Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:5].CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH2:31][OH:32])[CH:28]=2)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH2:31][OH:32])[CH:28]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:5]
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Yield: 51.9 %

Procedure:
A suspension of 2-amino-5-bromo-N,N-diethylbenzamide (Compound 3D, 326 mg, 1.20 mmol), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 0.33 g, 1.32 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (106.8 mg, 0.13 mmol) and potassium carbonate (0.50 g, 3.64 mmol) in 1,4-dioxane (4 mL, 50 mmol) to H2O (1 mL, 60 mmol) was evacuated and charged with argon (3×). The sample was irradiated in a microwave reactor for 30 min at 100° C. The crude product was concentrated in vacuo to a solid and purified using a Teledyne ISCO Combiflash® Rf system [0→5% MeOH in DCM] to yield the desired product (197 mg, 52%). 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=0.51 Hz, 1H), 7.71 (d, J=0.76 Hz, 1H), 7.36 (dd, J=2.02, 8.34 Hz, 1H), 7.22 (d, J=2.02 Hz, 1H), 6.81 (d, J=8.34 Hz, 1H), 4.24 (t, J=6.82 Hz, 2H), 3.33-3.60 (m, 6H), 2.05 (quin, J=6.57 Hz, 2H), 1.04-1.35 (m, 6H). MS (ESI): m/z 317.59 [M+H]+. UPLC: tR=0.74 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[C:14](Cl)(Cl)=[O:15].C([N:20](CC)CC)C>>[CH3:2][CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:14]([NH2:20])=[O:15])[C:5]1=[O:13])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: CCN(CC)CC
Product: CC(C)n1c(=O)n(C(N)=O)c2ccccc21
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
A 60% NaH/mineral oil dispersion (100 mg, 2.61 mmol) was washed with hexane and suspended in THF (1.0 mL). 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (115 mg, 0.653 mmol) was added to the suspension. This mixture was stirred for 15 minutes before adding it to a mixture of 2.38 mL (5.22 mmol) of 20% phosgene (toluene)/2.6 mL THF. The resulting mixture was stirred for 2.5 hours, filtered through celite, and concentrated. The residue was redissolved in THF (2.0 mL) and the amine of Example 11J (166 mg, 0.653 mmol) was added with triethylamine (0.137 mL, 0.98 mmol). This mixture was stirred for 18 hours and then concentrated to dryness. The residue was dissolved in chloroform, washed with saturated aqueous K2CO3, water, and then dried over K2CO3. Filtration and concentration afforded an oil. Purification by chromatography on silica gel eluting with 5% methanol(NH3)/chloroform gave 86 mg (27%) of the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[CH:11]([S:13]([F:16])(=[O:15])=[O:14])=[CH2:12].O>C(O)(C)C>[F:16][S:13]([CH2:11][CH2:12][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)(=[O:15])=[O:14]
Reactant: C=CS(=O)(=O)F
Reactant: CCNc1cccc(C)c1
Solvent: O
Solvent: CC(C)O
Product: CCN(CCS(=O)(=O)F)c1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Ethyl-m-toluidine (66.5 g) (0.5 m) is dissolved in isopropyl alcohol (75 ml) and vinylsulfonyl fluoride (55 g, 0.5 m) is added dropwise over 1.25 hr. The reaction exotherms to 38° C. and the reaction mixture is stirred for 1 hr. at ambient temperature and drowned into 500 ml of ice and water. The product is collected by filtration, washed with water, and dried in air. The product melts at 32°-34° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[C:29](F)(F)C(O)=O.C=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(Nc2ncnc3cnc(NCC4CCNCC4)nc23)cc1Cl
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-piperidinylmethylamino]pyrimido[5,4-d]pyrimidine by reaction with trifluoroacetic acid and subsequent reductive amination with formaldehyde and sodium cyanoborohydride. Melting point: 198°-201° C.; Rf : 0.65 (alumina; methylene chloride/methanol=20:1)
Reaction SMILES: [CH2:1]([CH:8]1[CH:12]([C:13](OC)=[O:14])[O:11][C:10](=[O:17])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>C(O)C>[CH2:1]([C@H:8]1[C@@H:12]([CH2:13][OH:14])[O:11][C:10](=[O:17])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1OC(=O)NC1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Reaction time: 2 h

Procedure:
150 g of the 98:2 mixture of (4S,5S) and (4S,5R) isomers of methyl 4-benzyl-2-oxo-oxazolidine-5-carboxylate from Example 7B) are added at 15°-20° C. over 1.5 hours to a stirred solution of 20.8 g of NaBH4 in 360 ml of ethanol and stirred for 2 hours. The suspension is treated with 540 ml of water at 20° C. and the pH is brought to 7 with 165 ml of 3N hydrochloric acid. The suspension is stirred at 22° C. for 2.5 hours, left to stand at 4° C. for 18 hours, then filtered and the residue is washed with water and dried to give 111.6 g (84%) of 99% (4S,5S)-4-benzyl-5-hydroxymethyl-oxazolidin -2-one, m.p. 167.3°-168.9° C., [α]D20 : -79.4 ° (1% in methanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:16][C:15](OC)([O:17]C)[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:16][C:15](=[O:17])[C:13]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(OC)Cc2ccc(OCc3ccccc3)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1Cc2ccc(OCc3ccccc3)cc21
Reaction time: 1 h

Procedure:
H7.1 (270 mg, 1.00 mmol) was dissolved in 6 mL 5:1 THF and water. To this solution was added 0.5 mL 1N HCl, and the resulting mixture was stirred for 1 hour. The resulting mixture was then diluted with 20 mL EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and concentrated in the presence of silica gel. The residue was then purified by column chromatography with 10% EtOAc/hexane to afford H7.2 (204 mg, yield, 91.1%). MS ESI (pos.) m/e: 225.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Cl:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1Cl
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: [Na+]
Product: CN(Cc1cc(-c2ccccc2Cl)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-chlorophenyl)boronic acid (218 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-blue oil (yield 171 mg, 53%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:12](OC1C(=CC=CC=1)C=O)[CH:13]1[O:15][CH2:14]1.C(=O)C1C(=CC=CC=1)O>>[CH2:12]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH:13]1[O:15][CH2:14]1
Reactant: COc1cc(C=O)ccc1O
Reactant: O=Cc1ccccc1OCC1CO1
Solvent: O=Cc1ccccc1O
Product: COc1cc(C=O)ccc1OCC1CO1
Yield: 96 %

Procedure:
Vanillin glycidyl ether (3-methoxy-4-glycidyloxybenzaldehyde) was prepared in a similar manner to Method A, but starting from vanillin in place of p-hydroxybenzaldehyde. The yield was 96% of theory, the product having an epoxide content of 4.41 equivalents/kg (theoretical value 4.8 equivalents/kg). A sample was recrystallised from ethanol, giving 95% recovery of product having an epoxide content of 4.76 equivalents/kg, melting point 101° C. Salicylaldehyde glycidyl ether (o-glycidyloxybenzaldehyde) may be prepared in a like manner from salicylaldehyde.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:19]([NH:21][C@H:22]([CH:35]=[O:36])[CH2:23][C:24](=[N:30][NH:31][C:32]([NH2:34])=[O:33])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])[CH:16]([CH3:18])[CH3:17].C(Cl)Cl.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([CH:35]=[O:36])[CH2:23][C:24](=[N:30][NH:31][C:32]([NH2:34])=[O:33])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
1-Methylindole-2-carboxylic acid (88 mg, 0.5 mmol) and (3S)-3-(Valinyl)amino-4-oxobutanoic acid, t-butyl ester semicarbazone (163 mg, 0.5 mmol) were dissolved in DMF (1 mL) and methylene chloride (2 mL) then both DMAP (61 mg, 0.50 mmol) and EDAC (134 mg, 0.7 mmol) were added to the solution under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and an additional 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution. The ethyl acetate solution was washed successively with 5% KHSO4 solution, saturated sodium bicarbonate solution and brine solutions, dried over sodium sulfate, and concentrated to give a yellow foam. Trituration of the foam with ether afforded the title product as a slightly yellow powder (203 mg, 86%). TLC: (methanol/methylene chloride:5/95, silica gel): Rf =0.17.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH3:20][C:21]1[C:26]([S:27](Cl)(=[O:29])=[O:28])=[C:25]([CH3:31])[CH:24]=[C:23]([CH3:32])[C:22]=1[S:33](Cl)(=[O:35])=[O:34].[OH2:37]>CN(C=O)C>[CH3:32][C:23]1[CH:24]=[C:25]([CH3:31])[C:26]([S:27]([O:8][C:3]([C:4]([F:6])([F:5])[F:7])([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:2]([F:16])([F:17])[F:1])(=[O:29])=[O:28])=[C:21]([CH3:20])[C:22]=1[S:33]([O:35][C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)([C:2]([F:17])([F:1])[F:16])[C:4]([F:7])([F:6])[F:5])(=[O:37])=[O:34]
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1S(=O)(=O)Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(OS(=O)(=O)c2c(C)cc(C)c(S(=O)(=O)OC(c3ccc(C)cc3)(C(F)(F)F)C(F)(F)F)c2C)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
7.75 g (30 mmol) of 1,1,1,3,3,3-hexafluoro-2-p-tolylpropan-2-ol were dissolved in 45 ml of DMF, and 1.2 g (40 mmol) of NaH (80% strength dispersion in mineral oil) were added. After a clear solution had formed, 5.0 g (14 mmol) of 2,4,6-trimethylbenzene-1,3-disulfonyl chloride were added and the mixture was stirred for a further 72 hours at room temperature. The mixture was poured into water and the precipitated product was filtered off and dried. 7.8 g of 1,3,5-trimethyl-2,4-bis-(2,2,2-trifluoro-1-p-tolyl-1-trifluoromethylethoxy-sulfonyl)-benzene were obtained (colorless crystals, m.p.: 178° C. [from acetonitrile]).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][CH2:32][C:33](=O)[CH3:34])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[N:15]([CH2:14][CH2:13][CH2:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=3)[C:33]([CH3:34])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCCCc1ccc(CCCN)cc1
Reactant: CC(=O)CCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 75 %

Procedure:
A solution of 3-(4-pentylphenyl)propylamine (1.8 g, 8.8 mmol) and 1-(4-benzyloxyphenyl)-1,4-pentanedione (2.43 g, 8.7 mmol) and p-toluenesulfonic acid monohydrate (200 mg) in toluene (30 ml) was refluxed for 12 hours under heating and the solvent was removed under reduced pressure. The residue was silica gel chromatography (hexane:ethyl acetate=9:1) to give the object compound as an oily substance. 2.99 g, (yield 75%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13]O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.C1C=CC(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13][N:45]=[N+:46]=[N-:47])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(1-tert-butyloxycarbonylaminoethyl)-5-chlorobenzyl alcohol from the previous step (0.272 g, 0.96 mmol) in toluene (20.0 mL) at ambient temperature under nitrogen atmosphere was added DBU (0.15 mL g, 1.0 mmol) and DPPA (0.25 mL, 1.14 mmol). The mixture was stirred at ambient temperature for 18 h. The reaction was partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue purified by flash silica gel chromatography using dichloromethane as an eluent. 2-(1-(tert-butyloxycarbonylamino)ethyl)-5-chloro-benzylazide was obtained as a yellow oil after concentration of desired fractions in vacuo (0.28 g; HPLC RT 3.71 min, method A).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]OCCl>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:20])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 300 g of 3-benzyloxy-4-hydroxybenzaldeyde (obtained as described in example 62) in 600 ml of dimethylformamide was added to a suspension of 34.6 g of sodium hydride in 346 ml of dimethylformamide under stirring in nitrogen atmosphere. After complete dissolution of sodium hydride 116 g of chloromethyl methyl ether were added; stirring was continued for 30 minutes. The mixture was then diluted with water and extracted with ethyl ether. The combined organic phase was dried over sodium sulfate, filtered and evaporated. The residue was distilled (b.p. 178°-183° C./0.1 mm Hg) to give 3-benzyloxy-4-methoxybenzaldehyde, m.p. 30° C. (from petroleum ether, b.p. 30°-70° C.).
Reaction SMILES: S([O-])(O)(=O)=[O:2].[C:6]([C:10]1[S:11][S+:12]=[CH:13][C:14]=1[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:9])([CH3:8])[CH3:7].C(N([CH2:25][CH3:26])CC)C>C(O)C>[CH2:25]([O:2][C:10]1([C:6]([CH3:9])([CH3:8])[CH3:7])[C:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:13][S:12][S:11]1)[CH3:26]
Reactant: CC(C)(C)Cc1c[s+]sc1C(C)(C)C
Reactant: CCN(CC)CC
Reactant: O=S(=O)([O-])O
Solvent: CCO
Product: CCOC1(C(C)(C)C)SSC=C1CC(C)(C)C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a sample of 25 grams of the product prepared in Example 1B, i.e., 3-tert-butyl-4-neopentyl-1,2 dithiolium hydrogen sulfate, in 130 grams of ethanol was added 8.5 grams of triethylamine. The mixture was stirred for 15 minutes. The solvent was removed under diminished pressure and the residue extracted with ether. The ethereal solution was filtered and distilled under diminished pressure to remove the ether. There was isolated 17.1 grams (77.3% of theory) of 3-ethoxy-3-t-butyl-4-neopentyl 1,2-dithiole as an oil; n.m.r. (CCl4) τ in ppm, 3.81, 1H singlet (vinyl); 6.50 and 6.56, 2H two quartets (diastereotopic, J=7 cps, ethoxy); 7.22, 1H doublet (diastereotopic, J=15 cps. neopentyl proton); 7.82, 1H doublet (diastereotopic, J=15 cps neopentyl proton); 8.62, 9H singlet (t-butyl); 8.83, 3H triplet (J=7 cps, ethoxy); and 8.96, 9H singlet (t-butyl).
Reaction SMILES: O1CCCC1.C([Li])CCC.[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:54]=[CH:55][C:56]=1[O:57][CH2:58][C:59]1[N:60]=[C:61]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[O:62][C:63]=1[CH3:64])[CH2:29][N:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([O:43][CH:44]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45](Cl)=[O:46])[C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2.O>O1CCCC1>[CH3:64][C:63]1[O:62][C:61]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[N:60][C:59]=1[CH2:58][O:57][C:56]1[CH:55]=[CH:54][C:28]([CH2:29][N:30]2[C:42]3[CH:41]=[CH:40][CH:39]=[C:38]([O:43][CH:44]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:45]([N:19]4[C@@H:18]([CH2:11][C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH2:22][O:21][C:20]4=[O:23])=[O:46])[C:37]=3[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:27][C:26]=1[O:25][CH3:24]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: COc1cc(Cn2c3ccccc3c3c(OC(C(=O)Cl)c4ccccc4)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cn2c3ccccc3c3c(OC(C(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccccc4)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
9.1 mL of 2.44M n-butyllithium tetrahydrofuran solution was added thereto dropwise to tetrahydrofuran (30 mL) solution of 3.92 g of (S)-4-benzyl-2-oxazolidinone at −50° C. The mixture was stirred at −50° C. for 1 hour. Thereafter, the solution of the previously prepared (±)-{9-[3-methoxy-4-(5-methyl-2-phenyl-oxazole-4-ylmethoxy)-benzyl]-9H-carbazole-4-yloxy}phenylacetyl chloride in tetrahydrofuran (30 mL) was added thereto dropwise at −50° C. After the dropwise addition thereto, the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the prepared diastereomer mixture was purified by medium-pressure silica gel chromatography (ethyl acetate:n-hexane=5:1), and two types of the subject compound, 1.52 g of compound A (first fraction) and 1.2 g compound B (second fraction), were respectively prepared as pale brown powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[BrH:12]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCCO)cc1
Reactant: Br
Product: Cc1ccc(CCCBr)cc1

Procedure:
3-(4-Methylphenyl)propanol (2.13 g) was heated in 7 ml of 47% aqueous hydrobromic acid under reflux for 5 hours. The solvent was then distilled off under reduced pressure and, after addition of water, the residue was extracted with ether. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 1.75 g of 3-(4-methylphenyl)propyl bromide. Boiling point: 65° C./0.7 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([Cl:22])[N:3]=1.Cl>[OH-].[Na+]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:22])[CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(Cl)c2)cc1
Yield: 93.4 %

Procedure:
1.25 g (0.0035 mol) of N-[4-(2,6-dichloro-pyridin-4-yl-sulfamoyl)-phenyl]-acetamide were dissolved in 35 ml of 1N NaOH and boiled at reflux for 2 hours. After cooling the mixture was adjusted to pH 6 with 2N HCl and the precipitate which separated was filtered off. The material on the suction filter was washed well with water and dried. It was subsequently chromatographed on silica gel with ethyl acetate/hexane 1:2 ->1:1. There were obtained 1.04 g (93%) of 4-amino-N-(2,6-dichloro-pyridin-4-yl)-benzenesulfonamide as white crystals; m.p.: 209-211° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH2:11]([O:13][C:14]([C@@H:16]1[CH2:18][C@H:17]1[C:19](O)=O)=[O:15])[CH3:12].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[NH:10][C:19]([CH:17]3[CH2:18][CH:16]3[C:14]([O:13][CH2:11][CH3:12])=[O:15])=[N:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CC1c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
To a mixture of 3,4-diaminobenzonitrile (326 mg, 2.45 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (323 mg, 2.04 mmol), and triethylamine (1.44 mL, 10.2 mmol) in DMF (10 mL) was added HBTU (1.01 g, 2.66 mmol). After stirring at room temperature for 3 h, the mixture was poured into water, and the aqueous phase was extracted with EtOAc twice. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. To the residue was added acetic acid (10 mL), and the mixture was stirred at 90° C. for 12 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was poured into saturated sodium bicarbonate aqueous solution, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to give 210 mg (40%) of the title compound as a white amorphous: