C(O)C.[CH:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][CH2:11][C:12](OCC)=[O:13]>C(OCC)C>[Cl:10][CH:11]([CH:12]=[O:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCl
Reactant: CCOC=O
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
To a flask was added sodium (4.45 g, 194 mmol) and ethanol (56.5 mL, 968 mmol) and the mixture was stirred at room temperature for 4 hours until all of the metal had dissolved. Diethyl ether (100 mL) was added, followed by the slow addition of a solution of ethyl formate (17.20 mL, 213 mmol) and ethyl chloroacetate (22.79 mL, 213 mmol) in diethyl ether (100 mL). The reaction solution was stirred at room temperature for 16 hours. The resulting precipitate that formed was filtered and washed with ether, and dissolved in water. The aqueous layer was acidified with HCl (1N) to pH 4 and the product was extracted with diethyl ether (3×). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give ethyl 2-chloro-3-oxopropanoate (4.5 g, 29.9 mmol, 15.44% yield).