Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28](Br)[S:29][C:23]=2[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[S:29][C:23]=2[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)sc2C1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cc3c(s2)CN(C(=O)OC(C)(C)C)CC3)C1=O
Yield: 59.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 50 mg, 0.28216 mmol) was reacted with 2-bromo-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (90 mg, 0.28216 mmol), 1,4-dioxane (20 mL), copper iodide (5.3 mg, 0.0282 mmol), trans-1,2-diamino cyclohexane (9.69 mg, 0.08464 mmol) and potassium phosphate (179.6 mg, 0.84650 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 70 mg of 2[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (60% yield).
Reaction SMILES: [C:1]1([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C2C(=CC=C([F:32])C=2)N=CC=1C(OCC)=O.C1(NN)C=CC=CC=1>>[F:32][C:16]1[CH:15]=[CH:14][C:13]2[NH:12][CH:11]=[C:10]3[C:19](=[O:20])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:18]=2[CH:17]=1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Solvent: NNc1ccccc1
Product: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 3 of the synthesis of 4a, using 3b and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 7.16 (1H, t, J=13.67 Hz), 7.41 (2H, t, J=7.56 Hz), 7.55 (1H, dt, J=8.54, 2.93 Hz), 7.77 (1H, dd, J=9.27, 4.88 Hz), 7.90 (1H, dd, J=9.27, 2.93 Hz), 8.18 (2H, dd, J=7.58, 1.95 Hz), 8.73 (1H, s). m/z 280.5 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].CCN(C(C)C)C(C)C.[N:14]([CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O-:20])=[O:19])=[N+:15]=[N-:16]>>[N:14]([C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH2:2][C:3]#[N:4])=[O:19])=[N+:15]=[N-:16]
Reactant: N#CCCl
Reactant: [N-]=[N+]=NC(Cc1ccccc1)C(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: N#CCOC(=O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Reaction time: 12 h
Yield: 50 %

Procedure:
Chloroacetonitrile (1 mL) and DIPEA (310 mg, 0.411 mL, 2.41 mmol) were added to 2-azido-3-phenylpropanoate and stirred for 12 h. The solvent was removed under reduced pressure and SiO2 flash chromatography (40-50% ethyl acetate in hexanes) afforded (250 mg) of a white solid in 50% yield. Rf 0.5 in 50% ethyl acetate in hexanes; 1H NMR (500 MHz, CDCl3) δ 7.37 (t, J=7.6 Hz, 2H), 7.32-7.29 (m, 1H), 7.25 (t, J=7.6 Hz, 2H), 4.77 (t, J=1.0 Hz, 1H), 4.18 (dd, J=6.2, 1.8 Hz, 1H), 3.21 (dd, J=14.0, 5.8 Hz, 1H), 3.08 (dd, J=13.9, 8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 168.8, 135.1, 129.3, 129.1, 127.8, 113.7, 62.9, 49.3, 37.7; HRMS (ESI) m/z calcd for C11H10N4O2Na [M+Na]+ 253.070. found 253.071.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([CH2:31][CH3:32])[CH2:6][CH2:7][N:8]1[C:28](=[S:29])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:30])C>FC(F)(F)C(O)=O.O>[CH2:31]([CH:5]([CH2:6][CH2:7][N:8]1[C:28](=[S:29])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:30])[C:4]([OH:33])=[O:3])[CH3:32]
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4cccc(C(F)(F)F)c4)cc3n2C1=S
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC(CCN1C(=O)c2cc3oc(-c4cccc(C(F)(F)F)c4)cc3n2C1=S)C(=O)O
Temperature: 70 °C

Procedure:
Compound 25 (100 mg, 0.22 mmol, prepared as described hereinabove) was dissolved in a mixture of trifluoroacetic acid and water (4:1; 3 ml) and the solution was heated to 70° C. for 7 hours.
Reaction SMILES: [C:1]([C:5]1[C:15]([F:16])=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[C:33]([F:42])[CH:32]=1)[CH3:30]>C(N(CC)CC)C>[C:1]([C:5]1[C:6]([F:17])=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:28][C@@H:29]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[C:33]([F:42])[CH:32]=2)[CH3:30])=[O:13])=[CH:14][C:15]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)c1c(F)cc(OCC(=O)O)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1cc(F)c(C(C)(C)C)c(F)c1)c1ccc(NS(C)(=O)=O)c(F)c1
Yield: 36.9 %

Procedure:
(4-tert-Butyl-3,5-difluorophenoxy)acetic acid (166 mg, 0.68 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (110 mg, 0.68 mmol), triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]-2-fluorophenyl}methanesulfonamide hydrochloride (183 mg, 0.68 mmol) were mixed by the same procedure as described in Example 1(e) to give 115 mg (37%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][CH:6]1[C:7]([CH2:23][O:24][CH3:25])=[CH:8][C@H:9]2[CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][CH:6]1[C:7]([CH2:23][O:24][CH3:25])=[CH:8][C@H:9]2[CH2:14][OH:15])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2CC1C(COC)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON1C(=O)N2CC1C(COC)=C[C@H]2CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 122 (1.7 g, 4.61 mmol) in THF (40 mL), TBAF (6.92 mL, 6.92 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. LCMS indicated the disappearance of starting material and formation of the desired product. The mixture was concentrated and purified by silica gel column (40 g, 50-100% Hex/EA) to give the title compound (1.050 g, 90%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:33]([N:36]([CH:39]([CH3:41])[CH3:40])[CH2:37][CH3:38])([CH3:35])C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:10][C:5]3[CH:6]=[CH:40][C:39]([N:36]4[CH:33]=[CH:35][CH:38]=[CH:37]4)=[CH:41][CH:4]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(-n4cccc4)cc3)C2)c1
Reaction time: 8 h
Yield: 185.8 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (44.4 mg, 0.10 mmol) in CH3CN (5 ml) was added 1-[4-Bromomethyl) phenyl]-H-pyrrole) (35.1 mg, 0.15 mmol) and diisopropylethylamine (35 μl, 0.20 mmol). The reaction was microwaved at 150° C. for 1 hour, then continued at room temperature overnight, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (56 mg, 94%). Calcd for C37H41F3N2O2 (M+H) 602.73, Found 603.5
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([C:20]2([O:28][CH3:29])[CH2:25][CH:24]([CH3:26])[O:23][CH:22]([CH3:27])[CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[CH3:29][O:28][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)[CH:15]=2)[CH2:25][CH:24]([CH3:26])[O:23][CH:22]([CH3:27])[CH2:21]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC1(c2cccc(O)c2)CC(C)OC(C)C1
Product: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CC(C)OC(C)C1
Yield: 91 %

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene (0.234 g) was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (0.2 g, less polar isomer) to give 4-methoxy-2,6-dimethyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran (0.29 g, 92%), m.p. 105°-107° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]#[N:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].P([O-])(OCC)(SCC)=[S:26]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](=[S:26])[NH2:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc(C3(C#N)CCOCC3)cc2)CC1
Reactant: CCOP([O-])(=S)SCC
Product: CC(C)N1CCC(Oc2ccc(C3(C(N)=S)CCOCC3)cc2)CC1
Yield: 74 %

Procedure:
The title compound (320 mg, 74%) was prepared from 4-[4-(1-isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile and diethyl dithiophosphate similarly to the procedure used for intermediate 50. LRMS APCI+ m/z 363 [MH]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][CH2:13][CH2:14][N:15]([CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH2:16][C:17](OC)=[O:18])=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][OH:18])[CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:29][CH:30]=1
Reactant: COC(=O)CN(CCCn1ccnc1)CCOc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCN(CCCn1ccnc1)CCOc1ccc(Cl)cc1

Procedure:
Lithium aluminium hydride (0.23 g) was added to a solution of methyl N-[2-(4-chlorophenoxy)ethyl]-N-[3-(imidazol-1-yl)propyl]glycinate (1.30 g) in THF (30 ml). The mixture was boiled under reflux for 4 hours and then cooled. Water (1 ml) was added followed by 5M sodium hydroxide solution (2 ml) and then more water (2 ml). The mixture was filtered to remove the precipitate using a filtration aid. The filtrate was washed with water, dried and evaporated to give 2-{N-[2-(4-chlorophenoxy)-ethyl]-N-[3-(imidazol-1-yl)propyl]amino}ethanol as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[C:20]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[OH:39])[C:31]([O:33][CH2:34][CH3:35])=[O:32])(=[O:22])[CH3:21]>[Cl-].[NH4+]>[C:20]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[O:39][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])(=[O:22])[CH3:21]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)c(C2CCCN2C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(C2CCCN2C(C)=O)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
15 g of potassium carbonate and 6.4 ml of benzyl bromide were added to a dimethylformamide (100 ml) solution of 12.4 g of ethyl 3-(1-acetyl-pyrrolidin-2-yl)-4-hydroxybenzoate, and the reaction liquid was stirred at 50° C. for 1 hour. The reaction liquid was cooled, diluted with aqueous saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=10/1 to 1/2 to 1/3) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31].Cl>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:29]([O:30][CH3:31])=[O:32])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(CCc2ccc(F)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(CCc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
Methyl 2-(4-fluorophenethyl)piperidine-4-carboxylate (3.89 g, 14.65 mmol) was dissolved in dichloromethane (150 mL). DIPEA (3.06 mL, 17.58 mmol) was added, followed by methyl carbonochloridate (1.615 mL, 20.51 mmol). The mixture was stirred at room temperature for 2 h. 0.1 HCl and DCM were added. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with satd NaHCO3, filtered through a phase separator and evaporated. Dimethyl 2-(4-fluorophenethyl)piperidine-1,4-dicarboxylate (3.19 g, 67%) was isolated. MS m/z 324 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](=[O:10])C)[CH:4]=[N:3]1.[Br:11]N1C(=O)CCC1=O>C1COCC1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[CH:8]=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cnn(C)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cn1ncc(C=O)c1CBr
Yield: 82.7 %

Procedure:
To a stirred solution of 1-(1,5-dimethyl-1H-pyrazol-4-yl)ethanone (471 mg, 3.42 mmol) in THF (13 ml) was added N-bromosuccinimide (637 mg, 3.58 mmol) and benzoyl peroxide (41 mg, 0.17 mmol) at room temperature under nitrogen, then the resulting mixture was refluxed for 20 h. After cooling, the reaction mixture was evaporated to remove the solvents. The residue was chromatographed on a column of silica gel eluting with ethyl acetate-hexane (1:1) gave the title compound as white solid (574 mg, 78% yield). 1H NMR (270 MHz, CDCl3) 2.47 (3H, s), 3.91 (3H, s), 4.87 (2H, s), 7.83 (1H, s). MS (ESI) m/z: 217 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([Cl:14])[C:8]2[C:9]([CH:13]=1)=[N:10][S:11][N:12]=2)=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[NH2:15][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[CH:13][C:9]2=[N:10][S:11][N:12]=[C:8]2[C:7]=1[Cl:14]
Reactant: COC(=O)c1cc2nsnc2c(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1c(C(=O)O)cc2nsnc2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution of 0.37 g (1.50 mmol) of 6-amino-7-chloro-benzo[1,2,5]thiadiazole-5-carboxylic acid methyl ester in 7.32 mL of dioxane and 0.92 mL of MeOH, is added 2.25 mL (2.25 mmol) of an aqueous solution of NaOH 1 N. The mixture is stirred at ambient temperature during 2 hours and then the solvents were evaporated. The residue is suspended in H2O and the mixture is acidified to pH 2-3 with an aqueous 1 N HCl solution. The reddish-violet precipitate obtained is filtrated and washed with a minimum of H2O. 291 mg (1.27 mmol) of the expected product can be isolated. The aqueous phase is extracted with EtOAc (2 times) and then the organic layer is washed once with brine, dried on Na2SO4, filtrated and concentrated under reduced pressure. 10 mg (43.54 ?mol) of the acid is obtained more giving a total amount of 301 mg (1.31 mmol, 87%) of a dark violet solid. LC/MS: 230/232 (M+1)+.
Reaction SMILES: COC[O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:8][CH:7]=1.Cl.O>C(O)C>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=1
Reactant: COCOCc1ccc(-c2nccs2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: OCc1ccc(-c2nccs2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 50.8 %

Procedure:
To a solution of 1-bromo-4-[(methoxymethyloxy)methyl]benzene (3.0 g) in tetrahydrofuran (52 mL) was added n-butyllithium (1.6 mol/L hexane solution, 9.3 mL) at −78° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added triisopropyl borate (2.6 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g). A mixture of the obtained 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g), 2-bromothiazole (1.2 g), cesium fluoride (2.2 g) and tetrakis (triphenylphosphine) palladium (0) (0.16 g) in 1,2-dimethoxyethane (40 mL), ethanol (10 mL) and water (10 mL) was stirred at 85° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g). To a solution of 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g) in ethanol (10 mL) was added 2 mol/L hydrochloric acid solution (5 mL), and the mixture was stirred at 50° C. for 5 hours. Concentrated hydrochloric acid (0.10 mL) was added to the mixture, and the mixture was stirred for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-1/1) to give 4-(thiazol-2-yl)benzyl alcohol (0.33 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]#[C:15][Si](C)(C)C)[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.Cl>[C:14]([C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])#[CH:15]
Reactant: COc1cc(C(=O)O)cc(C#C[Si](C)(C)C)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred solution of 3,4-dimethoxy-5-(trimethylsilanylethynyl)benzoic acid (5.56 g, 20 mmol) in THF (115 mL) at 0° C. was added TBAF (1.0 M solution in THF, 30 mL, 30 mmol). The resulting solution was stirred at 0° C. for 30 min, then the reaction mixture was diluted with 1 N HCl aqueous solution (200 mL), extracted with EtOAc (3×70 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give 3-ethynyl-4,5-dimethoxybenzoic acid (4.0 g). The product was used without further purification.
Reaction SMILES: [CH:1](=[C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC=C1CCc2c(O)cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC1CCc2c(O)cccc21

Procedure:
A mixture of 1-ethylidene-indan-4-ol (37 mg, 0.23 mmol) and 10% Pd/C (12 mg, 10% weight) in methanol (4 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to 1-ethyl-indan-4-ol (36 g, 97%)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[CH2:19][CH3:20])[C:5]1=[O:24])(=O)C.[CH3:25][N:26]([CH3:41])[CH2:27][CH2:28][N:29]([S:37]([CH3:40])(=[O:39])=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[CH3:25][N:26]([CH3:41])[CH2:27][CH2:28][N:29]([C:30]1[CH:31]=[CH:32][C:33]([NH:36]/[C:18](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[CH2:19][CH3:20])=[CH:34][CH:35]=1)[S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(CC)OCC
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(/CC)Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylene)-6-ethoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.3 (silica gel, methylene chloride/ethanol=5:1) C25H32N4O5S
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].CCN(CC)CC.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([S:11]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[Cl:1])[C:6]([OH:8])=[O:7])(=[O:13])=[O:12])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C(=O)O)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 4-chloro-3-(chlorosulfonyl)benzoic acid (200 mg, 0.784 mmol) and Et3N (130 μl, 0.938 mmol) in CH2Cl2 (5 ml) was added 1-(t-butoxycarbonyl)piperazine (161 mg, 0.864 mmol) at 0° C. This mixture was stirred at room temperature overnight, and then diluted with CH2Cl2, washed with 10% citric acid solution. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was suspended in Et2O, and the precipitate was collected by filtration to give crude 3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-chlorobenzoic acid (200 mg, 63.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[N:9][N:10]=2)[CH:7]=1.[SH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][OH:39]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:22]([Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:20][CH2:19][CH2:18][S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([S:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:38][OH:39])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:24])[CH3:23]
Reactant: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Br)cn12)(C(C)C)C(C)C
Reactant: OCc1ccccc1S
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Sc3ccccc3CO)cn12)(C(C)C)C(C)C
Temperature: 111 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
To a solution of aryl bromide of Example 7 (50.7 g, 0.10 moles) in toluene (250 ml) was added (2-sulfanylphenyl)methanol (16.8 g, 0.12 moles), sodium (tert)-butoxide (14.4 g, 015 moles) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (II) (0.41 g, 0.0005 moles). The resultant mixture was sparged with nitrogen for 10 minutes then heated at 111° C. for 16 hours. The reaction was cooled to 20° C., diluted with isopropyl acetate (200 ml) and washed with 2M hydrochloric acid solution (250 ml). The aqueous phase was extracted with isopropyl acetate (50 ml) and the combined organics were washed sequentially with 1M sodium hydroxide solution (250 ml) and 10% w/w sodium chloride solution (250 ml). The solvent was distilled under reduced pressure and replaced with (tert)-butyl methyl ether to give a final volume of 250 ml. The solution was cooled to 5° C. and granulated for 5 hours, then solid was collected by filtration to give the title compound as a white solid (38.5 g, 68%).