Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:3]=1[CH2:4][NH:5][C:6](=[O:44])[N:7]([C@H:9]([CH2:27][O:28][C:29](=[O:43])[NH:30][C:31]1[O:35][N:34]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:32]=1)[CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:13])[CH3:8].Cl.O1CCOCC1>CO>[F:42][C:38]1[CH:37]=[C:36]([C:33]2[CH:32]=[C:31]([NH:30][C:29](=[O:43])[O:28][CH2:27][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]3[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:2]=3[Cl:1])=[O:44])[CH2:10][CH2:11][C:12](=[O:13])[N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:35][N:34]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1cc(-c2cccc(F)c2)no1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCNCC1)COC(=O)Nc1cc(-c2cccc(F)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of (S)-tert-butyl 4-(4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(3-(3-fluorophenyl)isoxazol-5-ylcarbamoyloxy)pentanoyl)piperazine-1-carboxylate (0.3 g, 0.36 mmol, 1.0 equiv.) in MeOH (2 mL) at 0° C., was added HCl/dioxane (4 N, 0.9 mL, 3.6 mmol, 10 equiv.). The solution was stirred at RT for 1 h. The solvents were removed and the residue was purified on RP-HPLC using a mixture of acetonitrile and H2O with 0.1% TFA. The elute was diluted with EtOAc (10 mL) and then basified with saturated NaHCO3. The organic layer was dried and concentrated to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-oxo-5-(piperazin-1-yl)pentyl 3-(3-fluorophenyl)isoxazol-5-ylcarbamate (0.2 g, 92%). LRMS (M+H+) m/z 605.1.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1>>[F:25][C:22]1[CH:23]=[C:24]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:19]=[CH:20][C:21]=1[F:26]
Reactant: Fc1ccc(Br)cc1F
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(F)c(F)c1)O2

Procedure:
Reaction of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 1-bromo-3,4-difluorobenzene under the conditions described in Example 26 and extending the reaction time to 42 hours gave after chromatographic isolation (40 fold amount of silica gel using methylene chloride) and crystallization from petroleum ether colorless crystals of the title compound with m.p. 109°-112°.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1>C(Cl)Cl.CCOCC>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:14]1[CH2:15][CH2:16][CH2:17][C:13]1=[O:12]
Reactant: O[C@@H]1CCC[C@H]1Oc1cccc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCCC1Oc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
To a suspension of 327.43 g of pyridinium chlorochromate in one liter of methylene chloride is added 220 g of trans-1-hydroxy-2-(3-trifluoromethylphenoxy)cyclopentane in 500 ml of methylene chloride. The mixture is stirred for 2 hours 15 minutes. Another 50 g of the oxidizing agent is added and the mixture is stirred for 41/2 hours. The mixture is diluted with ether and decanted from a black residue which is washed with more ether. The combined solutions are filtered through silica gel. The solvent is removed. The residue is dissolved in ether and again filtered through silica-gel. The solvent is removed and the residue is distilled (bp 113°-116° C., 1.5 mm) to give 188 g of 2-(3-trifluoromethylphenoxy)cyclopentanone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([F:13])[CH:3]=1.[CH:14]1([C:19]([OH:32])([C:30]#[CH:31])[CH2:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[O:24][C:23](=[O:29])[CH:22]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(NC(C)C)(C)C.CN(C=O)C.[NH4+].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:14]1([C:19]([OH:32])([CH2:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[O:24][C:23](=[O:29])[CH:22]=2)[C:30]#[C:31][C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([F:13])[CH:3]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Reactant: CC(C)(C#N)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Temperature: 90 °C
Yield: 79.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (3.0 g, 12.4 mmol) in diisopropylamine (32 mL) and DMF (16 mL) was added 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (3.2 g, 12.4 mmol), PdCl2(PPh3)2 (350 mg, 4 mol %), CuI (71 mg, 3 mol %). The mixture was heated to 90° C. for 30 min before it was cooled down to room temperature. The reaction was diluted with aqueous NH4Cl, extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated to dryness. The mixture was purified by flash column chromatography (10-50% EtOAc in hexanes) to give the product (4.2 g, 79% yield). 1H NMR (300 MHz, CDCl3) δ: 1.65-1.76 (m, 14H), 1.79 (s, 6H), 1.82-1.85 (m, 1H), 2.24 (s, 1H), 2.59 (s, 1H), 2.67 (m, 2H), 5.46 (m, 1H), 7.11 (dd, J=12.15, 1.60 Hz, 1H), 7.18 (dd, J=8.10, 1.70 Hz, 1H), 7.45 (t, J=8.10 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C=O)c1
Temperature: 25 °C

Procedure:
3-Bromobenzaldehyde (30 g, 162 mmol), ethynyl-trimethyl-silane (30 mL, 211 mmol), triphenylphosphine (2.13 g, 8 mmol), palladium (II) acetate (0.91 g, 4 mmol) and triethylamine (540 mL, 0.3 M) were heated at 90° C. for 5 hours, after cooling to ambient temperature, the mixture was filtered. The filtrate was evaporated, and the residue was subjected to silica gel chromatography (hexane to 4:96 diethyl ether/hexane) to afford 3-trimethylsilanylethynyl-benzaldehyde 73(a1).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[Sn](CCCC)(CCCC)CCCC)([CH3:3])[CH3:2].I[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C(OCC)C.C>CN(C)C=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 3-isopropoxy-4-(tri-n-butyl-stannyl)-3-cyclobutene-1,2-dione (J. Org. Chem. 1990, 55, 5359-5364) (8.00 g, 18.65 mmol) in N,N-dimethyl-formamide (40 mL) was added 4-iodoanisole (4.85 g, 20.72 mmol). The flask was purged with nitrogen and cooled to 0° C. Benzylchloro-bis(triphenylphosphine)palladium (II) (0.942 g, 1.24 mmol) and cuprous iodide (0.355 g, 1.87 mmol) were added and the mixture was stirred at room temperature overnight. Diethylether (200 mL) was added and the mixture was washed successively with saturated aqueous ammonium chloride, 10% aqueous potassium fluoride and saturated brine. The organic phase was filtered through a plug of silica. The filtrate was dried (MgSO4) and concentrated to give crude product which was dissolved in hot ethyl acetate, decolorized (charcoal) and filtered. The filtrate was treated with hexane and allowed to cool. 3-Isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione preci-pitated as a light yellow solid (2.46 g, 54%): 1H NMR (DMSO-d6) δ7.89(d,2H), 7.15(d,2H), 5.45(hept, 1H), 3.82(s,3H), 1.48(d,6H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15]>C1COCC1>[OH:15][CH:14]([C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1)[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: O=Cc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: N#CCC(O)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a stirred solution of acetonitrile (2.46 g, 60 mmol, 3.13 mL) in THF (300 mL) at -78° C. was added N-BuLi (37.5 mL, 60 mmol, 1.6M) dropwise over 30 minutes. The resulting solution was stirred at -78° C. for 15 minutes and then 2-naphthaldehyde (6.24 g, 40 mmol) in THF (50 mL) was added dropwise over 45 minutes. The resulting mixture was stirred for an additional 20 minutes at -78° C. and quenched at -78° C. by the addition of saturated NH4Cl (60 mL). The mixture was warmed to room temperature and the THF removed in vacuo to give a white solid. The residue was partitioned between CH2Cl2 (250 mL) and H2O (200 mL, the layers were separated and the aqueous phase extracted with CH2Cl2 (1×250 mL). The combined organic layers were washed with H2O (1×250 ML), dried (Na2SO4) and concentrated in vacuo to give the title compound as a tan solid (7.88 g, 100%) which was homogeneous by TLC and NMR. This material was used as such without purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:25])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[CH:34][N:35]=2)[N:32]=1.C(=O)(O)[O-].[Na+]>>[C:13]1([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:3]([OH:25])[CH2:2][NH:1][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([N:33]=[CH:34][N:35]=4)[N:32]=3)[CH2:6][CH2:7]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: NCC(O)CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: OC(CNc1ccc2ncnn2n1)CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 56 %

Procedure:
0.675 g of 1-amino-3-[4-(diphenylmethoxy)piperidino]-2-propanol and 0.335 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine were stirred at 135-140° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate-tetrahydrofuran (2:1); the extract was washed with saline, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected, recrystallized from ethyl acetate and dried to yield 0.509 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:32][C@H:33]([NH2:36])[CH2:34][CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[C@@H:33]([NH:36][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=1)=[O:22])([CH2:34][CH3:35])[CH3:32]
Reactant: CC[C@H](C)N
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 0.11 mmol), (S)-butan-2-amine (9 mg, 0.12 mmol), and HATU (45 mg, 0.12 mmol). Then added acetonitrile (1 mL) followed by N,N-diisopropylethylamine (0.09 mL, 0.55 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 0-50% EtOAc) to afford 40 mg (71%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-sec-butyl)-amide as a white solid. [M+Na]+=519.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)OCC[O:10]1.Cl.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:10])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: Clc1ccc(C2(Cn3cncn3)OCCO2)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Cn1cncn1)c1ccc(Cl)cc1Br

Procedure:
A mixture of 456 parts of 1-[[2-(2-bromo-4-chlorophenyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole and 1584 parts of concentrate hydrochloric acid was stirred and refluxed for 4 hours. The whole was treated with a sodium hydroxide solution 50%. After stirring for a while, the precipitated product I was filtered off, washed with water and set aside. The filtrate was extracted first twice with 4-methyl-2-pentanone and then three times with trichloromethane. The 4-methyl-2-pentanone layers were dried, filtered and evaporated. The residue was stirred in 2-propanol. The precipitated product II was filtered off and set aside. The trichloromethane-layers were dried, filtered and evaporated. The residue was stirred in 2-propanol. The precipitated product was filtered off and purified, together with product I and product II which were set aside, by column chromatography over silica gel using a mixture of dichloromethane, ethanol and ammonium hydroxide (98.5:1:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2' -oxybispropane and 2-propanol. The product was filtered off and dried, yielding 17 parts parts of 1-(2-bromo-4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (62).
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH2:13]([C:15]1[NH:16][C:17]([CH2:22][OH:23])=[C:18](CO)[N:19]=1)[CH3:14].C(O)C>O1CCOCC1>[CH2:13]([C:15]1[NH:16][C:17]([CH2:22][OH:23])=[C:18]([Cl:1])[N:19]=1)[CH3:14]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: CCc1nc(CO)c(CO)[nH]1
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1nc(Cl)c(CO)[nH]1
Reaction time: 0.17 h

Procedure:
1.53 Grams (6.6 mmol) of trichloroisocyanuric acid was added little by little to a solution consisting of 2.03 g (13 mmol) of the 2-ethyl-4,5-bis(hydroxymethyl) imidazole, 100 ml of ethanol and 40 ml of 1,4-dioxane at room temperature with stirring over a period of about 10 minutes. The mixture was stirred at the same temperature for one hour, the solvent was distilled off under reduced pressure, the reaction product was extracted with ethanol, and the extract was evaporated to dryness under reduced pressure. The resulting solid product was then extracted with acetone, the extract was concentrated and was then subjected to the column chromatography (silica gel-acetone), and the effluent was further concentrated and was recrystallized from acetonitrile to obtain a 2-ethyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 0.78 g (yield, 37.4%). The TLC and spectra were measured to be the same as those of Example 3.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH3:2].C([Li])CCC.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.CCCCCC>[C:15]1([S:21]([N:8]2[CH:4]([S:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7]2=[O:9])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCSC1CCC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCSC1CCC(=O)N1S(=O)(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 65.7 %

Procedure:
To 3.1 g of 5-ethylthio pyrrolidin-2-one in 130 cm3 of tetrahydrofuran there is added at -65° C., 14.2 cm3 of a 1.6M solution of butyllithium in hexane. After 20 minutes, there is added 3.77 g of benzenesulphonyl chloride in 15 cm3 of tetrahydrofuran. After allowing to return to ambient temperature and concentrating to dryness under reduced pressure, 4 g of the expected product is obtained. m.p. 100°-113° C., crystallized from ethanol.
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.N([O-])=[O:16].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[OH:16][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=N[O-]
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cc2c(cn1)[nH]c1ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
0.75 g of 3-amino-β-carboline are dissolved in 85 ml of 6-molar sulfuric acid and at 0° C. mixed with a solution of 0.435 g of sodium nitrite in 10 ml of water. The reaction mixture is stirred for an hour at 0° C. and then added drop by drop to 320 ml of boiling 2-molar sulfuric acid and then refluxed for another 20 minutes. After standing overnight, the product is neutralized with sodium hydroxide and extracted with a mixture consisting of 10 parts of ethyl acetate and one part of ethanol. The ethyl acetate extract is washed once with water, dried and evaporated. The evaporation residue is recrystallized from dimethylformamide. Thus 0.2 g of 3-hydroxy-β-carboline are obtained
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][C:13](C)(C)C)=[O:11])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:5]=[C:4]([Cl:24])[N:3]=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:5]=[C:4]([Cl:24])[N:3]=1
Reactant: CC(C)(C)OC(=O)CCc1c(-c2ccccc2Cl)cc(Cl)nc1Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1c(-c2ccccc2Cl)cc(Cl)nc1Cl
Reaction time: 2 h
Yield: 64.4 %

Procedure:
tert-Butyl 3-[2,6-dichloro-4-(2-chlorophenyl)-3-pyridinyl]propanoate (2.44 g, 6.31 mmol) was dissolved in anisole (6 ml) and trifluoroacetic acid (30 ml) added and the solution allowed to stand at 21° for 2 h, then evaporated in vacuo. The residue was dissolved in toluene (40 ml)-methanol (10 ml), and a 2M solution of trimethylsilyldiazomethane in hexanes added (8 ml), and the solution allowed to stand for 0.5 h. The solution was evaporated in vacuo, and the resulting oil purified by flash chromatography over silica eluting with cyclohexane-ethyl acetate (100:0-65:35) to give the title compound as a viscous gum (1.40 g, 64%)
Reaction SMILES: [CH2:1]([N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH:2]=[CH2:3].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:3][CH2:2][CH2:1][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccccc1
Reactant: C=CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Product: N#Cc1ccc(N(CCCc2ccccc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized according to Example 84B from 4-[2-propen-1-yl(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and bromobenzene: MS (El) m/z 386 (M+, 6%), 281 (84%), 197 (100%), 170 (76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:30])[NH:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:16][CH:15]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:30])[NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCNC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of ethyl 3-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)propanoate (150 mg, 0.33 mmol, 1.00 equiv) in methanol (10 mL), water (2 mL) and sodium hydroxide (80 mg, 2.00 mmol). The resulting solution was stirred for 2 h at 25° C. and the resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 7-8 with hydrogen chloride. The resulting solution was extracted with chloroform (3×10 ml) and the organic layers combined and dried over sodium sulfate. This resulted in 31.5 mg (22%) of 3-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)propanoic acid as a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 8.56 (1H, s), 7.45 (1H, s), 7.29-7.32 (2H, d, J=8.1 Hz), 7.04-7.07 (2H, d, J=8.4 Hz), 6.79 (1H, s), 6.21 (1H, s), 4.16 (1H, m), 3.56-3.58 (2H, d, J=5.4 Hz), 3.27-3.29 (2H, d, J=6 Hz), 2.82-2.87 (1H, m), 2.59 (2H, s), 2.38-2.40 (4H, m). MS (ES, m/z): 422 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[N:8][N:9]([CH2:11][CH3:12])[CH:10]=1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[CH2:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[N:8]1)[CH3:12]
Reactant: CCOC(=O)c1cn(CC)nc1NS(=O)(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCn1cc(C(=O)O)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 0 °C
Reaction time: 96 h

Procedure:
To a solution of the title compound of Example 2, 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carboxylic acid ethyl ester (0.09 g, 0.18 mmol) in dioxane (4 mL) is added 2N sodium hydroxide (4 mL) at RT. The reaction mixture is stirred for 4 days. The reaction mixture is acidified with ice-cold 2 N hydrochloric acid (HCl) and placed in an ice bath for 1 h. The solid formed is separated, washed with water and dried under vacuum. The product, 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carboxylic acid is obtained as a white solid: MS [m/z] 481.1 [M-1]−.
Reaction SMILES: [C:1]([CH2:4][NH:5][CH2:6][CH:7]([O:14][Si](C(C)(C)C)(C)C)[CH2:8][N:9]([CH3:13])[C:10](=[O:12])[CH3:11])(=[O:3])[CH3:2].Cl>CO>[C:1]([CH2:4][NH:5][CH2:6][CH:7]([OH:14])[CH2:8][N:9]([CH3:13])[C:10](=[O:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)CNCC(CN(C)C(C)=O)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(=O)CNCC(O)CN(C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of N-[3-(acetylmethylamino)-2-(tert-butyldimethyl silanyloxy)propyl]-N-methylacetamide (1.12 g, 3.54 mmol) in methanol (23 mL), hydrogen chloride 4M dioxane solution (0.357 mL, 1.426 mmol) was added dropwise at 0° C. and the reaction was stirred at r.t. overnight. Solvent was evaporated and the residue triturated with petroleum ether and decanted. The oil obtained after trituration was dried under vacuum affording N-[3-(acetylmethylamino)-2-hydroxypropyl]-N-methylacetamide (681 mg, 95% yield).