Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.Cl>ClCC(Cl)(Cl)Cl>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([C:16]1[S:15][C:14]([CH3:13])=[CH:18][CH:17]=1)=[O:5]
Reactant: Cc1cccs1
Reactant: CCc1ccc(O)c(C(=O)Cl)c1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Product: CCc1ccc(O)c(C(=O)c2ccc(C)s2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-5-ethylbenzoyl chloride (6.08g, 0.036 mol) and 2-methylthiophene were mixed together in tetrachloroethane (20 ml), and stannic chloride (18.78g, 0.072 mol) in tetrachloroethane (20 ml) was added dropwise with stirring, the temperature of the mixture being at about 20° C. by cooling with an ice bath. The mixture was then stirred at room temperature for 3 hours and left to stand at room temperature overnight. The resulting pink solution was poured into ice and concentrated hydrochloric acid (10 to 20 ml), stirred until the ice had melted and extracted with chloroform. The chloroform extract was washed firstly with a saturated solution of sodium bicarbonate and secondly with a saturated solution of sodium chloride, was dried (over Na2SO4), filtered and evaporated to leave an oil which distilled to give the pure title product (4.36g), bp 133°-136° C./0.1 mm, nD21 1.6341.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CC[O:50]CC.[OH-].[Na+].OO>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[CH:9]([OH:50])[CH2:10][CH2:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)N2CCN(C(=O)CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Reactant: CCOCC
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CCN(C(=O)CCCC(O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of 6,6-bis-(4-fluoro-phenyl)-1-[4-(3,4,5,-trimethoxy-benzoyl)-piperazin-1-yl]-hex-5-en-1-one (1.3 g, 2.3 mmol) in dry THF (20 ml) was added NaBH4 (22 mg, 0.58 mmol) followed by dropwise addition of BF3.Et2O (0.2 ml, 1.43 mmol). The resulting mixture stirred at r.t. for 3 hrs and excess NaBH4 decomposed by addition of water(0.1 ml). The mixture was then oxidized by adding 3M NaOH (0.3 ml) followed by addition of H2O2 (0.5 ml, 3 mmol). After stirring for 1.5 hrs at 30-40° C., the mixture was washed with brine (30 ml). The organic layer dried over MgSO4 and evaporated. The residue was purified by column chromatography using EtOAc:hexane (3:1) to give the desired product in 64% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][O:15][CH2:16][C:17]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:18]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-6-nitrobenzothiazole (5.9 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (5.1 g) having the following physical properties.
Reaction SMILES: C1([O:7][S:8](=O)(=[O:10])[NH2:9])C=CC=CC=1.[F:12][C:13]([F:19])([F:18])[C:14]([CH3:17])([OH:16])[CH3:15]>>[F:12][C:13]([F:19])([F:18])[C:14]([O:16][S:8](=[O:10])(=[O:7])[NH2:9])([CH3:17])[CH3:15]
Reactant: CC(C)(O)C(F)(F)F
Reactant: NS(=O)(=O)Oc1ccccc1
Product: CC(C)(OS(N)(=O)=O)C(F)(F)F

Procedure:
Sulfamic acid 2,2,2-trifluoro-1,1-dimethyl-ethyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1,1,1-trifluoro-2-methyl-propan-2-ol to obtain sulfamic acid 2,2,2-trifluoro-1,1-dimethyl-ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(OCc2ccccc2)c1
Yield: 70.6 %

Procedure:
A solution of (E)-methyl 2-(2-((3-hydroxyphenoxy)methyl)phenyl)-3-methoxyacrylate (0.2 g, 0.63 mmol) obtained in Step 1, benzyl bromide (0.1 mL, 0.84 mmol) and cesium carbonate (0.31 g, 0.95 mmol) in 20 mL of acetonitrile (CH3CN) was stirred at room temperature for 3 hours after which the reaction solvent was removed by concentration in a vacuum. The residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum. The concentrate was purified by silica gel chromatography to afford (E)-methyl 2-(2-((3-(benzyloxy)phenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (0.18 g, yield 70%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid (5.05 g, 27 mmol) in 50 mL methanol was added 1 mL of 99% sulphuric acid. The mixture was refluxed overnight, allowed to cool and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated in vacuo to give the title product as a white solid (5.15 g, 26 mmol). 1H NMR (DMSO) δ 8.50 (1H, d), 8.30-8.27 (1H, m), 7.71 (1H, t), 3.90 (3H, s); LC-MS Rt 1.93 min.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH:3](O)[CH2:4][N+:5]([O-:7])=[O:6].S(Cl)(C)(=O)=O.C(N(CC)CC)C.O>ClCCl>[CH3:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CCCC(C)C(O)C[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(C)C=C[N+](=O)[O-]
Yield: 67.5 %

Procedure:
After dissolving 15.0 g of 3-methyl-1-nitro-2-hexanol in 100 ml of dichloromethane, 11.7 g of mesyl chloride and 18.8 g of triethylamine were gradually dropped thereto at 4° C., respectively. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for an hour. Water was added to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 9.0 g of 3-methyl-1-nitrohex-1-ene (yield: 81.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].O1CCCC1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[CH2:4][CH:5]([C:6]#[N:7])[C:8]#[N:9]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(Cl)cc1Cl
Yield: 68.9 %

Procedure:
Using 4.46 g of (2,4-dichlorobenzylidene)malononitrile, 20 ml of tetrahydrofuran, and a suspension of 0.19 g of sodium borohydride in 5 ml of ethanol, and according to the process described in Reference Production Example 8, there was obtained 3.10 g of (2,4-dichlorobenzyl)malononitrile (the intermediate (13)).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC1(C)OC[C@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 47) and 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 5) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as a white solid as a mixture of diastereomers (142.6 mg, 38%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.17 (m, 2H), 1.25 (s, 3H), 1.30 (s, 3H), 1.35-1.77 (m, 7H), 1.86-2.02 (m, 1H), 2.20-2.33 (m, 1H), 3.73 (dd, J=8.3, 5.9 Hz, 1H), 3.97-4.17 (m, 3H), 4.30-4.41 (m, 1H), 5.46 (dd, J=10.6, 4.2 Hz, 1H), 6.03 (d, J=2.6 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.31-7.55 (m, 3H), 7.59 (br s, 1H), 8.22-8.33 (m, 1H), 10.73-10.94 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=3)=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1>CCO>[CH3:1][C:2]1[O:7][C:6]([CH3:8])([CH3:9])[C:5]2[C:10]([O:14][C:15]3[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1
Reactant: CC1=Nc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2C(C)(C)O1
Solvent: CCO
Product: CC1=Nc2cccc(Oc3ccc(N)cn3)c2C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2,4,4-trimethyl-5-[(5-nitro-2-pyridyl)oxy]-3,1-benzoxazine (Intermediate 203, 220 mg, 0.70 mmol) in EtOH (3 mL) palladium on carbon 10% w/w (25 mg) was added and the resulting mixture was stirred for 40 minutes under hydrogen atmosphere (2 bar) at room temperature. The catalyst was filtered off and washed with EtOH (3×10 mL). The filtrate was concentrated to the title compound (185 mg) as greenish solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[F:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:21][CH:20]=1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Fc1ccc(S)cc1
Product: O=C1CCc2cc(OCCCCSc3ccc(F)cc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 4-fluorothiophenol.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:30]1([C:36]2[N:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]4[N:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37]=4)[CH2:31][CH2:32]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc2nc(N3CCNCC3)ncc2c1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3ncc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-piperazin-1-yl-quinazoline.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[CH2:16](Br)[CH:17]=[CH2:18].C>>[CH2:18]([N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1)[CH:17]=[CH2:16]
Reactant: O=C1Nc2ccccc2C12CCCNC2
Reactant: C=CCBr
Agent: C
Product: C=CCN1CCCC2(C1)C(=O)Nc1ccccc12

Procedure:
The compound was prepared according to PROCEDURE 1, Method B by reaction of spiro[indoline-3,3′-piperidin]-2-one with allyl bromide (1.1 equivalents). 13C NMR (CDCl3): δ 21.2, 31.3, 48.4, 53.3, 58.1, 61.6, 109.5, 117.2, 121.6, 125.7, 127.4, 134.3, 135.1, 140.0, 181.6; MS (CI, CH4): m/z (rel. int.) 243 (M+1, 100).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])[CH3:3].[C:32](O)(=[S:34])[CH3:33]>O1CCCC1>[C:32](=[S:34])([O:1][CH:2]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([O:11][CH3:12])=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH:5]=1)[CH3:3])[CH3:33]
Reactant: CC(O)=S
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)O)c(C)nc3OC)CC2)c1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)OC(C)=S)c(C)nc3OC)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
1-{([5-(1-Hydroxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(213 mg, 0.5 mmol) and thioacetic acid(72 μl, 1.0 mmol) were dissolved in tetrahydrofuran and was added into the above solution. The mixture solution was stirred at 0° C. for 1 hour and at room temperature for 1 hour and then was concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH3:1][C:2]1[NH:7][C:6]([S:8][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(=S)NC1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(SCc2ccccc2)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-5-pyrimidinecarboxylic acid, ethyl ester (400 mg., 1.24 mmole), potassium carbonate (270 mg., 2.0 mmole) and benzyl bromide (240 mg., 1.4 mmole) in acetone (7.0 ml.) is stirred at room temperature overnight. The solid is filtered off and the filtrate is diluted with ethyl acetate. The solution is washed with water and brine, and is dried over anhydrous magnesium sulfate. Evaporation of the solvent provides a light yellow solid which is triturated with isopropyl ether and filtered off to give 370 mg. of product. This material is combined with product from another run (150 mg.) and recrystallized from isopropyl etherdichloromethane to give 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-[(phenylmethyl)thio]-5-pyrimidinecarboxylic acid, ethyl ester as light yellow crystals; m.p. 129°-130°. TLC (silica gel; ethyl acetate:hexane, 40:60) Rf =0.39.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][C:23]([OH:25])=[O:24]>O1CCCC1>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:23]([OH:25])(=[O:24])[CH2:22][OH:20]
Reactant: O=C(O)CBr
Agent: OCc1nn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CO

Procedure:
2.4 g of sodium hydride (60% suspension in oil) are added to a solution of all the amount of 1-benzyl-3-hydroxymethylindazole obtained as described above, in 70 ml of tetrahydrofuran and the reaction mixture is heated to reflux under a stream of an inert gas (nitrogen). A solution of 3.5 g of bromoacetic acid in 40 ml of tetrahydrofuran is then added and the reaction mixture is refluxed for 90 minutes. After cooling, the reaction mixture is worked out in a standard manner and acidified. The resulting product is recrystallized from isopropanol. The ether of 1-benzyl-3-hydroxymethylindazole with glycolic acid is thus obtained (Compound I, R=R'=R"'=H), m.p. 136°-138° C.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]([CH:14]=[CH2:15])=[O:13].[N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>ClCCl>[OH:17][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12](=[O:13])[CH:14]=[CH2:15]
Reactant: O=Nc1ccccc1
Reactant: C=CC=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of acrolein (56 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=O)[O:13][C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C@@H:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)[CH:17]=2)=[CH:3]1.C[N:34](C=O)C>N.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:13])[NH:34][C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C@@H:24]3[CH2:28][O:27][C:26]([CH3:29])([CH3:30])[O:25]3)[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(OC[C@@H]4COC(C)(C)O4)c3)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3cccc(OC[C@@H]4COC(C)(C)O4)c3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
3-(1-Methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-phenyl]furan-2,5-dione (5.4 g, 13.7 mmol) was dissolved in DMF (50 mL) and was diluted with NH3 (aq.) (100 mL). The reaction mixture was then heated at 140° C. for 5 h, cooled to room temperature and then diluted with water. The product was extracted with EtOAc and the organic layer was washed with NaCl (sat.) and dried over sodium sulfate to give the crude product which was further purified by re-crystallization from dichloromethane and hexane to give 3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dione (5 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)C(C)(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 60% sodium hydride (2.30 g) and DMF (60.2 mL) was slowly added methyl 2-hydroxy-2-methylpropanoate (6.02 mL) under ice-cooling. Further, 4-(chloromethyl)phenyl methyl ether (7.83 mL) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:hexane=20:80) to obtain methyl 2-[(4-methoxybenzyl)oxy]-2-methylpropanoate (12.5 g) as a colorless oily substance.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([OH:16])[CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:3]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:3][CH:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(O)c1ccc2c(c1)CCCN2C(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(=O)c1ccc2c(c1)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
2.1 g of 1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]ethanol was dissolved in 10 ml of acetone, followed by the addition of 10 g of activated manganese dioxide. The obtained mixture was stirred at room temperature for 16 hours and filtered though Celite to remove the manganese dioxide. The filtrate was concentrated in a vacuum and the obtained residue was purified by silica gel column chromatography (10% ethyl acetate/n-hexane) to give 1.3 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.Cl.C([N:39]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>O.CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH2:39])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A mixture of {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (250 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), 1-hydroxybenzotriazole (100 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min. To the mixture was added aqueous ammonium hydroxide solution (25%, 1 mL). The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (150 mg, 60%) as pale yellow prisms. MS 519 (MH+). mp 131-132° C.