Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:24][O:23][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=3)[N:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:6]2=[O:22])[O:4][CH2:3]1>CO.CCOC(C)=O.[Pd]>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:6](=[O:22])[C:5]12[O:23][CH2:24][C:2]([CH3:25])([CH3:1])[CH2:3][O:4]1
Reactant: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(N)ccc21
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A mixture of methyl 2-(5,5-dimethyl-5′-nitro-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (344 mg, 0.982 mmol) and 10% w/w Pd/C (cat. amount) in MeOH/EtOAc 1:1 (50 ml) was hydrogenated at 15 psi in a Parr apparatus for 2 hours. The catalyst was removed by filtration, and the residue was evaporated affording crude methyl 2-(5′-amino-5,5-dimethyl-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (307 mg, 0.958 mmol, 98% yield) that was used in the following step without further purification. MS/ESI+ 321.0 [MH]+
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C>[N+:7]([C:10]1[C:18]2[NH:17][C:16](=[O:19])[N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2c([N+](=O)[O-])cccc21
Reaction time: 18 h

Procedure:
Cesium carbonate (1.75 g, 5.4 mmol) was added to a solution of 4-nitro-1,3-dihydro-2H-benzimidazol-2-one (800 mg, 4.5 mmol, described in Intermediate 31) and tert-butyl bromoacetate (0.791 mL, 5.4 mmol) in DMF (15 mL). After 18 h, the reaction was quenched with H2O (100 mL) and the solid precipitate was collected by filtration. The crude product was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—95:5, to give the title compound. MS: m/z=294 (M+1).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=2[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]3[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[C:27]=2[F:34])[CH2:8]1)=[O:6].[CH3:35][NH:36][CH3:37].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:33][C:28]1[C:27]([F:34])=[C:26]([NH:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][C@H:9]4[CH2:10][CH2:11][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:36]([CH3:37])[CH3:35])[CH2:8]4)[CH:14]=3)[N:19]=[CH:18][N:17]=2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)/C=C/CBr)C1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)/C=C/CN(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
580 mg of the compound obtained in step 1) was dissolved in 10 ml of tetrahydrofuran at 0° C., and 5 ml of a 1.0 M dimethylamine-containing tetrahydrofuran solution was added thereto. The resulting mixture was stirred at room temperature for one hour, a saturated sodium bicarbonate was added thereto, and the resulting solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol=30:1) to obtain the title compound (175 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:22]C(=O)C)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([OH:22])[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(O)c2)=C(C)C1=O
Yield: 61.2 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (22 mg, 0.059 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (12 mg, 0.0361 mmol, 61%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[CH3:31][O:32][CH2:33]Cl.O>C(Cl)Cl.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([O:21][CH2:31][O:32][CH3:33])[CH2:18]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COCCl
Reactant: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCOC1CN(C(=O)CCOCCc2ccc3sccc3c2)C1
Temperature: 5 °C
Reaction time: 17 h

Procedure:
In 8.5 mL of methylene chloride was dissolved 1.52 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-1-azetidinyl)-1-propanone, and 2.6 mL of N,N-diisopropylethyl-amine was added to the solution. After the resulting mixture was cooled to 5° C., 1.0 mL of chloromethyl methyl ether was added thereto, followed by stirring at room temperature for 17 hours. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene:ethyl acetate=3:1 to 1:1) to obtain 1.40 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-[3-(methoxymethoxy)-1-azetidinyl]-1-propanone as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)([C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc(CC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
A mixture of benzyl N-t-butoxycarbonyl-4-(3-methylbenzyl)-isonipecotate (2.36 g, 5.57 mmol), 5% palladium on charcoal (250 mg), and glacial acetic acid (3 mL) in methanol (75 mL), was hydrogenated at 50 psi. in a Parr shaker at room temp. overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to provide the title product as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:28])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[C:19]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=[C:15]3N=N2)=[N:6][CH:7]=1.[OH-:29].[NH4+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:28])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:16]2[C:15]([OH:29])=[CH:20][C:19]([CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCn1nnc2cc(Cc3cccnc3)cnc21
Reactant: [OH-]
Agent: [NH4+]
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2cccnc2)cc1O
Reaction time: 0.67 h

Procedure:
A mixture of 3-[4-(5-bromo-3-methylpyrid-2-yl)butyl]-6-(pyrid-3-ylmethyl)3H-1,2,3-triazolo[5,4-b]-pyridine (3.9 g) and polyphosphoric acid (ca. 35 g) was heated with stirring at 190°-200° C. for 40 minutes. The cooled residue was dissolved in aqueous ammonium hydroxide to give a solution of ca. pH 8 and extracted with chloroform (4×100 ml). The combined chloroform extracts were dried over magnesium sulphate, concentrated in vacuo to yield 0.6 g title compound (h) m.p. 162°-5° C. The aqueous fraction was evaporated to dryness to yield a pasty residue, which gave on extraction with hot chloroform a further 0.25 g (h) m.p. 163°-164° C. on evaporation. The residue was then heated under reflux with chloroform for 2 hr. and the chloroform solution was chromatographed on silica gel to yield 1.02 g title compound (i) m.p. 110°-112° c.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:5]=1>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)c1cc(N)cc(NS(C)(=O)=O)c1

Procedure:
3-methylsulfonylamino-5-nitro-benzoic acid methyl ester (32 g; 0.12 mol) was suspended in methanol (500 ml), 4 g (5% w/w; 4 g) was added and the mixture was hydrogenated at 4-5 bar. The reaction mixture was subsequently filtered on a Celite pad and the filtrate concentrated. 23 g (0.08 mmol; 66% yield) of a yellow powder were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cccc(F)c1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2cccc(F)c2)O3)nc1

Procedure:
2-(3-Fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 890 mg of 2-(3-fluorophenyl)chroman-4,6-diol (Example 9(b)). The product was purified by column chromatography using gradient elution with ethyl acetate-heptane (20%→33%) and then crystallised from a mixture of 2-propanol and acetone. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.48 (m, 1H), 7.35-7.31 (m, 2H), 7.26-7.19 (m, 3H), 7.02 (dd, 1H, J 8.8, 2.9 Hz), 6.91 (d, 1H, J 8.8 Hz), 5.67 (d, 1H, J 6.4 Hz), 5.34 (d, 1H, J 10.4 Hz), 4.98 (m, 1H), 2.36 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: [S:1]([CH2:5][CH2:6][NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)([OH:4])(=[O:3])=[O:2].[OH-].[K+].C(O)C.Cl>O>[S:1]([CH2:5][CH2:6][NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)([OH:4])(=[O:3])=[O:2]
Reactant: CCOC(=O)c1ccc(NCCS(=O)(=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCS(=O)(=O)O)cc1

Procedure:
A mixture of 4.4 g. of ethyl 4-(2-sulfoethylamino)benzoate, 2.3 g. of potassium hydroxide, 10 ml. of water, and 90 ml. of ethanol is stirred under reflux for 8 hours, allowed to cool, diluted with water, and brought to pH 4 with concentrated hydrochloric acid. The precipitate is collected by filtration, dried, and recrystallized from acetic acid to yield 4-(2-sulfoethylamino)benzoic acid as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:25])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1>>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:2]2[N:3]=[C:4]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)=[C:8]([CH3:25])[C:6]=3[N:7]=2)=[CH:41][N:42]=1
Reactant: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 96.6 %

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (1.49 gm) was reacted with 985 mg 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to yield 1.62 g tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate. 150 mg of this crude intermediate was subjected to General Procedure D and subsequently reacted with 84 mg D-lactic Acid via General Procedure B to give 106.3 mg of 399 after reverse phase HPLC purification. MS (Q1) 499.3 (M)+
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([N+:10]([O-])=O)=[N:8][CH:9]=1.[CH2:15]([OH:17])C>O.[Fe]>[Br:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([NH:10][CH:15]=[O:17])=[N:8][CH:9]=1
Reactant: CCO
Reactant: COc1cc(Br)cnc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1cc(Br)cnc1NC=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Iron (67.3 g) and ammonium chloride (129 g) were added to a solution of 5-bromo-3-methoxy-2-nitropyridine (56.0 g, CAS #152684-26-9) in ethanol (500 mL) and water (200 mL). The reaction solution was stirred at 80 to 90° C. for one hour and then left to cool to room temperature. The reaction solution was filtered through celite and washed with ethanol. Then, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with THF (84 mL). The THF solution was added dropwise to a mixed solution of formic acid (78.1 mL) and acetic anhydride (78.3 mL) at room temperature. Then, the reaction solution was stirred for one hour. Ice water (500 mL) was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were washed with water and then air-dried. The crystals were recrystallized from toluene to obtain 34.1 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:3]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1
Reactant: Cc1cc2c(cc1OC(C)C)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1OC(C)C)[nH]c(=O)n2C1CCNCC1
Reaction time: 1 h
Yield: 291.3 %

Procedure:
A solution of 1,1-dimethylethyl 4-{6-methyl-5-[(1-methylethyl)oxy]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D76) (0.14 mmol, 53 mg) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL) under argon at room temperature and was allowed to stir for 1 h. The mixture was then concentrated under reduced pressure, the residue was treated with 10% aqueous sodium carbonate solution and extracted 3 times with ethyl acetate. The organics were combined, dried and concentrated under reduced pressure to give the title compound (118 mg, >>100%). M+H 290.3.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[OH-].[Na+]>CO.C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2ccc(C(=O)O)cc21
Reaction time: 8 h
Yield: 248.6 %

Procedure:
Methyl 1-methyl-1H-indole-6-carboxylate 166 (1.24 mmol) was stirred with sodium hydroxide (0.59 g, 14.88 mmol) in a 2:2:1 mixture of methanol/THF/water (7.5 mL) for 36 hrs at rt to form a precipitate which was collected by filtration and lyophilized overnight to give the title compound 167 (0.54 g, 99% yield). MS: 175.06 (calc), 176.1 (obs).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[O:25]C)[C:18]=3[CH3:27])=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH3:27])=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=3)=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CO/C=C/c1cccc(-c2nnc(-c3ccc(OC(C)C)c(Cl)c3)s2)c1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{2-methyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazole (D96) (690 mg, 1.721 mmol) and sodium iodide (516 mg, 3.44 mmol) in Acetonitrile (20 mL) stirred under nitrogen at room temperature was added TMSCl (0.440 mL, 3.44 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 min. Water was added. The aqueous solution was extracted with EA for 3 times. The organic phase was washed with saturated Na2S2O3 solution and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-methylphenyl]acetaldehyde (D97) (666 mg) as a yellow oil, which was used for the next step without further purification. MS (ES): C20H19ClN2O2S requires 386.0. found 387.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:33]([O-])([OH:35])=[O:34]>>[CH3:1][C:2]1([CH3:12])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[C:9]([N+:33]([O-:35])=[O:34])[CH:10]=[CH:11][C:3]1=2
Reactant: CC1(C)OB(O)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OB(O)c2cc([N+](=O)[O-])ccc21
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A 22 L round-bottomed-flask equipped with a mechanical stirrer, thermocouple, 2 L dropping funnel and cold bath was charged with 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (508 g, 300 g contained, 1.85 mol) and trifluoroacetic acid (1.54 L). The solution was cooled to 5° C. Trifluoroacetic anhydride (722 mL, 5.56 mol, 3.00 eq) was added via dropping funnel over 15 min. After aging at 0-3° C. for 30 min, nitric acid (90% fuming, 108 mL, 2.31 mol, 1.5 eq) was added dropwise over 2 h 50 min keeping the internal temp below 5° C. After aging for 1 h, icewater (10.4 L) was added over 50 min maintaining the reaction temp below 15° C. to provide a slurry. The slurry was aged at 0° C. overnight to provide an orange suspension. The solids were collected on a frit, rinsed with cold water (5 L) and air dried under a stream of air to constant weight (ca 24 h) to provide 364 g of 3,3-dimethyl-6-nitro-3H-benzo[c][1,2]oxaborol-1-ol as a 92.4 wt % pure solid (88%). LC/MS: m/z 208 (M+H)'; 1H NMR (DMSO-d6) δ: 8.52 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.4, 2.2 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 1.50 (s, 6H)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[F:17].Cl.[CH3:19][NH:20][O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O.CN(C=O)C>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:20]([O:21][CH3:22])[CH3:19])=[O:13])=[CH:10][C:9]=1[F:17]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Oxalyl chloride (38.1 mL, 0.450 mol) was slowly added to a mixture of 4-bromo-3-fluorobenzoic acid (49.3 g, 0.225 mol) in methylene chloride (300 mL), then DMF (1.0 mL) was added and the reaction was stirred at RT for 2 h. The volatiles were removed under reduced pressure and co-evaporated with toluene for 3 times. The residue was then dissolved in methylene chloride (100 mL). The solution was added dropwise to a mixture of N,O-dimethyl-hydroxylamine hydrochloride (30.7 g, 0.315 mol) and potassium carbonate (120 g, 0.90 mol) in methylene chloride (300 mL) and water (300 mL). The reaction was stirred at RT for 2 h. The organic layer was separated. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the product (58.5 g, 99%). Analytical LCMS: (M+H)+=261.9/263.9.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][OH:9].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27](F)=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[C:34]#[N:35].C(=O)(O)[O-].[Na+]>CS(C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:9][CH2:8][C:4]3[S:3][CH:7]=[CH:6][CH:5]=3)=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[C:34]#[N:35]
Reactant: OCc1cccs1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(OCc4cccs4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33 %

Procedure:
To a mixture of sodium hydride (37 mg, 1.54 mmol) in 3 mL of dimethylsulfoxide is added 2-thiophenemethanol (48 mg, 0.42 mmol). The solution is stirred at room temperature for 45 minutes. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (150 mg, 0.38 mmol) is added and the reaction mixture is heated at 100° C. overnight, then cooled to room temperature. The reaction mixture is poured into saturated sodium bicarbonate and the solids are collected by filtration. Purification by flash column chromatography eluting with 1:1 hexane:ethyl acetate provides 61 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(2-thienylmethoxy)-3-quinolinecarbonitrile, mp 194-196° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:8]=2[CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:8]=2[CH:9]=1)=[O:4]
Reactant: CNC(=O)c1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc2c(N3CCNCC3)cccc2o1

Procedure:
tert-Butyl 4-(2-(methylcarbamoyl)benzofuran-4-yl)piperazine-1-carboxylate (5.8 g, 16.1 mmol) was stirred in dichloromethane (50 mL) and trifluoroacetic acid (12.4 mL, 161.4 mmol) at rt for 4 h. The solvent was removed by rotary evaporation. The residue was dissolved in dichloromethane and 20 mL of 7 N NH3 in methanol was added. The mixture was evaporated onto silica gel, which was added to a silica gel column and eluted with 0-10% methanol (7 N NH3) in dichloromethane. The collected fractions were combined and the solvent was removed by rotary evaporation to give the title compound. Yield: 3.66 g, 87%. MS m/z 260.6 [M+H]+.