Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:71][CH3:72])[CH2:42][CH2:43][C@@H:44]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH2:63])(=[O:62])=[O:61])=[CH:56][C:55]=1[S:64]([C:67]([F:70])([F:69])[F:68])(=[O:66])=[O:65])[CH2:45][S:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:71][CH3:72])[CH2:42][CH2:43][C@@H:44]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH:63][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:30])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)(=[O:61])=[O:62])=[CH:56][C:55]=1[S:64]([C:67]([F:68])([F:69])[F:70])(=[O:66])=[O:65])[CH2:45][S:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:34]([CH3:37])([CH3:35])[CH3:36])([CH3:33])[CH3:32]
Reactant: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Reactant: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
(R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 2.15 g, 5.10 mmol), (R)-4-(4-((2-(tert-butyldimethylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 65, 3.41 g, 5.10 mmol), DMAP (1.87 g, 15.29 mmol) and EDC (1.954 g, 10.19 mmol) were dissolved in DCM (17 ml). The reaction mixture was stirred at r.t. overnight, diluted with DCM (50 ml) and washed with NH4Cl solution (saturated, aq., 20 ml), saturated aq. NaHCO3 (20 ml) and brine (20 ml). The collected organic layer was dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 12 g silica gel, eluted with 0→20% MeOH in EtOAc) to provide the title compound (3.41 g, yield: 62%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([NH2:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[OH:11].[OH-].[K+].S(OC)(O[CH3:18])(=O)=O.O>CC(C)=O>[Cl:2][C:3]1[C:4]([O:11][CH3:18])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=1[NH2:9]
Reactant: Nc1c(Cl)ccc(O)c1Cl
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Cl)c(N)c1Cl

Procedure:
To a solution of 2,4-dichloro-3-aminophenol hydrochloride (GLSynthesis, 7.70 g, 35.9 mmol, 1.0 eq.) in acetone is added powdered potassium hydroxide 85% (9.48 g, 143.6 mmol, 4.0 eq.) in small portions. Then, dimethyl sulfate (5.13 ml, 53.9 mmol, 1.5 eq.) is added at such a rate that the internal temperature does not rise above 30° C. After 1 h stirring at room temperature water (50 ml) is added and stirring is continued for another hour. The solvent is evaporated and the residue is distributed between ethyl acetate (150 ml) and water (100 ml). The organic layer is isolated, dried over Na2SO4 and evaporated to give a yellow oil. Kugelrohr distillation affords the desired product as a colorless oil: b.p. 150° C./0.3 mbar, HPLC: tR=5.61 min (purity: 90%, gradient A), 400 MHz 1H-NMR (CDCl3) δ: 3.87 (s, 3H, OMe), 4.49 (br s, 2H, NH2), 6.30 (d, 1H, Ar—H4), 7.11 (d, 1H, Ar—H5).
Reaction SMILES: Cl.Cl.C(S[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]=1)C.Cl.[F:49][C:50]([F:54])([F:53])[CH2:51][NH2:52].C([O-])(=O)C.[Na+].C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:15]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:52][CH2:51][C:50]([F:54])([F:53])[F:49])=[NH:47])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: NCC(F)(F)F
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)SCC)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)NCC(F)(F)F)c1
Reaction time: 12 h
Yield: 86 %

Procedure:
Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride (1.074 g., 1.5 mmoles) was added to a slurry of 2,2,2-trifluoroethylamine hydrochloride (406 mg., 3.0 mmoles) and anhydrous sodium acetate (246 mg., 3.0 mmoles) in chloroform (10 ml.) and glacial acetic acid (0.3 ml., 5.3 mmoles). The mixture was held for 12 hours at room temperature. It was then diluted to 300 ml. with chloroform, washed with saturated aqueous sodium bicarbonate solution (2 × 50 ml.), washed with saturated aqueous sodium chloride solution (2 × 50 ml.), dried (Na2SO4) and filtered. The filtrate was acidified with a 10% solution of anhydrous hydrogen chloride in dioxane (5 ml.) and then evaporated in vacuo to a foam. The foam was recrystallized from 1,2-dimethoxyethane [974 mg., 86% yield, Rf 0.39 (4:1, benzene:ethanol on silicic acid), m.p.-forms a gel at 125°-127° C⟧
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].I[CH2:17][CH3:18].Cl>CN(C)C=O.O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:18]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(O)cc(OCC)c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of ethyl 3,5-dihydroxybenzoate (15.0 g) in N,N-dimethylformamide (180 ml) was gradually added sodium hydride (60% in oil, 3.30 g) at 0° C. and the mixture was stirred for 30 min. Iodoethane (12.9 g) was added and the mixture was further stirred for 2 hrs. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl 3-ethoxy-5-hydroxybenzoate (6.75 g, yield 39%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). Recrystallization from diethyl ether-hexane gave colorless needle-shaped crystals. melting point: 62–63° C.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CCOCC.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+]>[C:17]1([S:23]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: On1nnc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccccc1
Yield: 73 %

Procedure:
In 1 N aqueous sodium hydroxide (50 ml) is dissolved 1-hydroxy-6-chloro-1,2,3-benzotriazole (4.5 g) and thereto is added ether (10 ml). To the solution is added benzenesulfonyl chloride (6.0 g) with stirring under ice-cooling and the mixture is stirred at the same temperature for 75 minutes. The reaction mixture is filtered to give crystals. The filtrate is extracted with ethyl acetate (150 ml), and the extract is distilled to remove the solvent. The resulting crystals are combined with those obtained above and recrystallized from benzene-n-hexane to give 1-benzenesulfonyloxy-6-chloro-1,2,3-benzotriazole (6.0 g), melting point: 110°-110.5° C. Infrared spectrum (Nujor): 1200, 1086 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][C:3]=1[F:30].FC(F)(F)C(O)=O.[SH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].[OH-].[Na+]>C(Cl)Cl>[C:41]([CH2:40][CH2:39][S:38][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([F:30])[CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:43])=[O:42]
Reactant: O=C(O)CCS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Temperature: 0 °C
Yield: 52.4 %

Procedure:
While stirring under ice cooling, 1 g of 2-(7-chloro-6-fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine was added to a mixed solution of 8 ml of trifluoroacetic acid and 6 ml of methylene chloride, then 0.25 g of 3-mercaptopropionic acid was added to the solution and the mixture was stirred under ice cooling for 2 hours. After completion of the reaction, 180 ml of ice water was added the mixture, the mixture was adjusted to about pH 3 with a 1N-sodium hydroxide aqueous solution and then the aqueous layer was extracted with 200 ml of methylene chloride. The organic layer was washed with water and dried over anhydrous sodium sulfate and the residue obtained by removing the solvent under reduced pressure was recrystallized from ethyl acetate to obtain 0.63 g of the title compound as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.CO[CH:19](OC)[CH2:20][C:21]#[N:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:21]([C:20]1[CH:19]=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)#[N:22]
Reactant: Cc1ccc(C(=O)c2ccccc2N)cc1
Reactant: COC(CC#N)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c(C#N)cnc3ccccc23)cc1

Procedure:
A mixture of 2-amino-4'-methylbenzophenone (10 g), 3,3-dimethoxypropionitrile (10.9 g), p-toluenesulfonic acid. monohydrate (1.0 g) in toluene (120 ml) was heated under reflux for 4 hours. After addition of water, the reaction mixture was extracted with ethyl acetate and the extract was concentrated to dryness. The residue was purified by column chromatography on silica gel. Recrystallization from isopropyl ether afforded pale yellow prisms (5.67 g, 49%), m.p. 96°-97° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[N:21]=2)[C:17]#[N:18])[CH2:9][CH2:8]1)=[O:6].C[O-].[Na+].CO.[CH:37]([NH:39][NH2:40])=O>CO>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:21]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[CH:19]=[C:16]([C:17]3[NH:40][N:39]=[CH:37][N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: N#Cc1cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)nc(Nc2nccs2)c1
Reactant: NNC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(-c3ncn[nH]3)cc(Nc3nccs3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 25.2 mg of 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-6-(thiazol-2-ylamino)isonicotinonitrile obtained in Example 104 and 1 ml of methanol was added 0.3 ml of a 28% sodium methoxide-methanol solution, followed by stirring at room temperature for 5 hours. To the reaction solution was added a solution of 3.3 mg of formohydrazide in 1 ml of methanol. The reaction mixture was stirred at room temperature for 17 hours, and then heated under reflux for 24 hours. To the reaction solution was added a solution of 16.6 mg of formohydrazide in 1.5 ml of methanol, and further heated under reflux for 22 hours. The reaction solution was cooled to room temperature, and then concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=7/1) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1.C(N(CC)CC)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>O1CCCC1>[CH3:22][Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1
Reactant: CC1(c2cc(Br)ccc2O)OCCO1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(c2cc(Br)ccc2O[Si](C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
Under ice-cooling, to a solution of 3.11 g (12 mmol) of 2-(2-hydroxy-5-bromophenyl)-2-methyl-1,3-dioxolane in 24 ml of tetrahydrofuran was added dropwise succesively, 1.84 ml (13.2 mmol) of triethylamine and 1.68 ml (13.2 mmol) of trimethylsilyl chloride with stirring. The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was concentrated under reduced pressure to give 4.0 g of the crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16]([I:17])[N:11]3[N:10]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Nc2nn3ccnc3s2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Fc1ccc(Nc2nn3c(I)cnc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
(4-Fluoro-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl-amine (0.117 g, 0.50 mmol) was suspended in N,N-dimethylformamide (3 mL) and N-iodosuccinimide (0.124 g, 0.55 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 2 hours in the absence of light. The mixture was evaporated and the residue was purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.4:9.6 to 1:9) to give 0.13 g of (4-fluoro-phenyl)-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-amine as an off-white solid (72% yield).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(Sc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Sc2ccc(Cl)cc2)cc1
Yield: 54.4 %

Procedure:
In a manner similar to Example 16, 7.43 g of methyl α-bromo-α-[p-(p-chlorophenylthio)phenyl]acetate was reacted with 3.75 g of p-tert-butylphenol. Filtration of the crude reaction mixture yielded 5.4 g of white platelets, which yielded 4.8 g of white crystals, mp 106.5°-108.5° C on recrystallization from 100 ml of 80:20 hexane:chloroform.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[CH:11][C:12]3[S:17][C:16]4[N:18]=[CH:19][CH:20]=[N:21][C:15]=4[N:14]([CH2:22][O:23][CH3:24])[C:13]=3[CH:25]=2)=[CH2:8])[CH:2]=1.[H][H]>C(O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[CH:11][C:12]3[S:17][C:16]4[N:18]=[CH:19][CH:20]=[N:21][C:15]=4[N:14]([CH2:22][O:23][CH3:24])[C:13]=3[CH:25]=2)[CH3:8])[CH:2]=1
Reactant: [H][H]
Reactant: C=C(c1cccnc1)c1ccc2c(c1)N(COC)c1nccnc1S2
Agent: [Pd]
Solvent: CCO
Product: COCN1c2cc(C(C)c3cccnc3)ccc2Sc2nccnc21
Yield: 45.8 %

Procedure:
0.23 g of 8-[1-(pyridin-3-yl)vinyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in 10 ml of ethanol and then hydrogenated in the presence of 0.056 g of 10% palladium-carbon (moisture content: 50%) in a hydrogen gas stream at room temperature for 26 hours. Thus 0.106 g of the title compound was obtained as yellow crystals.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@@H:10]([OH:22])[CH2:11][C@@H:12]([C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([NH:15][CH2:16][CH3:17])=[O:14])=O)(C)(C)C.C(OC(N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](C(O)(C)C)C(NC)=O)=O)(C)(C)C.[C:58]([O:62][C:63]([NH:65][C@H:66]([C:73](O)=[O:74])[CH2:67][C:68]1[N:69]=[CH:70][S:71][CH:72]=1)=[O:64])([CH3:61])([CH3:60])[CH3:59].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>>[C:58]([O:62][C:63]([NH:65][C@H:66]([C:73]([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@@H:10]([OH:22])[CH2:11][C@@H:12]([C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[O:74])[CH2:67][C:68]1[N:69]=[CH:70][S:71][CH:72]=1)=[O:64])([CH3:60])([CH3:61])[CH3:59]
Reactant: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Yield: 80.5 %

Procedure:
A procedure similar to that described in Example 9(a) was repeated, except that 280 mg (0.675 mmoles) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-ethylhexanamide (prepared as described in Preparation 24) were used instead of the (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide, and 190 mg (0.7 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine, 0.4 ml (2.88 mmoles) of triethylamine, and 0.11 ml (0.688 mmoles) of diethyl cyanophosphate were also used, to give a powdery substance, which was then recrystallized from a mixture of diisopropyl ether and methylene chloride, to afford 309 mg of the title compound, melting at 189°-191° C.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1[CH:13]=[C:12]([CH:14]=[O:15])[O:11][CH:10]=1.Cl.C(OCC)(=O)C>C1COCC1>[O:11]1[CH:10]=[CH:9][CH:13]=[C:12]1[CH:14]([OH:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=Cc1ccco1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccco1
Yield: 91 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.96 g (10 mmol) of 2-furfural in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×3) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.77 g of the desired product (yield 91%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].[CH2:32](OC(OCC)CBr)[CH3:33]>CCO.O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][CH:32]=[CH:33][N:1]=4)=[CH:5][C:6]=3[O:30][CH3:31])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Reactant: CCOC(CBr)OCC
Solvent: O
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nccs4)cc3OC)ccc21
Temperature: 70 °C
Yield: 56.7 %

Procedure:
Ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (1.00 g, 2.3 mmol) (Example 146) and bromoacetaldehyde diethyl acetal (1.78 g, 9.2 mmol) were dissolved in EtOH (30 mL) and water (2 drops) was added. The mixture was heated at 70° C. for 18 h, and then the reaction mixture was cooled to rt, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc:hexane (v/v)=1:1) gave 610 mg (58%) of the title compound as a clear oil. LC-MS: RT=3.81 min; (M+H)+ 468.1.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][Cl:11].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH2:1]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:9]([CH3:8])[CH2:10][Cl:11])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(CCl)Cc1ccccc1
Reactant: C=CCCCCC
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1ccc(CC(C)CCl)cc1
Reaction time: 14 h
Yield: 75 %

Procedure:
25 parts by weight of hept-1-ene are added dropwise at 10° C. to a mixture of 42 parts by weight of 2-methyl-3-phenylpropyl chloride and 20 parts by weight of 96% strength sulfuric acid. Stirring is continued at room temperature for 14 hours. The crude product is dissolved in CHCl3, and the solution is washed with ice water, dried over Na2CO3 and distilled. 50 parts by weight of 3-(4-heptylphenyl)-2-methyl-propyl chloride are obtained; boiling point 114° C.-7° C./0.1 mm Hg, yield 75%(based on 2-methyl-3-phenylpropyl chloride).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH:19]([CH3:22])[CH2:20][OH:21]>O>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:18][CH:19]([CH3:22])[CH2:20][OH:21])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(N)CO
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: O
Product: CC(CO)Nc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Temperature: 130 °C

Procedure:
A mixture of 0.5 g of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine and 3 ml of 2-amino-1-propanol was heated at 130° C. for 24 hours, cooled and poured into water. The mixture was extracted with three 20 ml portions of dichloromethane. The combined extracts were washed with water, dried over magnesium sulfate and concentrated. The residual oil was dissolved in ethyl acetate and the solution passed through a short pad of silica gel. The filtrate was concentrated in vacuo and the residue was crystallized from dichloromethane-hexane to give 0.3 g of 2-[[6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl]amino]-1-propanol as white crystals, mp 143°-144° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([S:13][CH2:14][N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:17][S:16]2(=[O:29])=[O:28])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([S:13][CH2:14][N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:17]([CH3:1])[S:16]2(=[O:28])=[O:29])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1C(Cc2ccccc2)NS(=O)(=O)N1CSc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(Cc2ccccc2)C(=O)N(CSc2ccccc2)S1(=O)=O
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
Potassium t-butoxide (5.65 g, 50.35 mmol) was added to a solution of 2-phenylthiomethyl-4-phenylmethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (14.61 g, 41.93 mmol) in 250 ml of THF at 0° C. and the mixture was stirred at this temperature for 1/2 hour. To the above mixture was added methyl iodide (35.69 g, 251.58 mmol) at 0° C. and the resulting mixture was allowed to stir for 4.5 hours at room temperature. The resulting mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 12.53 g (82.4%) of 2-phenylthiomethyl-4-phenylmethyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide as a yellow solid.