Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.S(=O)(=O)(O)O.O.[C:20](=O)([O-])[O-].[K+].[K+]>CO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:20])=[O:12])=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1n[nH]c2ncccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)Cc1n[nH]c2ncccc12
Temperature: 70 °C

Procedure:
2-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetic acid (317 mg a crude) was dissolved in 15 mL methanol, and concentrated sulfuric acid 0.5 mL was added dropwise. It was heated to 70° C. and reacted for 12 hours. The reaction was monitored to be complete by LC-MS. 50 mL water was added, and the pH was adjusted to be weak basic with potassium carbonate. Methanol was rotate evaporated. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and rotate evaporated to dryness to obtain a light yellow solid 250 mg, at a yield over two steps of 73.6%.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O)C.[OH-].[Na+]>O>[ClH:1].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Cl)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(c2nc(N)c3ccccc3n2)CC1
Product: Cl

Procedure:
A mixture of 5 g of 2-chloro-4-aminoquinazoline, 5 ml of 4-methylpiperazine, and 10 ml of ethanol was heated at reflux overnight. The reaction mixture was diluted with 200 ml of water, made alkaline with 15 ml of 50 percent sodium hydroxide solution, and extracted with 500 ml of ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and filtered. The ether was removed by evaporation. The residue was dissolved in 500 ml of dry ether and treated with excess hydrogen chloride. Filtration afforded 1.5 g of 2-(4-methylpiperazinyl)-4-aminoquinazoline hydrochloride; m.p. 333°-334° with decomposition. The following analytical data were obtained:
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.CO.[C:12]([O:16][C:17]([N:19]1[CH2:53][CH2:52][CH2:51][C:21]2([CH2:50][CH2:49][N:24]3[C:25]4[C:30]([C:31]([C:32]5[C:33](=[O:48])O[C:35](=[O:47])[C:36]=5[C:37]5[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[N:39]([CH3:46])[CH:38]=5)=[C:23]3[CH2:22]2)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:53][CH2:52][CH2:51][C:21]2([CH2:50][CH2:49][N:24]3[C:25]4[C:30]([C:31]([C:32]5[C:33](=[O:48])[NH:3][C:35](=[O:47])[C:36]=5[C:37]5[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[N:39]([CH3:46])[CH:38]=5)=[C:23]3[CH2:22]2)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC3(CCCN(C(=O)OC(C)(C)C)C3)C4)C(=O)OC2=O)c2ccccc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC3(CCCN(C(=O)OC(C)(C)C)C3)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 16 h
Yield: 58 %

Procedure:
A mixture of 1.08 g of 1,1,1,3,3,3-hexamethyldisilazane and 0.11 g of methanol was added to a solution of 380 mg of 3-[1-(tert.butoxycarbonyl)-7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[1,2-a]indol]-10'-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 10 ml of DMF and the mixtue was stirred for 16 hours and subsequently poured into 50 ml of water. The resulting mixture was extracted with dichloromethane and the extracts were washed with sodium chloride solution, dried and concentrated. Chromatography of the residue on silica gel using dichloromethane/methanol (9:1) for the elution gave 220 mg of 3-[1-(tert.butoxycarbonyl)-7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[1,2-a]indol]-10'-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].[O-]CC.[Na+].O>C(O)C>[N+:8]([CH2:11][C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCOCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])CC1(O)CCOCC1
Yield: 33.7 %

Procedure:
A solution of tetrahydro-4H-pyran-4-one (45.0 g, 449 mmol) and nitromethane (36.5 mL, 674 mmol) in ethanol (27 mL) was treated with a solution of sodium ethoxide in ethanol (2.67 M, 8.40 mL, 22.5 mmol) using the method described in Part A of Example 9. The reaction mixture was transferred to a reparatory funnel and water (450 mL) was added. The mixture was extracted with ethyl acetate (3×900 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to a light brown oil. Ethyl acetate/hexanes was added and pale brown crystals formed that were isolated by filtration and dried to provide 4-(nitromethyl)tetrahydro-2H-pyran-4-ol (24.4 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH2:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1ccc(C(=O)Nc2ccc3c(c2)CCCC3=O)cc1
Yield: 90 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with 4-propylbenzoyl chloride (100 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-propyl-benzamide (140 mg, 0.45 mmol, 90% yield) as a white powder after purification by flash chromatography on silica gel (eluent :EtOAc/hexane 2/8 to 4/6).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH3:10])=[CH:3][C:2]=1[N:1]1[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: COc1ccc(C)c(N)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COc1ccc(C)c(-n2cccc2)c1
Temperature: 25 °C

Procedure:
A solution of 88.4 g (0.64 mole) of 3-amino-4-methylanisole in 1.4 liters of glacial acetic acid is heated to 106° and, at this temperature, 114 g (0.86 mole) of 2,5-dimethoxytetrahydrofuran are added in the course of 30 minutes. The mixture is then immediately cooled to room temperature and concentrated in a vacuum rotary evaporator. Distillation of the residue in a high vacuum yields 4-methyl-3-(pyrrol-1-yl)-anisole, b.p. 93°-95°/0.04 torr. Rf (toluene/ethyl acetate=10:1): 0.57.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:24]3[C:22]4[N:23]=[C:19]([NH2:18])[S:20][C:21]=4[CH:27]=[CH:26][CH:25]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Nc1nc2c(O)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), ((0.13 g, 0.5 mmol) and 2-amino-4-hydroxybenzothiazole (83 mg, 0.5 mmol, Astatech) in DMF (1 mL) was added potassium carbonate (0.14 g, 1 mmol) and the mixture was heated at 80° C. for 16 h with sirring. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc and brine. The layers were separated and the aq. layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography (2:1 hexanes: EtOAc) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 389 (M+1). Mp: 232.0–233.5° C. Anal. Calcd for C18H11F3N4OS: C, 55.67; H, 2.85; N, 14.43; S, 8.26. Found: C, 55.52; H, 3.08; N, 14.23; S, 8.36.
Reaction SMILES: C[O-].[Na+].[NH2:4]/[C:5](/[C:12]([F:15])([F:14])[F:13])=[CH:6]\[C:7](OCC)=[O:8].[CH3:16][N:17]=[C:18]=[O:19].O>CS(C)=O>[CH3:16][N:17]1[C:7](=[O:8])[CH:6]=[C:5]([C:12]([F:13])([F:14])[F:15])[NH:4][C:18]1=[O:19]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CN=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)cc(C(F)(F)F)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
To a pre-mixed solution of sodium methoxide (55 mmol, 2.97 g) and ethyl 3-amino-4,4,4-trifluorocrotonate (55 mmol, 10.0 g) in DMSO (19 mL, dried over molecular sieves) was added methyl isocyanate (55 mmol, 3.2 g) in DMSO (2.5 mL) over 15 min at 20° C. The solution was stirred for 15 min and then another portion of sodium methoxide (27.5 mmol, 1.34 g) was added. After stirring for 15 min at 20° C., methyl isocyanate (14 mmol, 0.8 g) was added at this temperature. After a further 15 min, the reaction mixture was allowed to warm to room temperature and was stirred overnight. The resulting yellow suspension was poured into water (50 mL) to obtain a light yellow solution. The neutral impurities were extracted into diethyl ether (3×50 mL). The aqueous layer was acidified with concentrated hydrochloric acid to afford a white solid. The solids were collected by filtration and were washed with water. After air drying, 6.79 g (63% yield) of 3-methyl-6-(trifluoromethyl)uracil was obtained as a white solid: mp 235-237° C. EI-HRMS m/e calcd for C6H5F3N2O2 (M+) 194.0303, found 194.0303.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:5]=1[C:6]#[N:7].[CH2:15]([OH:17])[CH3:16]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:5]=1[C:6](=[NH:7])[O:17][CH2:15][CH3:16]
Reactant: CCO
Reactant: COCc1ccc(OC)c(C#N)c1
Agent: Cl
Product: CCOC(=N)c1cc(COC)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-methoxy-5-methoxymethyl-benzonitrile (235 mg, 1.326 mmol) in anhydrous ethanol (15 mL) at room temperature. After 2 h, hydrogen chloride gas was stopped and the reaction vessel was sealed. After stirring at room temperature for 12 h, the reaction vessel was cooled to 0° C. and opened. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford ethyl 2-methoxy-5-methoxymethyl-benzimidate hydrochloride (340 mg, 99%).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[CH3:2].FC(F)(F)C(O)=O.[N+:22]([O-])([OH:24])=[O:23].N.O>>[CH2:13]([N:3]([CH2:1][CH3:2])[CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:22]([O-:24])=[O:23])[CH:10]=2)[CH2:5]1)[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: CCN(CC)C1Cc2ccccc2C1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCN(CC)C1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 7.5 °C
Reaction time: 5 h

Procedure:
To a solution of Example 226A (2.0 g, 10.57 mmol) in trifluoroacetic acid (80 ml, 1038 mmol) was added nitric acid (0.726 ml, 10.57 mmol) dropwise at 0° C. The mixture was stirred at 0-15° C. for 5 hours. The solution was poured into ice/water (20 mL) and the pH was adjusted to 10 with NH3/H2O. The mixture was extracted with methylene chloride (4×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH3:18][C:19]([CH3:21])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:18][C:19]1([CH3:21])[O:15][CH:12]([CH2:11][O:10][C:9]2[CH:16]=[CH:17][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=2)[CH2:13][O:14]1
Reactant: CC(C)=O
Reactant: CCC(C)Oc1ccc(OCC(O)CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC(C)Oc1ccc(OCC2COC(C)(C)O2)cc1

Procedure:
A mixture of 3-[4-(1-methylpropoxy)phenoxy]-1,2-propanediol (1.0 g, 4.2 mmol), acetone (0.24 g, 4.2 mmol) and p-toluenesulfonic acid (0.03 g) in 20 ml of petroleum ether is heated under reflux for 7 hours. Water generated from the reaction is removed. The final solution is concentrated to remove the solvent and the product is purified by column chromatography to give 2,2-dimethyl-4-[4-(1-methylpropoxy)phenoxymethyl]-1,3-dioxolane, MS m/e 280 (M+).
Reaction SMILES: [Cl-].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5].[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].O1CCOCC1>O.O1CCOCC1>[F:12][C:13]([F:18])([F:17])[C:14]([O-:16])=[O:15].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)C(F)(F)F
Agent: CCCC[n+]1ccn(C)c1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])C(F)(F)F

Procedure:
Analogously to Example 1, 23.0 g (0.132 mol) of 1-butyl-3-methylimidazolium chloride are reacted with 28.0 g of approx. 80% aqueous trifluoroacetic acid, CF3C(O)OH (50% excess). 100 ml of 1,4-dioxane are subsequently added, and 112 ml of HCl- and CF3C(O)OH-containing water/dioxane azeotrope are distilled off at atmospheric pressure (85-101° C.). After four further azeotropic distillations with 100 ml of 1,4-dioxane each time, a further 19 g of approx. 80% aqueous trifluoroacetic acid are added to the residue. 100 ml of 1,4-dioxane are subsequently added, and 105 ml of HCl- and CF3C(O)OH-containing water/dioxane azeotrope are distilled off at atmospheric pressure. After three further azeotropic distillations with 100 ml of 1,4-dioxane each time and drying of the distillation residue under reduced pressure at 1.3 Pa and 70° C., 1-butyl-3-methylimidazolium trifluoroacetate is obtained. The yield is approximately quantitative.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:12][CH3:13])=[O:3].[C:14]([O:19][CH2:20]C)(=[O:18])[C:15]([O-])=[O:16].C[O-].[Na+:24].[Na]>CO.CCOCC>[Na+:24].[CH3:13][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=1[C:2]([O-:3])=[CH:1][C:15](=[O:16])[C:14]([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: COc1cccc(OC)c1C(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(=O)C=C([O-])c1c(OC)cccc1OC
Reaction time: 8 h

Procedure:
A solution of 100 g of 2,6-dimethoxyacetophenone and 7.5 ml of ethyl oxalate in 520 ml of anhydrous MeOH is added slowly to a solution of sodium methylate prepared from 12.7 g of sodium and 285 ml of anhydrous MeOH. The reaction mixture is heated to reflux for 7 hours and left overnight at RT. It is poured into 2 liters of iso ether and left stirring for minutes. The expected product is obtained by filtration, washing with iso ether and drying under vacuum, m=120 g, m.p.=178° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6]CC)=O.[C:9]1([Mg][Cl:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[ClH:16].[C:9]1([C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:6])[CH2:3][NH2:2])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: NCC(O)(c1ccccc1)c1ccccc1

Procedure:
Treatment of ethyl glycinate hydrochloride (4.5 g) with phenylmagnesium chloride (from 0.39 mole each of bromobenzene and magnesium), as discussed by A. McKenzie and G. O. Wills J. Chem. Soc. 1925, 127, 283 (and references cited therein), affords the title compound (mp 191°-193° C.).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCCC1C=CC2[O:39][CH2:40][O:41]C=2C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[O:39]1[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][N:16]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]3)[C:14](=[O:15])[NH:13][C:11]3[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=3)=[CH:24][C:23]=2[O:41][CH2:40]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: BrCCc1ccc2c(c1)OCO2
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc3c(c2)OCO3)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 5-(2-bromo-ethyl)-benzo[1,3]dioxole and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C@@H:8]([CH3:11])[CH2:9]O)=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O>ClCCl>[ClH:14].[Cl:14][CH2:9][C@@H:8]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH3:11]
Reactant: C[C@@H](CO)Nc1ccncc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C[C@@H](CCl)Nc1ccncc1
Product: Cl
Yield: 98.5 %

Procedure:
(S)-2-(Pyridin-4-ylamino)-propan-1-ol (15 g) in dichloromethane (150 ml) was treated with thionyl chloride (59 g) whilst maintaining the temperature <10° C., and the resultant mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (20.1 g).
Reaction SMILES: [CH:1]1([NH2:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(O)C.[I-].C([N+]1(C)[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)C>O>[CH:1]1([N:13]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: NC1CC2CCCc3cccc1c32
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCN(C2CC3CCCc4cccc2c43)CC1
Yield: 14 %

Procedure:
To a mixture of 1,2,2a,3,4,5-hexahydroacenaphthylen-1-ylamine, potassium carbonate (3.89 g) and ethanol (60 ml) was added 1-ethyl-1-methyl-4-oxopiperidinium iodide (8.36 g) dissolved in water (15 ml), and the mixture was heated under reflux for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 1-(1,2,2a,3,4,5-hexahydroacenaphthylen-1-yl)piperidin-4-one (1.01 g, 14%) as an oil.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:30]=[CH:29][C:13]([O:14][CH:15]([C:19]3[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.[C:31]([OH:37])([C:33](F)(F)F)=[O:32].[C:38](#[N:40])C>>[N:1]1[N:2]([C:10]2[CH:30]=[CH:29][C:13]([O:14][CH:15]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:40][CH2:38][CH2:33][C:31]([OH:37])=[O:32])=[O:24])=[CH:27][CH:28]=3)[CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: CC#N
Reactant: O=C(O)C(F)(F)F
Reactant: CCCC(Oc1ccc(-n2cc3c(n2)CCCC3)cc1)c1ccc(C(=O)OC)cc1
Product: CCCC(Oc1ccc(-n2cc3c(n2)CCCC3)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Example 20 using methyl 4-(1-(4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenoxy)butyl)benzoate. Column: Waters Atlantis C18 4.6×50 mm, 5 μm; Modifier: TFA 0.05%; Gradient 95% H20/5% acetonitrile linear to 5% H20/95% acetonitrile over 4.0 min, hold at 5% H20/95% acetonitrile to 5.0 min. Flow: 2.0 mL/min.; Retention time: 3.39 minutes. MS (M+1): 462.2.
Reaction SMILES: [Cl-].N1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=1[O:17][CH3:18].[OH2:19]>CCOCC>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:14][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7]/[CH:10]=[CH:11]/[CH:12]([CH3:15])[CH3:13])=[CH:11][C:10]=1[O:17][CH3:18]
Reactant: O
Reactant: c1ccncc1
Reactant: COc1cc(CN)ccc1O
Agent: [Cl-]
Solvent: CCOCC
Product: COc1cc(CNC(=O)CCCC/C=C/C(C)C)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
By using a similar reaction vessel to that in Example 9, 5.7 parts of 8-methylnon-trans-6-enoyl chloride and 0.2 part of pyridine were added to a solution of 4.7 parts of 4-hydroxy-3-methoxybenzylamine in 25 parts of diethyl ether, and the mixture was stirred at room temperature for 4 hours. After 10 parts of water was added to the mixture and stirred for 5 minutes, the resultant mixture was allowed to stand for 5 minutes. The water layer in the lower layer was discharged. By almost completely removing ether under a reduced pressure, crude (E)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide was obtained. As a result of quantitative analysis of a slight amount of product by an HPLC, the purity of (E)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide was determined to be 90.5%. The irritant nature thereof to skin, especially, to mucosae was strong as nonylic acid vanillylamide obtained in Example 9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.CO>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc(N2CCCC2=O)c1
Temperature: 0 °C
Yield: 37 %

Procedure:
A suspension of 5-(2-oxo-pyrrolidin-1-yl)-isophthalic acid monomethyl ester (A75) (200 mg, 0.76 mmol, 1 equiv) in THF (20 ml) was cooled to 0° C. and treated with BH3-Me2S (2M solution in THF, 0.64 ml, 1.28 mmol, 1.3 equiv). The resulting mixture was refluxed for 1 h and then cooled to room temperature. MeOH (5 ml) was added and the resulting mixture was concentrated in vacuo. The residue was diluted with AcOEt (50 ml) and the resulting solution was washed with saturated aqueous NaHCO3 solution (30 ml) and 2N aqueous HCl solution (30 ml), dried over MgSO4 and concentrated in vacuo to give 3-hydroxymethyl-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B76) (70 mg, 37%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:3]=1[C:4]#[N:5].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>O>[S:23](=[O:26])(=[O:25])([O:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][S:23](=[O:26])(=[O:25])[NH2:24])[C:3]=1[C:4]#[N:5])[NH2:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: O
Product: N#Cc1c(NS(N)(=O)=O)cccc1OCCCCOS(N)(=O)=O
Yield: 63 %

Procedure:
Prepared as in Example 197a from 2-amino-6-(4-(tert-butyldimethylsilyloxy)butoxy)benzonitrile (Example 211b) and sulfamoyl chloride in 63% yield. MS 382 (M++H2O).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][CH2:16][C:17](Br)=[O:18].O>CN(C=O)C>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Cc1cnc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(NC(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-methyl-pyrazin-2-ylamine and cesium carbonate (11.2 g) dissolved in dry DMF (30 mL) was added by dropwise addition bromoacetylbromide (2.89 g) and the mixture stirred at rt for 2 hours. Water (200 mL) was added and the mixture extracted with ethyl acetate (2×100 mL) and dried over magnesium sulfate. Concentration of the extract to ˜50 mL and addition of isohexane (100 mL) gave the sub-titled compound as a solid (1.64 g).