Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:25])=[C:8]([CH:18]=[CH:19][C:20]=2[S:21]([CH3:24])(=[O:23])=[O:22])[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:17])[C:15]=2[OH:16])=[O:10])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([O:16][C:15]1[N:14]([CH3:17])[N:13]=[CH:12][C:11]=1[C:9](=[O:10])[C:8]1[CH:18]=[CH:19][C:20]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:6]([C:3]2[CH2:4][CH2:5][O:1][N:2]=2)[C:7]=1[CH3:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1C1=NOCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)c2cnn(C)c2OCc2ccccc2)ccc(S(C)(=O)=O)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
0.45 g of 4-[3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl]-5-hydroxy-1-methylpyrazole was dissolved in 15 ml of DMF, and 0.26 g of potassium carbonate, then 0.25 g of benzyl bromide were added. The resulting solution was stirred at room temperature overnight. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 0.42 g of the title compound as white crystals. m.p. 151.5~153° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][CH2:2]C([O-])(C)C.[K+].[CH2:8]([O:10][C:11]([C:13]1[C:18]([CH2:19][S:20]([CH2:23][C:24]2[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:34])(=[O:22])=[O:21])=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12])[CH3:9].ICC>CN(C)C=O>[CH2:8]([O:10][C:11]([C:13]1[C:18]([CH:19]([S:20]([CH2:23][C:24]2[C:29]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:34])(=[O:21])=[O:22])[CH2:1][CH3:2])=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12])[CH3:9]
Reactant: CCC(C)(C)[O-]
Reactant: CCOC(=O)c1nccnc1CS(=O)(=O)Cc1c(Cl)cccc1C(F)(F)F
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccnc1C(CC)S(=O)(=O)Cc1c(Cl)cccc1C(F)(F)F
Reaction time: 0.33 h

Procedure:
Potassium tert-pentoxide (0.155 ml, ˜1.7M solution in toluene, Aldrich 60435) was added drop wise to a cooled (0 to 5° C.) solution of 3-(2-chloro-6-trifluoromethyl-phenylmethanesulfonylmethyl)-pyrazine-2-carboxylic acid ethyl ester (Compound B13 of Table B) (0.1 g) in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and stirred cold for 20 minutes. Iodoethane (0.021 ml) was added to the cool dark red solution and stirred at this temperature for a further hour. The reaction mixture was partitioned between ether and 2M aqueous hydrochloric acid. The aqueous layer was extracted with further diethyl ether. The combined organic layers were washed further with water and brine, dried over magnesium sulfate and concentrated to give 3-[1-(2-chloro-6-trifluoromethyl-phenylmethanesulfonyl)-propyl]-pyrazine-2-carboxylic acid ethyl ester Compound No. D1 of Table D (0.106 g). MH+=451, RT=1.58 min.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:9]3[C:14]([N:15]=2)=[C:13]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[N:12]=[CH:11][N:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([C:7]2[N:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:9]3[C:14]([N:15]=2)=[C:13]([NH:16][CH2:17][CH2:18][CH:19]=[O:20])[N:12]=[CH:11][N:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCNc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCNc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To the solution of 3-(8,9-diphenyl-9H-purin-6-ylamino)propan-1-ol obtained in step 1 (0.77 g, 2.24 mmol) in dichloromethane was added Dess-Martin (1.4 g, 3.37 mmol) at room temperature and stirred for 2 hours at room temperature. The resulting reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer thus separated was dried over anhydrous MgSO4 and evaporated in vacuo to provide title compound (0.73 g, 94%) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:22])=[N:18][C:19]=1[O:20][CH3:21].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:22][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[C:19]([O:20][CH3:21])[N:18]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(N)nc1OC
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2cccnc2Cl)nc1OC
Yield: 66.4 %

Procedure:
The title compound (549 mg, 1.66 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol), 5,6-dimethoxypyridin-2-amine (424 mg, 2.8 mmol) and pyridine (0.6 mL, 7.5 mmol) in DCM (10 mL) using the methods of (IntC1).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH:12]C(=O)OC(C)(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH2:12]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CO[C@H]1Cc2ccccc2[C@H]1N
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To tert-butyl [(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate (253 mg, 0.961 mmol) was added a 4.00 M solution of HCl in 1,4-dioxane (5.00 mL) and the mixture was stirred for 10 min, after which a white solid crashed out. The suspension was concentrated in vacuo and co-evaporated with toluene to afford a white solid, which was dissolved in H2(D. The solution was adjusted to pH 10. via addition of Na2CO3. The mixture was then extracted with Et2O (3×30 mL) and the organic extracts were concentrated in vacuo to afford the title compound (150. mg, 99%). LC/MS: Rt=0.85 min, ES+ 164 (AA standard).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[S:12][C:13]([NH2:16])=[N:14][N:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([O:8][C:9]([C:11]1[S:12][C:13]([NH:16][C:25]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[N:14][N:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nnc(C(=O)OCc2ccccc2)s1
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1nnc(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of the product of Step (d) (0.1 g, 0.000425 mol) in THF (6.07 mL) was added benzyl isocyanate (0.0525 mL, 0.000425 mol), and the mixture was stirred overnight at room temperature. After 24 hours, the mixture was rotary evaporated and the concentrate was diluted with ethyl ether and dichloromethane. A solid was filtered and washed with ethyl ether. The mother filtrate was rotary evaporated and the residue triturated with ethyl ether and dichloromethane to give additional solids. The solids were combined to give 0.12 g of 5-(3-benzyl-ureido)-1,3,4-thiadiazole-2-carboxylic acid benzyl ester; mp 188-192° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])([O-])=O.C(OC1C=C(C=CC=1[N+]([O-])=O)C(OCC=C)=O)C=C.N>>[NH2:1][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7]
Reactant: C=CCOC(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCOC(=O)c1ccc([N+](=O)[O-])c(OCC=C)c1
Agent: N
Product: C=CCOC(=O)c1ccccc1N

Procedure:
The above nitro compound was reduced by the method described in example 1, for the reduction of allyl 3-allyloxy-4-nitrobenzoate, except using an aqueous solution of ammonia in place of sodium bicarbonate in the work-up, to give allyl 2-aminobenzoate.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:40])[CH:10]=1)(=[O:5])=[O:4])[CH3:2].FC(F)(F)C(O)=[O:44]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CS(O)(=O)=O>[CH3:6][S:3]([OH:4])(=[O:5])=[O:44].[CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:40])[CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OC(C)(C)C)c(F)c3)c2)c(C)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-{4-[({4′-[2-(ethylsulfonyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)amino]-2-fluorophenyl}propanoate (1.17 g, 2.05 mmol) in toluene (20 mL) was added trifluoroacetic acid (20 mL) under stirring at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/4) to give a colorless oil. The obtained oil was diluted with ethyl acetate, and methanesulfonic acid (0.12 mL) was added. The precipitated crystals were collected by filtration, washed and dried to give the title compound (1.00 g, yield 80%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH3:18]>CCO>[Cl:11][C:4]1[N:3]=[C:2]([NH2:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To an ice-cooled solution of 2,6-dichloro-3-nitropyridine (55.65 g, 288 mmol) in EtOH (500 ml) was added sodium carbonate (76.32 g, 720 mmol) followed by aqueous ammonia (35%, 21 ml). The reaction was then allowed to warm to rt, stirred at rt for 1 h, then at 50° C. for 1 h and then at 90° C. for 1 h. Another 20 ml of aqueous ammonia was added and heating continued at 90° C. for a further 1 h. Another 50 ml of aqueous ammonia was added and heating continued at 90° C. for a further 1 h. The reaction was cooled to rt, and the solid was filtered, washed with water (500 ml) and dried in vacuo to give the title compound as a yellow solid (37.25 g, 75%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(OC([O-])=O)([O:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O)=O>O1CCCC1>[N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCSCC1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
Thiomorpholine (5.0 ml, 53 mol) was dissolved in tetrahydrofuran (200 ml); triethylamine (8.1 ml, 58 ml) was added thereto; and the reaction mixture was stirred at room temperature. tert-Butoxycarbonyl dicarbonate (13.3 ml, 58 mmol) was added thereto and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure; and the residue was purified by silica gel column (eluent; hexane:ethyl acetate=from 80:20, 75:25 to 70:30) to yield the title compound as colorless crystals (10.4 g, 51 mmol).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][CH:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:6])C.[NH3:32]>C(O)C>[NH2:32][C:4](=[O:3])[C:5]([NH:7][CH:8]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:9]([O:11][CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:10])=[O:6]
Reactant: N
Reactant: CCOC(=O)C(=O)NC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: NC(=O)C(=O)NC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
A mixture of 10mM of DL-α-[(2-ethoxy-1,2-dioxoethyl)-amino]phenylacetic acid, diphenylmethyl ester in 50 ml. of ethanol containing 13mM of ammonia is stirred for 15 minutes. After a short time, a thick slurry forms. The product, DL-α-[(2-amino-1,2-dioxoethyl)amino]phenylacetic acid, diphenylmethyl ester, is filtered off and recrystallized from toluene in the form of white filaments, m.p. 168°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][S:17][C:12]=3[C:11](=O)[N:10]=2)=[C:4]([F:19])[CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=2[F:19])[N:10]=1
Reactant: O=c1nc(-c2cc(F)c(Cl)cc2F)[nH]c2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(-c2nc(Cl)c3sccc3n2)c(F)cc1Cl
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4(1H)-one and phosphorus oxychloride was stirred for four hours at 90° C. to give 4-chloro-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[N:23](COCC[Si](C)(C)C)[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].Cl.[OH-].[Na+]>CCO>[NH:23]1[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=[C:19]1[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:13][CH:14]=1
Reactant: CCn1nc(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1nc(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc21
Yield: 78.8 %

Procedure:
A mixture of 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1H-pyrazolo[4,3-b]pyridine (510 mg), 6 M HCl aqueous solution (5 mL), and EtOH (5 mL) was refluxed for 2 h. The reaction mixture was poured into 1 M NaOH aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (1/1) and recrystallized from MeOH to give the title compound (294 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH2:18].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH:18][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1nc(Cl)nc(Nc2c(Cl)cccc2Cl)n1
Yield: 91.2 %

Procedure:
2,4,6-trichloro-1,3,5-triazine (0.0266 mol) was added to 1,4-dioxane (50 ml) under Ar atmosphere. The solution was stirred until it became homogeneous, then 2,6-dichlorobenzenamine (0.0266 mol) and K2CO3 (0.0362 mol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. Water was added to the residue and the aqueous phase was extracted with CH2Cl2. The separated organic layer was washed with brine, dried with potassium carbonate, filtered and the filtrate was evaporated, yielding 7.52 g (91.2%) of N-(2,6-dichlorophenyl)-4,6-dichloro-1,3,5-triazin-2-amine (interm. 4).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:12]([NH:14][CH3:15])=[O:13])[CH:3]=[CH:2]1>CCO.[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH:3]=[CH:2]1
Reactant: CNC(=O)C=C(c1ccccc1)c1cccc2cc[nH]c12
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12

Procedure:
To a solution of 3-(1H-indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII in EtOH (8 ml) was added Degussa's catalyst (10% Pd/C wet, 55 mg). The reaction mixture was subjected to a hydrogenation reaction in a Parr apparatus at 50 psi of H2 for 20 hours. The reaction mixture was filtered through a celite pad, and the filter cake was washed with MeOH. The filtrate was concentrated affording 3-(1H-indol-7-yl)-N-methyl-3-phenyl-propionamide XIX as a white solid in quantitative yield (296 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[S:10][C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].CS(N(C1SC(C(OC(C)(C)C)=O)=CC=1)S(C)(=O)=O)(=O)=O>CN(C=O)C>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][N:5]([C:6]2[S:10][C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=2)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)c1ccc(NS(C)(=O)=O)s1
Reactant: ClCCN1CCOCC1
Agent: CC(C)(C)OC(=O)c1ccc(N(S(C)(=O)=O)S(C)(=O)=O)s1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(N(CCN2CCOCC2)S(C)(=O)=O)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 119.4 %

Procedure:
A mixture of tert-butyl 5-(methylsulfonamido)thiophene-2-carboxylate (int. 56) (773 mg, 2.79 mmol), 4-(2-chloroethyl)morpholine hydrochloride (778 mg, 4.18 mmol) and K2CO3 (963 mg, 6.97 mmol) in DMF (30 ml) was heated to 80° C. for 6 hours. In parallel a mixture of tert-butyl 5-(N-(methylsulfonyl)methylsulfonamido)thiophene-2-carboxylate (Int. 57) (420 mg, 1.182 mmol), 4-(2-chloroethyl)morpholine hydrochloride (330 mg, 1.772 mmol) and K2CO3 (408 mg, 2.95 mmol) in DMF (15 ml) was heated to 80° C. for 4 hours, stirred at RT overnight and heated to 80° C. for additional 2 hours. The two reaction mixtures were combined and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic layers were washed several times with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc=6/4 to EtOAc 100%) to afford tert-butyl 5-(N-(2-morpholinoethyl)methylsulfonamido)-thiophene-2-carboxylate (Int. 58) (1.3 g, 3.33 mmol, MS/ESI+391.0 [MH]+).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:20]([CH3:25])[C:21]([O:23]C)=[O:22])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>C(O)C>[C:1]1([CH3:26])[CH:2]=[CH:3][C:4]([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:20]([CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=3)[CH2:12]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(C)cc1)C2
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NC2Cc3ccc(C(C)C(=O)O)cc3C2)cc1
Reaction time: 0.5 h

Procedure:
1 ml of 15N sodium hydroxide solution is added to 1.2 g of methyl 2-(2-p-toluenesulphonamido-indan-5-yl)-propionate in 12 ml of ethanol and the mixture is boiled for 0.5 hour. The mixture is evaporated, the residue is dissolved in water and the reaction product is precipitated with hydrochloric acid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1.[O:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]1[CH:30]=[CH:29][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[O:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:2]3[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=3)[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: c1cc(C2=NCCO2)ccc1OCCCN1CCNCC1
Reactant: CSc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CSc1ccc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)nn1
Reaction time: 120 h
Yield: 11.2 %

Procedure:
A mixture of 2.4 parts of 3-chloro-6-(methylthio)pyridazine, 4.5 parts of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]piperazine, 1.6 parts of sodium carbonate and 80 parts of 1-butanol was stirred for 5 days at reflux temperature. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 0.7 parts (11.2%) of 3-[4-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]-1-piperazinyl]-6-(methylthio)pyridazine; mp. 163.1° C. (comp. 83).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:31])=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[C:21]([F:30])[CH:20]=2)[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.CCOC(C)=O>C1COCC1.CCCCCC>[F:30][C:21]1[CH:20]=[C:19]([C@@H:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:10][C:8]([C:5]2[N:6]=[CH:7][C:2]3[NH:1][C:33](=[O:35])[O:31][C:3]=3[CH:4]=2)=[O:9])[CH:24]=[CH:23][C:22]=1[O:25][C:26]([F:27])([F:29])[F:28]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cnc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1cc2oc(=O)[nH]c2cn1
Temperature: -78 °C

Procedure:
To a cooled (−78° C.) and stirred mixture of ((S)-5-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-hydroxypicolinamide (200 mg, 0.00045 mol) in THF (5 mL) was added TEA (0.31 mL, 0.002 mol, Spectrochem, India) and triphosgene (270 mg, 0.0009 mol, Spectrochem, India). The reaction mixture was stirred for 2 h at same temperature, slowly warmed to rt and stirred overnight. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was quenched with sat'd NaHCO3 (5 mL), extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography, silica gel (60-120 mesh) using 50-60% EtOAc in petroleum ether as the eluent, followed by further purification using Prep TLC plates, mobile phase 50% EtOAc in hexanes to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.79 (d, J=7.2 Hz, 1H), 9.00 (s, 1H), 8.53 (d, J=4.4 Hz, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 7.44-7.35 (m, 1H), 7.35-7.31 (m, 3H), 7.26-7.21 (m, 1H), 6.64 (d, J=7.6 Hz, 1H). MS (ESI, positive ion) m/z: 467.2 (M+H).