Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+]([O-])=O)=O.C([O-])([O-])=O.[K+].[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>CN(C=O)C>[CH3:27][O:26][C:22]([C:23]1[S:24][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[CH:12][C:3]=2[CH:1]=1)=[O:25]
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(C(=O)OC)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl 4-formyl-3-nitrobenzoate (6.68 g, 31.9 mmol) and K2CO3 (5.55 g, 38.3 mmol) in DMF (70 mL) was slowly added methyl thioglycolate (2.91 mL, 31.9 mmol). The mixture was stirred at RT for 1 h, then at 50° C. for 24 h. The resultant mixture was poured into H2O/ice and stirred until a precipitate formed. The green solid was filtered. 1H NMR (DMSO-d6) δ 8.72 (s, 1H), 8.25 (s, 1H), 8.12 (d, J=8.0 Hz), 7.95 (d, J=8.0 Hz), 3.87 (s, 6H). MS (EI): cal'd (MH+) 251.03, exp (MH+) 251.18.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The reaction sequence is shown in FIG. 5. Nε-(tert-butoxycarbonyl)-L-lysine (2 g, 8.12 mmol) was dissolved in methanol (40 ml) and water (40 ml), and the pH was adjusted to 8 with triethylamine. A solution of N-(benzyloxycarbonyl-oxy)succinimide in dioxane (2.4 g, 9.7 mmol in 20 ml) was added to the above mixture and the pH was maintained at 8-9 with triethylamine. The reaction mixture was stirred overnight. The solvent was removed by rotary evaporation to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine. Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine was treated with 0.2 M calcium carbonate (4 ml) and the aqueous layer was removed to obtain a white solid. The solid was resuspended in N,N-dimethylformamide(40 ml) and benzyl bromide (1.16 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was worked up with ethyl acetate and water, and the organic layer was dried over magnesium sulphate. The solvent was removed to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester which was purified by silica gel chromatography using 25% hexane in ethyl acetate as a solvent. To Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester (1 g, 2.2 mmol) in methylene chloride (10 ml) was added trifloroacetic acid at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then stirred for further 2.5 hr at room temperature. The solvent was removed and the crude product was obtained. Pure Nα-CBZ-L-lysine benzyl ester was obtained by silica gel chromatography.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[C:8]([Mg]Cl)#[CH:9]>C1COCC1>[OH:7][CH:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[C:8]#[CH:9]
Reactant: C#C[Mg]Cl
Reactant: O=Cc1ccc[nH]1
Solvent: C1CCOC1
Product: C#CC(O)c1ccc[nH]1

Procedure:
3-Hydroxy-3-(1H-pyrrol-2-yl)-1-propyne was prepared by Method B above using 2-pyrrolecarboxaldehyde (0.389 g, 4 mmol) (Aldrich) in THF (30 mL) and ethynylmagnesium chloride (20 mmol, 40 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 345 mg, 82%).
Reaction SMILES: [CH:1]([CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:11][CH2:12][CH2:13][C:14]([O:10][CH:3]([CH:1]=[CH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: O=C(Cl)CCCl
Reactant: C=CC(O)c1ccccc1
Product: C=CC(OC(=O)CCCl)c1ccccc1

Procedure:
Vinylbenzyl alcohol is condensed with 3-chloropropionyl chloride by conventional esterification procedures to produce the vinylbenzyl 3-chloropropionate. ##STR24##
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21](CC(O)(C)C)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.I[CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)CCI
Reactant: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(CCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-cyclopropyl-N-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide (80 mg), 1-iodo-3,3,3-trifluoropropane (108 mg), and K2CO3 (63 mg) in N-methyl-2-pyrrolidone (2 mL) is stirred at room temperature for 4 h and then at 60° C. over night. Since conversion of starting material is still incomplete, K2CO3 (63 mg) and two portions of 1-iodo-3,3,3-trifluoropropane (54 mg each) are added while stirring the reaction mixture for two more days at 80° C. Water is added to the reaction mixture and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with brine dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→50:50). The crude product is triturated with diethyl ether, filtered off, and dried to give the title compound. LC (method 3): tR=1.08 min; Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11]Br>C(O)(=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:11][CH2:9][C:8]([C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: CC(=O)c1cccnc1Br
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CBr)c1cccnc1Br
Temperature: 90 °C
Yield: 73.4 %

Procedure:
A solution of 1-(2-bromopyridin-3-yl)ethanone (2.10 g, 10.5 mmol) in acetic acid (28.0 mL) was treated with bromine (595 μL, 11.5 mmol) and heated at 90° C. for 1 h. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and further extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (10% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) gave the desired product (2.15 g, 73%). LCMS calculated for C7H6Br2NO (M+H)+: m/z=277.9, 279.9, 281.9. found: 277.7, 279.7, 281.8.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]C(C)(C)C)=[O:16])[N:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]#[C:34][CH3:35])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[N:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]#[C:34][CH3:35])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(Cc3ccccc3)CCC2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(Cc3ccccc3)CCC2C(=O)O)cc1
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl 1-benzyl-4-([4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylate (0.34 g, 0.68 mmol) in dicloromethane (2 mL) at 0° C. was added trifluoroacetic acid (1.23 mL). After 2.5 h the reaction mixture was allowed to warm to 25° C. whereupon an additional 1 mL of trifluoroacetic acid was added. After 18 h the reaction mixture was concentrated in vacuo to provide 1-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylic acid as a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[CH2:5][CH2:4][CH:3]1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1.C1(C)C=CC=CC=1>CCOCC>[OH:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:13])(=[O:14])[CH2:5][CH2:4][C:3]=1[C:15]([NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1)=[O:17]
Reactant: COC(=O)C1CCS(=O)(=O)c2ccccc2C1=O
Reactant: Cc1cc(N)no1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)CC2)no1
Yield: 53.8 %

Procedure:
A mixture of 17 g (0.05 mol) of crude methyl 2,3,4,5-tetrahydro-5-oxo-1-benzothiepin-4-carboxylate 1,1-dioxide, 6.0 g (0.061 mol) of 3-amino-5-methylisoxazole, and 350 ml of toluene was refluxed for 24 hours in a Soxhlet apparatus the thimble of which contained 20 g of Linde type 4A molecular sieve. The mixture was diluted with 500 ml of ether and the resulting precipitate (10 g) was collected and recrystallized from 400 ml of tetrahydrofuran to give 9.0 g of product mp 226°-228°. Recrystallization gave an analytical sample mp 227°-229°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCCCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCON=C(C(=O)O)c1csc(N)n1
Yield: 89.7 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetate (syn isomer, 64 g.), 2N-aqueous solution of sodium hydroxide (196 ml.), methanol (196 ml.) and tetrahydrofuran (300 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetic acid (syn isomer, 52.5 g.), mp. 146° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C(OO)(=[O:17])C.OO>C(O)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CC(=O)OO
Reactant: Fc1ccc(Br)cc1-c1cccnc1
Agent: OO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [O-][n+]1cccc(-c2cc(Br)ccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 3-(5-bromo-2-fluorophenyl)pyridine (2.52 g, 10.0 mmol) and peracetic acid (3.37 ml of a 36-40 wt % solution in acetic acid) in tetrahydrofuran (40 ml) was stirred at ambient temperature for 1 h and then heated at 50° C. for 2 h. Hydrogen peroxide (35 wt % solution in water, 1 ml) was added and the mixture heated at 50° C. for a further hour. The solvent was removed in vacuo and the residue diluted with water and layered with ethyl acetate. Solid sodium hydrogencarbonate was added to pH 8. The layers were separated and the organic layer washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (2-5%) gave 3-(5-bromo-2-fluorophenyl)pyridine-1-oxide as a white solid (2.00 g, 75%): δH (400 MHz, CDCl3) 7.09-7.14 (1H, m), 7.35-7.43 (2H, m), 7.52-7.57 (2H, m), 8.22-8.25 (1H, m), 8.42 (1H, t, J 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][Br:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cc(Br)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1CBr
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzyl alcohol (3.10 g, 15.1 mmol) in 30 mL of THF at 10° C. is added triphenyl phosphine (4.10 g, 15.6 mmol) followed by N-bromosuccinimide (2.67 g, 15.0 mmol). The ice bath is removed and the resulting solution is stirred for 20 min at room temperature. The crude product is purified by column chromatography eluting with 5% EtOAc/hexanes to give the title compound (3.90 g, 14.5 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[Br:16][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:15]
Reactant: [Br-]
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=O)C(Br)CC2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A mixture of 500 mg. (2.4 mmol) 6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one was dissolved in anhydrous ethanol (10 ml) and Chloroform (10 ml). To this solution was added pyridinium tribromide (0.768 g, 2.4 mmol). The reddish brown mixture was heated with stirring at 50° C. for 20 min. The reaction mixture was then cooled and the solvent was evaporated. Then water (20 ml) was added to the residue and it was then extracted with 50 ml of dichloromethane. The dichloromethane layer was then washed with 10% sodium bicarbonate solution (50 ml) followed by water (50 ml). The organic layer was then dried and the solvent was evaporated in vacuum to yield the crude product, 2-bromo-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one which was purified by column chromatography.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17](C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)(Cl)Cl>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][N:17]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:16][CH2:15]3)[CH:10]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[CH2:9]2)=[O:7])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1
Reactant: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)C(F)(F)F)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(S(C)(=O)=O)CC2)cc1

Procedure:
The title compound, MS: m/e=578.1 (M+H+), [α]58920=−19.14 (c=0.4545, chloroform), was prepared in accordance with the general method of example 102 (part1) and example 38 from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-p-tolyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and methane sulfonyl chloride.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)=O.CO.Cl>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[S:22][CH:23]=2)[CH3:15])=[CH:11][CH:12]=1
Reactant: CNC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNCCOc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Temperature: 25 °C

Procedure:
1.2 ml of borane/dimethyl sulfide complex are added to a solution of 0.38 g of N-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in 20 ml of absolute tetrahydrofuran, and the mixture is heated to reflux for three hours. The 4 ml of methanol are cautiously added dropwise to the reaction mixture, and the mixture is heated to reflux for one hour. After cooling to room temperature, ethereal hydrochloric acid is added. The resulting solution is evaporated, the resulting residue is taken up in 15 ml of water, and the solution is made alkaline with concentrated ammonia and extracted several times with methylene chloride. The combined extracts are dried with sodium sulphate, evaporated and purified on a silica gel column using methylene chloride/methanol=8:2 as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH2:13])[CH2:7][CH2:6]2.CCN(C(C)C)C(C)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:23](=[O:25])[CH3:24])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(N)C2
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(NC(C)=O)C2
Temperature: 0 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
To a stirred suspension of 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine (2.54 g; 14.3 mmol) in CH2Cl2 (20 mL) is added DIEA (3.4 mL) and the reaction mixture was cooled to 0° C. Acetyl chloride (1.22 mL; 17.1 mmol) is added dropwise at 0° C. and the reaction is allowed to warm to RT and stirred for 18 h. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered and the solvent removed under reduced pressure to provide a crude solid. Purification by flash chromatography (SiO2) eluting with hexanes-EtOAc affords 1.57 g (50%) of N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:11]Br>C(Cl)(Cl)(Cl)Cl>[Br:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: O=C(O)CC1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CC1CCCCC1Br
Yield: 1055.4 %

Procedure:
To a solution of cyclohexylacetic acid (10 g, 70 mmol), in 100 ml of CCl4 was added red phosphorus (6.32 g, 204 mmol). The mixture was heated to reflux and bromine (70.7 ml, 1.38 mmol) was added over 3 hours dropwise through the condenser via addition funnel. The reaction was heated at reflux for 5 hours before it was quenched slowly with water then washed with 10% Na2SO4, water, then into NaHCO3. The sodium bicarbonate solution was brought to acidic pH using 1 N HCl. The solid was collected and the aqueous filtrate was extracted into CHCl3, washed with saturated Na2HSO4 solution then with water. The organic layer was dried over Na2SO4, filtered and concentrated and combined with solid collected earlier to provide 3.22 g 2-bromo cyclohexyl acetic acid as a white solid. Yield 21%; MS: 219.1 (M−H)−
Reaction SMILES: [BrH:1].[CH:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6])([CH3:4])[CH3:3].BrBr>C(Cl)(Cl)Cl>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]([C:2]([Br:1])([CH3:4])[CH3:3])=[O:6])=[CH:12][CH:11]=1
Reactant: CC(C)C(=O)c1ccc(Cl)cc1
Reactant: Br
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(Br)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1 ml of hydrogen bromide/glacial acetic acid is added to 65.5 g (0.36 mole) of 4-chlorophenyl isopropyl ketone in 200 ml of chloroform and then 57.5 g (0.36 mole) of bromine is added dropwise at 30° C. The mixture is allowed to stir at room temperature for 30 minutes and then evaporated in vacuo. 86.6 g (92% of theory) of crude 2-bromo-2-propyl 4-chlorophenyl ketone are obtained, which is immediately reacted further.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[C:7](Cl)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])[CH:4]=[CH2:5].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].O>CN(C=O)C>[CH2:3]([C:6]1[C:11]([Cl:12])=[N:10][C:9]([CH3:13])=[N:8][C:7]=1[NH:18][C:17]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=1[Cl:15])[CH:4]=[CH2:5]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: C=CCc1c(Cl)nc(C)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(Cl)nc(C)nc1Nc1ccc(Cl)cc1Cl
Reaction time: 0.42 h
Yield: 37 %

Procedure:
Sodium hydride mineral oil dispersion (60%, 1.38 g, 34.5 mmol) was added to a stirred solution of pyrimidine (10) (3.50 g, 17.2 mmol) and 2,4-dichloroaniline (3.07 g, 18.9 mmol) in DMF (40 mL). After 25 min, the mixture was poured into water (100 mL) and extracted with dichloromethane. The combined extracts were dried (MgSO4), concentrated under vacuum, and the residue was chromatographed (elution with dichloromethane) to afford 2.09 g (37%) of pyrimidine (11) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH2:7][N:8]1[CH2:16][CH2:15][CH:14]2[NH:17][CH:10]([CH2:11][CH2:12][CH2:13]2)[C:9]1=[O:18].[O:24]=[C:25]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=1)[C:26](O)=[O:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH2:7][N:8]1[CH2:16][CH2:15][CH:14]2[N:17]([C:26](=[O:27])[C:25]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)=[O:24])[CH:10]([CH2:11][CH2:12][CH2:13]2)[C:9]1=[O:18]
Reactant: COc1cc(C(=O)C(=O)O)cc(OC)c1OC
Reactant: COc1ccc(CCN2CCC3CCCC(N3)C2=O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(CCN2CCC3CCCC(C2=O)N3C(=O)C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 3-(3,4-dimethoxyphenethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (27 mg, 0.09 mmol) in 3 ml DCM was added sequentially 2-oxo-2-(3,4,5-trimethoxyphenyl) acetic acid (23 mg, 0.1 mmol), EDC-HCl (20 mg, 0.1 mmol), HOBt (14 mg, 0.1 mmol), TEA (10 mg, 0.1 mmol) at room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The reaction mixture was purified with flash chromatography in EtOAc. TLC [EtOAc]: Rf=0.42
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](=[S:22])(OC1C=CC=CC=1C(O)=O)=O)([OH:3])=[O:2].[CH3:23][C:24]1[C:29]([OH:30])=[C:28]([CH2:31]S)[C:27]([CH:33]=[CH2:34])=[CH:26][N:25]=1>C(O)C>[CH3:23][C:24]1[C:29]([OH:30])=[C:28]([CH2:31][S:22][S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1]([OH:3])=[O:2])[C:27]([CH:33]=[CH2:34])=[CH:26][N:25]=1
Reactant: C=Cc1cnc(C)c(O)c1CS
Reactant: O=C(O)c1ccccc1OS(=O)(=S)c1ccccc1C(=O)O
Solvent: CCO
Product: C=Cc1cnc(C)c(O)c1CSSc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.02 moles of o-carboxyphenyl o-carboxybenzenethiosulfonate in 200 ml. of 95% ethanol is added 0.02 moles of fine powdered 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine. The reaction mixture is stirred overnight at room temperature and the resulting precipitate filtered to yield o-carboxyphenyl 2-methyl-3-hydroxy-5-vinylpyridin-4-ylmethyl disulfide.