Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[N:23]1[CH:24]=[CH:25][C:20]([C:19]2[O:26][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:17])([C:13]([F:14])([F:16])[F:15])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=3[N:18]=2)=[CH:21][CH:22]=1
Reactant: O=C(Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)C(F)(c1ccc2oc(-c3ccncc3)nc2c1)C(F)(F)F
Reaction time: 2.3 h

Procedure:
To a mixture of 0.79 g of N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide, 8 ml of tetrahydrofuran and 0.60 g of triphenylphosphine, 0.99 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 2.3 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(pyridin-4-yl)-5-(heptafluoroisopropyl)benzoxazole (hereinafter, referred to as “active compound 67”).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12]([OH:15])(=O)=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.S(Cl)([Cl:18])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:12]([Cl:18])(=[O:15])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c2cc(Cl)c(S(=O)(=O)O)cc2o1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)c(S(=O)(=O)Cl)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a stirred mixture of 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonic acid (˜10 g, 40 mmol) and CH2Cl2 was added thionyl chloride (5.8 cm3, 80 mmol) at room temperature, causing gas to be evolved. This was stirred at room temperature for two hours but the solid didn't dissolve and FIA only showed starting material. Therefore a few drops of DMF were added and the reaction heated to 50° C. overnight but no reaction occurred. The starting material was filtered off and then treated with neat thionyl chloride (15 cm3) and heated to 70° C. overnight, FIA now detected starting material and product, so the reaction was treated with DMF (2×1 cm3) to aid solvation, FIA showed completion of the reaction. The reaction was diluted with CH2Cl2 (100 cm3) then poured onto ice. The solid formed was filtered off and dried in vacuo yielding 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl chloride (4.6 g, 43%) as a fine white solid; δH (300 MHz; D6 DMSO) 7.09 (1H, s, Ar—H), 7.69 (1H, s, Ar—H) and 11.81 (1H, s, N—H); m/z (FIANEG) 266.0 [(M−H)−, 100%] and 268.0 [(M−H)−, 67%].
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:16][CH3:17])[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:8][C:7]1=O)([O:3][CH3:4])=[O:2].[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26]N)[CH3:19].C(Cl)(C)=O>CO>[CH3:4][O:3][C:1](=[O:2])[CH2:5][C:6]1([CH2:16][CH3:17])[C:7]2[NH:26][C:21]3[C:22](=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:18][CH3:19])[C:8]=2[CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH2:11]1
Reactant: CCc1ccccc1NN
Reactant: CCC1(CC(=O)OC)CCC(C2CC2)CC1=O
Solvent: CC(=O)Cl
Solvent: CO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)CCC3C1CC1
Temperature: 0 °C
Yield: 33.8 %

Procedure:
The mixture of diastereomeric ketones (40 mmol, 9.52 g) prepared in Step (d) and 2-ethylphenylhydrazine (40 mmol, 5.45 g) were heated at reflux in 172 ml of MeOH for 60 hours, cooled to 0° C. and treated with 80 mmol (6.28 g, 5.7 ml) of AcCl. The reaction was refluxed an additional 45 minutes followed by removal of solvent in vacuo. Flash chromatography afforded 4.58 g (13.5 mmol, 34%) of orange oil containing a mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)([CH3:13])[CH2:11][O:10][S:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:22]>CC#N>[C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)([CH3:13])[CH2:11][O:10][S:9]1(=[O:22])=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)c2)COS1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide (10.4 g, 28 mmol) in CH3CN (50 mL) at 0° C. was added RuO4 (0.5% in stabilized aq., 50 mg, 0.1% by weight) in H2O (10 mL) amd NaIO4 (8.9 g, 41.5 mmol, 1.5 eq) in H2O (35 mL). The mixture was stirred at RT for 2 h. The mixture was partitioned between Et2O (200 mL) and H2O (50 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (3×50 mL). The combined organic layer was dried (Na2SO4), and concentrated to give 10.8 g (100%) of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC4; R6=Me) as a white solid (˜10.8 g, yield: 100%). 1H NMR (CDCl3) 7.56 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.38-7.44 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 4.41 (dd, J1=9.3 Hz, J2=20.4 Hz, 2H), 2.01 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [C:1]([N:8]1[C:12](=O)[CH2:11][CH2:10][C@@H:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].BrCC1C=CC=CC=1.Br[C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][CH:29]=1>>[CH2:17]([O:16][C:14](=[O:15])[C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][CH2:11][CH2:12][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][CH:29]=1)[CH3:18]
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: BrCc1ccccc1
Product: CCOC(=O)[C@@H](CCCc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
(R)-2-tert-Butoxycarbonylamino-5-(4-tert-butoxy-phenyl)-pentanoic acid ethyl ester is prepared according to the procedure of Ding, Chuanyong.; Ma, Rujian.; Rong, Guobin. Preparation of w-Phenyl-(2S)—N-Boc-amino Acid Ethyl esters; Chinese Journal of Organic Chemistry Vol 26(12) 2006, 1694 &1695, replacing Ethyl Boc-L-pyroglutamate with Ethyl Boc-D-pyroglutamate & Bromomethyl-benzene with 1-Bromo-4-tert-butoxy-benzene in Example 2a, using preparation steps 2.2, 2.3, and 2.5; [M+H]+ 394
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([Cl:27])[C:14]=1[OH:28].O>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[C:15]([Cl:27])[C:14]=1[O:28][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(OCc2ccccc2)cc(Cl)c1OCCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A reaction vessel was charged with 5.10 g of 1,3-dibromopropane, 2.40 g of potassium carbonate and 50 ml of N,N-dimethylformamide, to which a solution of 4.24 g of 2,6-dichloro-4-(benzyloxy)phenol dissolved in 10 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 4.24 g of 3,5-dichloro-4-(3-bromopropyloxy)-1(benzyloxy)benzene (68% yield).
Reaction SMILES: [Mg].[CH2:2]([C:4]1[C:12]2[N:11]3[C@H:13]([CH3:18])[CH2:14][NH:15][C:16](=[O:17])[C:10]3=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3].[H][H].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO>[CH2:2]([C:4]1[C:12]2[N:11]3[C@H:13]([CH3:18])[CH2:14][NH:15][C:16](=[O:17])[C@@H:10]3[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCc1cccc2cc3n(c12)[C@H](C)CNC3=O
Reactant: [H][H]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Mg]
Solvent: CO
Product: CCc1cccc2c1N1[C@H](C)CNC(=O)[C@@H]1C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Magnesium turnings (87 mg, 3.6 mmol) were added to a solution of (R)-6-Ethyl-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (82 mg, 0.36 mmol) in methanol (4 mL). After hydrogen gas started to evolve, the reaction mixture was kept at 10-20° C. and stirred for 2 h to dissolve the magnesium completely. Then the reaction mixture was poured onto 3 mL ice-cold 1 M aq. HCl, neutralized with 1 M aq. potassium phosphate solution (pH 6.85), and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield the title compound (80 mg, 97%). White solid. ISP-MS: m/e=231.2 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:16]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([CH2:12][NH2:16])([OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A stirred solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol (60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:23])[C:11]3[C:16]([C:17]=2[N+:18]([O-:20])=[O:19])=[CH:15][CH:14]=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:4][CH:3]=1.[C:24]([O-:27])([O-])=[O:25].[K+].[K+]>CN(C=O)C.O>[C:24](=[O:25])([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:23])[C:11]3[C:16]([C:17]=2[N+:18]([O-:20])=[O:19])=[CH:15][CH:14]=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:4][CH:3]=1)[O:27][C:5]([CH3:8])([CH3:6])[CH3:4]
Reactant: COc1ccc2c([N+](=O)[O-])c(-c3ccc(O)cc3)[nH]c(=O)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c([N+](=O)[O-])c(-c3ccc(OC(=O)OC(C)(C)C)cc3)[nH]c(=O)c2c1
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-7-methoxy-4-nitroisoquinolin-1(2H)-one (50.0 mg, 0.16 mmol, 1.0 eq.), K2CO3 (22.15 mg, 0.16 mmol, 1.0 eq.), and Boc2 (34.9 mg, 0.16 mmol, 1.0 eq.) in DMF (1 ml) degassed with argon in a sealed tube is stirred at a.t. for 18 hours. The reaction medium is diluted with H2O. The organic phases are extracted with ethyl acetate (twice), washed with a saturated solution of NaCl (twice), dried over MgSO4 then concentrated under reduced pressure, in order to obtain a pure product (yield=100%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[Br:24][CH2:25][CH2:26]Br.O>CN(C=O)C>[Br:24][CH2:25][CH2:26][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:4]([Cl:3])=[CH:5][C:6]=1[N+:21]([O-:23])=[O:22]
Reactant: BrCCBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CCBr)c2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.20 g (5.00 mmol)) in DMF (7.0 ml), 4′-chloro-2′-nitro-p-toluenesulfonanilide (1.20 g (3.67 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, 1,2-dibromoethane (2.00 ml (23.2 mmol)) was added and the mixture was heated at 130° C. for one hour with stirring. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether. The extract was washed with 1% aqueous sodium hydroxide solution, a saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to make the residue crystalline. Hexane was added to the crystals and the crystals were collected while washing to give 1.12 g (70%) of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[F:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37](=[O:47])[C:38](=[O:46])[N:39]2[CH2:42][C:43](O)=[O:44])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:43](=[O:44])[CH2:42][N:39]1[C:40]2[C:36](=[CH:35][CH:34]=[C:33]([F:32])[CH:41]=2)[C:37](=[O:47])[C:38]1=[O:46]
Reactant: O=C(O)CN1C(=O)C(=O)c2ccc(F)cc21
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CN1C(=O)C(=O)c2ccc(F)cc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol) in DCM (15 ml), DMAP (0.058. g, 0.476 mmol), EDC (0.274 g, 1.428 mmol) and 2-(6-fluoro-2,3-dioxoindolin-1-yl)acetic acid (0.127 g, 0.571 mmol) were added in one portion at room temperature. The resulting solution was stirred at room temperature for 24 hours; the solvent was removed under vacuum and the residue was dissolved in ethyl acetate (40 ml), washed with a saturated solution of NaHCO3 (20 ml), with 1N HCl (20 ml) and finally with brine (20 ml). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude was purified by preparative HPLC (Method 1) and two pure fractions were isolated:
Reaction SMILES: [Cl-].[Li+].[CH:3]([Mg]Cl)([CH3:5])[CH3:4].[C:8](Cl)(=[O:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.[Cu]Cl>[CH3:4][CH:3]([CH3:5])[C:8](=[O:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium chloride (27 mmol) and copper (I) chloride (13.46 mmol) are weighed into a flame dried 250 mL round-bottomed flask fitted with low temperature thermometer. Dry THF (50 mL) is added and the mixture stirred at RT for 1 h to give a cloudy yellow-green solution. This is cooled to −55° C. and isopropylmagnesium chloride (6.75 mL of a 2 M solution in THF, 13.5 mmol) is added. After 15 min hydrocinnamoyl chloride (13.46 mmol) is added quickly at −60° C. and the mixture allowed to warm slowly to RT overnight. The mixture is quenched with water (100 mL) and 35% ammonium hydroxide (20 mL) is added. The mixture is stirred at RT for 1 h and then extracted with diethyl ether (3×50 mL). The combined ether extracts are washed with saturated brine (50 mL), dried (MgSO4), filtered and evaporated under reduced pressure to give 4-methyl-1-phenyl-pentan-3-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([OH:17])=[CH:10][C:9]=2[Br:18])=[O:5])[CH3:2].S(OCC)(O[CH2:23][CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:23][CH3:24])=[CH:10][C:9]=2[Br:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2cc(O)cc(Br)c2o1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(=O)c2cc(OCC)cc(Br)c2o1
Yield: 65.6 %

Procedure:
Into a 100 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is added 700 mg (2.24 mg, 1.0 equiv.) of 8-Bromo-6-hydroxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (Reference Example 23a). This material is dissolved in 50 mL of toluene, then 689 mg, 586 μL (4.47 mmol, 2.0 equiv.) of diethyl sulfate and 309 mg (2.24 mmol, 1.0 equiv.) of K2CO3 were added. The reaction was then heated to reflux for 24 hr. At the end of this time, monitoring by LC/MS reveals that the reaction is >than 95% complete. The reaction is then cooled, 100 mL of ethyl acetate is added and the organic layer is washed with 0.5N HCl solution, dried over Na2SO4, filtered and concentrated. The residues were subjected to flash chromatography, using 40% ethyl acetate in hexane as eluent. The purified fractions were concentrated to yield 500 mg (65%) of a colorless solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH2:15])[CH2:10][CH2:9]2.[CH3:27][N:28]=[C:29]=[S:30]>CCOCC>[CH3:27][NH:28][C:29]([NH:15][CH:11]1[C:12]2[C:8](=[CH:7][C:6](/[CH:5]=[CH:4]/[CH:3]([C:16]3[CH:17]=[C:18]([Cl:24])[C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=3)[C:2]([F:1])([F:25])[F:26])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)=[S:30]
Reactant: CN=C=S
Reactant: NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Solvent: CCOCC
Product: CNC(=S)NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in Et2O (5 mL) was added methylisothiocyanate (0.026 g, 0.35 mmol), and the mixture was stirred for 2 h at 25° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, 20% EtOAc in petroleum ether). The title compound was isolated as a liquid (65 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.18 (m, 3H), 6.58 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.4 Hz, 1H), 5.91-5.70 (br, 2H), 4.05 (m, 1H), 3.05-2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H); ESIMS m/z 492.17 ([M+H]+); IR (thin film) 3211, 1569, 1113, 806 cm−1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:25][CH2:26][CH2:27]Cl>CS(C)=O.O>[CH:7]1([NH:13][CH2:27][CH2:26][CH2:25][O:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2cc(OCCCNC3CCCCC3)ccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and cyclohexylamine (0.29 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-cyclohexyl-[3-(naphthalen-2-yloxy)-propyl]amine, solid. m.p. 98° C. (yield 0.61 gm, 88%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3Cl)[O:7]1)(=[O:3])[CH3:2].[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:12]([O:11][C@H:10]1[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3[NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:7][C@@H:6]1[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:14])[CH3:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1.15 g of [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (Toronto Research Chemicals) was placed in 20 mL of DMF (dimethylformamide) and stirred. To this solution was added 0.42 mL of cyclopentyl amine and 10 mL of DIPEA (diisopropylethylamine). The resulting mixture was stirred overnight at room temperature. The next morning, the solvent was removed and the residue purified using a dichloromethane/methanol 20:1 column to provide (2R,3R,4R,5R)-4-acetyloxy-2-(acetyloxymethyl)-5-[6-(cyclopentylamino)-2-iodopurin-9-yl]oxolan-3-yl acetate, a compound of formula (10).
Reaction SMILES: FC1C=C(O)C=CC=1CN1CCN(C)CC1.F[C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][C:35]=1[CH2:36][N:37]1[CH2:42][CH2:41]N(C)[CH2:39][CH2:38]1)[O:21][CH:22]1[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1.N1CC(OC2C=CC(CN3CCN(C)CC3)=C(F)C=2)C1.N1CCCC1.COC1C=CC(C=O)=C([C:79]([F:82])([F:81])[F:80])C=1>>[NH:24]1[CH2:23][CH:22]([O:21][C:20]2[CH:33]=[CH:34][C:35]([CH2:36][N:37]3[CH2:38][CH2:39][CH2:41][CH2:42]3)=[C:18]([C:79]([F:82])([F:81])[F:80])[CH:19]=2)[CH2:25]1
Reactant: COc1ccc(C=O)c(C(F)(F)F)c1
Reactant: CN1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2F)CC1
Agent: CN1CCN(Cc2ccc(O)cc2F)CC1
Agent: CN1CCN(Cc2ccc(OC3CNC3)cc2F)CC1
Solvent: C1CCNC1
Product: FC(F)(F)c1cc(OC2CNC2)ccc1CN1CCCC1
Yield: 20 %

Procedure:
Using similar protocols as described in Examples 29A, 29B, 29C and 29D employing pyrrolidine and 4-methoxy-2-(trifluoromethyl)benzaldehyde as starting materials afforded 0.58 g (20%) of 45A as an oil. 1H NMR (500 MHz, CDCl3): δ 1.78 (s, 4H), 2.53 (d, 4H), 3.71 (s, 2H), 3.80 (m, 2H), 3.93 (m, 2H), 5.01 (m, 1H), 6.87 (dd, 1H), 7.00 (d, 1H), 7.64 (d, 1H), MS (APCI+) m/z 301 [M+H]+.
Reaction SMILES: [C:1]([N@@:4]1[CH2:6][CH:5]1[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])(=[O:3])[CH3:2].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.[Cl-].[Cl-].[Zn+2]>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][N:14]=[N+:15]=[N-:16])[CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)C1CN1C(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CCOC(OCC)[C@@H](CN=[N+]=[N-])NC(C)=O
Temperature: 75 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
A mixture containing 3.26 g of 124 and 15 g of sodium azide in 140 ml of DMF was added 140 ml of ZnCl2 (1.0M solution in Et2O), The mixture was stirred at 75° C. for 3 days and then extracted with EtOAc. The organic layer was washed with water, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc=3:2) to yield 2.52 g of 125 (62%).
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][CH3:18])[C:14](S)=[N:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][CH3:18])[CH:14]=[N:13][N:12]=1
Reactant: CCCn1c(S)nnc1CO
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCCn1cnnc1CO
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of 90% nitric acid (18 ml) and water (26 ml) was added sodium nitrite (0.07 g) and then 3-hydroxymethyl-5-mercapto-4-propyl-4H-1,2,4-triazole (10 g) was slowly added for 0.5 hours at 45° C. After cooling to room temperature, and sodium carbonate was slowly added thereto to adjust pH to 7 at 0° C. The reaction mixture was concentrated under reduced pressure, methanol was added to the residue, and the precipitates were removed by filtration. The mixture was concentrated under reduced pressure, dichloromethane was added to the residue, the precipitates were removed by filtration, and the filtrate was concentrated to give 3-hydroxymethyl-4-propyl-4H-1,2,4-triazole (5.95 g) as a crude product.