Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CC(C)=O>[F:1][C:2]1[C:3]([O:13][CH2:21][CH2:22][O:23][CH3:24])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2ccc(O)c(F)c2n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc2ccc(C)nc2c1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a mixture of 8-fluoro-2-methylquinolin-7-ol (0.30 g, 1.69 mmol) and potassium carbonate (0.70 mg, 5.08 mmol) in acetone (7 mL) was added 1-bromo-2-methoxyethane (0.47 g, 3.39 mmol) and the mixture heated at 70° C. for 18 hours. Additional bromo-2-methoxyethane (0.150 mL) and potassium carbonate (0.35 g) were added and heating was continued for 16 hours. The mixture was partitioned between water and ethyl acetate and the layers were separated. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 25M; 25% ethyl acetate:hexanes) to afford 8-fluoro-7-(2-methoxyethoxy)-2-methylquinoline (0.217 g, 54%).
Reaction SMILES: C[CH:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[CH:7]=1.[N:15]([O-:17])=O.[Na+].[C:19](O)(=O)C>O>[N:15]([C:7]1[C:8]([NH2:13])=[N:9][C:10]([NH2:12])=[N:11][C:6]=1[O:5][CH2:4][CH:3]([CH3:19])[CH2:2][CH3:14])=[O:17]
Reactant: CC(C)CCOc1cc(N)nc(N)n1
Reactant: CC(=O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCC(C)COc1nc(N)nc(N)c1N=O
Reaction time: 8 h
Yield: 32 %

Procedure:
To a stirred solution of 51.0 g (0.26 mol) 6-(3-methylbutoxy)-2,4-diaminopyrimidine in 520 ml acetic acid (10% conc. in water) at 55-60° C. was added dropwise over a period of 25 min a solution of 23.5 g (0.34 mol) sodium nitrite in 105 ml water. Stirring was then continued for a further 1 h at 50-55° C. and overnight at room temperature. The resulting precipitate was filtered off with suction, washed with water and dried. The crude product was recrystallized from a 1:1 mixture of water/ethanol to yield 5-nitroso-2,4-diamino-6-(2-methylbutoxy)pyrimidine (19.0 g, 32%) as a violet solid.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:18](Br)[CH2:19][CH3:20]>>[CH3:1][CH:2]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CCCBr
Reactant: CC(C)CCCC(C)Oc1ccc(CO)cc1
Product: CCCOCc1ccc(OC(C)CCCC(C)C)cc1

Procedure:
By the process described in Example 1, p-[(1,5-dimethyl-hexyl)-oxy]-benzyl alcohol is reacted with propyl bromide to give p-[(1,5-dimethyl-hexyl)-oxy]-α-propoxy-toluene (boiling point = 198°-200° C/1.0 mmHg).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13]3C=CC=CC=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36].[F-].[K+].C[N:41](C=O)C>>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:12][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([C:13]#[N:41])[CH:10]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: O=C1CC(c2ccccc2)=NN1c1ccccc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: CN(C)C=O
Agent: [F-]
Agent: [K+]
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C#N)nn1-c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A mixture of 2,4-dihydro-2--phenyl-5-cyano-3H-pyrazol-3-one (Formula III: R1 =Ph; R2 =CN; R3 =H) (366 mg; 1.98 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (689 mg, 1.98 mmol), and KF (230 mg, 3.91 mmol) in 8 ml of DMF was stirred at room temperature for 3 hours and the resulting mixture was diluted with ice/water. The solid product was filtered, the residual solid was redissolved in ether/water, and the aqueous layer was extracted with ether (3×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo, and the residue was purified by column chromatography (silica gel; 12-50% ethyl acetate in hexane) and recrystallized from ethyl acetate/hexane to afford 420 mg (47%) of 4-isopropyl-6-methoxy-2-(1-phenyl-3-cyanopyrazol-5-yl-oxymethyl)-1,2-benziso thiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CN; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 114°-116° C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]#[N:9])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:2]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1cccc(-c2ccccc2)c1
Product: N#CC1(c2cccc(-c3ccccc3)c2)CCOCC1

Procedure:
This compound was synthesized from 2-([1,1′-biphenyl]-3-yl)acetonitrile as described in example 1 step 2 using 2-bromoethyl ether (0.5 g, 73%). 1H NMR (300 MHz, CDCl3) δ 7.72-7.71 (m, 1H), 7.62-7.57 (m, 3H), 7.51-7.45 (m, 4H), 7.42-7.37 (m, 1H), 4.15-4.10 (m, 2H), 3.99-3.91 (m, 2H), 2.28-2.20 (m, 4H).
Reaction SMILES: N#N.CC[O-].[Na+].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].[C:16](#[N:19])[CH:17]=[CH2:18]>>[CH2:14]([O:13][C:7](=[O:12])[CH:8]([C:9](=[O:10])[CH3:11])[CH2:18][CH2:17][C:16]#[N:19])[CH3:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=CC#N
Agent: CC[O-]
Agent: N#N
Agent: [Na+]
Product: CCOC(=O)C(CCC#N)C(C)=O
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to sodium ethylate (prepared from 62 mg sodium in 8 mL of EtOH) was added ethyl acetoacetate (9.7 mL, 76.1 mmol). Acrylonitrile (5 mL, 76.1 mmol) was then added dropwise at 40-45° C. and the reaction mixture was stirred at this temperature overnight. Ethanol was removed and the residue washed with 65 mL of water containing 3.5 mL of acetic acid, diluted with CH2Cl2 and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was distilled (bp=95-105° C. at 1 atm) to give the title compound. TLC:rf (7:3 hept-EA)=0.29.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](C)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH2:26](Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH3:26][CH2:12][CH2:11][O:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=[C:7]([CH:8]=1)[C:17]([CH2:16][CH2:15][C:14]([OH:19])=[O:20])=[O:18]
Reactant: O=C1CCC(=O)O1
Reactant: CCOc1ccc(C)cc1OCC
Reactant: ClCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCOc1cc(C(=O)CCC(=O)O)ccc1OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of 9.0 parts by weight of 3,4-diethoxytoluene, 6.0 parts by weigth of succinic anhydride and 100 parts by volume of carbon tetrachloride is added 27 parts by weight of anhydrous aluminum chloride. The mixture is stirred for 1 hour at 25° C. and mildly refluxed for 2 hours. After cooling, 70 parts by weight of ice and 70 parts by volume of concentrated hydrochloric acid are added to the mixture. Methylenedichloride is further added to the mixture and the whole mixture is shaken. The organic solvent layer is separated and extracted with a 2N-aqueous solution of sodium carbonate. The aqueous solution is adjusted with diluted hydrochloric acid to pH 2.5, whereby 3-(2'-methyl-4',5'-diethoxybenzoyl)-propionic acid is obtained as crystals. Recrystallization of the crystals gives 10.0 parts by weight of colorless plates melting at 116°-117° C.
Reaction SMILES: [CH:1](=[N+:8]([O-:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])=[CH2:18]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:18][CH:17]([S:19]([CH:22]2[O:16][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:23]2)(=[O:21])=[O:20])[O:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CS(=O)(=O)C=C
Reactant: [O-][N+](=Cc1ccccc1)Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(C1CC(c2ccccc2)N(Cc2ccccc2)O1)C1CC(c2ccccc2)N(Cc2ccccc2)O1
Yield: 25.9 %

Procedure:
A solution of 2.11 g (10 mmol) of N-benzylidenebenzylamine N-oxide and 1.09 g (5 mmol) of divinyl sulfone in 30 ml of toluene under a nitrogen atmosphere is heated at reflux temperature for 8 hours. The solvent is removed under reduced pressure to give 4.1 g of crude product which is then purified by preparative HPLC (Waters Prep 500A, silica gel, 3:1 heptane:ethyl acetate eluent) to give 0.70 g (26% yield) of a yellow amorphous solid.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]=[C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:10][CH2:9][N:8]2[C:18](=[O:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22](=[N:28][OH:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC)CC)C>ClCCl>[C:18]([N:8]1[CH2:9][CH2:10][C:11]2([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[O:29][N:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:12]2[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCC(N2CCCC2)=CC1c1ccccc1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(C)=O)C(c3ccccc3)C12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 1-(2-phenyl-4-(pyrrolidin-1-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone in dichloromethane (15 mL) was added a solution of ethyl 2-chloro-2-(hydroxyimino)acetate (4.709 mmol, 1.4 eq.) in dichloromethane (5 ml) at 0° C. Then triethylamine (1.4 eq.) was added dropwise at same reaction conditions and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with 10% citric acid solution and extracted with dichloromethane (3×). The combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, concentrated to dryness to give the desired product, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].CC(C)=O.[Cl:14][CH2:15][C:16](Cl)=[O:17].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:14][CH2:15][C:16]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)=[O:17]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)Nc1ccc(Cl)c(Cl)c1
Yield: 85.5 %

Procedure:
81 g (0.5 mol) of 3,4-dichloroaniline are dissolved 500 ml of acetone. 85 g (0.75 mol) of chloroacetyl chloride are poured in, over a period of 17 minutes, with stirring. The mixture is heated under reflux for 15 minutes, cooled and 350 ml of a 30% strength potassium carbonate solution in water (pH=8) are poured in. This solution is poured into a 2,000 ml Erlenmeyer flask and 500 ml of H2O+ice are added. The precipitate which appears is filtered off, washed with water, dried and recrystallised from benzene. 102 g (yield 85%) of N-chloroacetyl-3,4-dichloroaniline are thus obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:24])[C:20]=1[N:21]([CH3:23])[CH3:22])[CH:16]=[O:17]>O1CCOCC1>[CH3:23][N:21]([CH3:22])[C:20]1[C:19]([CH3:24])=[CH:18][C:15]([CH:16]2[O:17][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:14][C:13]=1[CH3:12]
Reactant: CC1(C)N=C1c1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1N(C)C
Solvent: C1COCCO1
Product: Cc1cc(C2OC(C)(C)N=C2c2ccccc2)cc(C)c1N(C)C

Procedure:
2.6 g of 2,2-dimethyl-3-phenyl-2H-azirine and 2,5 g of 3,5-dimethyl-4-(dimethylamino)benzaldehyde were exposed to light for 2 hours in 300 ml of 1,4-dioxane (with the light source described in Example 2). After purification as described in Example 12 and crystallization from n-pentane, there was obtained 5-[4(dimethylamino)-3,5-xylyl]-2,2-dimethyl-4-phenyl-3-oxazoline which melted at 91°-92° C. after drying for 2 hours at 50° C. and 13 Torr.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:23])[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:24].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[F:24][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])[N:8]([CH3:23])[C:7]=2[C:2]=1[C:28]1[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=1
Reactant: OB(O)c1ccncc1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(-c3ccncc3)c2n1C
Temperature: 140 °C
Yield: 18.8 %

Procedure:
A mixture of [(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine, (0.10 g, 0.26 mmol), 4-pyridylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 45 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 433 as a white solid (0.019 g, 20%). LCMS (Method K): RT 2.10 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.70 (1H, s), 8.70 (2H, s), 8.25-8.13 (2H, m), 7.95 (1H, d), 7.71 (1H, dd, J=8.80, 4.80 Hz), 7.53 (2H, d, J=17.59 Hz), 7.17 (1H, dd, J=10.45, 8.79 Hz), 5.85-5.73 (1H, m), 3.30 (3H, s), 1.66 (3H, d, J=6.75 Hz). Signals split due to presence of tautomers
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCc1ccccn1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccccn3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and 2-picolylchloride hydrochloride as described for compound 105. Crystallized from diethyl ether. M.p. 146°-147° C.
Reaction SMILES: C([O:9][CH2:10][C@H:11]1[O:16][C:15]([CH3:18])([CH3:17])[O:14][C@@H:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:9][CH2:10][C@H:11]1[O:16][C:15]([CH3:17])([CH3:18])[O:14][C@@H:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reaction time: 2 h

Procedure:
To a solution of (4R-cis)-6-[(benzoyloxy)methyl]-2,2-dimethyl-1,3 -dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared in step (a) above (30.00 g, 82.4 mmole) in methanol (275 ml) was added granular anhydrous potassium carbonate (5.68 g, 41.2 mmole) in one portion. The resulting heterogeneous solution was stirred vigorously for 2 hours to complete the hydrolysis. The progress of the reaction was followed by TLC analysis. (TLC: Rf =0.31 for the benzoyloxy starting material, Rf =0.17 for the title compound (silica gel, Ether:Hexane, 1:1, visualized by Ce(SO4)2 spray).
Reaction SMILES: N[CH2:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([OH:17])[CH:16]=2)[N:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]>CC(C)=O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([O:17][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH:16]=2)[N:5]=1
Reactant: CC(C)=CCBr
Reactant: Cc1ccc(Nc2nccc(OCN)n2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccnc(Nc2ccc(C)c(OCC=C(C)C)c2)n1
Yield: 62 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 5-(4-aminomethoxypyrimidin-2-ylamino)-2-methylphenol (15 mg, 0.07 mmol) and Cs2CO3 (21 mg, 0.07 mmol) in acetone (1 mL) was treated with 4-bromo-2-methyl-2-butene (7.5 μL, 0.22 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAC 8/2) in 62% yield (12 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=2)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[Cl:41].N1C=CC=CC=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][S:42]([C:37]4[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=4)(=[O:44])=[O:43])=[CH:28][N:27]=2)=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cn1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc2cc(Oc3ccc(N)cn3)ccc21
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc2cc(Oc3ccc(NS(=O)(=O)c4ccc(Cl)c(Cl)c4)cn3)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.6 %

Procedure:
A stirred solution of 4-[5-(5-aminopyridin-2-yloxy)-1-methyl-1H-indole-2-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (4.69 g, 10.4 mmol) in THF (250 mL) was ice cooled, then 3,4-dichlorobenzenesulfonyl chloride (3.7 g, 15.1 mmol) and pyridine (1.51 mL, 18.7 mmol) were added to the solution. The resulting mixture was stirred for 17 hours while gradually warming up to room temperature. Water was added to the mixture, and the aqueous layer was extracted with AcOEt. The extract was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=40:1) to afford 5.26 g of the title compound as a pale yellow powder.
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([OH:3])=[O:2].I([O-])(=O)(=O)=[O:15].[Na+]>CO.O.C(#N)C>[C:1]([CH2:4][S:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:15])([OH:3])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(O)CCCCCSCC(=O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCS(=O)CC(=O)O
Temperature: 5 °C

Procedure:
A chilled solution of 4.12 g of the 6-(carboxymethylthio)hexanoic acid of Example 1(a) in 130 ml MeOH was mixed with a chilled solution of 4.28 g sodium meta-periodate in 320 ml water. The mixture was maintained at about 5° C. for two days, after which it was diluted with two volumes of cold acetonitrile. Solid sodium iodate was removed by filtration and the filtrate was concentrated to an oily residue under reduced pressure. The oil was characterized by NMR and was not further purified. NMR (in Unisol-D): 10.2-10.5 (S, 2, COOH), 3.6-3.8 (S, 2, S(O)--CH2 --COOH), 2.7-3.1 (M, 2, --CH2 --S(O), 2.1-2.5 (M, 2, --CH2 --COOH), 1.4-1.9 (M, 6, --CH2 --) (also a small peak at=4.0 indicating some sulfone present).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:22]O>>[Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:22])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Reaction time: 48 h
Yield: 56 %

Procedure:
A mixture of 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (5.6 g, 21.9 mmol, Step-1 of Amine-5) and sulfuric acid (0.12 mL, 2.25 mmol) in methanol (40 mL) is refluxed with stirring for 2 days. After removal of the solvent, the residue is poured into 2M sodium hydroxide (100 mL) and extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo to give 3.28 g (56% yield) of the title compound as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.C(OC([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=O)(C)(C)C.O>C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]2([OH:27])[CH2:25][CH2:26][NH:21][CH2:22][CH2:23]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: OC1(c2ccc(Cl)cn2)CCNCC1
Reaction time: 0.5 h

Procedure:
Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at −78° C. and, after one hour, a solution of N-tert-butoxycarbonyl-4-piperidinone (2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was treated by method G. This resulted in the product with the molecular weight of 212.68 (C10H13ClN2O); MS(ESI): 213 (M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[CH:6]2[O:11][CH3:12].[Li]CCCC.[CH2:19]1[O:21][CH2:20]1.O>C1COCC1>[CH3:12][O:11][CH:6]1[C:7]2[C:3](=[C:2]([CH2:19][CH2:20][OH:21])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH:5]1[CH3:13]
Reactant: COC1c2cccc(Br)c2CC1C
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC1c2cccc(CCO)c2CC1C
Temperature: -110 °C
Reaction time: 0.67 h

Procedure:
To a solution of 20.0 g (82.9 mmol) of 4-bromo-2-methyl-methoxyindane in 200 ml of THF 33.2 ml of 2.5 M (83.0 mmol) n-BuLi in hexanes was added for 20 min at −80° C. This mixture was stirred for 40 min at this temperature, cooled to −110° C., and 4.38 g (99.4 mmol) of ethylene oxide was added by one portion at vigorous stirring. The resulting mixture was stirred for 12 h at room temperature, and then 10 ml of water was added. The organic layer was separated and evaporated to dryness. To the residue 200 ml of water was added, and the crude product was extracted with 3×100 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography using short column with Silica Gel 60 (40-63 um, d 110 mm, 190 mm; eluent: hexanes/ether=20/1). Yield 12.7 g (74%) of a ca. 1 to 1.2 mixture of two diastereomers.