Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:48]CC(C)=CC=C)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C2C(=CC(Cl)=CC=2)C(CCOC2C=CC(C(OC)=O)=CC=2)=C1CCNS(C1C=CC=CC=1OCC1C=CC=CC=1)(=O)=O)(C1C=CC=CC=1)C1C=CC=CC=1>CO.CCO.[Pd]>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[OH:48])(=[O:40])=[O:41])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CC=C(C)COc1ccccc1S(=O)(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: COC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3OCc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Solvent: CCO
Solvent: CO
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 104.9 %

Procedure:
4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-penta-2,4-dienyloxy)-benzensulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoic acid (0.55 g, 0.70 mmole), (Step 1, Example 183) Methyl 4-(2-{1-benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethy]-5-chloro-1H-indol-3yl}-ethoxy)benzoate, (0.55 g, 0.70 mmol), (Setp 1 , Example 184) and 10% Pd/C (55 mg) in MeOH (30 ml) and EtOH (20 ml) was hydrogenated. The resulting mixture was filtered through Celite and concentrated. The residue was chromatographed with 35-40% EtOAC/hexane to give the desired product (0.50 g, 95%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[Br:1][CH2:2][CH2:3][O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: C1=COCCC1
Reactant: OCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: BrCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 896.8 %

Procedure:
To a solution of 2-bromoethanol 24 (50.0 g, 40 mmol) in methylene chloride (500 mL) cooled to 0° C. was added 3,4-dihydro-2H-pyran (40.32 g, 48 mmol) followed by p-TSA.H2O (100 mg) was added. Reaction mixture was stirred at 0° C. for 5.0 h. The reaction mixture was washed with aq NaHCO3 and brine, dried over Na2SO4 and evaporated to give the product 25 (75.0 g, 90%). This crude product was taken to next step without purification.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=[O:19])[C:15]([Cl:18])([Cl:17])[Cl:16].[N+:20]([O-])([OH:22])=[O:21]>C(O)(C)C>[CH3:8][N:9]1[CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=[C:10]1[C:14](=[O:19])[C:15]([Cl:16])([Cl:17])[Cl:18]
Reactant: O=[N+]([O-])O
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)C(Cl)(Cl)Cl
Temperature: -40 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
An acetic anhydride solution (200 ml) containing 3 (45.2 g, 0.200 mol) was cooled to −40° C., and then fuming nitric acid (18.5 ml, 0.360 mol) was dropped into the solution at the same temperature. After stirring the mixture for 2 hours at a room temperature, isopropanol was added to precipitate a solid. The precipitated solid was collected by filtration to obtain a nitro substance 5 (27.2 g). The filtrate was distilled under a reduced pressure, and the obtained residue was subjected to silica gel column chromatography to further obtain 5 (10.7 g) from an elusion position of ethyl acetate-hexane (1:10, v/v). (Total yield: 70%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2([C:25]3[CH:26]=[CH:27][C:28]([C:40]4[CH:41]=[N:42][NH:43][CH:44]=4)=[CH:29][CH:30]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: COCCOc1ccc(C2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCOc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1

Procedure:
4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole following the procedure set out in Example 1, substituting tetrads triphenylphosphine palladium (0) as catalyst, the title compound was obtained. LC/MS: (PS-A2)Rt 3.27 [M+H]+ 478.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][CH:18]=1>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:23][C:21]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][CH:18]=[C:17]([O:16][CH3:15])[N:22]=1)[CH3:14]
Reactant: COc1ccc([N+](=O)[O-])c(C)n1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1nc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of potassium ethoxide (0.55 g, 6.55 mmol) in diethyl ether (20 mL, anhydrous) and ethanol (4 mL) was added diethyl oxalate (894 μL, 6.55 mmol) and the reaction mixture was stirred for 30 min prior to the addition of 6-methoxy-2-methyl-3-nitropyridine (Preparation 33, 1.0 g, 5.95 mmol) in diethyl ether (8 mL). The resulting red suspension was stirred at rt, under argon, for 20 h. The mixture was filtered, the solid washed thoroughly with diethyl ether then dried. The red solid was then taken up in hot water and the solution cooled to 0° C. The precipitate was filtered, washed with cold water, and dried to give the title compound as a beige solid. δH (CDCl3): 1.40 (3H, t), 4.07 (3H, s), 4.39 (2H, q), 6.74 (1H, d), 7.57 (1H, s), 8.40 (1H, d), 13.82 (1H, s).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>O1CCCC1>[CH2:1]([N:8]=[C:16]=[S:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=NCc1ccccc1
Temperature: -10 °C
Reaction time: 2.75 h

Procedure:
A solution of benzylamine (5.4 g, 0.05 mole) and triethylamine (15.4 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and filtered. The filtrate was treated with charcoal, then filtered and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column using hexane:ethyl acetate (90:10) as the eluant to yield benzyl isothiocyanate as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)=O)cc1C
Yield: 96.9 %

Procedure:
A mixture of 1 (4 hydroxy-3-methylphenyl)-ethanone 5.0 g, methyl iodide 5.70 g, potassium carbonate 20.0 g and acetone 200 ml was stirred with heating under reflux for six hours. The reaction mixture was filtered and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure to give 1-(4-methoxy-3-methylphenyl)-ethanone 5.3 g.
Reaction SMILES: [NH2:1][C:2](=O)[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2](=[S:24])[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Temperature: 90 °C
Reaction time: 6 h
Yield: 109.9 %

Procedure:
To a mixture of tert-butyl 1-amino-2-methyl-1-oxopropan-2-ylcarbamate (10 g, 49 mmol) in toluene (200 mL) was added Lawesson's reagent (CAN 19172-47-5, 10 g, 25 mmol). The suspension was heated to 90° C. and stirred for 6 h. After evaporation of solvents, the residue was purified by column chromatography (silica gel, 120 g) eluting with 30% ethyl acetate in petroleum ether to yield the title compound (6 g, 56%); MS: m/e 241.2 [M+Na]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:24][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:14]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=[CH:12][CH:13]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cccn2S(=O)(=O)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 168 h
Yield: 70.7 %

Procedure:
Under nitrogen atmosphere, to a solution of 1-benzenesulfonyl-1H-pyrrole (284 g, 1.37 mol) in dichloromethane (1.0 L) were added p-toluoyl chloride (318 g, 2.06 mol) and boron trifluoride ether complex (350 g, 2.47 mol), and the mixture was allowed to stand at room temperature for 7 days. The reaction solution was washed successively with 1N aqueous hydrochloric acid solution (750 mL×2), 1N aqueous sodium hydroxide solution (750 mL) and saturated saline (100 mL), dried, and filtered. The filtrate was concentrated under atmospheric pressure until about 500 ml, and thereto was added hexane (500 mL). The reaction mixture was further concentrated until about 500 ml, cooled to 10° C., and the resulting crystals were collected by filtration. The obtained crystals were washed successively with hexane and toluene to give the title compound (315 g, 71%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19]1[O:22][CH:20]1[CH3:21]>>[O:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C@@H:20]([OH:22])[CH3:21])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CC1CO1
Agent: [Al+3]
Agent: [Cl-]
Product: C[C@H](O)COc1ccc(Oc2ccccc2)cc1
Yield: 83 %

Procedure:
In Example 2, 16 mg of tri-tert-ethoxy aluminum was used in place of anhydrous aluminum chloride, and the color of the catalyst solution changed from brown to slightly greenish brown by the addition of tri-tert-ethoxy aluminum. Then 4-phenoxyphenol and propylene oxide were added to the slightly greenish brown catalyst solution to achieve the reaction in the same manner as described in Example 2. Thus (S)-(+)-1-(4-phenoxyphenoxy)-2-propanol was obtained in 83% yield and the optical purity was 90% e.e.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[Cl:10][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:33]=2[F:32])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)c1ccc(F)cc1F
Yield: 80.2 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (2.0 g, 5.4 mmol) and triethylamine (0.66 g, 6.5 mmol) were dissolved in anhydrous tetrahydrofuran (30 ml) and stirred under ice cooling. To this solution was slowly added 2,4-difluorobenzoyl chloride (0.96 g, 5.4 mmol) and solution refluxed for 2 hr. Another batch of 2,4-difluorobenzoyl chloride (0.19 g, 1.1 mmol) was added and solution refluxed for 2 hr. Solvent was removed in vacuo and the product purified by column chromatography on silica gel using hexane-ethyl acetate (3:1) as the eluent to afford the title compound (2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH:14]=[O:15])[C:5]#[N:6].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@:24]([OH:39])([C@H:31]([S:33][CH:34]([CH2:37]O)[CH2:35][OH:36])[CH3:32])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C@H:14]2[O:36][CH2:35][C@H:34]([S:33][C@H:31]([CH3:32])[C@:24]([C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])([OH:39])[CH2:25][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[CH2:37][O:15]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A mixture of 4.63 g (23.0 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile [produced as described in Step 1(II) above], 8.73 g (24.3 mmol of (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [produced as described in Japanese Patent Application (Kokai) Hei 8-333350)], 5.07 g (26.7 mmol) of p-toluenesulfonic acid monohydrate and 200 ml of anhydrous tetrahydrofuran was allowed to stand at ambient temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated using a rotary evaporator and dried in vacuo. The resulting residue was dissolved in 150 ml of anhydrous tetrahydrofuran and the resulting mixture was then evaporated to dryness in vacuo using a rotary evaporator. This procedure was repeated twice more. A solution of the resulting residue in 150 ml of anhydrous tetrahydrofuran was poured into a saturated aqueous sodium hydrogen carbonate solution with stirring. The product was then extracted with ethyl acetate and the organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residual oil was purified by chromatocraphy on a silica gel (500 g) column using a 2:1 mixture of ethyl acetate and hexane as the eluant to give 9.35 g (yield 74%) of the title compound as a yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([CH2:21]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[C:15]1([CH2:21][O:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 50.0 grams (0.29 mole) of 3-bromophenol and 120.0 grams (0.87 mole) of potassium carbonate in 400 mL of N,N-dimethylformamide was stirred, and heated to 80° C. To this was added portionwise, 36.1 mL (0.30 mole) of phenylmethyl bromide during a 20 minute period. Upon completion of addition, the reaction mixture was stirred at 80° C. during a one hour period. After this time, the reaction mixture was allowed to cool to ambient temperature, where it was diluted with 600 mL of water. The mixture was extracted with 600 mL of diethyl ether. The extract was then washed with three 50 mL portions of water, and then it was concentrated under reduced pressure to a residual solid. The solid was recrystallized with 250 mL of methanol, yielding 68.3 grams of 3-(phenylmethoxy)phenyl bromide. The. NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1]Br.[N:3]1[NH:4][C:5](=[O:10])[NH:6][C:7](=[O:9])[CH:8]=1>O>[Br:1][C:8]1[C:7](=[O:9])[NH:6][C:5](=[O:10])[NH:4][N:3]=1
Reactant: BrBr
Reactant: O=c1cn[nH]c(=O)[nH]1
Solvent: O
Product: O=c1[nH]nc(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 26 h
Yield: 46.4 %

Procedure:
Bromine (2.506 mL, 48.6 mmol) was added to a suspension of 1,2,4-triazine-3,5(2H,4H)-dione (commercially available from Aldrich, 2.5 g, 22.11 mmol) in Water (40 mL). The mixture was stirred at room temperature for 26 hours. A white precipitate was formed. The solid was recovered by filtration and recrystallized from water (15 mL at reflux temperature) affording the title compound 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (1.97 g, 10.26 mmol, 46.4% yield) as a white crystalline solid.
Reaction SMILES: C(OC(N1CCC(C(N2C3N=CN=CC=3C(C([O-])=O)=C2C)C)CC1)=O)(C)(C)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH:42]([N:44]2[C:48]3[N:49]=[C:50](Cl)[N:51]=[CH:52][C:47]=3[C:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[C:45]2[CH3:59])[CH3:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[H][H]>CO.[Pd]>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH:42]([N:44]2[C:48]3[N:49]=[CH:50][N:51]=[CH:52][C:47]=3[C:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[C:45]2[CH3:59])[CH3:43])[CH2:40][CH2:41]1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2nc(Cl)ncc12
Agent: [Pd]
Agent: Cc1c(C(=O)[O-])c2cncnc2n1C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Product: CCOC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2ncncc12
Yield: 75 %

Procedure:
tethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, Intermediate 9. A mixture of compound ethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (75 mg, 0.16 mmol) and Pd/C(10 mg) in methanol (10 mL) was stirred under 50 psi of hydrogen at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give product ethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (50 mg, yield: 72%). LRMS (M+H+) m/z: calcd 450.2. found 451.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-:25].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:25])[C:8]=1[CH3:24]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 48.3 %

Procedure:
2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2% purity; 10.7 g (43.7 mmol)) was added little by little such that the internal temperature did not exceed −15° C. After the addition, a 10% sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using acetone (198 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (12.6 g) (HPLC purity 99.3%, yield 48.3%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([O:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
This was prepared as follows:- A solution of benzyl bromide (10.26 g; 60 mmol) and 4chloro-3-nitrophenol (8.7 g; 50 mmol) in DMF (250 ml) was treated with Na2CO3 (10.6 g; 0.1 mol) and the mixture was stirred at room temperature for 3 days. The mixture was poured into water and extracted with Et2O. The organic phase was washed with brine and dried over MgSO4. The residue was purified by flash chromatography eluting with CH2Cl2 to give 5-benzyloxy-2-chloro-nitrobenzene as a pale yellow solid (12.32 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:4]=2[N:3]=1.[CH2:19]([O:21][C:22](=O)[O:23]CC)[CH3:20].[Li+].CC([N-]C(C)C)C>C1COCC1>[C:15]([O:14][C:12]([N:5]1[C:4]2[N:3]=[C:2]([CH2:1][C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Reactant: CCOC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
The compound was prepared according to the procedure as described in WO 00/33838. To a solution of 2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine (1.4 g, 5.6 mmol) and diethylcarbonate (2.5 g, 20 mmol) in THF (10 ml) was added LDA (8 ml of 2M solution in hexane) at −78° C. and stirred at −78° C. for 40 minutes. The reaction was quenched with saturated NH4Cl and extracted with ethylacetate (2×100 ml). Combined organic solution was concentrated and purified on silica gel column to give 1.5 g (83%) yellow oil. NMR (CD3OD) δ 1.25 (t, 3H, J=7.10 Hz), 1.51 (s, 9H), 1.88-1.97 (m, 2H), 2.75 (t, 2H, J=6.59 Hz), 3.74-3.80 (m, 4H), 4.10-4.20 (m, 2H), 7.0 (d, 1H, J=7.61 Hz), 7.39 (d, 1H, J=7.47 Hz).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(OCC)C>CN(C)P(N(C)C)(N(C)C)=O.C(=O)(O)[O-].[Na+]>[CH:16]1[C:14](=[O:15])[N:13]=[C:11]2[N:10]([C@@H:1]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]3[O:12]2)[CH:17]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Temperature: 135 °C
Yield: 91.8 %

Procedure:
To a suspension of uridine (200 g, 819 mmoles) in hexamethylphosphoramide (HMPA) (400 ml) was added sodium bicarbonate (5.3 g, 63.1 mmoles, 0.077 equivalents (eq.)) and diphenyl carbonate (228.1 g, 1064.7 mmoles, 1.3 eq.). The mixture was heated to 135° C. for 11 h. After cooling to room temperature, diethyl ether (2 l) was added and the precipitate was filtered off. The solid was washed three times with ether (3×1 l). Water (1 l) was added to the filtrate, the aqueous layer was separated and extracted three times with methylene chloride (3×l). The aqueous phase was evaporated to dryness. The combined solids were recrystallized from hot methanol to yield 170 g (92%) of 2,2'-anhydrouridine. The spectral properties agreed with those reported in the literature (Hampton and Nichol (1966) Biochemistry 5:2076).