Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]([OH:16])=[O:15].[C:17]([C:21]1[N:22]=[C:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([CH2:35]Cl)=[CH:31][C:29]=3[CH:30]=2)[S:24][CH:25]=1)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:35][C:32]1[CH:33]=[CH:34][C:28]3[O:27][C:26]([C:23]4[S:24][CH:25]=[C:21]([C:17]([CH3:19])([CH3:18])[CH3:20])[N:22]=4)=[CH:30][C:29]=3[CH:31]=1)[N:9]=[C:8]2[C:14]([OH:16])=[O:15]
Reactant: COc1ccc2[nH]nc(C(=O)O)c2c1
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C(=O)O)nn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Sodium hydride (60% in mineral oil, 7.79 g) was added into a solution of 5-methoxy-1H-indazole-3-carboxylic acid (17.0 g) in N,N-dimethylformamide (400 ml) at room temperature under nitrogen atmosphere. After 30 minutes, 4-tert-butyl-2-[5-(chloromethyl)benzofuran-2-yl]thiazole (29.76 g) was added to the solution over 5 minutes. After being stirred continuously for 3 hours at 45° C., the reaction mixture was poured into water (2 l) and the reaction vessel was washed with water (200 ml). After combining the washing mixture to the aqueous mixture, the resulting mixture was made acidic with 10% hydrochloric acid aqueous solution (500 ml) and stirred vigorously for one hour. The precipitate was collected by filtration, washed with water and air-dried for one day. The crude product was washed with a mixture of isopropyl alcohol and isopropylethyl ether (7:3) and dried in vacuo to give 5-methoxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indazole-3-carboxylic acid (36.5 g).
Reaction SMILES: [NH2:1][C:2](=[N:26][OH:27])[C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>CC(C)=O>[C:35]([O:27][NH:26][CH:2]([NH2:1])[C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[CH:5][CH:4]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C(N)=NO)cc2)CC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)ONC(N)c1ccc(OCCCN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A solution of Example 2C (0.11 g, 0.29 mmol) and triethylamine (400 μL, 2.9 mmol) in acetone (10 mL) was treated with a solution of acetyl chloride (200 μL, 2.8 mmol) in acetone (1 mL) over 30 minutes, stirred for 1 hour, and concentrated. The concentrate was partitioned between water and dichloromethane. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (Na2SO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 95:5 dichloromethane:methanol to afford 106 mg (87%) of the desired product.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:17](=S)=[S:18]>C(O)C.O>[SH:18][C:17]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nc2ccccc2n1-c1ccccc1
Yield: 74 %

Procedure:
To 18.6 g (0.10M) of N-phenyl-o-phenylenediamine in 100 ml ethanol, 4.8 g (0.12M) of sodium hydroxide in 20 ml water is added followed by 13 g (0.17M) of carbon disulfide. The mixture is heated to reflux for 5 hours. The reaction mixture is poured into 300 ml water and solid is collected. The crude material is recrystallized from ethanol and the recrystallized material weighs 25 g (74% yield) and melts at 195°-7° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][C:11]([CH3:14])([O-:13])[CH3:12].[K+]>O1CCCC1.C(OCC)(=O)C>[C:11]([O:13][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1)([CH3:14])([CH3:12])[CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: Clc1cc(I)cc(Cl)n1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cc(I)cc(Cl)n1

Procedure:
To a solution of 2,6 dichloro-4-iodo pyridine (1 g, 3.65 mmol) in 15 mL tetrahydrofuran was added 1M potassium tert-butoxide (4.02 mL, 4.02 mmol) and the solution heated at reflux for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine and dried over magnesium sulfate, filtered and concentrated. The crude material was used without further purification. MS (DCI) m/e 312.0 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COCCN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCNCCNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.57 g of tert-butyl (2-bromoethyl)carbamate (7.0 mmol, 0.7 equivalents) were initially charged in 98.5 ml of acetonitrile, 0.87 ml of 2-methoxyethylamine (750 mg, 10.0 mmol, 1 equivalent) and 3.5 ml of N,N-diisopropylethylamine (2.58 g, 20 mmol, 2 equivalents) were added and the mixture was stirred at 80° C. overnight. The mixture was concentrated and the residue was purified on a silica gel column (mobile phase: dichloromethane/methanol gradient: from 50:1 to 30:1 to 10:1, then dichloromethane/2 N ammonia in methanol: 10:1). This gave 1.69 g (99% of theory; purity about 90%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1.[OH-].[Na+]>CO>[Cl:22][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]2)[C:3]([OH:23])=[O:2])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COC(=O)C(CC1CCC(=O)C1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid methyl ester (1.02 g, 2.84 mmol) in methanol (7.1 mL) was treated with a 1N aqueous sodium hydroxide solution (6.0 μL, 6.0 mmol). The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo to remove methanol. The resulting aqueous residue was diluted with water (100 mL) and acidified to pH=3 with a 1N aqueous hydrochloric acid solution then extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting yellow oily solid was triturated with ethyl acetate/petroleum ether to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid (800.0 mg, 82%) as a white solid: mp 164-167° C.; (ES)+-HRMS m/e calcd for C15H17ClO5S (M+H)+ 345.0558. found 345.0561.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]2[N:21]([CH3:22])[CH:20]=[CH:19][C:16]2=[N:17][CH:18]=1>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]2[N:21]([CH3:22])[CH:20]=[CH:19][C:16]2=[N+:17]([O-:9])[CH:18]=1
Reactant: Cn1ccc2ncc(Br)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1ccc2c1cc(Br)c[n+]2[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Chloroperbenzoic acid (77 wt %, 3.46 g, 15.4 mmol) was added to a stirred solution of 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine (2.96 g, 14.0 mmol) in DCM (60 mL) at 0° C. The reaction mixture was stirred at RT for 4 hours and then concentrated and purified by silica gel chromatography (7% MeOH/DCM) to give the title compound as a brown semi-solid, which was used without further purification (3.8 g). ESI-MS m/z [M+H]+ calc'd for C8H7BrN2O, 227, 229; found 227, 229.
Reaction SMILES: CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].F[C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]>O>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[O:22][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
To a 100 ml flask fitted with a magnetic stirrer and drying tube is added dimethyl sulfoxide (50 ml), anhydrous potassium carbonate (3.6 g, 0.026 mole) and 2-chloro-4-trifluoromethylphenol (4.8 L g, 0.024 mole). This mixture is stirred at room temperature overnight. 5-Fluoro-2-nitrobenzamide (4.5 g, 0.024 mole) is added rapidly and the reaction mixture stirred at room temperature for 24 hours. The reaction mixture is poured into water (300 ml) and triturated with carbon tetrachloride (50 ml). The water and carbon tetrachloride insoluble solid is collected by filtration and dried under vacuum to afford 1.2 g of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzamide, mp 139°-43° C. Anal. Calcd. for C14H8ClF3N2O4 : C, 46.62; H, 2.23; Cl, 9.83; N, 7.76. Found: C, 45.77; H, 2.30; Cl, 10.62; N, 7.91.
Reaction SMILES: [NH3:1].CO.Cl[S:5]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)(=[O:7])=[O:6]>C1COCC1>[S:5]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)(=[O:7])(=[O:6])[NH2:1]
Reactant: O=S(=O)(Cl)c1ncn2ccsc12
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 2 M ammonia/methanol solution (4 ml) was added to a solution of 0.44 g of 7-chlorosulfonylimidazo[5,1-b]thiazole in 10 ml of THF. The mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1) to give 0.34 g of 7-sulfamoylimidazo[5,1-b]thiazole.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[CH3:26][NH:27][CH2:28][CH3:29]>>[CH2:28]([N:27]([CH3:26])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH:23]([CH3:25])[CH3:24])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:29]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(C(C)C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C18H20FN5O2, 357.2
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]1[NH:25]N=C[CH:22]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[S:33]1C=C(B(O)O)N=[CH:34]1>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]1[N:25]=[CH:34][S:33][CH:22]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc2nc(-c3ccn[nH]3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: OB(O)c1cscn1
Product: Cc1cc2nc(-c3cscn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 1.5 h

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(thiazol-4-yl)quinolin-6-yl)acetic acid (76) was prepared following the procedure for (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid of Example 70 except that thiazol-4-ylboronic acid was used instead of 1H-pyrazol-5-ylboronic acid and the in the final step the reaction was stirred for 1.5 hours. 1H-NMR: 400 MHz, (CD3CN) δ: 9.07 (d, J=2.0 Hz, 1 H), 8.58 (d, J=2.0 Hz, 1 H), 8.17 (d, J=9.2 Hz, 1 H), 8.02 (s, 1 H), 7.93 (d, J=9.2 Hz, 1 H), 7.59 (m, 3 H), 7.35 (d, J=7.6 Hz, 1 H), 5.25 (s, 1H), 2.64 (s, 3 H), 0.98 (s, 9 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:5]2[N:22]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]([N:15]3[CH2:16][CH2:17][N+:18]([CH3:21])([O-:31])[CH2:19][CH2:20]3)[N:5]2[N:22]=1
Reactant: Cc1nc2n(n1)C(N1CCN(C)CC1)=Nc1ccccc1C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc2n(n1)C(N1CC[N+](C)([O-])CC1)=Nc1ccccc1C2

Procedure:
To a solution of 5 g of 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine in 50 ml of methylene chloride is added in portions 3.75 g of m-chloroperbenzoic acid with stirring at 0°. The mixture is then stirred at room temperature overnight and evaporated to dryness. The foamy residue is passed through 100 g of Amberlite IRA-400 ion exchange resin using water as eluent. Evaporation of the eluent gives 2-methyl-5-(4-methyl-4-oxido-1-piperazinyl)-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][Si:29]([CH2:32][CH2:33][O:34][CH2:35]Cl)([CH3:31])[CH3:30]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]1[N:18]([CH2:35][O:34][CH2:33][CH2:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(O)CC1c1nc(-c2ccc(Br)cc2)cn1COCC[Si](C)(C)C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg) was dissolved in DMF (8 mL), and NaH (54 mg) was added. The mixture was stirred over 10 min. and SEM-Cl was added slowly, and then stirred for 2 hours. The mixture was quenched with 3 mL of sat. NH4Cl and was taken up in ethyl acetate (100 mL). The organic phase was washed with saturated sodium bicarbonate (1×100 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 20-50% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (648 mg, 98%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:25]1([CH2:24][CH2:23][CH2:22][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: BrCCCn1ccnc1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCCn1ccnc1
Yield: 37.5 %

Procedure:
Using General Procedure A: 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (91.3 mg, 0.341 mmol), 1-(3-Bromo-propyl)-1H-imidazole (129 mg, 0.680 mmol), KI (5.6 mg, 0.034 mmol), DIPEA (0.18 mL, 1.02 mmol), and DMF (3.4 mL) were stirred at 60° C. overnight. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 90:5:5) followed by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) afforded the free base of the title compound (48 mg, 38%) as a colorless oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:39])[CH2:30][CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>>[CH3:39][N:29]([CH3:28])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:37][CH:38]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CCN(C)C)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(2-dimethylamino-ethyl)-aniline
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>CN(C1C=CN=CC=1)C.C1COCC1>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:20](=[O:19])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:6]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A mixture of 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (439 mg, 1.2 mmol), BOC2O (261 mg, 1.2 mmol), DMAP (10 mg), and THF (10 mL) was stirred at RT for 1 h then concentrated in vacuo to give the crude product. The product was purified by flash chromatography using 1-2% MeOH in CH2Cl2 as the eluent to give tert-butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate as a white solid (110 mg, 26%). 1H NMR (DMSO-d6) δ 10.59 (s, 1H), 8.39 (dd, 1H, J=8.8, 1.1 Hz), 8.32 (dd, 1H, J=10.3, 2.4 Hz), 8.15 (ddd, 1H, J=9.1, 2.5, 1.0 Hz), 7.67 (dd, 1H, J=8.8, 8.8 Hz), 7.45 (s, 1H), 1.44 (s, 9H); MS (ESI−) m/z 349.08 (M−H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)c1ccc(CC(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-tert-butyl-phenyl acetic acid (5.0 g, 26.04 mmol) in DMF (30 mL) at rt were added Cs2CO3 (12.72 g, 39.06 mmol) and benzyl bromide (4.89 g, 28.6 mmol). The reaction mixture was stirred for overnight at room temperature and then the reaction mixture was heated at 100° C. for 1 h and cool to rt. The solvent was removed under reduced pressure and poured into cold 1 N HCl (50 mL). The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure, dried under vacuum. (4-tert-butyl-phenyl)acetic acid benzyl ester was obtained as a yellowish liquid. (5.96 g, 81%): 1H NMR (300 MHz, CDCl3): δ 7.37-7.33 (m, 7H), 7.25 (dd, J=5.4, 13.2 Hz, 2H), 5.14 (s, 2H), 3.65 (s, 2H), 1.32 (s, 9H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[N:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C=CC=CC=1.[O:28]=[CH:29][C:30]([Cl:33])([Cl:32])[Cl:31].C(=O)([O-])[O-].[K+].[K+].OOS([O-])=O.[K+]>C1(C)C=CC=CC=1.CCCCCC>[Cl:31][C:30]([Cl:33])([Cl:32])[CH:29]1[O:28][N:8]1[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Temperature: 120 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
20.0 g (53.0 mol) of triphenyl(t-butoxycarbonylimino)phosphorane was suspended in 80 mL of toluene, mixed with 8.84 g (60.0 mmol) of anhydrous chloral and heated at 120° C. for 4 hours under reflux. After cooling to room temperature, 300 mL of hexane was added, and the resulting white solid was separated by filtration. The filtrate was concentrated under reduced pressure. The resulting brown liquid was dissolved in 200 mL of chloroform, and simultaneous addition of 3.74 g (50.0 mmol) of potassium carbonate in 20 mL of ice-cold water and 4.94 g (15 mmol) of OXONE (2 KHSC5.KHSC4.K2SC4, supplied from Du Pont) in 40 mL of ice-cold water and 1 hour of stirring under cooling with ice were repeated three times. After removal of the aqueous layer, simultaneous addition of aqueous potassium carbonate and aqueous OXONE (2 KHSC5.KHSC4.K2SC4, supplied from Du Pont) and 1 hour of stirring under cooling with ice were repeated three times, similarly. After removal of the aqueous layer, simultaneous addition of aqueous potassium carbonate and aqueous OXONE and 1 hour of stirring under cooling with ice were repeated three times, similarly. After removal of the aqueous layer, 11.2 g (150 mmol) of potassium carbonate in 60 mL of ice-cold water and 14.8 g (45 mmol) of OXONE in 120 mL of ice-cold water were added simultaneously, and the reaction solution was stirred for 1 hour of stirring under cooling with ice. After removal of the aqueous layer, aqueous potassium carbonate and aqueous OXONE were simultaneously added, the reaction solution was stirred for 1 hour of stirring under cooling with ice, similarly. After removal of the aqueous layer, aqueous potassium carbonate and aqueous OXONE were simultaneously added, the reaction solution was stirred for 1 hour of stirring under cooling with ice, similarly. After removal of the aqueous layer, the chloroform layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate {100:0 (volume ratio, hereinafter the same applies) to 80:20} as the eluent to give 10.3 g of the desired product as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1>[CH3:15][S:16]([O:5][CH:3]1[CH2:4][N:1]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:2]1)(=[O:18])=[O:17]
Reactant: OC1CNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Azetidin-3-ol (3.3 g) and DIPEA (20 mL) are dissolved in dry tetrahydrofuran (40 mL). After 30 min the reaction mixture is cooled to 0° C. and methanesulfonyl chloride (10.9 g) is added dropwise. After stirring for 2 hours at ambient temperature, the mixture is concentrated under vacuum, partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. Chromatography of the residue on silica gel (cyclohexane/ethyl acetate 70:30) gives the title compound. Yield: 5 g.