Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[C:12](=[O:25])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=2[F:24])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37](B(O)O)[CH3:38]>>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:11]([CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH2:37][CH3:38])[CH:3]=2)[C:12](=[O:25])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]([Cl:23])[C:14]=2[F:24])=[CH:28][CH:29]=1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CCB(O)O
Reactant: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(Br)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1
Product: CCc1cc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)ccc1F

Procedure:
The title compound was prepared in analogy to example 3, using N-[2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide (Example B178) and ethylboronic acid. 538.3 [ISP (M+H)+]
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[F:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([Cl:29])=[C:31]([F:38])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1Cl

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-chloro-3-fluoro benzaldehyde. MS (ESI) m/z 519.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:30]([CH:29]=[CH2:28])(=[O:32])=[O:31])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CS(=O)(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of N-(3-bromophenyl)-4,6-quinazolindiamine (315 mg, 1 mmol) and triethylamine (0.5 mL) in THF (50 mL) at 0° C. was dropwise added 2-chloroethylsulfonyl chloride (490 mg, 3 mmol). After the solution was stirred at 0° C. for 10 min, it was chromatographed on silica gel with 10% methanol in chloroform to give 212 mg of ethenesulfonic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as an light yellow solid: HRMS (m/e): M+403.9937. Modified a method from A. A. Goldberg, J. Chem., Soc., 464 (1945).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].N(OC(C)(C)C)=O.N[C:15]1[C:16]([Cl:33])=[CH:17][C:18]([F:32])=[C:19]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[CH:20]=1.[ClH:34]>C(#N)C.[Cu](Cl)Cl>[Cl:34][CH:2]([CH2:3][C:15]1[CH:20]=[C:19]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C:18]([F:32])=[CH:17][C:16]=1[Cl:33])[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: Nc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COC(=O)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl

Procedure:
In 20 ml of acetonitrile were dissolved 3.44 g of methyl acrylate and 0.62 g of t-butyl nitrite, and 0.65 g of copper (II) chloride was added. Under stirring, 1.16 g of N-(5-amino-4-chloro-2-fluorophenyl)phthalimide was added thereto in small portions, followed by stirring at room temperature for 1 hour. 3N Hydrochloric acid was added to the reaction mixture. After stirring, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:5) to give 0.98 g of the title compound (No. 4 of Table 1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:31][CH2:32][CH2:33][CH3:34])=[C:15]([C:17]2[NH:18][C:19](=[O:30])[C:20]3[C:25]([CH3:26])=[N:24][N:23]([CH2:27][CH2:28][CH3:29])[C:21]=3[N:22]=2)[CH:16]=1)(=[O:10])=[O:9]>>[CH3:26][C:25]1[C:20]2[C:19](=[O:30])[NH:18][C:17]([C:15]3[CH:16]=[C:11]([S:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)(=[O:10])=[O:9])[CH:12]=[CH:13][C:14]=3[O:31][CH2:32][CH2:33][CH3:34])=[N:22][C:21]=2[N:23]([CH2:27][CH2:28][CH3:29])[N:24]=1
Reactant: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Reactant: C1COCCN1
Product: CCCOc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1

Procedure:
The title compound was prepared from morpholine (0.451 g, 0.0052 mol) and 6-(5-chlorosulphonyl-2-n-propoxyphenyl)-3-methyl-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Preparation 8; 0.55 g, 0.0013 mol), according to the procedure of Example 14, and was obtained as colourless needles (0.403 g, 65%), m.p. 161-163° C., after crystallisation from ethyl acetate-hexane. Found: C,55.68; H,6.16; N,14.85. C22H29N5O5S requires C,55.56; H,6.15; N,14.73%.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].N1CCCCC1.Cl>C(O)C>[CH3:1][S:2][CH:3]([C:9]1[CH:14]=[C:13]([CH:15]=[C:23]2[S:19][C:20](=[O:25])[NH:21][C:22]2=[O:24])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(SC)c1cc(C=O)ccc1OC
Reactant: O=C1CSC(=O)N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(SC)c1cc(C=C2SC(=O)NC2=O)ccc1OC
Temperature: 0 °C
Yield: 60.1 %

Procedure:
Ethyl 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetate (7.50 g, 28.0 mmol), thiazolidine-2,4-dione (3.94 g, 33.6 mmol), piperidine (2.80 mL, 28.3 mmol) and ethanol (100 mL) were mixed and refluxed for 14 hours. After allowed to stand for cooling, concentrated hydrochloric acid was added under cooling with ice and stirring to make the reaction mixture acidic. Ice water was added thereto and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with ethanol and water, and then dried to obtain 6.18 g (60%) of the title compound as yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH:27]([CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: Nc1ccccc1
Product: COc1ccc(-c2nc(CNc3ccccc3)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Example 56, 2-chloromethyl-4- (3,4-dimethoxyphenyl ) -6,7-dimethoxyquinazoline was reacted with aniline to give 2-anilinomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline. This compound was recrystallized from ethanol. Colorless prisms, mp. 199°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C(O)(=O)C>[Fe].CO>[NH2:13][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[OH:12]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(Cl)c(N)c1O
Temperature: 25 °C
Yield: 81 %

Procedure:
A 100-mL single-neck round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with methyl 4-chloro-3-nitrosalicylate (1.00 g, 4.32 mmol), glacial acetic acid (23 mL) and methanol (18 mL). The stirred solution was then treated with 325 mesh iron powder (2.41 g, 43.2 mmol) and heated at reflux for 30 min. After this time, the reaction was cooled to room temperature and filtered through a pad of celite 521. The pad was rinsed with methanol (10 mL) and the filtrates combined and partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and washed with water (2×100 mL) then dried over sodium sulfate. The suspension was filtered and the filtrate treated with decolorizing carbon (0.50 g) and warmed to reflux. The suspension was then re-filtered hot through a pad of celite 521 and the resulting filtrate concentrated to dryness under reduced pressure to afford methyl 3-amino-4-chlorosalicylate in 81% yield (0.70 g) as white solid: 1H NMR (300 MHz, CDCl3) δ 7.19 (d, J=2.7 Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 3.95 (br s, 2H), 3.94 (s, 3H); MS (ESI) m/z 202 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1C=C(F)C=[CH:4][N:3]=1.[C:9]([N:16]1CCC(N)C[CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:23][CH2:24][N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:30]=[C:29]([N:25]2[CH2:24][CH2:23][CH:17]([NH:16][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:28][CH2:26]2)[CH:31]=[CH:4][N:3]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccnc(Cl)c2)CC1
Yield: 62 %

Procedure:
To a mixture of 2-chloro-4-fluoropyridine (1.00 g, 7.60 mmol) and Boc-4-aminopiperidine (1.98 g, 9.09 mmol) in NMP (10 mL) was added DIPEA (1.86 mL, 10.6 mmol). Argon was bubbled through the cloudy solution for 5 minutes before the reaction mixture was heated in the microwave for 2×30 minutes to 150° C. The mixture was then poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 50 g, 0 to 50% ethyl acetate in heptane) afforded the title compound (1.47 g, 62%) as a white solid.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH2:5]([O:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([O:27]C)[N:16]2[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:12]([NH2:29])[N:11]=1)[CH2:6][CH2:7][CH3:8].CCN(C(C)C)C(C)C.CS(C)=O>CN(C=O)C>[NH2:29][C:12]1[N:11]=[C:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:27])[N:16]2[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH3:4])[CH2:23][CH2:22]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCC)CC3)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
1-Iodopropane (0.1 mmol) was weighed into a vial and an aliquot (0.4 ml, 0.12 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine (0.418 g mg, 1.2 mmol) suspended in DMF (4.8 ml) was added to each tube. DIPEA (40 μl, 0.229 mmol) was added finally to each tube, the tube was heated at 50° C. for 18 hours. An additional portion of 1-iodopropane (15 μl) and DIPEA (20 μl) was added to each tube and heating continued for a further 18 hours. DMSO (200 uL) was added and the solution and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.2 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The material was redissolved in methanol (0.5 ml), and applied to top of 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 ml). The cartridge was eluted with methanol (1.5 ml) and the solvent was removed to give the title compound (5.1 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]([O:21][C:22](=[O:40])[C@@H:23](NC(OC(C)(C)C)=O)[CH2:24]C2C=CC(O)=CC=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl.C(O)C>[C:8]1([CH:14]([O:21][C:22](=[O:40])[CH2:23][CH3:24])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
Triethylamine (4.0 g, 39 mmol) was added dropwise to a suspension of (S)-2-[[(1,1-dimethylethoxy)carbonyl]-amino] -3-(4-hydroxyphenyl)propanoic acid diphenylmethyl ester (17.0 g, 38 mmol) and N-phenyl-N-trifluorosulfonyl -1,1,1-trifluoromethyl sulfonamide (13.6 g, 38 mmol) in dichloromethane (170 mL) at 0° C. After 1 hour the reaction mixture was warmed to room temperature and washed with 1N sodium hydroxide (2×25 mL), saturated aqueous sodium bicarbonate (2×25 mL) and water (2×25 mL). The organic layer was dried (K2CO3), filtered and concentrated. Recrystallization of the solid from hexane gave (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[4-trifluoromethyl)sulfonyl]oxy]phenyl]propanoic acid diphenylmethyl ester (13.7 g, 24 mmol) in 62% yield, mp. 110°-112° C., [α]D -14.23° (0.12% in ethanol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[C:17]=2[CH:16]=[CH:15][N:14]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:23]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)(=[O:25])=[O:24])[C:17]=2[CH:16]=[CH:15][N:14]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cccc2cnccc12)N1CCNCC1
Reaction time: 15 h
Yield: 87.8 %

Procedure:
In 100 ml of methylene chloride were added 6.0 g of piperazine and 1.2 g of anhydrous potassium carbonate, and to the mixture was added dropwise 30 ml of a methylene chloride solution containing 2.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution was stirred at a temperature of 15° C. to 25° C. for 15 hours, and then the reaction solution was washed with water, dried with anhydrous magnesium sulfate, and the methylene chloride was distilled therefrom. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 2.14 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35) in a yield of 89%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[C:20](Cl)(=[O:22])[CH3:21]>C1COCC1>[C:20]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:22])[CH3:21]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
6-Nitroindoline (3.0 g, 18.3 mmol) is dissolved in THF (45 mL) and Et3N (3.4 mL, 24.4 mmol) at 0° C. Acetyl chloride (1.5 mL, 21 mmol) is added dropwise. The mixture is stirred at room temperature for 30 minutes. The mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated to yield 1-acetyl-6-nitroindoline (3.8 g, 100%) as a yellow solid.
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].C(N)=O>O>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6]
Reactant: O=C(O)C(=O)O
Agent: [V+5]
Agent: [O-2]
Solvent: O
Solvent: NC=O
Product: O=C([O-])C(=O)[O-]

Procedure:
(STEP 2): To 40 ml of water is added 0.495 gram of vanadium pentoxide, 1.09 grams of oxalic acid and 2.47 grams of formamide at room temperature with stirring to form vanadium oxalate, and this solution was then mixed with 23.0 grams of the 5.0 wt. % V2O5 on titanium dioxide anatase powder (prepared as described above in Step 1) and 1.18 grams of Sb2O3 (which were first dispersed in 20 ml of water). The resulting mixture was heated with stirring at 65° C. to evaporate the majority of the water follcwed by drying in an oven (101 kPa) at 110° C. for 16 hours. The resulting solid was then calcined in a flowing oxygen gas stream at 450° C. for 2 hours, followed by crushing and screening to form -20 +40 mesh particle size. The catalyst formed by the above impregnation procedure was determined by calculation (based on the vanadium salt, antimony salt, and the weight of the titanium dioxide particles) to contain 4.8 wt. % Sb2O3 and 6.8 wt. % V2O5 on the TiO2.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][CH:14]=[CH2:15])[CH2:11][CH2:10][C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:7]=2[CH:20]=1.CN(C=[O:25])C.O>[Cl-].[Na+].O.[Pd](Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14](=[O:25])[CH3:15])[CH2:11][CH2:10][C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:7]=2[CH:20]=1
Reactant: C=CCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)=O)CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of palladium chloride (96 mg) and curious chloride (218 mg) in DMF-water (7-1 ml) was stirred at 60° C. for 18 hours under oxygen atmosphere. To the reaction system was added a solution of methyl 7-bromo-1-(2-propenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (500 mg) in DMF-water (7-1 ml) was added, and the mixture was stirred at 60° C. for 7 hours. To the reaction system was added saturated brine, 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 residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4→1:2) to give methyl 7-bromo-1-(2-oxopropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (311 mg) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:19][N:18]=[N:17][N:16]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]([CH3:21])[N:18]=[N:17][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1nnn[nH]1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [2-(1H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester (0.23 g, 0.84 mmol, preparation described in example I-6, Step C), crushed potassium carbonate (0.58 g, 4.2 mmol) and iodomethane (0.26 ml, 4.2 mmol) in dimethylformamide (4.7 ml) was stirred at room temperature for 1 h. Water was added and the reaction mixture was extracted with chloroform. Drying and solvent evaporation gave a mixture of regioisomers; separation and purification by reverse phase preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave [2-(1-methyl-1H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester; 1H NMR (CDCl3, 400 MHz) δ 7.66 (d, 1H, J=7.4 Hz), 7.58 (m, 1H), 7.46 (m, 1H), 7.33 (d, 1H, J=7.6 Hz), 4.17 (d, 2H, J=6.3 Hz), 4.05 (s, 3H), 1.41 (s, 9H) and [2-(2-methyl-2H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester; 1H NMR (CDCl3, 400 MHz) δ 8.06 (d, 1H, J=7.4 Hz), 7.61 (d, 1H, J=7 Hz), 7.44 (m, 2H), 5.82 (bs, 1H), 4.52 (d, 2H, J=6.5 Hz), 4.44 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>Cl>[CH3:13][C:12]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of 161.0 g of α,α,α-trifluoro-m-toluidine in 500 ml of 2N hydrochloric acid, at room temperature, with vigorous agitation, is added rapidly 102.0 g of acetic anhydride. An exothermic reaction occurs and the temperature is allowed to rise spontaneously to about 50°. Subsequently, the mixture is allowed to cool to room temperature, and then cooled in ice. The crystalline solid is filtered to give 189.3 g of α,α,α-trifluoro-m-acetotoluidide.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:7]=[C:6]([CH2:8][N:9]([CH:19]([CH3:21])[CH3:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[NH:5][CH:4]=1.[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>O1CCCC1>[CH:19]([N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:8][C:6]1[N:5]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:4]=[N:3][CH:7]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N(Cc1cnc[nH]1)c1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N(Cc1cncn1COCC[Si](C)(C)C)c1cccc([N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
To sodium hydride (149 mg, 55% in mineral oil, 3.42 mmol) in tetrahydrofuran (240 ml) was added a solution of (3H-imidazol-4-ylmethyl)-isopropyl-(3-nitro-phenyl)-amine (685 mg, 2.63 mmol) in tetahydrofuran (100 ml) and stirring was continued for 45 min at room temperature. The reaction mixture was cooled with an ice bath and 2-(trimethylsilyl)ethoxymethylchloride (439 mg, 2.63 mmol) was added. After stirring the suspension overnight the reaction was quenched with saturated sodium bicarbonate solution. Tetrahydrofuran was evaporated and the residue was extracted with ethyl acetate twice. The combined organic layers were washed with water, dried over magnesium sulphate and evaporated. The residue was purified using flash chromatography (SiO2; eluent: heptane/ethyl acetate=80:20) to yield a light yellow oil, (0.20 g, 20%); MS (ISP): 391.3 ((M+H)+.).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.Cl>O.CS(C)=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccc(Cl)cc3)cc2)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To 12 ml of dimethylsulfoxide is dissolved 1.12 g of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione, and 480 mg of 50% sodium hydride in oil is added to the solution. The mixture is stirred at room temperature for 15 minutes, to which is added 0.81 g of 4-chlorobenzyl chloride. The whole mixture is stirred at 50° C. for 4 hours. Water is added to the mixture and the mixture is acidified with 2 N-hydrochloric acid. The mixture is subjected to extraction with ether. The extract is washed with water and dried. Ether is distilled off to give an oily substance. The oily substance is subjected to column chromatography on 30 g silica gel, elution being carried out with cyclohexane-ethyl acetate (2:1). By the above procedure there was obtained 425 mg of 5-[4-(4-chlorobenzyloxy)benzyl]thiazolidine-2,4-dione.