Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].[CH:35]1([N:38]([CH3:45])[CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:35]1([N:38]([CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][N:41]2[C:31](=[O:33])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH3:45])[CH2:36][CH2:37]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: CN(C[C@@H]1CCCN1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCC[C@H]1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.9 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (104 mg, 0.2 mmol), cyclopropyl-methyl-(S)-1-pyrrolidin-2-ylmethyl-amine (53 mg, 0.34 mmol), HOBt (43 mg, 0.32 mmol), EDAC (65 mg, 0.34 mmol) and TEA (0.06 mL) in DMF (3 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was dried, concentrated and purified on a silica gel column to give 89 mg (68%) of the titled compound.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][C:12]2[C:13](=[O:23])[CH:14]=[C:15]([C:18]([O:20]CC)=[O:19])[O:16][CH:17]=2)=[CH:9][CH:8]=1>C(Cl)Cl.O>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]2[C:13](=[O:23])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[O:16][CH:17]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cc(=O)c(Oc2ccc(OC)cc2)co1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cc(=O)c(Oc2ccc(O)cc2)co1

Procedure:
Boron tribromide (8.8 ml) was added dropwise to a stirred solution of ethyl 5-(4-methoxyphenoxy)-4-oxo-4H-pyran-2-carboxylate (4.35 g) in methylene chloride (50 ml) causing gentle reflux. The solution was heated under reflux for a further 2 hours, then cooled and carefully diluted with water (25 ml). The solid title product was recrystallised from water (mp 257°-258° C. with decomposition).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:24]=[CH:23][CH:22]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(-c2ccccc2)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(-c4ccccc4)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-biphenyl-3-yl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.08 min; [M+H]+=453.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[CH3:17][C:18]([CH3:20])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]2[O:1][C:18]([CH3:20])([CH3:17])[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[C:3]=2[CH:4]=1)=[O:7]
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(O)c(-n2cccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)-n1cccc1C(C)(C)O2

Procedure:
The mixture of methyl 4-hydroxy-3-(pyrrol-1-yl)benzoate (4.0 g), acetone (40 ml) and p-toluenesulfonic acid (0.8 g) in toluene (80 ml) was heated under reflux for 15 hours under stirring. The solvent was removed by evaporation and to the residue was added a mixture of ethyl acetate and water. The mixture was adjusted to pH 8 with potassium carbonate and the separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and n-hexane (1:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was triturated with a mixture of diisopropyl ether and n-hexane to give 8-methoxycarbonyl-4,4-dimethyl-4H-pyrrolo[2,1-c][1,4]-benzoxazine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2.[Br:17]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:17][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[Cl:1]
Reactant: O=c1[nH]c2ccc(Cl)c([N+](=O)[O-])c2[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Br)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 28 °C
Reaction time: 120 h
Yield: 40.1 %

Procedure:
To a stirred solution of 6-chloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione (35 mg, 0.14 mmol) in DMF (0.35 mL), N-bromosuccinimide (39 mg, 0.22 mmol) was added and the solution was stirred at 28° C. for 5 days. The resulting solution was then diluted with water (3.5 mL) and the yellow solid was filtered, washed with water (2.0 mL) and dried to obtain 42 mg crude product as a yellow powder. It was purified by successive crystallization (three times) from DMSO-water (3:1) to furnish 18 mg (44%) of pure title compound as shining yellow flakes, m.p.>350° C.; 1H NMR (DMSO-d6): δ7.483 (s, 1H), 12.222 (s, 1H), 12.323 (br s, 1H); IR (KBr, cm-1): 3418, 3118, 1700, 1550, 1400, 1350, 1006, 675,562.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[S:15](=[O:19])(=[O:18])(N)[NH2:16]>O1CCOCC1.C(OC(C)C)(C)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([S:15]([NH2:16])(=[O:19])=[O:18])[CH3:1])([CH3:11])([CH3:13])[CH3:12]
Reactant: NS(N)(=O)=O
Reactant: CNCCCCNC(=O)OC(C)(C)C
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: CN(CCCCNC(=O)OC(C)(C)C)S(N)(=O)=O
Temperature: 100 °C
Yield: 63.8 %

Procedure:
A mixture of tert-butyl 4-(methylamino)butylcarbamate (4 g, 19.77 mmoles) and sulfuric diamide (7.6 g, 4 eq) in dioxane (10 mL) was heated at 100° C. in a microwave oven during 30 minutes. The RM was then concentrated in vacuo, and DCM was added. The resulting white precipitate of sulfuric diamide in excess was filtered off, and the filtrate was successively washed with diluted HCl, then brine, dried over magnesium sulfate, filtered and concentrated. Trituration in diisopropyl ether afforded 3.55 g (64% yield) of tert-butyl 4-(methyl(sulfamoyl)amino)butylcarbamate 10b as a white solid; m/z 282 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[O:24]1[CH2:25][CH2:26][N:21]([C:2]2[C:8]3[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=3[S:6][C:5]3[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=3[N:3]=2)[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2N1CCOCC1

Procedure:
Reflux a mixture of 3.035 gm. (10 mmole) of the 11-chloro ester of Example 6, 2.61 mg. (30 mmmole) of morpholine and 30 ml. of dry acetonitrile under an argon atmosphere for 40 hours. Add 50 ml. of ice-water to the reaction mixture and extract twice with 50 ml. portions of ethyl acetate. Wash the combined extracts with 50 ml. of water and then with 50 ml. of saturated aqueous sodium chloride solution. Dry over magnesium sulfate and evaporate. Chromatograph the residue over silica gel eluting with 1:9 ethyl acetate in toluene. Recrystallize from diisopropyl ether to obtain the title product, (m.p. 114°-115° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[C@H:4]([C@H:12]([CH2:14][CH3:15])[CH3:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:17])=[O:16])[C@H:12]([CH2:14][CH3:15])[CH3:13])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:25][CH2:24]1
Reactant: CC[C@H](C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC[C@H](C)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-isoleucinamide (772 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1221 mg) in 2-propanol (10 mL) was added piperidinium acetate (523 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (770 mg).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([NH:7][C:8]([C:10]1[S:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[C:11]=1[O:20][CH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:9])([CH3:6])[CH3:5].Cl>CO.[OH-].[Na+]>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][O:20][C:11]1[C:12]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=2[S:14][C:10]=1[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:31])=[O:2])=[O:9]
Reactant: COC(=O)C(C)(C)NC(=O)c1sc2ccc(F)cc2c1OCc1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NC(=O)c1sc2ccc(F)cc2c1OCc1nc2ccccc2s1)C(=O)O
Yield: 59.8 %

Procedure:
138 mg 2-{[3-(Benzothiazol-2-ylmethoxy)-5-fluoro-benzo[b]thiophene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 2 ml methanol and 1 ml 1 M aqueous sodium hydroxide solution was refluxed for 0.5 h. The reaction was acidified with 2 M hydrochloric acid, and the precipitated product was collected by filtration, dissolved in ethyl acetate, dried over sodium sulphate adding also active charcoal, filtrated, concentrated in vacuo, and the resulting crude product was crystallized from diethylether to yield 0.08 g 2-{[3-(Benzothiazol-2-ylmethoxy)-5-fluoro-benzo[b]thiophene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]1[CH2:40][C:39]2[CH:38]=[C:37]([OH:41])[CH:36]=[CH:35][C:34]=2[C@@H:33]2[C@@H:24]1[C@H:25]1[C@@:29]([CH2:31][CH2:32]2)([CH3:30])[C@@H:28]([OH:42])[CH2:27][CH2:26]1)[CH2:8][CH2:9][CH3:10]>O.CO>[CH2:7]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]1[CH2:40][C:39]2[CH:38]=[C:37]([OH:41])[CH:36]=[CH:35][C:34]=2[C@@H:33]2[C@@H:24]1[C@H:25]1[C@@:29]([CH2:31][CH2:32]2)([CH3:30])[C@@H:28]([OH:42])[CH2:27][CH2:26]1)=[O:2])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCSCCCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCS(=O)CCCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 18 h

Procedure:
A solution of sodium metaperiodate (0.016 g.) in water (0.5 ml.) was added to a solution of 7α-11-n-butylthioundecyl)oestra-1,3,5(10)-triene-3,17β-diol (Example 32; 0.035 g.) in methanol (1 ml.) and the mixture was stirred at laboratory temperature for 18 hours, evaporated to dryness and evaporated from toluene to remove the last traces of water. The residue was extracted three times with acetone and the combined extracts were evaporated to dryness. There was thus obtained as an oil 7α-(11-n-butylsulphinylundecyl)oestra-1,3,5(10)-triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:7].[H][H]>CO.Cl.[Pt]=O>[OH:7][CH:6]([CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:5]1[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=1
Reactant: [H][H]
Reactant: O=C(c1ccncc1)c1cccc(C(F)(F)F)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: OC(c1cccc(C(F)(F)F)c1)C1CCNCC1

Procedure:
A solution of 25.1 g (0.1 mole) of 4-(m-trifluoromethylbenzoyl)pyridine in 150 ml methanol and 10 ml concentrated hydrochloric acid was shaken with one gram of platinum oxide at an initial pressure of fifty psi of hydrogen. The hydrogen uptake was complete in ten hours. The catalyst was filtered off. After removal of the methanol under reduced pressure, the residue was dissolved in water and made basic with sodium hydroxide. Extraction with benzene and concentration of the benzene solution gave crude 4-(alpha-hydroxy-m-trifluoromethylbenzyl)piperidine. Yield 20.2 grams.
Reaction SMILES: [C:1]1([C:7]2([CH:12]=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:15][NH3+:16].N1C=CC=CC=1>C(O)C>[C:1]1([C:7]2([CH:12]=[N:16][OH:15])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH3+]O
Reactant: O=CC1(c2ccccc2)CCCC1
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: ON=CC1(c2ccccc2)CCCC1
Yield: 66 %

Procedure:
A mixture of the above aldehyde (3.4 g, 20 mmol) and hydroxylammonium chloride (2.9 g, 42 mmol) in a mixture of absolute ethanol (30 ml) and pyridine (3.3 g, 42 mmol) was heated at reflux for 2 h. The solvent was evaporated in vacuo, the residue was treated with absolute ethanol (50 ml) and the suspension filtered. The solvent was evaporated from the filtrate in vacuo and the residue crystallised from a 4/1 mixture of n-heptane and ethyl acetate to give 2.5 g of 1-phenyl-1-cyclopentanecarboxaldehyde oxime.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1>C(Cl)Cl>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:2][CH3:1])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: To a mixture of 1250 ml of a 40% aqueous solution of methylamine and 1250 ml of methylene chloride, cooled in an ice bath, is added with stirring a solution of 500 g of 4-chlorobenzoyl chloride in 625 ml of methylene chloride. After the addition (50 minutes), the mixture is stirred for an additional 2 hours. The white precipitate is filtered off and air dried and the methylene chloride layer of the filtrate is dried and evaporated to give the crude 4-chloro-N-methyl-benzamide, which, after crystallization from 1200 ml of methanol, melts at 158°-161°; an additional amount of the product is recovered from the mother liquor, m.p. 158°-160°.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][OH:17])[CH:3]=1.O.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(CO)cc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CC#N
Product: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution (80 mL) of [5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (7.1 g) in acetonitrile were added tetra-n-propylammonium perruthenate (0.63 g), N-methylmorpholine N-oxide hydrate (4.2 g) and molecular sieves 4A powder (3.5 g) and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 4.6 g, 71%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([C:24]([O:26]CC)=O)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([C:24]([NH2:29])=[O:26])[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2ccccc2n1
Solvent: O
Product: NC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture compound 3 (0.2 g) and NH3 (7N in MeOH, 10 mL) was heated to 50° C. for 14 hours. After cooling to room temperature, the reaction was titrated with water, and the solid was collected, washed with water and dried to obtain compound 5 as a white solid (0.11 g, yield 60%): 1H-NMR (400 MHz, CDCl3): δ 8.34 (d, 1H, 8.3 Hz), 8.25 (d, 114, 8.3 Hz), 8.15 (br, 1H, NH), 8.01 (dt, 1H, 1.3 & 8.1 Hz), 7.86 (d, 211, 8.9 Hz), 7.73 (dt, 1H, 1.3 & 8.1 Hz), 7.39-7.44 (m, 2H), 7.13-7.23 (m, 5H), 5.99 (br, 1H, NH); LC/MS: m/z=342.5 [M+H]+ (Calc: 341.4).
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:20]([NH:25][NH2:26])(=O)[CH:21]([CH3:23])[OH:22]>CO>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:20]([CH:21]([OH:22])[CH3:23])=[N:25][N:26]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Reactant: CC(O)C(=O)NN
Solvent: CO
Product: CC(O)c1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
1 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione is refluxed for 1.5 hours in 50 ml of absolute methanol with 2 g of lactic acid hydrazide. The precipitated 7-chloro-5-(o-chlorophenyl)-2-(2-lactoylhydrazino)-3H-thieno[2,3-e]-1,4-diazepine is dried and refluxed for 4 hours in 120 ml of absolute xylene. The solution is evaporated and the product recrystallized from ethyl acetate containing active carbon to yield 2-chloro-4-(o-chlorophenyl)-9-(α-hydroxyethyl)-6H-thieno[3,2-f]-s- triazolo[4,3-a][1,4]diazepine of melting point 118°-120° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([OH:20])(=[O:19])[CH2:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1>O>[C:1]([O:16][C:15]1[CH:17]=[CH:18][C:10]([CH2:9][C:8]([OH:20])=[O:19])=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(CC(=O)O)ccc1O
Solvent: O
Product: COc1cc(CC(=O)O)ccc1OC(C)=O
Reaction time: 8 h

Procedure:
Specifically, acetic anhydride (120 mL) was added to 30.0 g (165 mmol) homovanillic acid and the mixture was allowed to reflux for 6 hours. The solvent was evaporated, leaving an oil which was poured into 1L H2O and allowed to stir overnight. The solid was collected and dried in vacuo to give 33.1 g of 4-acetoxy-3-methoxyphenylacetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([O:21][C:22]2[CH:34]=[CH:33][C:25]3[C:26](=O)[O:27]C(C)(C)[O:29][C:24]=3[CH:23]=2)=[C:16]([F:35])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH3:37]>C(O)(C)C>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([O:21][C:22]2[CH:34]=[CH:33][C:25]([C:26](=[O:27])[NH2:37])=[C:24]([OH:29])[CH:23]=2)=[C:16]([F:35])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCN(Cc1cc(F)c(Oc2ccc3c(c2)OC(C)(C)OC3=O)c(F)c1)C(=O)OC(C)(C)C
Reactant: N
Solvent: CC(C)O
Product: CC(C)CCN(Cc1cc(F)c(Oc2ccc(C(N)=O)c(O)c2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[4-(2,2-Dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-yloxy)-3,5-difluoro-benzyl]-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1d-3: 1.0 g) was dissolved in 2.0 mL of a 2 M solution of ammonia in isopropanol. The resulting solution was then treated with 1.5 mL of a saturated aqueous ammonia solution and the resulting mixture heated at 80° C. After 8 hours, the reaction mixture was cooled to ambient temperature and concentrated with a rotary evaporator. The residue was diluted with ethyl acetate and the organic solution was washed twice with water, once with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in heptane to afford the title compound (I-1e-3).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[O:21]=[C:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]>O1CCCC1>[CH3:38][O:37][C:35]([CH2:34][CH2:33][CH2:32]/[CH:31]=[CH:30]\[CH2:29][CH:23]1[C:22](=[O:21])[CH2:27][CH2:26][O:25][CH2:24]1)=[O:36]
Reactant: O=C1CCOCC1
Reactant: COC(=O)CCC/C=C\CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CCC/C=C\CC1COCCC1=O
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
To a solution of lithium diisopropylamide (2.40 mmol) in tetrahydrofuran (5 ml), prepared from diisopropylamine (0.35 ml) with n-butyllithium (1.7 ml, 1.5 M solution in hexane) using an usual manner, was added 4-oxotetrahydropyran (220 mg) in tetrahydrofuran (2 ml) at -78° C. and the mixture was stirred for 30 minutes at the same temperature. To the resulting solution was added methyl(Z)-7-bromo-5-heptenate (500 mg) in tetrahydrofuran (2 ml) at -78° C. After being stirred at room temperature for 5 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride and the solution was extracted with ethyl acetate. The organic layer was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (10 g) with a mixture of n-hexane and ethyl acetate (4:1) as an eluent to give 3-[(Z)-6-methoxycarbonyl-2-hexenyl]-4-oxo-tetrahydropyran (100 mg) as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:13]([N:26]1[CH2:29][CH:28](OS(C)(=O)=O)[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CC#N>[CH:13]([N:26]1[CH2:29][CH:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:8]=[CH:9][CH:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)[CH2:27]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CC(N3CCN(c4ncccn4)CC3)C2)cc1

Procedure:
To a solution of 2-piperazin-1-yl-pyrimidine (2.48 g, 15.10 mmol, Alfa) and methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (4 g, 12.6 mmol, Oakwood) in CH3CN (40 mL) was added DIPEA (2.63 mL, 15.10 mmol) at room temperature. The resulting mixture was then refluxed for 2 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was washed with aqueous NaHCO3 (2×) and then extracted with 1N HCl (2×). The aqueous layer was cooled and then pH adjusted with 1N NaOH. The resulting mixture was extracted with CH2Cl2 (2×). The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by MPLC to yield 2-[4-(1-benzhydryl-azetidin-3-yl)-piperazin-1-yl]-pyrimidine.