Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH2:21][C:22]([NH:24][CH:25]3[CH2:28][CH2:27][CH2:26]3)=[O:23])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:35][N:36]([CH3:40])[C:37]([N:32]1[CH2:31][CH2:30][CH:29]([N:20]([C:6]2([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:21][C:22](=[O:23])[NH:24][CH:25]2[CH2:26][CH2:27][CH2:28]2)[CH2:34][CH2:33]1)=[O:38]
Reactant: CN(C)C(=O)Cl
Reactant: O=C(CN(C1CCNCC1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)C(=O)N1CCC(N(CC(=O)NC2CCC2)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Reaction time: 1 h
Yield: 22.7 %

Procedure:
At room temperature, rac-2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-4-yl-amino}-N-cyclobutyl-acetamide (77 mg, 0.154 mmol) and dimethylcarbamyl chloride (14 mg, 0.185 mmol) and K2CO3 were mixed in about 2 ml CH2Cl2. After stirred for about 1 h, the solution was concentrated and the crude product was purified by chromatography to obtain 20 mg solid rac-4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid dimethylamide.
Reaction SMILES: [OH:1][C:2]1N=C2C=C(OCC3SC=C(C(C)C)N=3)C=CN2C(=O)C=1.[CH2:23]([C:25]1[CH:26]=[C:27]([CH2:30][CH2:31][C:32]2[CH:48]=[CH:47][N:35]3[C:36](=[O:46])[CH:37]=[C:38]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[N:39]=[C:34]3[CH:33]=2)[S:28][CH:29]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[C:27]([CH2:30][CH2:31][C:32]2[CH:48]=[CH:47][N:35]3[C:36](=[O:46])[C:37]([CH:2]=[O:1])=[C:38]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)[N:39]=[C:34]3[CH:33]=2)[S:28][CH:29]=1)[CH3:24]
Reactant: CC(C)c1csc(COc2ccn3c(=O)cc(O)nc3c2)n1
Reactant: CCc1csc(CCc2ccn3c(=O)cc(N4CCOCC4)nc3c2)c1
Product: CCc1csc(CCc2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)c1

Procedure:
Reactions were performed in the same manner as in Example 1, (I) by using 8-[2-(4-ethyl-2-thienyl)ethyl]-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (122 mg, 0.33 mmol) as a starting material. As a result, 52 mg (40% for the three steps) of the title compound in orange color was obtained.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:19](=[O:21])[NH2:20])[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]=2[C:9]([CH3:29])=[CH:8][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:22]([N:11]1[C:10]2[C:9]([CH3:29])=[CH:8][CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][C:16]=2[C:19](=[O:21])[NH2:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)COc1ccc(C)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A slurry of 32 mg (0.0795 mmol) of [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl]oxyacetic acid methyl ester in 1 ml of tetrahydrofuran and 3.5 ml of methanol was treated with 0.3 ml of an aqueous 2 N sodium hydroxide solution and stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between 1:1 ethyl acetate/tetrahydrofuran and 0.2 N HCl solution. After another extraction with 1:1 ethyl acetate/tetrahydrofuran, the extracts were washed with brine, dried over magnesium sulfate and concentrated to afford (27 mg) of the title compound. mp. 253-254° C. ESIMS m/e 389 (M++1), 387 (M+−1) NMR (300 MHz, d6-DMSO): δ12.83 (br, 1H); 7.75 (br, 1H); 7.53 (d, J=8.2, 1H); 7.41-7.34 (m, 2H); 7.28-7.17 (m, 3H); 7.07 (m, 2H); 6.90 (d, J=7.2, 2H); 6.49 (d, J=8.1, 1H); 5.89 (s, 2H); 4.79 (s, 2H); 2.52 (s, 3H).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC>[Br:1][CH:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: BrBr
Reactant: O=C(COCc1ccccc1)c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(Br)OCc1ccccc1
Reaction time: 2 h

Procedure:
Bromine (1.4 g, 8.8 mmol) is added dropwise with stirring to a solution of 2-benzyloxy-acetophenone (2.0 g, 8.8 mmol) in dry ether (30 ml) at room temperature. After stirring for additional 2 h the solution is washed with water and dried over sodium sulfate. Evaporation of the filtered solution yields the title compound. 1H-NMR (CDCl3, 400 MHz): 7.83-7.81 (m, 1H); 7.49-7.38 (m, 6H); 7.06-7.00 (m, 2H); 5.18 (s, 2H), 4.52 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH:9]([CH2:10]OS(C)(=O)=O)[CH2:8][C:7]1=[O:16].[I-:23].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH:9]([CH2:10][I:23])[CH2:8][C:7]1=[O:16]
Reactant: COc1ccc(CN2C(=O)CC2COS(C)(=O)=O)c(OC)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CN2C(=O)CC2CI)c(OC)c1
Reaction time: 8 h
Yield: 104.3 %

Procedure:
A mixture of 37.5 g (0.107 mole) of 1-(2,4-dimethoxy-benzyl)-4-(mesyloxymethyl)-2-azetidinone prepared according to the preceding paragraph, 250 ml of anhydrous acetone, and 56.3 g (0.376 mole) of sodium iodide is heated to boiling for 8 hours. To the mixture a further amount of 18.8 g (0.125 mole) of sodium iodide are added and the mixture is stirred for a further 8 hours under boiling. The mixture is evaporated to dryness on a water-bath (internal temperature 50° C.), the residue is rubbed with 100 ml of water and the oil thus obtained is extracted with 100 ml of dichloromethane. The aqueous layer is extracted three times with 50 ml of dichloromethane each. The united dichloromethane layers are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. Thus 40.3 g of 1-(2,4-dimethoxy-benzyl)-4-(iodomethyl)-2-azetidinone are obtained. Yield: 98%.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].C(O)C.[CH2:17]([O:24][C@@H:25]([CH3:31])[CH2:26][C:27](=[O:30])[CH2:28]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:3](=[O:4])[CH3:5])[CH2:28][C:27](=[O:30])[CH2:26][C@@H:25]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:31])[CH3:9]
Reactant: C[C@@H](CC(=O)CBr)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)C[C@H](C)OCc1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl acetoacetate (1.0 g, 7.7 mmol) in ethanol (30 mL), 20% sodium ethoxide/ethanol solution (3.1 mL, 7.7 mmol) was gradually added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Thereafter, under ice-cooling, a solution of the above (4S)-4-(benzyloxy)-1-bromopentan-2-one (2.1 g, 7.7 mmol) in ethanol (6.0 mL) was gradually added, and the mixture was stirred at room temperature for 3 hours. After the reaction, ethanol was distilled off under reduced pressure and 1N hydrochloric acid (0.20 L) was added to acidify it. After it was extracted with ethyl acetate and successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure. It was purified by silica gel column chromatography (ethyl acetate/hexane, 1:3, v/v) to give the title compound (1.6 g, 65%) as an oil.
Reaction SMILES: Cl.C[O:3][C:4](=[O:9])[CH:5]([OH:8])[CH2:6][NH2:7].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([NH:7][CH2:6][CH:5]([OH:8])[C:4]([OH:3])=[O:9])=[O:21])=[CH:14]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C(O)CN
Agent: Cl
Product: O=C(NCC(O)C(=O)O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(RS)-3-amino-2-hydroxypropionic acid methyl ester hydrochloride (6.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (6.6 mmol) were coupled according to Procedure A (except that acid, then base extraction was performed, and during the first acid wash a precipitate appeared so the mixture was filtered and the filtrate carried on in the usual manner of Procedure A). The crude product (920 mg) was dissolved in methanol and treated with 1N NaOH (6.6 mL) for 2 hours at 25° C. 1N NaOH was added (6.6 mL) and the mixture was concentrated, the residue dissolved in ethyl acetate, and the resulting solution washed with 2N HCl, brine, dried, and concentrated. The resulting colorless solid was stirred in chloroform and filtered giving the title substance: Yield 763 mg, 40%; HPLC (60/40) 2.86 minutes (89%); mp 214-215° C.; PBMS 283/285 (MH+, 100%); 1H NMR (DMSO-d6) δ11.78 (s, 1H), 8.62 (t, 1H), 7.70 (d, 1H, J=2 Hz), 7.42 (d, 1H, J=8.7 Hz), 7.17 (dd, 1H, J=2, 8.7 Hz), 7.14 (d, 1H, J=2 Hz), 4.18 (dd, 1H, J=5, 8 Hz), 3.58 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[C:19]1([C:25]2[O:26][CH:27]=[CH:28][C:29]=2B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:19]1([C:25]2[O:26][CH:27]=[CH:28][C:29]=2[C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:3]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1ccoc1-c1ccccc1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
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: O
Solvent: COCCOC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccoc1-c1ccccc1
Temperature: 80 °C
Yield: 6.7 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (300 mg, 0.940 mmol), (2-phenylfuran-3-yl)boronic acid (265 mg, 1.41 mmol), Na2CO3 (299 mg, 2.82 mmol) and Pd(PPh3)4 (54.3 mg, 0.047 mmol) in DME (3.6 mL) and water (1.1 mL) was heated to 80° C. for 4 h under Ar atmosphere. The mixture was diluted with water, extracted with AcOEt, washed with NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=80/20 to 0/100) and recrystallized with AcOEt/heptane to yield the title compound (23.9 mg, 7% yield) as a pale yellow solid: mp 159-163° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.63 (1H, d, J=8.0 Hz), 6.99 (1H, d, J=1.9 Hz), 7.32-7.43 (3H, m), 7.54-7.60 (2H, m), 7.69-7.76 (2H, m), 7.78-7.82 (1H, m), 7.85 (1H, d, J=1.9 Hz), 7.85-7.92 (1H, m), 8.96 (1H, d, J=8.0 Hz). Anal. Calcd for C21H13F3N2O2.0.3H2O: C, 65.05; H, 3.54; N, 7.22. Found: C, 65.20; H, 3.63; N, 7.29.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[CH:9][CH:8]=1.CN(C)[CH:22]=[O:23]>O1CCCC1>[CH3:18][C:16]1([CH3:19])[CH2:15][O:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:22]=[O:23])=[CH:8][CH:9]=2)=[N:17]1
Reactant: CN(C)C=O
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C=O)cc2)=N1
Temperature: 25 °C

Procedure:
n-Butyl lithium (9.44 ml, 2.5N solution in hexanes) was added to a solution of 2-(4-bromophenyl)-4,5-dihydro-4,4-dimethyl-oxazole [A. I. Meyers et al., J.O.C., 1974, 39, 2787] (5 g) in tetrahydrofuran (80 ml) at −78° C. The reddish solution was stirred at −78° C. for 15 minutes before dimethylformamide (2.3 g) was added dropwise. The resulting deep red solution was allowed to warm to room temperature, quenched with ammonium chloride solution and extracted into ether. The combined extracts were washed with brine, dried (sodium sulphate) and evaporated to dryness in vacuo. The residue was purified by column chromatography (30% ethyl acetate/hexane) to afford the title compound as a colourless liquid, 3.01 g.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=2)[O:5][C:6]=1[C:7]1[N:11]=[CH:10][NH:9][N:8]=1.CCN(C(C)C)C(C)C.[CH3:32][Si:33]([CH2:36][CH2:37][O:38][CH2:39]Cl)([CH3:35])[CH3:34]>CN(C=O)C>[I:1][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=2)[O:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:39][O:38][CH2:37][CH2:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[N:8]=1
Reactant: CC(=O)Nc1cc(-c2nc(I)c(-c3nc[nH]n3)o2)c(C)cn1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(-c2nc(I)c(-c3ncn(COCC[Si](C)(C)C)n3)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a solution of N-{4-[4-iodo-5-(1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (6.2 g, 15 mmol) in DMF (60 mL) was added DIEA (4.0 mL, 23.0 mmol). The reaction mixture was allowed to stir at rt for 2 h and then SEM-Cl (4.1 mL, 23.0 mmol) was added. The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was purified by column chromatography to give N-{4-[4-iodo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (2.7 g) plus another SEM regioisomer (1.2 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: Oc1cccnc1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To prewashed NaH (3×20 ml hexane) (2.52 g active NaH, 105 mmol) in dimethylformamide (DMF) (50 ml) is added 3-hydroxypyridine (10.0 g, 105 mmol) in DMF (50 ml) with cooling over 0.5 hour. The reaction mixture is stirred at RT for 1 hour and is then cooled to 15°. To this is rapidly added 4-chlorobenzyl chloride (16.25 g, 99.8 mmol) in 5 ml of DMF. The reaction is allowed to warm to RT, and is then poured into ice and extracted with chloroform (3×). The chloroform layers are combined, washed with water and with brine, dried over calcium sulfate and rotoevaporated. The crude product is poured into ice and extracted with ether (3×). The combined ether layers are washed with water and with brine, and dried over calcium sulfate to give 3-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]2)[CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:22][C:18]1[CH:19]=[C:20]([CH3:21])[N:16]([CH2:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:9][CH2:10]2)=[O:23])[N:17]=1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3N)CC2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3NC(=O)c3ccccc3)CC2)n1
Reaction time: 60 h
Yield: 100 %

Procedure:
The 1-[4-(2-amino-phenyl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone (0.042 g, 0.136 mmol) is dissolved in 1.5 mL of CH2Cl2. To this is added diisopropylethyl amine (0.046 mL, 0.250 mmol) and benzoyl chloride (0.018 mL, 0.150). The mixture is stirred for 60 h. The reaction is quenched with 2 mL of saturated NH4Cl and extracted in the reaction vial with 2×2 mL of CH2Cl2. The organic phase is concentrated. The residue is purified using a SiO2 prep plate eluting with (75% EtOAc/hexanes) to give 58.1 mg of N-(2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-phenyl)-benzamide in 100% Yield. MS: MH+=418.2.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[N:6]=1.O.O.O.C([O-])(=O)C.[Na+]>[Pd].C(O)C>[F:12][C:9]([F:10])([F:11])[C:8]([NH:7][C:5]1[N:6]=[CH:2][S:3][CH:4]=1)=[O:13]
Reactant: O=C(Nc1csc(Br)n1)C(F)(F)F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(Nc1cscn1)C(F)(F)F

Procedure:
A mixture of 50 g. (0.182 mole) of 2-bromo-4-trifluoroacetamidothiazole 36.5 g. (0.268 mole) of sodium acetate, trihydrate and 16.6 g. of 10% palladium on carbon in 1.5 l. of absolute ethanol is hydrogenated at 1 atmosphere over 18 hours at room temperature. The catalyst is filtered off and washed well with ethanol. The filtrate is evaporated to dryness and the residue extracted several times with warm methylene chloride. The combined extracts are evaporated to dryness and the residue crystallized from carbon tetrachloride (activated carbon treatment) to give 25 g. (70%) of heavy white crystals m.p. 138°-9° C. Recrystallization of the second crop obtained from the mother liquor raises the yield to 28.5 g. (80%). The product can also be satisfactorily recrystallized from ethanol/water mixtures.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16](=[O:20])(=[O:19])[NH:17][CH3:18])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([NH:17][CH3:18])(=[O:20])=[O:19])=[CH:12][C:8]=2[C:9]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[S:29][N:28]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:31]=3)[CH2:33][CH2:34]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Product: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Yield: 72 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methylsulfamoyl-benzoic acid (Example A29) and 3-phenyl-5-piperazino-1,2,4-thiadiazole. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as an off-white solid (yield 72%). MS (m/e): 528.5 (M+H+, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:10]([OH:12])=O)[S:6][C:7]=1[CH:8]=[O:9])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:35][C:36]1([CH3:56])[O:40][C@@H:39]([CH2:41][O:42][C:43]2[C:52]([CH3:53])=[CH:51][C:46]([C:47]([NH:49]O)=[NH:48])=[CH:45][C:44]=2[CH2:54][CH3:55])[CH2:38][O:37]1>CN(C=O)C>[CH3:35][C:36]1([CH3:56])[O:40][C@@H:39]([CH2:41][O:42][C:43]2[C:52]([CH3:53])=[CH:51][C:46]([C:47]3[N:49]=[C:10]([C:5]4[S:6][C:7]([CH:8]=[O:9])=[C:3]([CH2:1][CH3:2])[CH:4]=4)[O:12][N:48]=3)=[CH:45][C:44]=2[CH2:54][CH3:55])[CH2:38][O:37]1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@H]1COC(C)(C)O1
Reactant: CCc1cc(C(=O)O)sc1C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H]4COC(C)(C)O4)c(CC)c3)no2)sc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-ethyl-5-formyl-thiophene-2-carboxylic acid (20 mg, 0.109 mmol), HOBt (18 mg, 0.131 mmol), and EDC HCl (23 mg, 0.120 mmol) in DMF (0.75 mL) is stirred at rt for 5 min before (S)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine (34 mg, 0.109 mmol) is added. The mixture is stirred at rt for 1 h, then at 85° C. for 2 days. The title compound is isolated as a colourless oil (28 mg) by separating the reaction mixture by prep. HPLC (column: Atlantis T3, 30×75 mm, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of formic acid); LC-MS: tR=1.06 min; [M+1]+=457.19.
Reaction SMILES: [CH2:1]1[CH2:28][O:27][C:3]2([CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C@@H:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:2]1>C(Cl)Cl>[CH2:28]1[CH2:1][O:2][C:3]2([CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:27]1
Reactant: CCCCC[C@H](O)CC[C@H]1CCC2(OCCO2)[C@@H]1CCCCCCC(=O)OC
Solvent: ClCCl
Product: CCCCCC(=O)CC[C@H]1CCC2(OCCO2)[C@@H]1CCCCCCC(=O)OC

Procedure:
To a mixture of 14.5 g. of chromium trioxide-pyridine complex in 110 ml. of dry methylene chloride is added with stirring 4.82 g. of 1-methyl 9,9-(ethylenedioxy)-15(S)-hydroxy-prostanoate (Example 134) in 17 ml. of methylene chloride. The resulting dark brown mixture is stirred at ambient temperature for 18 hours. The mixture is filtered and the mother liquor is taken to dryness. The residue is taken up in ether and washed successively with ice cold 5% sodium hydroxide, saturated sodium chloride solution, 30% sodium phosphate monobasic solution and water dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure to afford 4.17 g. (98%) of product as an oil; λ max 5.71, 5.82μ (carbonyl groups).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[OH:28].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cnc(Oc2ccc(Cl)cc2Cl)nc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14.8 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (170 mg), 2,4-dichlorophenol (112 mg), cesium carbonate (225 mg), and N,N-dimethyl formamide (2 mL) was stirred at room temperature for 15 hours, and then at 100° C. for 10 hours. To the reaction liquid was added ethyl acetate (30 mL), followed by washing with saturated brine (20 mL) and a saturated aqueous ammonium chloride solution (20 mL) in this order, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-ethyl acetate) to obtain 4-{[2-(2,4-dichlorophenoxy)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (36 mg) as a brown oily substance.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:35]2[CH:36]=[CH:37][O:33][CH:34]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: OB(O)c1ccoc1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Product: COc1c(-c2ccoc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Yield: 45 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with furan-3-yl boronic acid (7.2 mg, 0.064 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (10.6 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 1 H) 7.84 (d, J=8.09 Hz, 1 H) 7.80 (t, J=1.84 Hz, 1 H) 7.68-7.75 (m, 2 H) 7.54-7.64 (m, 2 H) 7.50 (t, J=6.07 Hz, 1 H) 7.35 (d, J=2.57 Hz, 1 H) 7.08 (d, J=1.47 Hz, 1 H) 6.57 (s, 1 H) 5.68 (d, J=8.09 Hz, 1 H) 3.47 (s, 2 H) 3.30 (s, 3 H) 2.96 (s, 3 H).