Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21]CC)=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([OH:21])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:31])([F:32])[F:33]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
Ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (320 mg, 0.647 mmol) was dissolved in a MeOH/THF/H2O (10 mL/10 mL/5 mL) mixture, LiOH (163 mg, 3.88 mmol) was added. The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and evaporated under reduced pressure. Purification was achieved by re-crystallization in hexane/ether mixture to give 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (220 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.74 (d, 2H), 7.55 (d, 2H), 7.01 (s, 2H), 4.44 (q, 2H), 3.68 (t, 1H), 1.98 (m, 2H), 1.61 (m, 1H), 1.54 (m, 1H), 0.95 (d, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OS(C(F)(F)F)(=O)=O)=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccc(Cl)cc2c(=O)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)c2ccc(Cl)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A mixture of ethyl 7-chloro-2-methyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (2.90 g, 7 mmol), phenylboronic acid (1.02 g, 8.4 mmol) and sodium carbonate (1.85 g, 17.5 mmol) in toluene (20 ml), ethanol (4 ml) and water (4 ml) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (0.46. g, 4 mmol) and the mixture was refluxed under heating under an argon atmosphere for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-2-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate (1.70 g, 71.1%) as crystals.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([CH3:32])[CH:24]=1>CN(C)C=O.C(N(CC)C=O)C>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:11]2)=[O:28])=[C:25]([CH3:32])[CH:24]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: Cc1cc(Br)ccc1C(=O)Cl
Agent: CCN(C=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (3 g, 15.2 mmol) in N,N-dimethylformamide under nitrogen was added solid potassium carbonate (6.3 g, 45.6 mmol). A solution of the crude 4-bromo-2-methylbenzoyl chloride (22.8 mmol) in N,N-diethylformamide was added dropwise, and the mixture stirred at room temperature for 15 minutes. Excess potassium carbonate was filtered off, the filtrate was washed with water and the aqueous layer was extracted with chloroform. The extracts were dried over anhydrous sodium sulfate, evaporated to dryness and the residue dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided the title compound (3.2 g) as a foam which crystallized upon sonication from ethanol hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1nc(C)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1nc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 32 %

Procedure:
This compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-methoxy-6-methyl-[1,3,5]triazine in analogy to example 1c. It was purified by chromatography on Si—NH2 (Isolute) using ethyl acetate as an eluent to give the title compound as a slightly yellowish solid in 32% yield.
Reaction SMILES: [SH:1][CH:2]([CH3:13])[C:3]([N:5]1[CH:9]([C:10](O)=[O:11])[CH2:8][S:7][CH2:6]1)=[O:4]>O>[CH3:13][CH:2]1[S:1][C:10](=[O:11])[CH:9]2[CH2:8][S:7][CH2:6][N:5]2[C:3]1=[O:4]
Reactant: CC(S)C(=O)N1CSCC1C(=O)O
Solvent: O
Product: CC1SC(=O)C2CSCN2C1=O
Reaction time: 4 h
Yield: 50.8 %

Procedure:
Polyphosphoric acid (36 g) was added to N-(2-mercaptopropanoyl)thiazolidine-4-carboxylic acid (1.5 g, 6.78 mmol) and the mixture stirred at 50° for a period of 4 hours. The reaction mixture was then dissolved in water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give 0.7 g of 6-methyl-1H,3H-thiazolo[4,3-c][1,4]thiazine-5,8-dione as a pale yellow oil.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][NH:5][CH2:6][C:7]#[C:8][C:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[S:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[CH:10]=1>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[CH:10]=[C:9]([C:8]#[C:7][CH2:6][N:5]([CH3:4])[CH2:2][CH2:1][OH:3])[C:15]=2[CH:16]=1
Reactant: CNCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Reactant: C1CO1
Solvent: CCO
Product: CN(CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21)CCO

Procedure:
A solution of 2 ml. of ethylene oxide in 10 ml. of ethanol is treated with a solution of 0.6 g. of N-methyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylamine in 5 ml. of ethanol and stirred at room temperature for about 14 hours. The solvent is evaporated and the residue partitioned between water and ether. The ethereal phase is washed with a dilute aqueous ammonia solution, dried over sodium sulfate and evaporated, whereby there is obtained 2-{[3-(8-chloro-dibenzo[b,f]thiepin-10yl)-2-propynyl]-methylamino}-ethanol which melts at 86°-88° C. after recrystallization from ether/n-pentane.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7]CC)=[O:6])[C:3]=1[C:13]([O:15]CC)=O.NC1C=CC=C(C(OC)=O)C=1C(OC)=O.[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][C:34]1=O.[Cl-].[Cl-].[Cl-].[Al+3]>CO>[O:15]=[C:13]1[C:38]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:42]=3[CH2:41][CH2:40][C:39]=2[NH:1][C:2]2[C:3]1=[C:4]([C:5]([OH:7])=[O:6])[CH:10]=[CH:11][CH:12]=2
Reactant: CCOC(=O)c1cccc(N)c1C(=O)OCC
Reactant: O=C1CCc2ccccc2C1
Agent: COC(=O)c1cccc(N)c1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: O=C(O)c1cccc2[nH]c3c(c(=O)c12)-c1ccccc1CC3
Temperature: 80 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of diethyl 3-aminophthalate and dimethyl 3-aminophthalate (1.0 g, 3.82 mmol), 3,4-dihydronaphthalen-2(1H)-one (0.61 g, 4.2 mmol), and aluminum trichloride (0.51 g, 3.82 mmol) was placed in a sealed tube and heated to 80° C. for 1 hour and then 130° C. for additional 4 hours. The mixture was cooled to room temperature, treated with methanol and concentrated. The remaining residue was chromatographed on silica gel using eluant of 3.2% methanol in dichloromethane and then purified by recrystalization in ethyl acetate and methanol to give the product (0.36 g, 30%) as a light brown solid. MS (ESI) m/e [M+1]+292.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[CH:10]([NH:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=4)[N:15]=3)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]1[C:9]2[CH:10]([NH:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:33](=[O:34])[CH2:32][N:29]5[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]5)[CH:20]=4)[N:15]=3)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: CCOc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Product: CCOc1cccc2c1C(Nc1ccc3cc(NC(=O)CN4CCN(C)CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-(4-ethoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine (Example 175) (200 mg, 0.49 mmol) and commercially available (4-methyl-piperazin-1-yl)-acetic acid (74 mg, 0.65 mmol) in accordance with the general method 14 described in example 119 and was obtained as an off-white solid (200 mg, 93%); MS: m/e=462.2 (M+H+).
Reaction SMILES: C([N:4](CC=C)[CH:5]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][CH3:29])=[CH:23][CH:22]=1)[C:6]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]([F:20])[CH:10]=1)=[O:7])C=C.CN1C(=O)CC(=O)N(C)C1=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:4][CH:5]([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][O:28][CH3:29])=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([Si:16]([CH3:17])([CH3:18])[CH3:19])=[C:11]([F:20])[CH:10]=1)=[O:7]
Reactant: C=CCN(CC=C)C(C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1)c1ccc(COC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: C1CCOC1
Product: COCc1ccc(C(N)C(=O)Nc2cc(F)c([Si](C)(C)C)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide (6.79 g, 14.81 mmol) and 1,3-dimethylbarbituric acid (4.85 g, 31.09 mmol) in THF (120 mL) was added Pd(PPh3)4 (0.684 g, 0.59 mmol), and the mixture was stirred overnight at room temperature under argon atmosphere. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (NH, solvent gradient; 50→100% ethyl acetate/hexane) to give crude 2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide (4.00 g) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[F:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[CH:28][CH:27]=1.[I-].[Na+]>CN(C)C=O>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:34][CH2:33]2)=[O:31])=[CH:38][CH:39]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Temperature: 20 °C
Yield: 26.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.7 g), triethylamine (3.5 cc), 4-(4-fluorobenzoyl)piperidine (5.2 g) and sodium iodide (3.7 g) in dimethylformamide (100 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (8 cc), 2-{2-[4-(4-fluorobenzoyl)piperidino}ethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.9 g) is obtained, m.p. 145° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([OH:31])[CH3:30])=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:24]=[CH:25][C:26]([C:29](=[O:31])[CH3:30])=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(C(C)O)cc2)cc1OC1CCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(C(C)=O)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
A solution of (R)-4-{2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[4-(1-hydroxyethyl)-phenyl]ethyl}pyridine from Example 5 (205 mg, 0.49 mmol) in CH2Cl2 (4 mL) was added to a suspension of pyridinium chlorochromate (272 mg, 1.3 mmol) and molecular sieve in CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 hour before the volatiles were evaporated. The residue was then triturated in EtOAc and filtered over celite. Evaporation of the filtrate afforded a residue which was purified by flash-chromatography (silica gel, hexane/EtOAc 25:75) to afford the title compound as a white foam (39 mg, 19%). 1H NMR (400 MHz, CDCl3): d 1.55 (m, 2H), 175 (m, 6H), 2.55 (s, 3H), 3.30 (d, 2H), 3.80 (s, 3H), 4.20 (t, 1H), 4.65 (m, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 6.90 (d, 2H), 7.25 (d, 2H), 7.85 (d, 2H), 8.40 (d, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:23])[CH:9]([C:17]2[S:21][N:20]=[C:19]([CH3:22])[N:18]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH2:24]>N1C=CC=CC=1.N1CCCCC1>[C:1]1([NH:7][C:8](=[O:23])[CH:9]([C:17]2[S:21][N:20]=[C:19]([CH3:22])[N:18]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[S:24])[NH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S
Reactant: Cc1nsc(C(CCCCCC#N)C(=O)Nc2ccccc2)n1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1nsc(C(CCCCCC(N)=S)C(=O)Nc2ccccc2)n1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
To a stirred mixture of 7-cyano-2-(3-methyl[1,2,4]thiadiazol-5-yl)heptanoic acid phenylamide (2021044) (0.55 g, 1.7 mmol) in pyridine (120 mL) and piperidine (30 mL) was slowly bubbled hydrogen sulphide for 15 min. The resultant mixture was then stoppered and stirred at 50° C. for five days. The solvent was removed under reduced pressure, water (150 mL) was added to the residue, and the resultant solution was extracted with dichloromethane (3×150 mL). The crude product (1.6 g) was purified by preparative liquid chromatography to afford 2-(3-methyl-[1,2,4]thiadiazol-5-yl)-7-thiocarbamoyl heptanoic acid phenylamide (2021036) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([CH2:27][O:28]C)[O:10][N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([CH2:27][OH:28])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COCc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(C)=O)cc2)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3CO)c2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
To a stirred solution of 1-(4-{4-[3-(4-fluoro-phenyl)-5-methoxymethyl-isoxazol-4-yl]-imidazol-1-yl}-phenyl)-ethanone (239 mg, 0.61 mmol) in dry dichloromethane (4 mL) was added slowly boron tribromide (0.17 mL, 0.3 mmol) at dry ice-acetone bath cooling temperature. After complete addition, the resulting mixture was stirred at −78° C. for 15 min, and −15° C. for 35 min, and then allowed to warm up to room temperature for 20 min. The reaction was quenched with saturated sodium bicarbonate (30 mL). The organic layer was separated, and the aqueous phase was extracted with dichloromethane and ethylacetate. The combined organic extracts were then dried over sodium sulphate and evaporated. Purification by preparative HPLC afforded the title compound (35 mg, 15%) which was obtained as an off-white solid. MS: m/e=378.0 [M+H]+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=O)[CH:13]=2)[CH2:3][CH2:2]1.[CH3:26][NH:27][CH2:28][CH2:29][OH:30].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[O:25])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CNCCO
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N(C)CCO)cc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
To a stirred mixture of 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (70 mg, 0.21 mmol, STEP 2) and 2-(methylamino)ethanol (31 mg, 0.41 mmol) in dimethylformamide (2 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (67 mg, 0.35 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (60 mg, 0.41 mmol) at room temperature. After stirring at room temperature for 18 hours, the reaction mixture was quenched with sodium hydrogencarbonate aqueous solution (5 mL), and extracted with ethyl acetate (50 mL×2). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=10:1 as an eluent). The residue was suspended with diethyl ether, and collected by filtration to afford the title compound as a white solid (24 mg, 24%):
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[C:8]([C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=1>O1CCOCC1>[Br:1][CH:11]([C:10]([C:8]1[CH:9]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=1[O:18][CH3:19])=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Reactant: BrBr
Solvent: C1COCCO1
Product: CCOC(=O)C(Br)C(=O)c1cc(Cl)ccc1OC
Reaction time: 1 h

Procedure:
Bromine (0.70 mL, 13.6 mmol) was added to a solution of ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (3.39 g, 13.2 mmol) in dioxane (25 mL) and stirred for 1 hour. The reaction was poured onto ice water, extracted with ethyl acetate, the organics washed with water and brine and evaporated to dryness to give ethyl 2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (method 1) [M+H]+=337.2, RT=3.84 min.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(OC(=O)C)(=O)C.[CH3:12][C:13]1([CH3:23])[C:22]2[C:17](=[CH:18]C=C[CH:21]=2)[CH2:16][CH2:15][CH2:14]1>C1C=CC=CC=1.O>[CH3:12][C:13]1([CH3:23])[C:14]2[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1](=[O:4])[CH2:21][CH2:22]1
Reactant: CC(=O)O
Reactant: CC1(C)CCCc2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CCC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A solution of 350 ml of glacial acetic acid and 170 ml of acetic anhydride was cooled to 0° C. and CrO3, 25.0 g (0.25 mol) carefully added in small portions. The resulting mixture was stirred for 30 minutes before 120 ml of benzene was added. 1,2,3,4-tetrahydro-1,1-dimethylnaphthalene was added slowly as a solution in 30 ml of benzene. Upon completing the addition the reaction was stirred for 4 hours at 0° C. The solution was diluted with H2O (200 ml) and extracted with Et2O (5×50 ml). The combined organic layers were washed with water, saturated aqueous NaCO3, and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, and distillation afforded 16.0 g (74%) of the product as a pale-yellow oil, bp 93-96° C./0.3 mm Hg 1H NMR (CDCI3): δ 8.02 (1H, dd, J=1.3, 7.8 Hz), 7.53 (1H, m), 7.42 (1H, d, J=7.9 Hz), 7.29 (1H, m), 2.74 (2H, t, J=6.8 Hz), 2.02 (2H, t, J=6.8 Hz), 1.40 (6H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[N:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1.CC(O)=O.O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Cn1nc(-c2ccccc2)nc1N
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)nn2C)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 19.1 %

Procedure:
To a solution of 1-methyl-3-phenyl-1,2,4-triazol-5-amine (320 mg, 2 mmol) in 10 mL dry pyridine was added 529 mg (2.23 mmol) of 3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at room temperature under Argon. After 21 h, the pyridine was removed in vacuo and flashed off with toluene. The salt was partitioned between EtOAc and water. The EtOAc phase was extracted alternately with 1M NaOH and H2O. The basic phase was made acid (pH˜3) with 1M HCl and extracted with EtOAc. The organic phase was evaporated in vacuo, toluene was added and was again evaporated in vacuo to give a white solid. The product was taken up in hot HOAc (16 mL), diluted with H2O (10 mL) and seeded to give 143 mg of white needles with mp 279-280° C. after drying in vacuo.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([S:15][CH3:16])[C:5]=1[O:17][CH3:18]>O.C(O)C>[Br:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:15][CH3:16])[C:5]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1ccc(Br)c(OC)c1SC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(Br)ccc(C(=O)O)c1SC

Procedure:
A solution of potassium hydroxide (2.0 g) in water was added to a solution of ethyl 4-bromo-3-methoxy-2-(methylsulphenyl)-benzoate (4.5 g) in ethanol. The resulting solution was stirred and heated at reflux for 3 hours. After cooling, the mixture was evaporated to dryness and the residue was dissolved in water and washed with ethyl acetate. The aqueous solution was acidified to pH 1 and extracted with ethyl acetate, dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-bromo-3-methoxy-2-(methylsulphenyl)benzoic acid as a white solid, NMR (CDCl3) 2.5(s,3H), 3.9(s,3H), 7.4(s,2H), 10.9(bs,1H).