Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][N+:15]([O-])=O)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C=CC=1OC)C=C[N+]([O-])=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH2:13][CH2:14][NH2:15])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=C[N+](=O)[O-])ccc1OCc1ccccc1
Agent: COc1ccc(C=C[N+](=O)[O-])cc1OCc1ccccc1
Product: COc1cc(CCN)ccc1OCc1ccccc1

Procedure:
Substitution of a like quantity of 4-benzyloxy-3-methoxy-β-nitrostyrene for the 3-benzyloxy-4-methoxy-β-nitrostyrene used above and substantial repetition of the foregoing procedure affords, as an oil, 4-benzyloxy-3-methoxy phenethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=[N:19][N:18]=[C:17]1[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].NN>C(O)C>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][C:17]1[N:16]2[C:10]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:22][CH2:21][C:20]2=[N:19][N:18]=1
Reactant: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Product: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1C, 2',5-dichloro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is refluxed with hydrazine to give 1-[2-(dimethylamino)ethyl]-8 -chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 150°-153° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>>[CH:8](/[S:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: C(=C\c1ccccc1)\SCc1ccccc1

Procedure:
A solution of phenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure, part A, to form Z-styryl benzylsulfide. The title compound was obtained in 65% yield by oxidation of the sulfide according to the General Procedure, part B. 1HNMR (CDC13) δ 4.50 (2H, s), 6.65 (1H, d, JH,H=11.2), 7.18-7.74 (10H aromatic+1H ethylenic).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]O.[C:11]([CH2:13][C:14](O)=[O:15])#[N:12]>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:13]([C:11]#[N:12])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1CO
Reactant: N#CCC(=O)O
Product: N#Cc1cc2ccc(Cl)cc2[nH]c1=O
Yield: 16 %

Procedure:
2-Amino-4-chlorobenzyl alcohol (3 g, 19.29 mmol) and cyanoacetic acid (3.61 g, 42.44 mmol) were reacted in a similar manner as described in Example 1 to give 0.63 g of 7-chloro-3-cyano-2(1H)-quinolone. mp 306°-309° C. This nitrile (0.46 g) was dissolved in 1-methylpyrrolidinone and treated with triethylammonium hydrochloride (0.465 g) and sodium azide (0.44 g). The reaction was heated to 140° C. for 1 h, cooled, acidified (HCl), and extracted with ethyl acetate (2×). The combined organic phases were extracted into dilute sodium hydroxide (2×) and washed with diethyl ether. The aqueous layer was acidified and the precipitate which formed was extracted into ethyl acetate (3×). The combined organic phases were washed with water and then evaporated to give the title compound as a powdered brown solid; mp 327° C. (dec) (DMF, acetone, water). (Found: C, 48.61; H, 2.47.C10H6ClN5O requires C, 48.50; H, 2.44%); δH (360 MHz, DMSO-d6) 7.36 (1H, d, dd, J=8.4 and 2.0 Hz, 6-H), 7.44 (1H, d, J=2.0 Hz), 8.01 (1H, d, J=8.4 Hz, 5-H), 8.98 (1H, s, 4-H), 12.3-12.7 (1H, vbr s, NH); m/z (EI+) 247 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][CH:23]=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1Cl
Yield: 98.4 %

Procedure:
A mixture of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (3.95 g, 14.9 mmol) and commercially available 3-aminopyrazole (1.24 g, 14.9 mmol) in acetic acid (40 mL) was refluxed for 5.5 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (4.57 g, 98%) as a yellow solid. MS (EI) 311.2 [(M)+]; mp 114° C.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1COCCN1
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCOCC1

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and morpholine.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[H-].[Na+].[Cl:54][CH2:55][CH2:56]Cl.O>CN(C)C=O>[Cl:54][CH2:55][CH2:56][N:2]([CH3:1])[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: ClCCCl
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCCl)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reaction time: 0.33 h

Procedure:
314 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) was dissolved in 8 mL N,N-dimethylformamide, then 21 mg sodium hydride was added thereto and stirred for 20 minutes, and 0.35 mL 1,2-dichloroethane was added thereto and stirred at room temperature for 2 hours. Further, 0.35 mL 1,2-dichloroethane was added thereto and stirred at 60° C. for 24 hours. Water was added to the reaction solution which was then extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated, and then the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 325 mg of the title compound as a colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C([O-])(=O)C.[Na+]>CCO.O>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(C=O)s1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=NO)s1
Yield: 75.7 %

Procedure:
To a solution of 5-methylthiophene-2-carboxaldehyde (4.0 g, 31.8 mmol; Aldrich) in EtOH (24 mL) was added a solution of hydroxylamine hydrochloride (3.28 g, 47.2 mmol; Aldrich) in water (6 mL) and then a solution of sodium acetate (5.20 g, 67.5 mmol) in water (6 mL after which the mixture heated at reflux for 1 h. The mixture, after cooling, was concentrated in vacuo, and the residue diluted with water and extracted with CH2Cl2 (25 mL×2). The combined extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated. The residual oily solid was triturated with Et2O (˜20 mL) to obtain 3.4 g (76% yield) of the title compound as an off-white powder: HPLC: 1.69 min (at 254 nm); LC/MS m/z 142 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 2.53 (3H, s, CH3), 6.77 (1H, d, J=3.7 Hz, Th—H), 7.21 (1H, d, J=3.7 Hz, Th—H), 7.63 (1H, s, Th—H), 9.22 (1H, br, OH); 1H NMR (500 MHz, DMSO-d6) δ ppm 2.46 (3H, s, CH3), 6.83 (1H, dd, J=3.5, 1 Hz, Th—H), 7.26 (1H, d, J=3.5 Hz, Th—H), 7.71 (1H, s, Th—H), 11.65 (1H, s, 6-NOH); 13C NMR (125.8 MHz, CDCl3) δ ppm 15.4 (CH3), 125.0 (CH), 129.1 (C), 132.5 (CH), 141.4 (CH), 147.0 (C); HRMS (ESI) calcd for C6H8NOS (M+H) 142.0327, found 142.0327 (δ+0.3 ppm). 1H— and 13C-NMR indicated this material was predominantly one geometric isomer. The mother liquor, after concentration gave 0.79 g (18% yield) of the title compound, whose 1H-NMR indicated a ˜1:1 mixture of two geometric oxime isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-:23])=[C:10]([CH3:14])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(-c2ccc(F)cc2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2ccc(F)cc2)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 203 %

Procedure:
To a solution of 1.50 g (8.0 mmol) of 4-(4-Fluoro-phenyl)-2-methyl-pyridine in 25 ml of methylene chloride were added 5.93 g (24 mmol, 3.0 equiv.) of 70% m-Chloroperbenzoic acid. The reaction was stirred for 6 h at room temperature. The reaction was worked up with 50 ml 5% sodium bicarbonate solution. The aqueous phase was extracted twice with 40 ml of methylene chloride. The combined organic phases were washed with 30 ml of brine, dried over magnesium sulfate, and concentrated in vaccuo to yield 3.3 g of a yellow oil which was purified by flash chromatography (ethyl acetate/methanol 9:1) to yield the title compound (1.31 g, 80%) as a crystalline light brown solid, MS (ISP): m/e=204.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:6]=2[O:5][CH:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+].O>CO.O>[N:14]([CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:6]=2[O:5][CH:4]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc2c(CBr)coc12
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc2c(CN=[N+]=[N-])coc12
Temperature: 25 °C
Yield: 94.9 %

Procedure:
3-bromomethyl-7-methoxybenzofuran (565 mg) and sodium azide (230 mg) were dissolved in methanol-water (5:1, 10 ml) and the solution was refluxed for 1 hour. After cooling the reaction solution to room temperature, the reaction solution was poured into water layer (30 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=9/1) using silica gel to obtain the desired compound (452 mg, yield: 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:14]([CH2:15][CH2:16][OH:17])[CH3:13])=[O:6]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1F
Reactant: CNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
3-Chloro-2,4-difluorobenzoylchloride (CAS no. 157373-00-7) (211 mg, 1 mmol) in DCM (1 mL) was added to a stirred solution of 2-(methylamino)ethanol (83 mg, 1.1 mmol) in a mixture of DCM (1 mL) and 10% sodium hydroxide solution (1 mL) at 0° C. The mixture was warmed to room temperature and stirred for approximately 4 hours. The two layers were separated and the aqueous layer was extracted with DCM (3×30 mL). The organic layers were combined, dried (MgSO4), filtered and evaporated to afford the product (180 mg, 61%). 1H NMR δ (400 MHz, CDCl3): 3.01 (s, 3H), 3.37 (t, 1H), 3.74 (t, 2H), 3.92 (t, 2H), 7.06 (td, 1H), 7.28-7.37 (m, 1H).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21](O)=[O:22])[C:2]1=[O:3].S(Cl)[Cl:29]>C(Cl)Cl>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([Cl:29])=[O:22])[C:2]1=[O:3]
Reactant: ClSCl
Reactant: O=C(O)c1ccccc1CCCCCCOc1cc2ccccc2oc1=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1CCCCCCOc1cc2ccccc2oc1=O
Temperature: 35 °C
Reaction time: 5 h

Procedure:
After about 5 g of coumarin-oxyhexylbenzoic acid (compound 3) (about 13.075 mol, about 1 eq) was added to about 100 ml of methylene chloride under nitrogen atmosphere, about 1.71 g of thiochloride (about 14.383 mol, about 1.1 eq) was added thereto and the mixture was stirred at about 35° C. for about 5 hours. Then, the reaction mixture was subjected to evaporation to remove the solvent and recrystalized with ethylacetate/hexane, to obtain coumarin-oxyhexylbenzoyl chloride (compound 4).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a mixture of aluminum chloride (59.0 g) and dichloromethane (500 ml), ethyl chloroglyoxylate (45.4 ml) was added dropwise at 0° C. After stirring for 15 minutes, anisole (40.1 ml) was added dropwise at 0° C., and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was poured onto ice (500 g), and the mixture was stirred for 1 hour at room temperature The dichloromethane layer separated was washed with saturated aqueous sodium chloride, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and ethyl 4-methoxyphenylglyoxylate (43.6 g, yield 60%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:50][CH3:51])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13]1)[CH:8]=[C:7]2[O:21][C@@H:22]1[CH2:26][N:25]([C:27]([NH:29][C@:30]2([C:35]([O:37]CC)=[O:36])[CH2:32][C@H:31]2[CH:33]=[CH2:34])=[O:28])[C@H:24]([C:40](=[O:49])[N:41]([CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH2:48])[CH3:42])[CH2:23]1.CCCC(C(O)=O)CCC=CCCCCCCCCCC>>[Cl:1][C:2]1[C:3]([O:50][CH3:51])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[N:13]1)[CH:8]=[C:7]2[O:21][C@@H:22]1[CH2:26][N:25]([C:27]([NH:29][C@:30]2([C:35]([OH:37])=[O:36])[CH2:32][C@H:31]2[CH:33]=[CH2:34])=[O:28])[C@H:24]([C:40](=[O:49])[N:41]([CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH2:48])[CH3:42])[CH2:23]1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Agent: CCCCCCCCCCC=CCCC(CCC)C(=O)O
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)N[C@]1(C(=O)O)C[C@H]1C=C
Yield: 60 %

Procedure:
Compound 117 was synthesized from compound 116 as a white solid in 60% yield, following the procedure as described for compound 55c.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:9][C:10]([CH3:15])=[CH:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3]>C(O)C.[C].[Pd]>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:9][CH:10]([CH3:15])[CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3]
Reactant: CC(=CC(=O)O)Oc1ccc(Oc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [Pd]
Solvent: CCO
Product: CC(CC(=O)O)Oc1ccc(Oc2ccccc2)c(NS(C)(=O)=O)c1
Yield: 87.1 %

Procedure:
6.5 g of 3-(3-methylsulfonylamino-4-phenoxyphenoxy)-3-methylacrylic acid was suspended in 200 ml of ethanol. Thereto was added 1.3 g of 10% palladium-carbon. The mixture was subjected to hydrogenation at 40°-50° C. at atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration and the solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from toluene to obtain 5.69 g (yield: 87%) of 3-(3-methylsulfonylamino-4-phenoxyphenoxy)-3-methylpropionic acid having a melting point of 121°-124° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(=O)([O-])O.[Na+]>C(O)CO>[N:1]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1ccc2ccccc2n1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: c1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a solution formed by dissolving 4.31 g of anhydrous piperazine in 30 ml of ethylene glycol, 818 mg of 2-chloroquinoline was added, and stirred at 140° C. for 2 hours. After cooling the reaction mixture, saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=2:1) to provide 1.09 g (100%) of 2-piperazin-1-ylquinoline.
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:10](=O)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][C:17]2[C:12](=[CH:10][C:2]3[C:1]([N:7]=2)=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:13]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2nc3ccccc3cc2c1

Procedure:
The title compound can be prepared from N-phenyl-5-methoxy isatin of example 10 and 10% KOH by heating 2 hours on a steam bath. The solution is filtered, then acidified to pH 1 with conc. sulfuric acid. The product is collected by filtration.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25]C(=O)OC(C)(C)C)[S:22][N:21]=4)[CH:18]=3)[N:13]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[S:22][N:21]=4)[CH:18]=3)[N:13]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nsc(N)n4)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a mixture of tert-butyl (3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.49 g, 0.8 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. The reaction was stirred for 2 h at RT. The solvent was then removed in vacuo and the residue was triturated with Et2O to give 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (0.23 g, 56.2%). MS (ESI, pos. ion) m/z: 506.1 (M+1). To a solution of 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (0.23 g, 0.45 mmol) in 1-4-dioxane (10 mL) was added 10% aq NaOH (5 mL) and the reaction was heated at 100° C. for 2 h. The reaction was quenched with ice cold H2O to give a pale yellow precipitate. The precipitate was filtered, washed with ice cold H2O and dried under vacuum. The crude product was purified with preparative HPLC (eluent: 20-80% AcCN in H2O with 0.1% TFA) to give 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (45 mg, 28.3%). MS (ESI, pos. ion) m/z: 352.1 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ 11.81 (s, 1H), 9.19 (s, 1H), 8.20-8.18 (m, 2H), 7.92 (dd, J=8.4, 1.2 Hz, 1H) 7.86 (brs, 2H), 7.63 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 4.32-4.29 (m, 1H), 1.29 (d, J=6.4 Hz, 6H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][CH:16]([CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[CH2:17][CH:18](O)[CH:19]([CH3:21])[CH3:20]>C(Cl)Cl>[Cl:15][CH:16]([CH2:23][C:24]([Cl:25])([Cl:26])[Cl:27])[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(O)CC(Cl)CC(Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CC(C)=CCC(Cl)CC(Cl)(Cl)Cl

Procedure:
Into a 500 ml flask equipped with stirrer, dripping funnel and reflux condenser, there were introduced 12 g of P2O5 in 250 ml of methylene-chloride (CH2Cl2), then dropwise and under stirring, a solution of 10.8 g of 5,7,7,7-tetrachloro-2-methyl-heptan-3-ol (see Example 6) in 50 ml of CH2Cl2.
Reaction SMILES: O.[ClH:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)=[N:13][C:12]=2[C:25]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:26])=[CH:7][CH:6]=1.CO>[C].[Pd].O1CCOCC1>[ClH:2].[NH2:22][C:18]1[CH:17]=[C:16]([C:14]2[NH:15][C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=3)=[C:12]([C:25]([NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[O:26])[N:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)Nc2nccs2)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2[nH]c(-c3cccc(N)c3)nc2C(=O)Nc2nccs2)cc1
Yield: 12.2 %

Procedure:
5-(4-Methoxyphenyl)-2-(3-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide hydrochloride monohydrate (1.0 g) was suspended in a mixed solvent of methanol (100 ml) and dioxane (100 ml), and 10% palladium carbon (containing water 50%, 0.5 g) was added to carryoutcatalyticreductionatnormalpressure. Thereactionmixture was filtered and concentrated. The obtained crude crystals were recrystallized from methanol to give 2-(3-aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide hydrochloride 3/2 hydrate (110 mg), melting point 245° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (5.00 g, 14.7 mmol), isobutyl-amine (7.36 mL, 73.4 mmol) in DMSO (35 mL) at RT according to the general procedure C. Obtained as a yellow solid (5.39 g, 97%).