Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[Cl:31]>>[Cl:31][C:23]1[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=1[NH:11][C:10]1[N:6]([CH2:5][CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])[N:7]=[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])ccc1Cl)OCC

Procedure:
Analogously to the process described in Example 9A/Step 1, 1.0 g (3.62 mmol) of the compound of Example 4A and 941 mg (3.98 mmol) of 1-bromo-2-chloro-5-nitrobenzene gave 1.26 g (80% of theory) of the title compound. In this case, the reaction time in the microwave reactor was 1 h at a temperature of 140° C. Chromatographic isolation of the product was by MPLC (mobile phase cyclohexane/ethyl acetate 1:2).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:21]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:30])[C:8]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccn1)CC(C)(C)O2
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(c1cccc[n+]1[O-])CC(C)(C)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.3 %

Procedure:
261 mg of 6-acetyl-3,4-dihydro-2,2 -dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 20 ml of dichloromethane at room temperature and 250 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 3 days the mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 2%-5% (v/v) methanol/chloroform for the elution. The resulting foam was triturated with methylcyclohexane and the solid obtained was recrystallized from t-butyl methyl ether to give 20 mg of 2-(6-acetyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 132°-133° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([N:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH2:8][CH2:9][CH3:10].[C:24]([O-])(=[O:26])C.[Na+]>CN(C)C=O>[CH:24]([C:20]1[CH:21]=[CH:22][C:23]2[N:11]([CH:6]=[CH:7][CH2:8][CH2:9][CH3:10])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:26]
Reactant: CC(=O)[O-]
Reactant: CCCC=Cn1c2ccccc2c2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC=Cn1c2ccccc2c2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (9.1 g, 60mmol) was added to dimethylformamide (17 mL) at 0° C. with strong stirring over 15 minutes. Upon complete addition, the orange solution was stirred at 0° C. for a further 10 minutes. N-pentenyl-carbazole (10.5 g, 45 mmol) was gradually added to the iminium salt and the mixture was heated at 100° C. for 1.5 hours, then cooled to room temperature and added to ice. The ice slurry was adjusted to a pH of 6 with saturated sodium acetate solution and the crude product was extracted with dichloromethane (2×50 mL), dried (Na2SO4), and concentrated. Traces of dimethylformamide were removed under high vacuum to give 9.6 g of 3-formyl-N-pentenyl-carbazole as a brown oil. The material was used at this level of purity in the next step of the synthesis.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[C:6]2[N:11]([CH:12]=1)[CH:10]=[C:9]([C:13]#[N:14])[CH:8]=[CH:7]2>CN(C)C=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:12]1[N:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1cc2ccc(C#N)cn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2ccc(C#N)cn2c1Br
Temperature: 80 °C
Yield: 66.5 %

Procedure:
A solution of bromine (0.33 ml, 6.40 mmol. 1.0 equiv) in 10 ml of N,N-dimethylformamide is added under an atmosphere of argon at 0° C. to a solution of 2-methyl-indolizine-6-carbonitrile (1.0 g, 6.40 mmol) in 5 ml of N,N-dimethylformamide. The reaction mixture is heated in a microwave for 3 minutes at 80° C. After cooling, the reaction mixture is diluted with EtOAc and concentrated aqueous NaHCO3 solution. The aqueous phase is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (hexane/EtOAc 4:1, +0.2% NEt3) affords the title compound (1.0 g, 53%). 1H NMR (400 MHz, d6-DMSO): δ=8.97 (t, J=1.4 Hz, 1H), 7.56 (s, 1H), 7.28 (d, J=9.3 Hz, 1H), 6.87 (dd, J=9.3/1.5 Hz, 1H), 2.15 (d, J=1.0 Hz, 3H). MS (ES+): 236 (M+H)30.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]([NH2:20])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:30])[C:5]=2[CH:14]=1)(=[O:19])[NH2:20]
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(N)=O)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(N)=O)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
564 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxamide were dissolved in 20 ml of dichloromethane at room temperature and 540 mg of m-chloroperbenzoic acid were added. After stirring at room temperature overnight the mixture was washed with sodium bisulphite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and evaporated to give a solid which was recrystallized from isopropanol to yield 164 mg of 2-(6-carbamoyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 248°-250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1(=O)[CH:18]2[CH:13]([CH2:14][CH:15]=[CH:16][CH2:17]2)[C:12](=[O:19])[CH:11]=[CH:10]1.Cl.C([O-])(O)=O.[Na+]>CO.C(OCC)(=O)C>[OH:19][C:12]1[CH:11]=[C:10]2[C:9]([NH:1][C:2]3[C:3]([S:8]2)=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:18]2[CH2:17][CH:16]=[CH:15][CH2:14][C:13]=12
Reactant: Nc1ccccc1S
Reactant: O=C1C=CC(=O)C2CC=CCC12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1cc2c(c3c1CC=CC3)Nc1ccccc1S2
Reaction time: 1 h

Procedure:
A solution of 2-aminothiophenol (385 mg) in methanol (3 ml) was added to a solution of 4a, 5, 8, 8a-tetrahydro-1,4-naphtoquinone (Ref.: Ber. 62, 2361 (1929)) (500 mg) in methanol (10 ml) and stirred for 1 hour. Then conc. HCl (2 ml) was added and the mixture was stirred for another 2 hours. Ethyl acetate was added to the reaction mixture followed by a solution of NaHCO3. The organic layer was decanted, dried and evaporated to dryness. The resulting oily residue was chromatographed on silica gel (CH2Cl2) to afford the title compound.
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[CH3:19][Li]>C1COCC1>[F:12][S:11]([F:16])([F:15])([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:17])[CH3:19])=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: CON(C)C(=O)c1ccc(S(F)(F)(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxy-N-methyl-4-(pentafluoro-λ6-sulfanyl)benzamide (Preparation 42, 3.0 g, 10.3 mmol) in THF (100 mL) at 0° C. was added drop-wise methyl lithium (1.5M solution, 10.3 mL, 15.5 mmol). The reaction was stirred at 0° C. for 2 hours, then quenched with a saturated aqueous solution of ammonium acetate. The reaction was extracted with ethyl acetate and dried over MgSO4 before concentrating in vacuo to afford the title compound that was used without further purification.
Reaction SMILES: [CH:1]1(OC(=O)[C@@H](NC(OCC2C=CC=CC=2)=O)COC(C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([S:31][CH2:32][C@@H:33]([NH:37][C:38]([O:40][CH2:41][CH:42]1[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[C:34]([OH:36])=[O:35])([CH3:30])([CH3:29])[CH3:28]>>[CH:1]1([O:35][C:34](=[O:36])[C@H:33]([NH:37][C:38]([O:40][CH2:41][CH:42]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=3[C:49]3[C:54]2=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:39])[CH2:32][S:31][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Reactant: CC(C)(C)SC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: CC(C)(C)SC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC1CCCC1

Procedure:
This was prepared in the same manner as (S)-2-Benzyloxycarbonylamino-3-tert-butoxy-propionic acid cyclopentyl ester (Method A, Stage 1) but from (S)-3-tert-Butylsulfanyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid. 1H NMR (300 MHz, CDCl3), δ: 1.30 (9H, s, (CH3)3), 1.55-1.95 (8H, m, CH2×4), 3.05 (2H, d, CH2, J=4.8 Hz), 4.20-4.30 (1H, m, CH), 4.40 (2H, d, CH2, J=7.5 Hz), 4.65 (1H, m, CH), 5.25 (1H, m, CH), 5.70 (1H, d, NH, J=7.8 Hz), 7.30-7.50 (4H, m, ArH×4), 7.65 (2H, d, J=7.5 Hz, ArH×2), 7.80 (2H, d, J=7.5 Hz, ArH×2).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](Cl)=[O:12])[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:20][CH:19]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:30])[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2cccnc12
Reactant: CCOC(=O)C(C)c1ccc(CCN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(CCNC(=O)c2cccc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.0 g Quinoline-8-carbonyl chloride (m.p. 156°-160° C.) are added to 6.0 g ethyl 2-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride in 50 ml methylene chloride and a solution of 7 ml triethylamine in 20 ml methylene chloride slowly added dropwise at 0° C. The reaction mixture is thereafter stirred for 2 hours at ambient temperature, subsequently shaken out 6 times with 2 N aqueous sodium hydroxide solution and twice with 2 N hydrochloric acid, and the methylene chloride phase is then dried and evaporated. The residue is taken up with diethyl ether, undissolved material is filtered off and the diethyl ether is evaporated. Ethyl 2-{4-[2-(quinoline-8-carboxamido)-ethyl]-phenyl}-propionate (oil) remains behind in a yield of 8.0 g (91% of theory). This ester is saponified with 2.0 g sodium hydroxide in 50 ml 80% ethanol by heating under reflux for 2 hours. The reaction mixture is thereafter evaporated to dryness, the residue is taken up in water and diethyl ether, the layers are separated and the aqueous layer acidified. The 2-{4-[2-(quinoline-8-carboxamido)-ethyl]-phenyl}-propionic acid obtained is again reprecipitated by dissolving in dilute aqueous sodium bicarbonate solution and acidifying with hydrochloric acid, whereafter it is recrystallized from 50% isopropanol and then from toluene. The yield is 2.3 g (31% of theory); m.p. 143°-144° C.
Reaction SMILES: CS(O[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH2:7][CH3:8])(=O)=O.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C(N(CC)CC)C>C(Cl)Cl>[N:25]1([CH:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:22][CH3:23])=[O:24])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH3:8])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1c[nH]cn1
Reactant: CCC(OS(C)(=O)=O)c1ccc(-c2ccc(C(=O)NC)cc2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(c1ccc(-c2ccc(C(=O)NC)cc2)cn1)n1ccnc1
Temperature: 50 °C
Yield: 38.3 %

Procedure:
A mixture of 1-(5-(4-(methylcarbamoyl)phenyl)pyridin-2-yl)propyl methanesulfonate (0.02 g, 0.057 mmol), 1H-imidazole (0.008 g, 0.114 mmol) and triethylamine (0.03 mL, 0.114 mmol) in DCM (10 mL) was stirred and refluxed at 50° C. for 3 h. The mixture was then cooled to room temperature, poured out into ice water (50 mL) and extracted with DCM (2×50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated under vacuo. The resulting residue was purified by preparative TLC using 5% methanol in dichloromethane and the product isolated as off white solid (0.007 g, 39% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.91 (d, 1H), 8.46 (d, 1H), 8.12 (d, 1H), 7.91 (d, 2H), 7.80 (d, 3H), 7.39 (d, 1H), 7.31 (s, 1H), 6.89 (s, 1H), 5.37 (t, 1H), 2.78 (d, 3H), 2.27 (m, 2H), 0.89 (t, 3H). LC-MS: m/z 321.5 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8](=[O:24])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH:22]=[O:23])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=[O:32])C.S(=O)(O)[O-].[Na+].ClCCl>N1C=CC=CC=1>[CH:1]1([N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8](=[O:24])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([OH:32])=[O:23])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(C)=O
Reactant: COC(=O)CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C(=O)O)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(N-cyclohexyl-4-(3-formyl-4-nitrophenyl)oxybutyramidyl)acetate (3.5 g) in dry pyridine (20 ml) under a blanket of nitrogen was added solid tetra-N-butylammonium permanganate portionwise over 1 hour. The reaction was stirred at room temperature for 1 hour and was then poured into ethyl acetate/6M hydrogen chloride (100 ml each). Solid sodium bisulfite was added to decolorize the solution and the layers were separated. The aqueous layer was washed with ethyl acetate (2×50 ml). The combined organic layers were washed with 1M HCl (3×50 ml) and brine (2×50 ml), dried, filtered and evaporated to give a syrup which foamed at high vacuum from dichloromethane to yield methyl 2-(N-cyclohexyl-4-(3-carboxy-4-nitrophenyl)oxybutyramidyl)acetate.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[N:22]=[C:21]([C:4]2=[CH:3][CH:2]=1)[N:20]=[C:19]1[C:23]2[C:28]([C:17](=[N:18]1)[N:16]=[C:15]1[C:29]4[C:34]([C:13](=[N:14]1)[N:12]=[C:11]1[C:35]5[C:40]([C:9](=[N:10]1)[N:8]=3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][CH:26]=[CH:25][CH:24]=2.[Cu:41].S(=O)(=O)(O)O>>[CH:25]1[CH:24]=[C:23]2[C:19]3[N-:18][C:17]([C:28]2=[CH:27][CH:26]=1)=[N:16][C:15]1=[N:14][C:13]([C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:12][C:11]1[N-:10][C:9](=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[CH:39]2)[N:8]=[C:7]1[C:5]2[C:4]([C:21](=[N:22]1)[N:20]=3)=[CH:3][CH:2]=[CH:1][CH:6]=2.[Cu:41]
Reactant: c1ccc2c(c1)C1=NC2=NC2=NC(=NC3=NC(=NC4=NC(=N1)c1ccccc14)c1ccccc13)c1ccccc12
Agent: [Cu]
Agent: O=S(=O)(O)O
Product: c1ccc2c(c1)-c1nc-2nc2[n-]c(nc3nc(nc4[n-]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21

Procedure:
100 Part of crude copper phthalocyanine was treated in 500 parts of a 98% sulfuric acid aqueous solution at room temperature for 2 hours, and filtered. The resultant solid was washed with water and dried to give an α-form crude copper phthalocyanine. Thereafter, the α-form crude copper phthalocyanine was treated in the same way as in Example 1 to give a β-copper phthalocyanine pigment.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[Na].Cl.O.[CH2:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: Cl
Agent: [Na]
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2ncn(CCC(CO)CO)c2n1
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.31 g, 1.0 mmol) in a solution of sodium benzoxide (1 M in benzyl alcohol, 2 ml) was stirred at 70° for 1 hour. The resulting solution was allowed to cool, hydrochloric acid (5 M, 0.4 ml) and water (0.6 ml) were added and the solution was stirred for 1 hour at room temperature. The solution was then partitioned between chloroform and water. The aqueous layer was neutralised with aqueous sodium bicarbonate and extracted with chloroform. The combined organic layers were washed with aqueous sodium bicarbonate, dried (magnesium sulphate) and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (10:1, 5:1) to afford 2-amino-6-benzyloxy-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine as a white crystalline solid (0.17 g, 50%), m.p. 146°-147.5° C.; λmax (EtOH) 212 (32,300), 250 (8,380), and 283 (10,100) nm; νmax (KBr) 3340, 3220, 1655, 1605, and 1580 cm-1 ; δH [(CD3)2SO] 1.3-1.6 (1 H, m, 3'-H), 1.72 (2 H, q, J 7 Hz, 2'-H), 3.38 (4 H, AB part of ABX, 2×4'-H), 4.03 (2 H, t, J 7 Hz, 1'-H), 4.36 (2 H, t, J 5.5 Hz, D2O exchangeable, 2×OH), 5.47 (2 H, s, PhCH2), 6.37 (2 H, s, D2O exchangeable, 2-NH2), 7.3-7.6 (5 H, m, C6H5), and 7.84 (1 H, s, 8-H); (Found: C, 58.89; H, 6.12; N, 19.87%; C17H21N5O3 requires C, 59.46; H, 6.16; N, 20.40%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][OH:13])[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:28]([O:35][CH2:36]Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][O:13][CH2:36][O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: ClCOCc1ccccc1
Reactant: CCOC(=O)[C@H]1[C@@H](CCO)CCN1C(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@@H](CCOCOCc2ccccc2)CCN1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6 g of cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol in 75 ml of methylene chloride containing 7.3 ml of diisopropylethylamine, to which is added 5.1 ml of 85% benzyloxymethyl chloride, is stirred 31/2 hours at room temperature. The solution is washed with water and saturated aqueous sodium bicarbonate. The solution is then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (1:4) to yield cis ethyl 1-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si:25]([O:32][CH2:33][C@H:34]([CH3:56])[O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:45][C:46]2[CH:51]=[CH:50][C:49]([S:52]([CH3:55])(=[O:54])=[O:53])=[CH:48][CH:47]=2)[CH:44]=1)[C:39]([OH:41])=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.[CH3:66][O:67][CH2:68][C:69]1[N:70]=[C:71]([NH2:74])[S:72][CH:73]=1>CN(C=O)C>[Si:25]([O:32][CH2:33][C@H:34]([CH3:56])[O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:45][C:46]2[CH:47]=[CH:48][C:49]([S:52]([CH3:55])(=[O:53])=[O:54])=[CH:50][CH:51]=2)[CH:44]=1)[C:39]([NH:74][C:71]1[S:72][CH:73]=[C:69]([CH2:68][O:67][CH3:66])[N:70]=1)=[O:41])([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27]
Reactant: COCc1csc(N)n1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Reaction time: 4 h
Yield: 57 %

Procedure:
HATU (446 mg, 1.17 mmol) was added to 3-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]benzoic acid (450 mg, 0.94 mmol) followed by addition of DMF (4.5 mL), DIPEA (0.42 mL) and 4-(methoxymethyl)-1,3-thiazol-2-amine (160 mg, 1.11 mmol) and the reaction was stirred under argon for 4 h. The solvent was evaporated and the residue was dissolved in saturated aqueous sodium hydrogencarbonate (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated aqueous ammonium chloride (30 mL) then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:2 to 2:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (325 mg, 56%).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C=CC(COC#CC2C=CC=CC=2)=C[CH:38]=1>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:36]5[CH:35]=[CH:34][N:33]=[CH:32][CH:38]=5)=[CH:28][CH:29]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:17])[F:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C(#Cc1ccccc1)OCc1ccncc1
Reactant: O=C1C(n2cc(-c3ccc(Oc4cccnc4)cc3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Product: O=C1C(n2cc(-c3ccc(OCc4ccncc4)cc3)nn2)CCc2c(F)cccc2N1CC(F)(F)F

Procedure:
Prepared as for 6-fluoro-3-{4-[4-(pyridin-3-yloxy)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 4-(pyridine-4-ylmethoxy)ethynylbenzene as the alkyne.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8]O)[CH:5]=[CH:4][N:3]=[CH:2]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:11][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCn1ccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: BrCCCn1ccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
A mixture of 1H-imidazole-1-propanol (1.00 g, 3.65 mmol—prepared according to patent: WO 9722596 A1), carbon tetrabromide (1.80 g, 5.47 mmol) and triphenyl phosphine (1.43 g, 5.47 mmol) was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel. Elution with 10% methanol in dichloromethane yielded the title compound (425 mg, 35% yield) as a pale yellow solid:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[CH3:14].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[CH3:14])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC1Oc2c(C)c(C)c(O)c(C)c2S1
Solvent: c1ccncc1
Product: CCCC1Oc2c(C)c(C)c(OC(C)=O)c(C)c2S1
Yield: 95.6 %

Procedure:
A mixture of 1.6 g of 5-hydroxy-4,6,7-trimethyl-2-propyl-1,3-benzoxathiole (prepared as described in Example 42), 0.8 g of acetic anhydride and 10 ml of pyridine was reacted at room temperature for 15 hours and the reaction mixture was then treated and purified in the same manner as described in Example 4, to give 1.8 g of the title compound as a pale yellow oily substance.