Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:35])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](Cl)=[O:30])[O:20]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:24][C:23]1([CH3:25])[C:19]([CH3:18])([CH3:35])[O:20][B:21]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)=[O:30])[O:22]1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: CC1(C)OB(c2cccc(C(=O)Cl)c2)OC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2cccc(C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 13 h
Yield: 41.7 %

Procedure:
A mixture of benzyl 4-aminobenzoate (4.39 g, 19.3 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (4.30 g, 16.1 mmol) and N,N-diisopropylethylamine (7.49 g, 57.9 mmol) in methylene chloride (50 mL) was stirred at ambient temperature for 13 h. After this time, the reaction was concentrated under reduced pressure and purified by chromatography (silica, heptane to 1:3 ethyl acetate/heptane) to afford benzyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (3.07 g, 78% pure by mass, 27% yield) as a light yellow sticky foam that was used without further purification.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[NH:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38]([OH:40])=[O:39]>>[C:38]([C@@H:37]1[CH2:41][CH2:42][CH2:43][N:36]1[C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])([OH:40])=[O:39]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: NCCSC(=O)N1CCC[C@H]1C(=O)O
Yield: 159.8 %

Procedure:
N-triphenylmethyl-2-paranitrophenoxycabonylthioethylamine (300 mg) and L-proline (356 mg) were subjected to similar reactions to those described in References 2 and 4 to give 2-((S)-2-carboxypyrrolidino)carbonylthioethylamine (crude formate: 216 mg). The product was dissolved in anhydrous methanol (5 ml). Triethylamine (573 μl) and mitomycin A (287 mg: 1.0 molar equivalent) were added to the reaction solution which was then treated in a similar manner to that described in Example 1 to obtain Compound 31 (112 mg) in the form of grayish blue powders with a yield of 51%.
Reaction SMILES: [C:1]1([C:7]2[NH:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21]>C(Cl)Cl>[CH2:20]([O:14][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:13][CH2:12][CH2:11][N:10]=1)[CH3:21]
Reactant: CC[O+](CC)CC
Reactant: O=C1C=C(c2ccccc2)NCCN1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NCCNC(c2ccccc2)=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
3.8 g. (20 mmol.) of 7-phenyl-1,2,3,4-tetrahydro-1,4-diazepine-5-one (Compound XXV) were suspended in 100 ml. of dry methylene chloride stirred under nitrogen at room temperature. 4.0 g. (21 mmol.) of triethyloxonium tetrafluoroborate were added portionwise to the stirred suspension so as to maintain the reaction mixture at a temperature of 20°-25° C., the reaction being slightly exothermic. After the addition was completed, the reaction mixture was stirred for an additional 30 minutes at room temperature. The reaction mixture was then washed with cold dilute sodium hydroxide solution and dried over anhydrous sodium sulfate. The methylene chloride was evaporated off at reduced pressure and ether was added to the residue. A small amount of solid that did not dissolve was removed by filtration, and the filtrate was evaporated at reduced pressure to yield an oil which crystallized overnight in a refrigerator yielding the crude product (3.5 g.), m.p. 89°-93.5° C. Recrystallization from ether/heptane yielded the pure product as white crystals (1.6 g.), m.p. 94°-95.5° C. A second crop (1.6 g.) was obtained from the mother liquor, m.p. 89°-93° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([NH2:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: CC(C)(C)OC(=O)N1CCCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[CH:40]=O.[Na]>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:40][C:31]3[CH:32]=[CH:33][C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:30]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccc4ccccc4n3)CC1)O2
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) in 1 M Na2CO3, was stirred for 10 minutes, then extracted with DCM and treated with quinoline-2-carbaldehyde (96 mg, 0.61 mmol) and sodium triacethoxyborohydride (159 mg, 0.750 mmol) following the procedure described in Example 55, Step A, giving (E)-3-{1′-(quinolin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (196 mg) as a yellow solid. The ester was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-(quinolin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (190 mg) as an orange solid (hydrochloride salt). The acid was suspended in DCM (5 ml), TEA (0.16 ml, 1.16 mmol) was added, and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-(quinolin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (162 mg) as a yellow solid. The compound was then was dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.4 ml, 1.6 mmol) as described in Example 55, Step D, giving a yellow solid (145 mg, di-hydrochloride salt)
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:37])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:37])[C:5]([C:3]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2cc3c(O)c(C(=O)NCCC(=O)O)nc(-c4cccnc4)c3n(Cc3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (44 mg, 0.089 mmol), β-alanine (636 mg, 7.1 mmol) and NaOMe solution (10.7 mL, 5.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 34 mg of the title compound as a yellow solid. MS: (+) m/z 551.39 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14].O.[NH2:16]N>CS(C)=O>[Cl:1][C:2]1[C:7]([NH:8][NH2:16])=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14]
Reactant: NN
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: CS(C)=O
Solvent: O
Product: NNc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Pentachloronitrobenzene containing 5-10% hexaxchlorobenzene, (3.0 g, 10.1 mmole) was dissolved in dimethylsulphoxide (35 ml). Hydrazine hydrate (1.25 g, 25 mmole) was added dropwise with stirring at 25° C. A slight 4°-5° C. increase in temperature was recorded and the solution became red-brown. After approximately 20 minutes a white solid began to be precipitated. Stirring was continued for one hour after which time TLC (1:1 ethyl acetate: 60°-80° C. petrol) indicated that the reaction was complete. The mixture was poured into stirred water (200 ml) and the solid filtered off and dried at 50° C. overnight. The TLC and IR was identical to an authentic sample of pentachlorophenylhydrazine. Yield=2.27 g, 80%.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)([O-:11])=[O:10].C(#N)C>C(Cl)Cl>[Cl:1][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[CH:20][C:12]=2[N+:9]([O-:11])=[O:10])[NH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
N-Chlorosuccinimide (1.23 g, 9.25 mmol) is added to a solution of 4-nitroindole (1.5 g, 9.25 mmol, Aldrich) in methylene chloride (75 mL). The resulting mixture is heated to reflux for 16 hours. Acetonitrile (10 mL) is added to the mixture and heating is continued for another 16 hours. The reaction is cooled to room temperature and the methylene chloride is removed by rotary evaporation. The residue is taken up in ethyl acetate and washed with water. The ethyl acetate layer is dried over magnesium sulfate, filtered and the solvents removed by rotary evaporation. The crude material is purified via silica gel column chromatography using 30% ethyl acetate/hexane as the eluent. The product containing fractions are combined and the solvents removed by rotary evaporation to yield 1.35 g of 3-chloro-4-nitroindole as an orange solid (74%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]1[CH2:13][C@:14]3([CH2:24][C:8]=1[CH:7]=2)[C:22]1[C:17](=[N:18][CH:19]=[CH:20][CH:21]=1)[NH:16][C:15]3=[O:23].S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]1[CH2:13][C@:14]3([CH2:24][C:8]=1[CH:7]=2)[C:22]1[C:17](=[N:18][CH:19]=[CH:20][CH:21]=1)[NH:16][C:15]3=[O:23]
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3cc(CO)cnc3cc1C2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3cc(CCl)cnc3cc1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (7S)-3-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (970 mg, 3.06 mmol) in CH2Cl2 (30 mL) was added thionyl chloride (2.23 mL, 30.1 mmol) and the resulting mixture was stirred at ambient temperature for 2 h, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (30 mL) and CH2Cl2 (30 mL). The layers were separated and the aqueous layer was extracted further with CH2Cl2 (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title. MS: m/z=336 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[C:21]([CH3:24])=[CH:22][N:23]=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15](=[O:16])[NH:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[C:21]([CH3:24])=[CH:22][N:23]=1)(=[O:12])=[O:13])=[O:4]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cnc(N)c(=O)n1C
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1ncc(C)n(C)c1=O
Yield: 47 %

Procedure:
A mixture of 1.218 g of 2-methoxycarbonylphenylsulfonyl isocyanate, 0.7 g of 3-amino-1,6-dimethylpyrazin-2-one and 15 ml of absolute dioxane is refluxed for 3 hours. The reaction mixture is evaporated to dryness and the residue is crystallized by treatment with acetone. 0.9 g of 3-[3-(2-methoxycarbonylphenylsulfonyl)-ureido]-1,6-dimethylpyrazin-2-one with a melting point of 192°-193° C. are thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][NH:9][C:10]([C:23]2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=[O:39]>ClCCl>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:39])[CH3:23])[N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1ccn(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CC(=O)NCCn1ccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(3-bromo-1H-pyrazol-1-yl)-N-tritylethanamine obtained in Step B (100 mg) and triethylsilane (38.8 μL) in dichloromethane (1.2 mL) was slowly added trifluoroacetic acid (1.2 mL) under ice-cooling. The reaction mixture was warmed to room temperature, stirred for 3 hr, and concentrated under reduced pressure. To a solution of the obtained residue and acetic anhydride (32.7 μL) in dichloromethane (2.0 mL) was added triethylamine (97.0 μL) under ice-cooling, and the mixture was stirred for 2 hr. To the reaction mixture was added dichloromethane, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (40.0 mg).
Reaction SMILES: [Br-].[C:2]([O-:5])(=[O:4])[CH3:3].[Na+].[Cl:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[CH:10][C:11]([CH3:16])=[C:12]([CH:15]=1)[C:13]#[N:14]>CN(C=O)C.O>[C:2]([O:5][CH2:16][C:11]1[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]([Cl:7])=[CH:15][C:12]=1[C:13]#[N:14])(=[O:4])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Reactant: CC(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc([N+](=O)[O-])c(Cl)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
The above partially purified bromide was dissolved in DMF (300 mL) and cooled to 0° C. Sodium acetate (18.0 g, 0.22 mol) was added. The mixture was stirred at 60° C. for 30 min. After cooling, the mixture was diluted with H2O and extracted with EtOAc. The EtOAc extract was washed with H2O (2×), dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel and elution with hexanes:EtOAc (9:1) yielded a front fraction containing 5-chloro-4-nitro-2-methylbenzonitrile and dibromide. Further elution with hexanes:EtOAc (2:1) gave the title compound (19.5 g, 47%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[N:12]([CH2:29][CH2:30][CH2:31]Cl)[C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:33][CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[N:12]([CH2:29][CH2:30][CH2:31][N:39]3[CH2:40][CH2:41][CH:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]3)[C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc2c(c1)N(CCCCl)c1cccc(S(=O)(=O)N(C)C)c1S2
Reactant: OCCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc2c(c1)N(CCCN1CCC(CCO)CC1)c1cccc(S(=O)(=O)N(C)C)c1S2
Temperature: 130 °C
Yield: 73.2 %

Procedure:
A mixture of 2-heptyloxy-6-dimethylsulphamoyl-10-(3-chloropropyl)phenothiazine (24.3 g.), 4-hydroxyethylpiperidine (7.1 g.) and sodium bicarbonate (16.1 g.) in dimethylformamide (180 cc.) is heated at about 130°C. for 8 hours with stirring. After cooling, the reaction mixture is evaporated to dryness under reduced pressure (15 mm.Hg) with heating to 65°C. The residue is taken up in distilled water (300 cc.) and then extracted with methylene chloride (total 560 cc.). The combined organic extracts are acidified by addition of a solution of methanesulphonic acid (57.6 cc.) in water (250 cc.). The organic phase is washed with an 8% aqueous solution of sodium hydroxide (total 300 cc.) and then with distilled water (total 1 litre), and is finally dried over sodium sulphate. On evaporation of the solvent under reduced pressure (15 mm. Hg) at 40°C., crude 2-heptyloxy-6-dimethylsulphamoyl-10-[3-(4-hydroxyethylpiperidino)propyl]-phenothiazine (21.1 g.), in the form of a brown viscous oil, is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)=[O:6]
Reactant: COC(=O)C1CCNCC1
Reactant: COC(=O)c1ccc(O)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1ccc(O)c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate is prepared in analogy to the process described in Example IX, method 1, from 2-hydroxy-5-carbomethoxybenzoic acid [CAS No. 79128-78-2] and methyl piperidine-4-carboxylate hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)(O)[CH3:12].CC(O)=O.[H][H]>CCO>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)[CH3:12]
Reactant: [H][H]
Reactant: COc1cc(C)c(C(C)(O)c2ccc(OC)c(C(C)C)c2)c(C)c1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C)c(C(C)c2ccc(OC)c(C(C)C)c2)c(C)c1
Yield: 78.8 %

Procedure:
A solution of 1-(2,6-dimethyl-4-methoxyphenyl)-1-(3-isopropyl-4-methoxyphenyl) ethanol (400 mg, 1.218 mmol) in 4.4 mL of 9% (v/v) AcOH in EtOH containing 10% Pd/C (40 mg) was hydrogenated at 1 atm at room temperature. When hydrogen uptake was complete (12 hours), the catalyst was filtered off and the filtrate was diluted with 50 mL of ether, washed with sat. NaHCO3 solution (3×10 mL), water (30 mL) and brine (3×10 mL). The solvent was evaporated to yield 300 mg (0.96 mmol, 79%) of 1-(2,6-dimethyl-4-methoxyphenyl)-1-(3-isopropyl-4-methoxyphenyl) ethane as an oil. This material was used in the next step without further purification; 1HNMR (CDCl3) & 1.16 (dd, 6H), 1.63 (d, 3H), 2.12 (s, 6H), 3.27 (heptet, 1H), 3.81 (s, 6H), 4.54 (q, 1H), 6.54 (s, 2H), 6.75 (d, 1H), 6.88 (d, 1H), 7.04 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C@@H:13]2[CH2:15][O:14]2)[C:5]=1[NH2:6])([O-])=O.[O:16]1CCC[CH2:17]1>[Ni]>[O:14]1[CH2:15][C@H:13]1[CH2:12][O:11][C:7]1[C:5]2[NH:6][C:17](=[O:16])[NH:1][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1c(OC[C@@H]2CO2)cccc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Ni]
Product: O=c1[nH]c2cccc(OC[C@@H]3CO3)c2[nH]1
Reaction time: 8 h

Procedure:
2-Nitro-6-[(2S)oxiranylmethoxy]aniline (0.20 g, 0.96 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Excess Raney Ni was added and the mixture hydrogenated under an atmosphere of hydrogen overnight. The mixture was filtered through a Celite pad. To the anhydrous tetrahydrofuran solution was added with cooling anhydrous N,N-diisopropylethylamine (0.365 mL) followed by phosgene in toluene (0.525 mL). The solvent was partially removed and the title compound collected by filtration (0.10 g, 0.49 mmol).
Reaction SMILES: C([C:5]1([OH:17])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[CH:10][CH:11]=2)[O:6]1)CCC.CS([O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH2:12]([O:17][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([O:22][CH2:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][CH3:37])[CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[CH:11]=2)[O:6]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC1(O)CCc2ccc(F)c(F)c2O1
Reactant: CC[C@H]1CC[C@H](C2CCC(COS(C)(=O)=O)CC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC1CCc2cc(OC[C@H]3CC[C@H]([C@H]4CC[C@H](CC)CC4)CC3)c(F)c(F)c2O1

Procedure:
To 20.5 g of 2-butyl-7,8-difluorochroman-2-ol which was dissolved in 70 mL of DMF, 25 g of 4-(trans-4-ethylcyclohexyl)cyclohexylmethyl methanesulfonate and 11.4 g of anhydrous potassium carbonate were added, and heated to reflux for 3 hours. The reaction solution was poured into 10% hydrochloric acid, stirred for a while, and extracted with toluene. An organic layer was washed using 10% hydrochloric acid twive, water, a 5% sodium hydroxide aqueous solution twice, water, a saturated sodium hydrogen carbonate aqueous solution twice, and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the obtained brown solid material was purified by carrying out column chromatography (silica gel, hexane/toluene), recrystallization (hexane), recrystallization (acetone), and recrystallization (acetone), to obtain 14.7 g of 2-butoxy-7,8-difluoro-6-(trans-4-(trans-4-ethylcyclohexyl)cyclohexylmethoxy) chroman (If) as a colorless crystal.
Reaction SMILES: N1C=CN=C1.[C:6]1([CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)[OH:7].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O.O>[Si:14]([O:7][C:6]1[CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1

Procedure:
A solution of 2.9 parts of imidazole, 1.99 parts of hydroquinone and 3 parts of tert-butyldimethylsilyl chloride in 10 mL of dimethylformamide was stirred at room temperature for 1 hr 45 min. The reaction was monitored by TLC showed formation of product. The reaction mixture was diluted with 50 mL of deionized water and product was extracted with 2×50 mL of ether. The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel with 5% ethyl acetate-hexanes to yield 2.24 parts 4-(tert-butyldimethylsilyloxy)phenol. NMR was used to confirm the following structure.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8](=[O:11])[CH2:9]Br)=[C:5]([CH3:7])[N:6]=1.[C:12]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH2:27])[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:27][CH2:9][CH:8]([OH:11])[C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)COc1ccc(CC(C)N)cc1
Reactant: Cc1nc(C)c(C(=O)CBr)s1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2sc(C)nc2C)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2,4-dimethyl-5-bromoacetyl-thiazole with 2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine, followed by reduction and purification of the base on a silica gel column using ethyl acetate/methanol=17:3.