Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:26])[N:7]([CH2:14][CH:15]([C:20]1([CH3:25])OCC[O:21]1)[C:16]([O:18][CH3:19])=[O:17])[C:8]2=[O:13])([O-:3])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:26])[N:7]([CH2:14][CH:15]([C:20](=[O:21])[CH3:25])[C:16]([O:18][CH3:19])=[O:17])[C:8]2=[O:13])([O-:3])=[O:2]
Reactant: COC(=O)C(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)C(C)=O

Procedure:
Methyl 2-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared in the same manner as described in the above example 6 (1) from methyl 3-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.24 g, 0.67 mmol) and p-toluenesulfonic acid monohydrate (51 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[S:23][C:24]([S:27][C:28]4[CH:33]=[CH:32][N:31]=[C:30]([C:34](O)=[O:35])[C:29]=4[F:37])=[CH:25][N:26]=3)=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][C:40]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([OH:44])[CH2:41][CH2:42][CH3:43].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[F:37][C:29]1[C:30]([C:34](=[O:35])[NH:38][CH2:39][C:40]([OH:44])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:41][CH2:42][CH3:43])=[N:31][CH:32]=[CH:33][C:28]=1[S:27][C:24]1[S:23][C:22]([NH:21][C:18]2[N:19]=[CH:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[CH:16][CH:17]=2)=[N:26][CH:25]=1
Reactant: CCCC(O)(CN)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3ncc(Sc4ccnc(C(=O)O)c4F)s3)nc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccc(NC4CCN(C(=O)OC(C)(C)C)CC4)cn3)s2)c1F)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirring solution of 4-(2-(5-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)pyridin-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinic acid (586 mg, 1.072 mmol), 1-amino-2-phenylpentan-2-ol (479 mg, 2.672 mmol), EDAC (621 mg, 3.239 mmol), HOBt (235 mg, 1.739 mmol) in NMP (7 mL) was added i-Pr2NEt (0.93 mL, 5.339 mmol) and stirred overnight. LCMS showed complete reaction, which was poured into ˜50 mL water and a solid precipitated. The solid was collected by filtration, washed with water and was allowed to air dry. The product was obtained (838 mg, 100%) as a solid: LC/MS (M+H)+: 708. HPLC ret. time (Condition M): 1.95 min.
Reaction SMILES: C[CH:2]1[CH2:5][CH2:4][C:3]1([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[C:21](=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]2([C:6]([O:8][CH3:21])=[O:7])[CH2:4][CH2:5][CH2:2]2)=[CH:10][CH:11]=1
Reactant: CC1CCC1(C(=O)O)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccc(Cl)cc2)CCC1

Procedure:
To a solution of methyl 1-(4-chlorophenyl)cyclobutanecarboxylic acid (5.0 g, 23.73 mmol) in anhydrous methanol was added 1 mL of the concentration of sulfuric acid. The mixture was refluxed for overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL), dried over MgSO4. The crude product was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:8]=[N:7][C:6]=2[N:5]([CH3:19])[C:3]1=[O:4].ClC1C=CC=C(C(OO)=[O:28])C=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]3[O:28][CH2:18]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:19])[C:3]1=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c2c(ncn2CCCCC2CO2)n(C)c1=O

Procedure:
A solution of 31 g of 1,3-dimethyl-7-(5-hexenyl)xanthine and 34.9 g of m-chloroperbenzoic acid (70% pure) in 700 ml of chloroform was stirred at room temperature for 48 hours. The mixture was shaken with 10% strength sodium dithionite solution until the test with starch-iodide paper was negative, and washed with sodium bicarbonate solution and then with water to neutrality, dried and evaporated under reduced pressure.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([O:23][CH3:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[Li]CCCC.CN(C=O)C>>[CH3:24][O:23][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH:8]=[O:9])=[CH:14][CH:15]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: COC1(c2ccc(Br)cc2)CCC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COC1(c2ccc(C=O)cc2)CCC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S1-A) using 1-bromo-4-(1-methoxycyclobutyl)-benzene (140 mg, 0.58 mmol), n-BuLi (363 μl, 1.6M solution in hexane, 0.58 mmol) and DMF (90 μl, 1.16 mmol). The isolated residue was purified by flash column chromatography (1:9 ether/pentane) to give 4-(1-methoxycyclobutyl)-benzaldehyde (76 mg, 69%) as a colourless oil. 1H NMR (CDCl3, 300 MHz): δ 10.03 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 2.96 (s, 3H), 2.45-2.39 (m, 4H), 1.99 (m, 1H), 1.73 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([NH:6][CH2:7][CH:8]1[O:22][C:11]2=[C:12]3[C:17](=[C:18]([CH3:20])[CH:19]=[C:10]2[CH2:9]1)[NH:16][C:15](=[O:21])[CH:14]=[CH:13]3)=[O:5])[CH3:3].[H][H]>O.[Pd]>[NH2:1][C@@H:2]([C:4]([NH:6][CH2:7][CH:8]1[O:22][C:11]2=[C:12]3[C:17](=[C:18]([CH3:20])[CH:19]=[C:10]2[CH2:9]1)[NH:16][C:15](=[O:21])[CH2:14][CH2:13]3)=[O:5])[CH3:3]
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@@H](C)N)C2
Agent: [Pd]
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNC(=O)[C@@H](C)N)C2
Yield: 49.4 %

Procedure:
The compound obtained in Example 228 (680 mg, 2.0 mmol) was dissolved in water (30 ml). To the obtained solution, 10% palladium-on-carbon (600 mg) was added, followed by stirring at 80° C. for 10 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was purified by silica gel column chromatography (chloroform: methanol =5:1). The obtained crystals were dissolved in methanol (5 ml), and 4N-HCl dioxane (1 ml) was added thereto while cooling on ice. The mixture was condensed under reduced pressure. The resultant residue was recrystallized from methanol--ether, to obtain 300 mg of the title compound as colorless powdery crystals (44.1%).
Reaction SMILES: CN(C)C=O.[C:6]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH2:22]Cl)[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:24])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C(OCC)(=O)C.O>[C:6]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH2:22][NH:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:24])=[CH:8][CH:7]=1
Reactant: Cc1nc2ccc(CCl)cc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(CNCc3ccccn3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To an N,N-dimethylformamide (3 ml) solution of 1-(biphenyl-4-ylmethyl)-6-chloromethyl-2-methylbenzimidazole (0.597 g) and potassium carbonate (0.350 g), 2-aminomethylpyridine (0.372 g) is added and the solution is stirred for two hours at 60° C. Water and ethyl acetate are added and extraction is performed. An organic layer is washed with water (twice). The solvent is removed under reduced pressure and a residue is obtained. The residue is purified through silica gel column chromatography (eluate: chloroform/methanol=9/1). Recrystallization is performed in a mixture solvent of ethyl acetate and hexane and thus, 1-(biphenyl4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl) aminomethyl]benzimidazole 0.300 g is obtained. 1H-NMR (CDCl3, δ): 2.57 (3H, s), 3.91 (2H, s), 3.93 (2H, s), 5.35 (2H, s), 7.08-7.14 (3H, m), 7.23 (2H, d, J=7.3 Hz), 7.30-7.35 (2H, m) 7.41 (2H, t), 7.50-7.55 (4H, m), 7.57 (1H, dt, J=1.8 and 7.6 Hz), 7.68 (1H, d, J=8.1 Hz), 8.53 (1H, d, J=4.9 Hz).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=2[S:12][C:13]=1[C:14](=O)[CH3:15]>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:8][C:9]1[C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=2[S:12][C:13]=1/[C:14](=[N:7]/[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])/[CH3:15]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(=O)c1sc2ccccc2c1Br
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C/C(=N\S(=O)C(C)(C)C)c1sc2ccccc2c1Br
Reaction time: 24 h

Procedure:
A mixture of titanium (IV) ethoxide (2.272 mL, 10.97 mmol), 2-methyl-2-propane-sulfinamide (0.665 g, 5.49 mmol) and 1-(3-bromobenzo[b]thiophen-2-yl)ethanone (1.40 g, 5.49 mmol) in THF (15 mL) was heated to reflux overnight. After 24 h, the reaction was equilibrated to rt and poured into 100 mL of brine. The solid was removed by filtration through celite and the pad was rinsed with 100 mL of EtOAc. The organic layer was stirred over MgSO4, filtered and concentrated under reduced pressure to give an orange oil. The product was purified by column chromatography on a silica column using 20 to 40% gradient of EtOAc-hexane as eluent to give (E)-N-(1-(3-bromobenzo[b]thiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide as an orange oil: 1H NMR (400 MHz, CDCl3) δ 1.34 (s, 9H), 2.98 (s, 3H), 7.35-7.45 (m, 2H), 7.65-7.73 (m, 1H), 7.83 (dd, J=7.3, 2.1 Hz, 1H).
Reaction SMILES: [CH:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[F:27][C:28]1[CH:49]=[CH:48][CH:47]=[CH:46][C:29]=1[CH:30]=[C:31]1[C:36](=[O:37])[C:35](=[CH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[CH2:34][NH:33][CH2:32]1>C(Cl)Cl>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH:38]=[C:35]1[C:36](=[O:37])[C:31](=[CH:30][C:29]2[CH:46]=[CH:47][CH:48]=[CH:49][C:28]=2[F:27])[CH2:32][N:33]([C:14]([CH:13]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:18][C:17]([OH:16])=[O:19])=[O:15])[CH2:34]1
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC=CC(CC(=O)O)C(=O)N1CC(=Cc2ccccc2F)C(=O)C(=Cc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dodecenyl succinic anhydride (179 mg, 0.67 mmol) and triethylamine (0.18 ml, 1.29 mmol) were added to a solution of compound 1 (200 mg, 0.64 mmol) in dry methylene chloride and stirred at room temperature for 2 h. The mixture was chromatographed on a silica column, and the title compound 26 was eluted from the column using 10% methanol:chloroform as eluant. The compound 26 was obtained as yellow thick syrup (352 mg, 95% yield). Rf (10:90 methanol:chloroform)=0.26. 1H NMR (300 MHz, CDCl3): δ 7.90-7.80 (m, 3H, 2C═CH, vinyl-H), 7.42-7.00 (m, 9H, Ar—H, vinyl-H), 5.30-5.05 (m, 4H), 5.00-4.95 (m, 2H), 4.82-7.78 (m, 2H), 4.65-4.40 (m, 4H), 2.85-2.70 (m, 2H), 2.50-2.40 (m, 2H), 2.30-2.10 (m, 4H), 2.08-1.90 (m, 4H), 1.90-1.70 (m, 2H), 0.91 (t, 3H, J=6.4, CH3). 13C NMR (75 MHz, CDCl3): δ 185.81, 173.27, 170.15, 161.96 (d, J=55.2), 159.45 (d, J=53.7), 135.38, 134.29, 133.30, 133.10, 131.52, 130.78, 130.51, 125.33, 124.78, 124.23 (d, J=3.1), 122.47 (d, J=13.3), 122.22 (d, J=14.8), 116.32 (d, J=18.9), 116.22 (d, J=21.8), 115.93 (d, J=25.7), 46.45 (d, J=3.2), 46.48 (d, J=3.1), 35.27, 33.08, 31.92, 29.9, 29.19, 29.44, 29.16, 28.86, 25.05, 24.21, 22.67, 14.13. ESI Mass calculated for C35H41F2NNaO4 (M+Na)+600.29. found 600.20.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[S:18][CH2:19][CH3:20])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O>[Zn].C(O)C>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([S:18][CH2:19][CH3:20])=[C:9]([S:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:8])=[O:7])[CH:14]=1
Reactant: CCSc1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCSc1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 10 h
Yield: 86.5 %

Procedure:
13.3 g of zinc powder are added in portions to a mixture of 12 g of N-tert-butyl-2-ethylmercapto-5-nitrobenzenesulfonamide, 17.7 g of ammonium chloride, 50 ml of water and 200 ml of ethanol and the mixture is stirred at 70° C. for 10 hours. After the solid has been filtered off and washed out with ethyl acetate, the filtrate is concentrated under reduced pressure. The residue from the filtrate is taken up in ethyl acetate and the mixture is washed with water. After drying over magnesium sulfate, the organic phase is concentrated. 9.4 g of the desired aniline are thus obtained;
Reaction SMILES: [NH3:1].Cl.CO[N:5]=[CH:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1>CO>[C:6]([C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1)(=[NH:5])[NH2:1]
Reactant: CON=Cc1ccc(O)c(C(=O)O)c1
Reactant: N
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 40 ml of methanol and 20 ml of liquid ammonia, was added 4.0 g of 5-methoxyiminomethylsalicylic acid hydrochloride. The mixture was stirred overnight at room temperature. A colorless gelatinous substance precipitated from the reaction mixture was washed with methanol, and washed with a water-acetone (20 ml-80 ml) mixture to obtain 2.6 g of 5-amidinosalicylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.CCN(CC)CC.[F:17][C:18]1([F:33])[O:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3([C:30](Cl)=[O:31])[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:30]([C:27]2([C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:33])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:28]2)=[O:31])[CH:5]=[C:4]([CH3:9])[CH:3]=1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1cc(N)nc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
To a solution of 6-chloro-4-methylpyridin-2-amine (300 mg, 2.1 mmol) and Et3N (1.8 mL, 13 mmol) in dichloromethane (5 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (1.6 g, 6.3 mmol) in dichloromethane (5 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (10 mL) and was washed with 1N aqueous HCl (1×20 mL) and saturated aqueous NaHCO3 (1×20 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexane to yield N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (700 mg, 91%). ESI-MS m/z calc. 366.1. found 366.9 (M+1)+. Retention time 2.15 minutes.
Reaction SMILES: [CH3:1][Si:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][O:5][C:6](=[O:34])[C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=[C:9]([O:17][C:18]2[CH:23]=[CH:22][C:21]([P:24]([O:30]C(C)C)([O:26]C(C)C)=[O:25])=[CH:20][CH:19]=2)[CH:8]=1.C[Si](N[Si](C)(C)C)(C)C.[Si](Br)(C)(C)C>C(Cl)Cl>[CH3:36][Si:2]([CH3:1])([CH3:35])[CH2:3][CH2:4][O:5][C:6](=[O:34])[C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[CH:20][C:21]([P:24]([OH:30])([OH:26])=[O:25])=[CH:22][CH:23]=2)[CH:10]=[C:11]([O:13][CH:14]([CH3:15])[CH3:16])[CH:12]=1
Reactant: CC(C)Oc1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(C(=O)OCC[Si](C)(C)C)c1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: CC(C)Oc1cc(Oc2ccc(P(=O)(O)O)cc2)cc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a solution of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid 2-trimethylsilanyl-ethyl ester (5.0 g, 9.30 mmol) in CH2Cl2 (100 mL) was added HMDS (31.7 Ml, 149 mmol), and TMS-Br (9.8 mL, 74.5 mmol). The mixture was stirred at rt for 16 h. The solvent was evaporated and the residue was diluted with water and acidified to pH 2-3 with aqueous HCl. Extracted into EtOAc (2×). The extract was washed with dilute HCl, water, and brine. Dried (MgSO4) and evaporated to provide 2.74 g of 3-Isopropoxy-5-(4-phosphono-phenoxy)-benzoic acid 2-trimethylsilanyl-ethyl ester. 1H NMR (500 MHz, DMSO-d6): δ 7.71 (dd, J=13, 9 Hz, 2H), 7.22 (dd, J=3, 2 Hz, 1H), 7.11 (dd, J=9, 3 Hz, 2H), 7.03 (dd, J=3, 2 Hz, 1H), 6.92 (t, J=3 Hz, 1H), 4.67 (m, 1H), 4.34 (t, 2H), 1.27 (d, J=6 Hz, 6H), 1.05 (t, 2H), 0.01 (s, 9H).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27]C(=O)C4C=CC=CC=4)[CH2:18][CH2:17]3)=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[CH:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:6]=2[CH:1]=1
Reactant: O=C(OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Benzoic acid 2-[2-(4-dibenzo[b,f][1,4]-thiazepin-11-yl-piperazin-1-yl]-ethoxy]-ethyl ester (1.5 g, 2.97 mmol), ethanol (10 ml) and 50% NaOH (1 ml) were charged into a reaction flask. Then the mixture was stirred at 80° C. for 2 h. The reaction mixture was evaporated in vacuo. Ethyl acetate (20 ml) and saturated NaCl-water (15 ml) were added to the residue. The water phase was separated. To the organic phase was added 1 M HCl (10 ml). To the combined water phase was added 50% NaOH until the pH was 12 and saturated NaCl-water (10 ml). The alkaline water phase was extracted twice with ethyl acetate (10 ml). The combined organic phase was washed with saturated NaCl-water (10 ml), dried with Na2SO4 and evaporated. Yield of quetiapine 0.93 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NC
Yield: 56.7 %

Procedure:
This material was prepared by reacting 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (87 mg, 0.35 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (99 mg, 0.42 mmole) and Cs2CO3 (342 mg, 1.05 mmole) in a manner analogous to that described for example 1 to give a yellow solid (89 mg, 37%). 1H NMR (DMSO-d6, 300 MHz), δ8.52 (1H, d, J=5.56 Hz), 8.33 (1H, m), 7.98 (1H, d, J=2.27 Hz), 7.89 (1H, s), 7.81 (1H, d, J=8.59 Hz), 7.40 (1H, s), 7.33 (1H, dd, J=2.27, 8.84 Hz), 7.02 (1H, s), 6.97 (1H, d, J=5.31 Hz), 3.98 (3H, s), 3.00 (2H, q, J=7.58 Hz), 2.83 (3H, d, J=4.80 Hz), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:7]1)[CH2:2][CH:3]([CH3:5])[CH3:4].[F:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([NH:27][NH:28][CH:29]([CH3:31])[CH3:30])=[O:26])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([NH:27][N:28]([C:17](=[O:19])/[CH:16]=[CH:15]/[C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=2)[CH:29]([CH3:30])[CH3:31])=[O:26])=[CH:23][CH:22]=1
Reactant: CC(C)NNC(=O)c1ccc(F)cc1
Reactant: CC(C)CCn1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCn1cc(/C=C/C(=O)N(NC(=O)c2ccc(F)cc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-isopentyl-1H-indol-3-yl)acrylic acid (170 mg, 0.66 mmol), 4-fluoro-N′-isopropylbenzohydrazide (194.3 mg, 0.99 mmol) and HATU (376.4 mg, 0.99 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.17 ml, 0.99 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that ivory (E)-4-fluoro-N′-(3-(1-isopentyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained (160.0 mg, 55.7%).
Reaction SMILES: [CH2:1]([C:4]1([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:6][CH2:5]1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>[OH-].[Na+]>[CH2:1]([C:4]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCCC1(C(=O)O)CC1
Yield: 95 %

Procedure:
A stirred mixture of 21.0 g (0.11 mol) of tertbutyl 1-n-propylcyclopropanecarboxylate and 13.0 g (0.11 mol) of trifluoroacetic acid was refluxed for 3 hours and then added to 20 ml of dilute sodium hydroxide solution. After extraction of the byproducts with diethyl ether, the aqueous phase was acidified with dilute hydrochloric acid and again extracted with diethyl ether. This ether phase was then worked up in a conventional manner to obtain the product. Yield: 95%; colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:31].CO.N>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=[O:31]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCOCC1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6-Methoxy-7-(3-morpholinopropoxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.85 g) was stirred in methylene chloride (20 ml) and methanol (20 ml) and methanolic ammonia (2M, 100 ml) was added. The reaction was stirred at ambient temperature for 48 hours, evaporated to dryness, and then stirred in diethyl ether for 1 hour. The reaction mixture was filtered affording 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one as a solid, (1.22 g, 90%); NMR: 1.9 (m, 2H), 2.4 (broad m, 6H), 3.55 (m, 4H), 3.88 (s, 3H), 4.12 (m, 2H), 7.1 (s, 1H), 7.41 (s, 1H), 7.94 (s, 1H); m/s: M+H+ 320.