Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[N:21]([CH3:22])[N:20]=[C:19]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[N:18]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][N:12]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:13]([C:10]1[O:9][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:17]3[N:21]([CH3:22])[N:20]=[C:19]([CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[N:18]=3)[N:6]=2)=[N:12][N:11]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
tert-Butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (36.81 g, 76.12 mmol) was added to a solution of 2,2,2-trifluoroacetic acid (100 mL, 1305.87 mmol) in DCM (100 mL). The mixture was stirred for 3 hours at room temperature. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (1.5 L) and added to vigorously stirred concentrated ammonia (150 mL) in water (400 mL). The aqueous was washed with DCM (400 mL) and the combined organic solutions were dried with magnesium sulfate, filtered and concentrated to dryness to afford 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (30.0 g, 103%) as a yellow solid:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.CC(C)([O-])C.[Na+]>>[CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][N:12]2[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: c1ccc(CN2C[C@H]3NCC[C@H]32)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: c1ccc(CN2C[C@@H]3[C@H]2CCN3c2cccnc2)cc1
Yield: 98 %

Procedure:
The product from Example 18E (260 mg, 1.0 mmol) and 3-bromopyridine were processed as described in Example 1E, except that a larger amount of sodium tert-butoxide (384 mg, 4.0 mmol) was used to neutralize the salt. The crude product was purified by chromatography (SiO2, CH2Cl2:MeOH, 95:5, Rf 0.3) to provide the title compound (0.26 g, 98% yield). 1H NMR (CD3OD, 300 MHz) δ 2.40 (m, 2H), 3.20 (m, 2H), 3.50-3.80 (m, 4H), 4.10 (m, 1H), 4.50 (m, 1H), 7.00-7.60 (m, 9H); MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:15]1C(=O)N([Cl:22])C(=O)C1.[ClH:23]>CC(O)=O.CCOCC>[ClH:22].[Cl:23][CH2:15][C:9]([C:8]1[CH:7]=[N:6][CH:5]=[CH:4][C:3]=1[C:2]([F:1])([F:14])[F:13])=[O:11]
Reactant: COC(=O)c1cnccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(CCl)c1cnccc1C(F)(F)F
Reaction time: 18 h
Yield: 49 %

Procedure:
In a 100 mL flask was placed 1.84 g (9.7 mmol, 1 eq) of methyl 4-trifluoromethylnicotinate in 25 mL of 1 M HCl in CH3COOH. To this was then added 1.3 g of NCS (9.7 mmol, 1 eq) and the reaction allowed to stir overnight (18 h). The mixture was then transferred to a 500 mL Erlenmeyer flask and to this was added 300 mL of 2 M HCl in Et2O with stirring. This resulted in a white precipitate which was then filtered to provide 1.2 g (49%) of the desired 2-chloro-1-[4-(trifluoromethyl)-3-pyridinyl]ethanone hydrochloride as a white solid. 1H-NMR (DMSO-d6) δ 9.21 (s, 1H), 9.02 (d, 1H), 7.94 (d, 1H), 5.19 (s, 2H).
Reaction SMILES: C([NH:3][C:4](CC(C)=C)(C(OCC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.[CH:19]([NH:21][CH2:22][C:23]([NH:25][CH:26]([CH2:31][CH:32]=[CH2:33])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[O:20]>C(Cl)Cl.CO>[NH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:33][CH:32]=[CH:31][CH:26]([NH:25][C:23](=[O:24])[CH2:22][NH:21][CH:19]=[O:20])[C:27]([O:29][CH3:30])=[O:28]
Reactant: C=C(C)CC(NC=O)(C(=O)OCC)C(=O)OCC
Reactant: C=CCC(NC(=O)CNC=O)C(=O)OC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(N)CC=CC(NC(=O)CNC=O)C(=O)OC

Procedure:
Using the procedure of preparation B of Example 1, diethyl (formylamino)-(2-methyl-2-propenyl)-propanedioate in Step 2 was replaced by methyl 2-[(N-formylglycyl)-amino]-2-(2-propenyl)ethanoate to obtain the expected product with an Rf=0.2 in a methylene chloride/methanol (9:1) mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[CH:21][NH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: Cc1cccc(C(=O)CC(=O)C(F)(F)F)c1
Product: Cc1cccc(-c2cc(C(F)(F)F)n3ncc(C#N)c3n2)c1
Yield: 54.3 %

Procedure:
Reaction of 1-(3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230 mg, 1.0 mmol), prepared from commercially available 3-methyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (164 mg, 54%). MS (ISP) 303.2 [(M+H)+]; mp 202° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.O>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13])[CH2:16][CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C#C[Si](C)(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (25) (200 mg, 0.58 mmol), PdCl2(Ph3P)2 (16 mg, 0.03 mol %) and CuT (6 mg, 0.05 mol %) in triethylamine (1.2 mL) was heated to reflux. (Trimethylsilyl) acetylene (100 μL, 0.7 mmol) was added, and the bright yellow solution quickly turned orange then went brown within a minute. The reaction mixture was stirred for 3 h, cooled to room temperature, diluted with H2O (20 mL), and extracted with CHCl3 (3×15 mL). The combined organics were washed with saturated NaCl (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-[(trimethylsilyl)ethynyl]benzoate 26 (185.5 mg): 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 3.74 (s, 3H), 3.25 (br s, 2H), 2.95 (br s, 2H), 1.49 (br s, 2H), 1.34 (br s, 2H), 0.79 (br s, 3H), 0.56 (br s, 3H), 0.06 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:5])[CH3:4].[N+]([C:17]1[CH:18]=[C:19]([CH:22]=[O:23])[S:20][CH:21]=1)([O-])=O.O>CS(C)=O>[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:21]2[S:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)([CH3:5])[CH3:4]
Reactant: O=Cc1cc([N+](=O)[O-])cs1
Reactant: CC(C)Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2ccc(C=O)s2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.9 %

Procedure:
NaH (60%, 480 mg, 12.0 mmol) was added in several portions to a stirred solution of Example 17A (1.52 g, 10.0 mmol) in DMSO (15 mL) at room temperature. After 20 min, 4-nitrothiophene-2-carbaldehyde (1.57 g, 10.0 mmol) was added in one portion. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with ether (2×). The ether layer was washed with 10% NaOH (1×), brine (1×), dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate: hexane gradient to give the desired product as a brown oil (206 mg, 7.8%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]1=2)=[O:4].[CH2:18]([N:20](CC)CC)[CH3:19].Cl.C(N)C>O1CCOCC1.O>[CH2:18]([NH:20][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]1=2)=[O:4])[CH3:19]
Reactant: CCN(CC)CC
Reactant: O=C(CCl)N1CCSc2ccc([N+](=O)[O-])cc21
Agent: CCN
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCNCC(=O)N1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a stirred solution of 2-chloro-1-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanone (855 mg, 3.14 mmol) in dioxane (15 mL) and triethylamine (0.881 mL, 6.27 mmol) was added ethanamine hydrochloride (1.278 g, 15.68 mmol) as a solution in water (7.50 mL). The resulting mixture was stirred vigorously at room temperature over the weekend. The mixture was then diluted with water and extracted with dichloromethane (2×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:9 (2M NH3 in methanol):ethyl acetate, giving the desired product (775 mg, 88%). 1H NMR (DMSO-d6) δ 8.37 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.7, 2.4 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 3.97-3.90 (m, 2H), 3.52 (s, 2H), 3.37-3.33 (m, 2H), 2.58-2.50 (m, 2H), 2.07 (brs, 1H), 1.00 (t, J=7.0 Hz, 3H); ESI-MS (m/z, %): 282 (MH+, 100).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52]O>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([O:27][CH2:52][C:48]1[O:47][CH:51]=[CH:50][CH:49]=1)[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: OCc1ccco1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCc3ccco3)cccc2[nH]1
Reaction time: 2 h

Procedure:
DEAD (2.1 ml, 13.65 mmol) is slowly added to a solution of 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 g, 9.75 mmol), triphenylphosphine (3.58 g, 13.65 mmol) and furan-2-yl-methanol (1.18 ml, 12.26 mmol) in 10 ml of THF, so that the temperature always remained below 30° C. Stirring is continued for 2 hours and the solvent is then evaporated. The crude residue is purified by chromatography (cyclohexane:EtOAc/95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(O)[CH3:10].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:10]
Reactant: COC(=O)c1ccc(C(C)(O)c2cc(Cl)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)c2cc(Cl)ccc2Cl)cc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To the intermediate from Step A (75 mg, 0.23 mmol) in a screw cap tube was added DCM (2 mL), Et3SiH (0.4 mL) and TFA (0.4 mL). The closed tube was then heated at 75° C. for 1.5 hours. The solution was cooled and concentrated. To the residue, which is a mixture of the title compound and methyl 4-[1-(2,5-dichlorophenyl)vinyl]benzoate (1/1), was added DCM (4 mL) and PtO2 (15 mg). The solution was stirred under a hydrogen atmosphere (balloon) for 3 hours. The hydrogen was purged and the solution filtered. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound LCMS1 4.19 min. (M+H)=309
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A mixture of 0.152 g (0.43 nmmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 1.0 g (6.40 mmol) of 1-(3-aminopropyl)-4-methylpiperazine was heated with stirring in a 170° C. oil bath (pot T=ca. 160° C.) for 3 hours. The excess amine was evaporated at reduced pressure. Water (5 mL) was added, and the separated gum was extracted into 50 mL of 10% methylene chloride-ether. The organic phase was washed three times with 10 mL of water, dried (potassium carbonate), charcoaled, filtered, and concentrated. The remaining gum was dissolved in 3 mL of ether. The crystals that separated on inducement were filtered and washed with ether; wt 0.033 g; mp 170-172° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCOC(=O)CCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 1.42 g of 2,4-dihydroxy-3-propylacetophenone, 2 g of ethyl 4-bromobutyrate, 1.5 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred overnight at room temperature. After addition of 100 ml of water to the reaction mixture, the product was extracted with 30 ml of toluene. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus formed was applied to silica gel column chromatography and eluted with toluene to provide 1.5 g of ethyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyrate as an oily product. In a solution of 2 g of potassium hydroxide dissolved in 40 ml of 80% methanol was dissolved 1.3 g of the oily product and the solution was allowed to stand for one hour. To the reaction mixture was added 20 ml of water and methanol was distilled off under reduced pressure. The aqueous solution thus obtained was acidified by 5% hydrochloric acid and extracted by ethyl acetate. The extract thus formed was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off to provide 1.1 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-butyric acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[NH2:4])[CH3:2].C1C=CC=CC=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:5][CH3:6])[NH:4][C:13](=[O:15])[CH3:14])[CH3:2]
Reactant: CCN(N)CC
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCN(CC)NC(C)=O

Procedure:
N',N'-diethylacethydrazide was prepared following essentially the teaching of Hinman and Fulton, J. Amer. Chem. Soc. 80, 1895-1900 (1958). A mixture of 8.2 g (0.094 mole) of freshly distilled N,N-diethylhydrazine and 75 ml of benzene was added to a three-necked 250-ml round bottom flask equipped with a stirrer, a thermometer and a pressure equilibrating addition funnel capped with a drying tube. The flask was cooled in an ice bath. To this stirred solution was added 12.3 g (0.12 mole) of acetic anhydride. The ice bath was removed and the reaction mixture was heated for 1 hr. at 48°-58°. A fractional distillation of the reaction mixture gave a cut, b.p. 83°-84° at 3 mm, which melted at 47.5°-49.5°. NMR (CCl4, TMS) τ 1.0 (3 H, t), 1.9 (3 H, s), 2.6 (2 H, quad), 8.5 (1 H, broad).
Reaction SMILES: C([C:3]1[NH:4][CH:5]=[C:6](C=O)[N:7]=1)C.C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.N1CCCCC1.[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][C:38]1=[O:46]>CN(C=O)C>[NH:4]1[CH:5]=[CH:6][N:7]=[C:3]1[N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][C:38]1=[O:46]
Reactant: CCc1nc(C=O)c[nH]1
Reactant: O=C1Cc2ccccc2N1
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C1Cc2ccccc2N1c1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-ethyl-4-formylimidazole attached to 2-chlorotrityl resin (4, 78 mg, 0.052 mmol based on 0.67 mmol/g loading), DMF (0.9 ml) and piperidine (0.1 ml) was gently stirred for 45 min. at ambient temperature, afterwhich was added 2-indolinone (5, 70 mg, 0.523 mmol). The resultant mixture was gently stirred and heated at 80° C. for 20 h. The resin was filtered and washed with 30 ml each of acetone, water, dichloromethane, methanol, and another portion of acetone. Finally, the resin was air dried for 20 min.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[CH:16][C:17]=3[CH3:21])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:26])(=O)=O>>[Cl:26][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([CH3:22])[CH:15]=[CH:16][C:17]=2[CH3:21])[S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(C)c2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Product: Cc1ccc(C)c2c1C(=O)N(CCl)S2(=O)=O
Yield: 51 %

Procedure:
The 0.07 g sample of material obtained in the early fractions from the chromatographic separation described above in Preparation 16A consisting predominantly of 2-phenylthiomethyl-4,7-dimethylsaccharin was reacted with 0.05 ml of sulfuryl chloride in MDC and the product recrystallized from cyclohexane-ethyl acetate to give 20 mg (51%) of 2-chloromethyl-4,7-dimethylsaccharin, mp 107°-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:35]=[CH:36][C:37]([C:39]([NH:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[CH:38][C:22]=3[N:21]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:47]([O:53][CH2:54]Cl)(=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:35]=[CH:36][C:37]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH2:54][O:53][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:45])=[O:40])=[CH:38][C:22]=3[N:21]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(-c2nc3cc(C(=O)NCCC(=O)O)ccc3n2CCCCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)n2CCCCc1ccccc1

Procedure:
Prepared by reacting 2-(4-benzyloxycarbonylamidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-1-(4-phenyl-butyl)-benzimidazole with pivaloyloxymethylchloride in dimethylsulphoxide in the presence of potassium carbonate with the addition of potassium iodide at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)([CH2:13][CH2:14][O:15][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9]1)=[O:7]
Reactant: COc1ccc(C2(CCO)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (0.43 g, 0.97 mmol), triethylamine (3.3 mL, 2.4 mmol), and anhydrous dichloromethane (30 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.082 mL, 1.06 mmol) at such a rate that the temperature of the reaction mixture does not rise above 2° C. Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract 3 times with 1M hydrochloric acid solution and 2 times with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound: Rf=0.48 (silica gel, 20/1 ethyl acetate/methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:11][CH:10]=1.[ClH:23].[CH3:24][O:25][NH2:26].C([O-])(=O)C.[Na+]>C(O)C>[CH3:24][O:25][N:26]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[CH:10][CH:11]=1.[ClH:23]
Reactant: CON
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CON=C(c1ccccc1)c1ccc(Nc2ccccc2N)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-aminophenylamino)benzophenone (Compound 101. 0.29 g, 1mmol) and O-methylhydroxylamine hydrochloride (0.30 g, 3.5 mmol) in ethanol (10 ml) was added sodium acetate (0.30 g, 4 mmol). The reaction mixture was refluxed for 25 hours, cooled to room temperature, filtered, and evaporated in vacuo. The residue was treated with diluted ammonium hydroxide (10 ml) and extracted with ethyl acetate (2×25 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo. The residue was dissolved in diethyl ether and acidified with hydrochloric acid in diethyl ether. The hydrochloride of the title compound instantaneously precipitate. The precipitate was triturated with ethyl acetate and washed with diethyl ether to yield the title compound as a hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[C:17]([O-:21])(=[O:20])[CH2:18][CH3:19].[Na+].C(OC(=O)CC)(=O)CC>>[CH3:19][C:18](=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=2)=[CH:10][CH:11]=1)[C:17]([OH:21])=[O:20]
Reactant: Cc1ccc(Oc2ccc(C=O)cc2)cn1
Reactant: CCC(=O)[O-]
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Product: CC(=Cc1ccc(Oc2ccc(C)nc2)cc1)C(=O)O
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A mixture of 5 g of 4-(2-methyl-5-pyridyloxy)benzaldehyde, 5 g of sodium propionate and 35 ml of propionic anhydride was stirred for 3 hours at a temperature of 150° to 155° C. and then concentrated under reduced pressure. Water was added to the mixture which was then heated to crystallize the product. The resulting crystals were separated by filtration, washed with water and recrystallized from a mixture of acetic acid and water to obtain 3.3 g (52% yield) of 2-methyl-3-[4-(2-methyl-5-pyridyloxy)phenyl]propenoic acid as colorless needles having a melting point of 211°-213° C. Recrystallization from a mixture of methanol and isopropyl alcohol yielded colorless prisms having a melting point of 211°-214° C.