Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:9]([OH:18])=[C:10]([C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][C:13]=1[OH:14].[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1.Cl>CC(C)=O.CCOC(C)=O>[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[C:9]([OH:18])[C:8]=2[Cl:7])=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: BrCc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(CBr)cc2)c(Cl)c1O

Procedure:
Add K2CO3 (1.48 g, 10.7 mmol) to a solution of 1-(3-chloro-2,4-dihydroxy-phenyl)ethanone (2.00 g, 10.7 mmol) and 1,4-bis(bromomethyl)benzene (2.83 g, 10.7 mmol) in acetone (100 mL). Cool and work up with a 10% HCl solution and EtOAc. Triturate in acetone to remove insoluable material. Dry, filter, and concentrate. Purify the residue by flash chromatography on silica gel (731 mg, 18%): MS (esi negative) m/z 368.9 (rel intensity) (M−H, 55%), 367.0 (45%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:10][C:6]1[CH2:7][CH2:8][CH2:9][C:5]=1[CH2:4][CH2:3][O:2][CH3:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COCCC1CCCC1=O
Product: COCCC1=C(OC(C)=O)CCC1

Procedure:
The subject compound is prepared from 2-(2-methoxyethyl)cyclopentan-1-one (Example 895) and acetic anhydride by the procedure of Example 10. The product is an oil, b.p. 60°C. (0.2 mm.)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH2:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
To a solution of 1-fluoro-2-methyl-4-nitrobenzene (2.02 g, 13.0 mmol) and 4-amino-3-nitrophenol (2.22 g, 14.4 mmol) in DMF (20 mL) was added cesium carbonate (5.28 g, 16.2 mmol). After heating to 60° C. for 10 hours, the mixture was diluted with water (100 mL) and filtered. The precipitate was washed with water and air-dried to provide the product (3.28 g, 87%) as dark solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([S:39]([N:38]([CH3:43])[CH3:37])(=[O:41])=[O:40])[CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: Fc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5ncc(F)cn5)CC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
To a solution of 2-((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (20 mg, 0.049 mmol) and triethylamine (0.014 mL, 0.097 mmol) in CH2Cl2 (0.7 mL) at 0° C. was added dimethylsulfamoyl chloride (17.4 mg, 0.122 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt for 3 h. The reaction mixture was quenched with sat. aq. NaHCO3 (1 mL) and extracted with CH2Cl2 (3×1 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 40% EtOAc) to afford 4-(2-((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)benzo[d]thiazol-6-yl)-N,N-dimethyl-5,6-dihydropyridine-1(2H)-sulfonamide (15 mg, 0.027 mmol, 57% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 2H), 7.64 (d, J=1.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.40 (dd, J=8.5, 1.9 Hz, 1H), 6.07 (dt, J=3.2, 1.8 Hz, 1H), 5.45 (tt, J=7.7, 3.7 Hz, 1H), 4.17 (ddd, J=13.4, 7.2, 3.9 Hz, 2H), 3.98-3.92 (m, 2H), 3.70 (ddd, J=13.4, 8.3, 3.6 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 2.86 (s, 6H), 2.69-2.61 (m, 2H), 2.21-2.12 (m, 2H), 2.00-1.88 (m, 2H). LCMS (m/z)=519 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1.CCOCC>[F:14][C:11]1([F:15])[CH2:12][CH2:13][CH:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH2:9][CH2:10]1
Reactant: O=C(CCCCl)NC1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCCN1C1CCC(F)(F)CC1
Yield: 55 %

Procedure:
Heat the mixture of 4-chloro-N-(4,4-difluoro-cyclohexyl)-butyramide (0.41 g, 1.7 mmol) and 0.69 g of NaH in 17 mL of THF to 70° C. for overnight. Dilute the reaction mixture with Et2O. Filter the precipitate through a pad of celite. Wash the organic layer with saturated aqueous NaCl, dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford 0.19 g of the title compound: mass spectrum (m/z): 204 (M+1).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11]>S(=O)(=O)(O)O>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][CH:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCCC1
Agent: O=S(=O)(O)O
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 35 °C

Procedure:
To 758 g (7.7 moles) of cyclohexanone were added 260 g (1.44 moles) of anhydrous dextrose, followed by 20 ml of concentrated sulfuric acid. The mixture was heated to 35° C. and monitored by TLC. The flow rate of the desired product using Solvent A was Rf =0.95.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:29]([O:32][CH2:33][C:34]1[CH2:41][S:40][CH:39]2[N:36]([C:37](=[O:43])[CH:38]2[NH2:42])[C:35]=1[C:44]([OH:46])=[O:45])(=[O:31])[CH3:30]>C1COCC1>[C:29]([O:32][CH2:33][C:34]1[CH2:41][S:40][CH:39]2[N:36]([C:37](=[O:43])[CH:38]2[NH:42][C:11](=[O:13])[CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:35]=1[C:44]([OH:46])=[O:45])(=[O:31])[CH3:30]
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc4c(c3)CCO4)C2SC1
Temperature: 0 °C

Procedure:
A solution of 10 mmole of 2,3-dihydo-5-benzofuranyl acetic acid and 10 mmole of triethylamine in 100 ml of THF is cooled to about 0° C. While stirring, isobutylchloroformate (10 mmole) is added and the temperature maintained at 0° C. for 15 minutes. A cold solution of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (10 mmole) and 10 mmole of triethylamine in 80 ml of 50% aqueous THF is added to the previously prepared solution. The mixture is stirred at 5° C. for 1 hour and at room temperature for 1 hour. Then the THF is evaporated and the residue is dissolved in water and washed with ethyl acetate. The aqueous phase is covered with ethyl acetate and the pH is adjusted to 3 with 6N hydrochloric acid. The mixture is filtered and the layers separated. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [O-]S([O-])=O.[Na+:5].[Na+].C([O-])(O)=O.[Na+].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1>O.O1CCOCC1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19]([O-:21])=[O:20])[CH:18]=1.[Na+:5]
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Br)cc1S(=O)[O-]
Temperature: 70 °C
Reaction time: 1.33 h

Procedure:
To a solution of Na2SO3 (1.42 g) and NaHCO3 (0.948 g) in H2O (17 ml) at 70° C. was added a solution of 5-bromo-2-methoxybenzene-1-sulfonyl chloride (2 g) in dioxane (17 ml) dropwise. The reaction mixture was stirred at 70° C. for 80 minutes and cooled to room temperature. The solvent was removed under vacuum to yield sodium 5-bromo-2-methoxybenzenesulfinate as white solid. The solid was placed under high vacuum overnight and used without further purification.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>C(OCC)(=O)C>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Yield: 83.86 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in ethyl acetate (70 mL) respectively, lithium bromide (0.15 g, 1.74 mmol) was added at 20° C., reacted for 12 h. White solid was obtained by filtration (6.11 g, yield: 83.86%).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:4]>CO.O>[OH:4][CH2:3][C:5]1[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][N:20]=2)=[O:18])[CH2:10][CH2:9]1
Reactant: O=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2CO)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 1 h
Yield: 57.5 %

Procedure:
NaBH4 (5 mg, 0.12 mmol) was added to stirred a mixture of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-formyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (50 mg, 0.1 mmol) in MeOH (2 mL) and stirring was continued for 1 hr. The reaction mixture was diluted with water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue was purified by recrystallisation from CHCl3 in hexane mixture to afford 25 mg (58% yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-hydroxymethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 435.2, 93.8%, 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.0 (m, 1H), 7.8 (m, 2H), 7.5 (m, 2H), 7.4 (m, 2H), 7.2 (m, 1H), 7.1 (m, 1H), 7.0 (m, 1H), 6.9 (m, 1H), 5.0 (m, 1H), 4.7 (m, 1H), 4.5 (m, 2H), 3.7 (m, 3H), 3.5 (m, 2H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C(P(CCCCCCCC)CCCCCCCC)CCCCCCC.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].C(O)(=O)C>C(OCC)C>[CH2:38]([O:37][C:33](=[O:36])[CH2:34][CH2:35][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[CH3:39]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)CC(C)=O
Agent: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)CCC(C(C)=O)C(C)=O
Reaction time: 65 h

Procedure:
To a mixture of 70 g of 2,4-pentandione and 1.72 g of trioctyl phosphine, 45 g of ethyl acrylate was added dropwise over 40 minutes, keeping the temperature at 0–5° C. by cooling. After stirring for 65 hours, 2 ml of acetic acid and 150 ml of diethyl ether were added, and the solution was extracted with an aqueous sodium carbonate solution and water. The organic layer was dried, and 4-acetyl-5-oxohexanoic acid ethyl ester was isolated by fractional distillation.
Reaction SMILES: CO[C:3]([CH:5]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:7]([C:21]#[N:22])[CH2:6]1)=[O:4].[NH2:23][NH2:24].[Cl-].[Na+].C(Cl)Cl>C(Cl)(Cl)Cl>[C:21]([N:7]1[C@H:8]2[C:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10]([CH2:9]2)=[CH:11][NH:12]4)=[CH:19][CH:5]([C:3]([NH:23][NH2:24])=[O:4])[CH2:6]1)#[N:22]
Reactant: COC(=O)C1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C#N)C1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#CN1CC(C(=O)NN)C=C2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
950 mg of 6-cyano-9,10-didehydroergolinecarboxylic acid methyl ester (3.2 mmol) is dissolved in 100 ml of chloroform and 18 ml of anhydrous hydrazine and stirred for one hour in an ice bath and for 3 hours at room temperature. The mixture is distributed between saturated sodium chloride solution and methylene chloride; the organic phase is washed with water, dried with magnesium sulfate, and evaporated (crude product 739 mg). The product is chromatographed on silica gel with methylene chloride, ethyl acetate, and methanol, yielding the pure 6-cyano-9,10-didehydroergolinecarboxylic acid hydrazide. A solution of 950 mg (3.2 mmol) of this hydrazide in 100 ml of tetrahydrofuran is cooled in an ice bath and combined in succession with 11 ml of a saturated solution of hydrogen chloride in toluene (about 0.7N), 3.5 ml of a 1N lithium nitrite solution in tetrahydrofuran, and 22 ml of the above hydrogen chloride solution. Under ice cooling, the mixture is agitated for 20 minutes, then diluted with 140 ml of dioxane, and heated for 30 minutes in an oil bath preheated to 80° C. After cooling in an ice bath, 20 ml of 0.2N hydrochloric acid is added thereto, the mixture is allowed to stand for 20 minutes and evaporated to dryness. The residue is made into a solution with a small amount of methanol, distributed between chloroform and sodium bicarbonate, the aqueous phase is washed with chloroform, the organic phase respectively several times with water, dried with magnesium sulfate, and evaporated. 1.0 g of the crude 8-amino-6-cyano-9,10-didehydroergoline is dissolved in 15 ml of pyridine, combined with 0.6 ml of acetyl chloride, and ice is added after one hour; the mixture is distributed between saturated bicarbonate solution and methylene chloride; the organic phase is dried and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])C.O.C(=O)(O)[O-].[Na+]>C(O)=O>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:8]([N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:21]=[O:23])=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CCOC(=O)c1ccc(N(C=O)Cc2ccc(Cl)cc2)cc1
Temperature: 55 °C
Yield: 67 %

Procedure:
Ethyl 4-(4-chlorobenzylamino)-benzoate (7.2 g; 0.025 mole) was dissolved in formic acid (80%; 70 ml) and the solution was heated to 55° C. with stirring. Acetic anhydride (25 ml) was added dropwise at this temperature, allowed to cool to room temperature and stirred for 1 hour. The reaction mixture was added to iced water (100 ml) and the aqueous mixture was neutralised with solid sodium bicarbonate. The product was extracted into dichloromethane (2×100 ml), washed with water (1×100 ml), dried (anhydrous MgSO4) and evaporated. Pure N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-formamide (5.32 g; 67%) was obtained by chromatography on silica-gel in dichloromethane followed by crystallisation from ethanol. M.p. 72°-3° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][N+:12]([O-])=O)=[CH:6][CH:5]=1.[H][H].[ClH:19]>CO.[Pd]>[ClH:19].[F:1][C:2]([F:15])([F:16])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])C=Cc1ccc(OC(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCc1ccc(OC(F)(F)F)cc1
Yield: 57 %

Procedure:
A solution of (4-trifluoromethoxy benzaldehyde (1 g, 5.26 mmol) and nitromethane (0.96 g, 15.8 mmol) in acetic acid (10.6 mL) is treated with ammonium acetate (1.01 g, 13.2 mmol) is heated under microwave to 150° C. for 15 minutes. The reaction mixture is diluted with water, and extracted three times with DCM (50 mL). The combined extracts are washed sequentially with 2 N sodium hydroxide, water, and brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to yield 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (1.23 g) as a solid. A portion of 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (0.504 g, 2.16 mmol) is hydrogenated with hydrogen in a balloon, 10% Pd/C (115 mg, 5 mol %) in MeOH (22 mL) containing concentrated hydrochloric acid (0.27 mL) at room temperature for 15 hours. The mixture is filtered and filtrate is concentrated to a solid that is washed with diethyl ether to obtain 2-(4-trifluoromethoxy-phenyl)-ethylamine hydrochloride [0.3 g, 57%, Intermediate (12)] as a solid. LC/MS: MS: 206 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[N:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([N:4]5[CH2:3][CH:2]([CH3:1])[CH2:6][S:5]5(=[O:7])=[O:8])=[CH:17][CH:16]=4)=[O:15])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CC1CN(c2ccc(C(=O)O)cc2)S(=O)(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)CS3(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
4-(4-Methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 15 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (170 mg) described in Preparation Example 83 were dissolved in tetrahydrofuran (10 mL), 1-hydroxybenzotriazole 1 hydrate (139 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (225 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7]([F:15])([F:14])[O:6][C:5]2([F:17])[F:16]>C(O)(=O)C.O.[Fe]>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([F:17])([F:16])[O:6][C:7]2([F:14])[F:15])=[CH:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc2c(cc1Cl)C(F)(F)OC2(F)F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc2c(cc1Cl)C(F)(F)OC2(F)F
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution wherein electrolytic iron powder (5.59 g, 100.0 mmol) is in acetic acid (100 ml) and water (10 ml), an acetic acid (20 ml) solution of 5-chloro-6-nitro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran (5.43 g, 20.0 mmol) was added dropwise at 50 to 60° C. over a period of about 10 minutes and further stirred for 30 minutes. The reaction solution was then filtered and water was poured into the filtrate. After the solution was extracted with ethyl acetate, the organic layer was washed with a saturated sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 4.46 g of 6-amino-5-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[Br:13]Br>C(Cl)Cl>[Br:13][CH2:11][C:10]([C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1cc(F)c(F)cc1F
Solvent: ClCCl
Product: O=C(CBr)c1cc(F)c(F)cc1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A 1 L 3-neck round bottom flask was charged with 1-(2,4,5-trifluorophenyl)ethanone (49.7 g, 285 mmol) and DCM (350 mL). The flask was equipped with a 250 mL dropping funnel that contained a solution of bromine (14.6 mL, 283 mmol) in DCM (125 mL). This solution was added to the reaction flask over about 1 h at about 23° C. Once addition of the solution was complete, the reaction mixture was stirred for about 1 h at about 23° C. Ice water was added to the reaction flask and the layers were stirred for about 15 min. The layers were separated and the organic solution was then washed with water and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid (70.3 g, 97%): LC/MS (Table 1, Method b) Rt=2.20 min; MS m/z 251.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[NH2:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1.N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:5])[N:10]2[N:11]=[C:12]([SH:14])[N:13]=[C:9]2[N:8]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(S)nc2n1
Temperature: 125 °C
Yield: 81.6 %

Procedure:
A mixture of 2,4-pentanedione (6.46 g, 64.6 mmol), 3-amino-5-mercapto-1,2,4-triazole (7.5 g, 64.6 mmol), glacial acetic acid (230 mL), and piperidine (0.58 mL, 5.9 mmol) was added to a 500 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath to a gentle reflux at 125° C. The mixture was heated for 45 hours, and solids remained visible in the flask throughout the heating period. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 and 254 nm. The starting material 3-amino-5-mercapto-1,2,4-triazole elutes rapidly with retention time of 1.05 min, and the product elutes with retention time of 1.87 min. The mixture was cooled to room temperature. Solids were isolated by filtration, rinsed with 75 mL of acetic acid, and then dried under reduced pressure to afford the title compound as a pale yellow powder (9.5 g, 82% yield). A sample of 120 mg was recrystallized in warm acetic acid to afford 60 mg (50% recovery) of fine off-white needles, while the crude powder was used in the next step. 1H NMR (DMSO-d6+CDCl3, 400 MHz) δ ppm: 14.05 (br s, 1H), 7.25 (s, 1H), 2.67 (s, 3H), 2.56 (s, 3H). (NMR from crystalline material.)