Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:47][O:46][C:40]1[CH:39]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH3:45]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(OC)c1
Reactant: COC(=O)c1sccc1NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
After adding 30 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 25 μl of triethylamine to a solution of 80 mg of {2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (36d)) in 3 ml of DMF, the mixture was stirred at 85° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of methanol and 2 ml of THF. After adding 35 ul of acetic acid and 56 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 15 hours. Next, 2 ml of an aqueous 1N sodium hydroxide solution was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. After adding 2 ml of 1N hydrochloric acid to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 70 mg of 3-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:28])=O>CN(C)C=O>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:28])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1.15 h

Procedure:
To a mixture of acid 1 (10.0 g, 79 mmoles) in 100 ml of oxalyl chloride was added one drop of dimethylformamide. The mixture was stirred for 1.15 h at 23° and then the excess oxalyl chloride was distilled off at 23° and 10-20 torr to give acid chloride 2 as a brown oil, 11.4 (100%). ##STR182##
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH:50](O)[CH3:51])[CH2:45][CH2:44]1>>[CH3:51][CH:50]([O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)[CH2:49][N:46]1[CH2:47][CH2:48][O:43][CH2:44][CH2:45]1
Reactant: CC(O)CN1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OC(C)CN2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 1-morpholinopropan-2-ol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-methyl-2-morpholin-4-yl-ethyl ester. MS (ES+) m/z calcd. for C38H43Cl2F2N4O5: [(M+H)+]: 743. found: 743.
Reaction SMILES: [CH2:1]([N:5]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([O:32]C)=[O:31])[CH2:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]([N:5]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:22]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([OH:32])=[O:31])[CH2:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CC(C)C)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of methyl 1-isobutyl-8-[4-(2-propoxyethoxy)phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (1.20 g) in a mixture of ethanol-THF (10-5 ml) was added an aqueous 1N sodium hydroxide solution (5.2 ml) at room temperature. The mixture was stirred at 60° C. for 16 hours and cooled to 0° C., 1N Hydrochloric acid (6 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropylether to give 1-isobutyl-8-[4-(2-propoxyethoxy)phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (0.96 g) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=C(C)[C:3]=1[CH2:4][O:5][C:6]1[C:7]([N+:12]([O-:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.C(OC(=O)C)(=[O:22])C.S(=O)(=O)(O)O.[C:32]([OH:35])(=O)[CH3:33]>[O-2].[O-2].[O-2].[Cr+6]>[CH:1]([C:2]1[CH:18]=[CH:17][CH:16]=[C:33]([CH:32]=[O:35])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([N+:12]([O-:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:22]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1COc1cccnc1[N+](=O)[O-]
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: O=Cc1cccc(C=O)c1COc1cccnc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(2,6-dimethylbenzyloxy)-2-nitropyridine (2.6 g) in a mixture of acetic acid (26 ml), acetic anhydride (39 ml) and sulfuric acid (5 ml) was added chromium trioxide (2.5 g) portionwise during a period of 20 minutss at 10° C. After being stirred for 2 hours at the same temperature the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl alcohol and the solution was made strongly basic to litmus with an aqueous solution of 24% sodium hydroxide with ice-cooling. After being stirred for 2.5 hours at an ambient temperature, the mixture was diluted with ice water. The resulting precipitates were filtrated off and dried to give a mixture (1.29 g) of 3-(2,6-diformylbenzyloxy)-2-nitropyridine and 3-(2-formyl-6-methylbenzyloxy)-2-nitropyridine.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9](SC)[C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1>[Ni].O.C(O)(C)C>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC1C(=O)Nc2cccc(-c3ccccc3)c21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: O=C1Cc2c(cccc2-c2ccccc2)N1

Procedure:
A stirring solution of 3.5 g. (0.014 mole) of 4-phenyl-3-methylthioindolin-2-one in 75 ml. of tetrahydrofuran was treated portionwise with 20 g. of a commercial Raney nickel/water suspension. The mixture was filtered through Celite and the filtrate was concentrated to give a yellow solid. The solid was recrystallized to give a yellow solid. This solid was recrystallized from benzene to yield 1.6 g. (57%) of product as an off-white solid. An analytical sample was prepared from isopropanol; m.p. 192-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C@H:19]1[CH2:21][O:20]1.Cl.[CH:23]12[O:30][CH:27]([CH2:28][CH2:29]1)[CH2:26][NH:25][CH2:24]2>CN(C=O)C>[OH:20][C@H:19]([CH2:21][N:25]1[CH2:24][CH:23]2[O:30][CH:27]([CH2:28][CH2:29]2)[CH2:26]1)[CH2:18][O:17][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:14][CH2:15][N:16]=3)[C:10]([NH2:13])=[N:11][C:12]=2[C:3]=1[O:2][CH3:1]
Reactant: C1CC2CNCC1O2
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Agent: Cl
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2CC3CCC(C2)O3)ccc2c1N=C(N)N1CCN=C21
Yield: 271.1 %

Procedure:
A solution of 7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate F, 0.195 g, 0.68 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.506 g, 3.38 mmol, 10 equiv.) in DMF (4.5 mL) was heated in a microwave reactor for 45 min. at 140° C. The resulting mixture was concentrated under reduced pressure. The residue was treated with a 4:1 CH2Cl2/isopropanol solution (25 mL), washed with a saturated sodium bicarbonate solution (25 mL), dried (anh. sodium sulfate) and concentrated under reduced pressure. The resulting residue was purified using MPLC to give N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine (0.74 g, 16%): HPLC ret. time 0.70 min.; mass spectrum m/z 402 ((M+1)+, 7%).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:17])([F:16])[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:6]([F:17])([F:16])[F:5]
Reactant: O=S(Cl)Cl
Reactant: Oc1ccccc1C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Oc1ccccc1C(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2.28 ml) was added to a solution of 2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (3.0 g) and pyridine (1.23 ml) in toluene (50 ml). The reaction was stirred at room temperature for 1 hr, after which time the toluene was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and 1N HCl (100 ml). The organics were separated and dried over magnesium sulfate, filtered and solvent removed in vacuo to afford the title compound as a clear oil (3.0 g). 1H NMR (CDCl3): δ 5.93 (m, 1H), 6.90 (d, J=4.52 Hz, 1H), 7.10 (m, 1H), 7.35 (m, 1H), 7.69 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2].[CH3:22][CH:23]([CH3:26])[C:24]#[CH:25]>[Cu]I>[Cl:16][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([C:25]#[C:24][CH:23]([CH3:26])[CH3:22])[CH:11]=1)[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: C#CC(C)C
Agent: [Cu]I
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#CC(C)C)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To 2.000 g (4.624 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 267 mg (0.231 mmole) tetrakis(triphenylphospine)palladium(0), 88 mg (0.462 mmole) copper (I) iodide, 40 mL degassed toluene, 1.930 mL (13.87 mmole) degassed TEA, and 0.473 g (6.94 mmole) 3-methyl-1-butyne. The mixtures was stirred overnight at room temperature. The mixture was concd and the resulting oil was purified using reverse phase chromatography to afford 1.573 g (91%) of a yellow crystalline solid: 1H NMR (CDCl3/400 MHz) 1.26 (d, 6H, J=6.8 Hz), 1.34 (t, 3H, J=7.2 Hz), 2.80 (septet, 1H, J=6.8 Hz), 4.27-4.35 (m, 2H), 5.78 (q, 1H, J=6.8 Hz), 7.09 (d, J=2.4 Hz), 7.31 (d, 1H, J=2.4 Hz), 7.59 (s, 1H); MS (ES+) 373 (M+1, 100): MS (EI) 372 (M+, 22), 303 (100), 275 (35).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:30]C)[C:24]=3[O:28]C)[NH:19][C:18]2=[O:32])[CH2:11][CH2:10]1>Br.C(O)(=O)C>[OH:28][C:24]1[C:23]([OH:30])=[CH:22][CH:21]=[C:20]2[C:25]=1[C:26](=[O:27])[N:17]([CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]1)[C:18](=[O:32])[NH:19]2
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccc(OC)c(OC)c3c2=O)CC1
Agent: Br
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccc(O)c(O)c3c2=O)CC1
Yield: 47.1 %

Procedure:
A solution of 3-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-5,6-dimethoxyquinazolin-2,4-(1H,3H)dione (1.6 g. 2.66M) in hydrobromic acid (48% aqueous, 9.6 ml) and glacial acetic acid (26.2 ml) was heated at reflux for 18 hours. The reaction mixture was cooled and the resulting solid was filtered, washed with ether (30 ml), hexane (30 ml) and dried under high vacuum at 62° C. overnight to give a crude product as a white solid. The crude product was recrystallized from methanol (75 ml). The product was dried under high vacuum at 62° C. for 2 days to afford 5,6-dihydroxy-3-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl quinazolin-2,4(1H,3H)-dione (dihydrobromide) as a white solid, (A): 0.72 g (yield 47.1%) mp=283°-286° C. A second crop precipitated out of the filtrate. It was filtered and dried under high vacuum at 62° C. for 6 days to afford additional 5,6-dihydroxy-3-2-[4-(2-methoxy-phenyl)-1-piperazinyl]ethyl quinazolin-2, 4(1H,3H)-dione (monohydrobromide monohydrate) as a white solid: (B) 0.54 g. yield 39.7%, mp=223°-227° C. The total yield of product was 86.8%.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:4].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([N:5]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:13](=[O:15])[CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=2)=[O:4]
Reactant: COC(=O)N(c1ccccc1)c1ccccc1CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 100 °C
Yield: 80.9 %

Procedure:
A mixture of [2-(methoxycarbonyl-phenyl-amino)-phenyl]-acetic acid (16 g, 55.5 mmol) and polyphosphoric acid (29 g, 167 mmol in terms of P2O5) is heated to 100° C. for 4 hours. To the reaction mixture, water (41 ml) is added dropwise at 85–100° C. with stirring and cooling. At 65° C. toluene (41 ml) is added and the mixture is stirred for 30 min. The two phases are separated and washed. The organic phases are concentrated and allowed to crystallize at 0° C. to yield 12 g of pure title compound (80%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][NH2:23]>>[ClH:1].[ClH:1].[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: NCC(O)CN
Product: Cl
Product: NCC(O)CNc1cc(-c2ccc(Cl)cc2)nc2ccccc12

Procedure:
The title compound, m.p. 283-287° C., and MS: m/e=328.2 (M+H+), was prepared from 4-chloro-2-(4-chloro-phenyl)-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: [OH:1]O.O.[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:19]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:17][C:16]=2[CH:32]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C.O1CCCC1>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:19]([S:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:1])=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:17][C:16]=2[CH:32]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: OO
Reactant: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Sc1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1S(=O)c1ccccc1
Temperature: 100 °C

Procedure:
Hydrogen peroxide in water (0.15 ml of 30% w/v, 1.3 mmol) was added to a solution of ethyl 6-(benzyloxy)-3-(phenylsulfanyl)benzo[b]thiophene-2-carboxylate (Example 17--500 mg, 1.2 mmol) in acetic acid (5 ml) and tetrahydrofuran (5 ml). The mixture was heated to 100° C. for 3 hours. The solvents were removed by evaporation under reduced pressure, and the residue was partitioned between diethyl ether and aqueous sodium bicarbonate solution. The organic layer was separated, dried (magnesium sulfate) and concentrated under vacuo, and the residue was crystallised from dichloromethane and diisopropyl ether to give the title compound as a colourless solid (455 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][C:24]([CH3:27])=[N:25][N:26]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:29][CH3:30].[OH-].[Na+].CN(C)C=O>O>[CH2:29]([N:26]1[N:25]=[C:24]([CH3:27])[S:23][C:22]1=[N:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH3:30]
Reactant: CCBr
Reactant: COc1ccc(N2CCN(c3ccc(Nc4nnc(C)s4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)sc1=Nc1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Reaction time: 4 h
Yield: 25.3 %

Procedure:
A mixture of 10.6 parts of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-1,3,4-thiadiazol-2-amine, 0.5 parts of bromoethane, 4 parts of sodium hydroxide pellets and 188 parts of N,N-dimethylformamide was stirred for 4 hours at 40°-50° C. After the addition of water, the crystallized product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane, methanol, ethyl acetate and hexane (48:2:30:20 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 2.9 parts (25.3%) of N-(3-ethyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine; mp. 175.4° C. (int. 14). The second fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.5 parts (56.7%) of N-ethyl-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-1,3,4-thiadiazol-2-amine; mp. 186.8° C. (int. 15).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC1(C)CC(=O)c2ccc(-c3ccc(C#N)cc3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-cyanophenyl boronic acid according to the procedure described in example 21. MS (ESI) m/z 262; HRMS: calcd for C18H15NO+H+, 262.12264; found (ESI, [M+H]+), 262.1237.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]4=[O:39])=[CH:25][C:24]=3[F:40])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:40][C:24]1[CH:25]=[C:26]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:22][CH2:21]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CN4CCN(C(=O)OC(C)(C)C)CC4)CC3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CN4CCNCC4)CC3)c(F)c2)C(=O)O1

Procedure:
A solution of 0.490 g of 4-[2-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (0.87 mmol) in 2 ml dichloromethane was treated with 2 ml of TFA. The reaction was monitored by TLC. The solvent was evaporated and the residue dissolved in water. The water layer was neutralized with ammonium hydroxide and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].Cl.N1C=CC=C[CH:32]=1>>[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](=[O:26])[CH2:32][NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=3[Cl:11])[NH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: c1ccncc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 100 %

Procedure:
Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (10 g, 36.6 mmol) in anhydrous pyridine (100 mL). Add 4-nitrobenzoyl chloride (7.47 g, 40.27 mmol) and stir for 5 hours. Pour into 1N hydrochloric acid (500 mL) and extract into ethyl acetate. Evaporate the solvent in vacuo and dry at 70° C. under vacuum to give the title compound (15.75 g, 100%); mp 283°-86° c.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][CH:8]([Cl:12])[C:9](Cl)=[O:10].[NH2:13][C:14]1[N:18]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[C:21]([Cl:30])[C:20]=2[Cl:31])[N:17]=[CH:16][CH:15]=1>ClCCl>[Cl:7][CH:8]([Cl:12])[C:9]([NH:13][C:14]1[N:18]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:27])[F:28])=[C:21]([Cl:30])[C:20]=2[Cl:31])[N:17]=[CH:16][CH:15]=1)=[O:10]
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl
Reactant: O=C(Cl)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(Cl)Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 93.5 %

Procedure:
15.3 g (0.145 mol) of anhydrous sodium carbonate and 4.76 ml (0.048 mol) of 98% strength dichloroacetyl chloride are added in succession, at 5° C. to 10° C., to 8.0 g (0.024 mol) of 5-amino-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole in 80 ml of dichloromethane. The mixture is stirred for 4 hours at 5° C.-10° C. and for 13 hours at room temperature. The mixture is diluted with 80 ml of dichloromethane, filtered, and washed in succession with water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed from the solvent in vacuo. 10.0 g (93.5% of theory) of 5-dichloroacetamido-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 156° C.-161° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[C:4]([CH3:11])[CH:3]=1.[N:12]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:10]=[N:12][N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CNc1cc(Br)cc(C)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Br)cc2c1nnn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 5-bromo-N1,3-dimethylbenzene-1,2-diamine (Step 85.2) (2.5 g, 11.62 mmol) in HCl cc (15 mL, 494 mmol) cooled down to 0° C. was slowly added a solution of NaNO2 (0.962 g, 13.95 mmol) in water (25 mL). The resulting mixture was allowed to warm up and stir at RT for 2 hr. NaOH was added until basic pH, a precipitate occurred. The resulting solid was filtrated off, washed with water and dried under reduced pressure to afford the title product (2.5 g, 9.95 mmol, 86% yield) as beige solid. tR: 0.93 min (LC-MS 2); ESI-MS: 228 [M+H]+ (LC-MS 2).