Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][O:35][CH3:36].[I-].[K+]>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([CH2:33][CH2:34][O:35][CH3:36])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 60 °C
Yield: 19.3 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.122 mmol) in 2 mL of DMF, triethylamine is added (34 uL, 0.244 mmol) followed by 1-bromo-2-methoxyethane (36 uL, 0.256 mmol). A spatula tip of potassium iodide was added and the reaction heated at 60° C. for 48 hours. The reaction was cooled and then partitioned between EtOAc (50 mL) and water (25 mL). The organic layer was washed with water (5×15 mL) to remove DMF. The EtOAc layer was the dried with Na2SO4 and then concentrated to yield an off-white solid. The solid was recrystallized from EtOAc-hexanes to yield 11 mg (19%) of title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.88 (s, 1 H), 7.80 (d 1 H), 7.58 (s, 1 H), 7.35 (m, 5 H), 7.15 (d, 1 H), 6.66 (s, 1 H), 5.64 (s, 2 H), 3.80 (m, 2H), 3.45 (t, 2H), 3.30-3.05 (m, 6 H), 2.70-2.50 (m, 2 H), 2.25 (m, 1 H), 1.97 (m, 1H); ES-MS m/z 468.2 [M+H]+, HPLC RT (min) 2.17.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:19][CH2:18]2)=[O:14])[C:5]1=[O:37])([CH3:3])[CH3:2].Cl>C1COCC1>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH2:21][CH2:22]2)=[O:14])[C:5]1=[O:37])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)OC(C)(C)C)CCOCC3)CC2)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)O)CCOCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.1 %

Procedure:
To a stirred solution of tert-butyl 4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (3.67 g, 7.13 mmol, step 6) in THF (80 mL) was added conc. HCl (40 mL) at 0° C. and the resulting mixture was stirred for 20 h at room temperature. The mixture was concentrated to remove the solvent and the residue was poured into sat. NaHCO3 aq. The mixture was extracted with CH2Cl2 for three times and the organic layer was dried over Na2SO4. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting MeOH/CH2Cl2 (1:10) to give 3.01 g (92%) of the title compound. The product was recrystalized from THF to give the titled compound (0.893 g) as white crystals.
Reaction SMILES: [C:1]([C:9]1[N:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17](N(C)C1C=CC=CC=1)=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:27].[Na+].CO>O>[CH:5]1[CH:6]=[CH:7][C:2]([C:1]([C:9]2[N:10]3[CH2:11][CH2:12][CH:13]([C:17]([OH:18])=[O:27])[C:14]3=[CH:15][CH:16]=2)=[O:8])=[CH:3][CH:4]=1
Reactant: CN(C(=O)C1CCn2c(C(=O)c3ccccc3)ccc21)c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1ccc2n1CCC2C(=O)O
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A mixture of 34.4 g (100 mmol) 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide, 25 g sodium hydroxide in 25 mL water, and 80 mL methanol was refluxed for 5 hours. The mixture was cooled to room temperature, stirred under nitrogen for sixteen hours, and then diluted with 80 mL of water. The mixture was extracted with toluene (2×50 mL), and the aqueous and organic phases were separated. The aqueous phase was acidified with 6 N hydrochloric acid (110 mL). The resulting precipitate was extracted several times with dichloromethane (1×150 mL), (1×75 mL), (1×50 mL). The combined extract was treated with FILTROL® (activated clay decolorizing agent) (4.5 g) for 30 minutes, filtered, and concentrated by atmospheric distillation. Hexane (190 mL) was added and the entire mixture allowed to cool to room temperature and then further cooled to 0° C. to −5° C. The product, 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (ketorolac) was collected by filtration, washed with 100 mL of hexane/dichloromethane (7:3 v/v), and dried at 60° C. to 70° C. under vacuum, to yield ketorolac (21.3 g, 83.4% yield), mp 152° C. to 162° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[N+:10]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][NH:2][CH2:1]2)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CNC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)CNC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of isoindoline (2 g, 16.8 mmol) at 0° C., was added slowly concentrated H2SO4 (10 mL). Then a mixture of 70% HNO3 (2.1 mL, 33.6 mmol) and concentrated H2SO4 (2 mL) was added. After addition the mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into ice water. The mixture was carefully neutralized with 50% aq. NaOH to pH 10 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 5-nitroisoindoline as a brown solid. LCMS calc.=165.1; found=164.9 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.11 (d, J=8.0 Hz, 2H); 7.39 (d, J=7.8 Hz, 1H); 4.33 (s, 4H); 2.31 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17].C1C(=O)N([Br:25])C(=O)C1.O>CN(C=O)C>[Br:25][C:5]1[O:4][C:3]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccoc1C=C1C(=O)Nc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)oc1C=C1C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of 3-((3-methylfuran-2-yl)methylene)indolin-2-one (330 mg, 1.47 mmol) in DMF (7.0 mL) was added NBS (265 mg, 1.49 mmol) in DMF (1.0 mL) at 0° C. The reaction was stirred at 0° C. for 1 h and added H2O (13 mL). The resulting precipitate was collected by filtration to yield desired 3-((5-bromo-3-methylfuran-2-yl)methylene)indolin-2-one (320 mg). LCMS (ES): m/z 304 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])=[N:16][CH:15]=[CH:14][CH:13]=2>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)cnc2cccnc12
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3cccnc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (19.1 g, 0.156 mol) was added over a period of 12 minutes to a mixture of 1-[(3-amino[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (28.95 g, 0.125 mol) in pyridine (300 mL). The reaction mixture was stirred at ambient temperature for 4 hours and then at reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature overnight and then concentrated under high vacuum. The residue was dissolved in 5% potassium carbonate (200 mL) and then extracted with dichloromethane (200 mL). The extract was filtered to remove some insoluble material, dried over magnesium sulfate, filtered, and then concentrated under high vacuum. The residue was dissolved in dichloromethane (150 mL) and eluted through a short column of alumina. The eluent was concentrated under reduced pressure and air dried to provide 31.9 g of 1-(2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol.
Reaction SMILES: C(S([C:6]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:9]=[C:8]([O:23][C:24]2[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:28][CH:29]=2)[N:7]=1)(=O)=O)C.C(Cl)(Cl)Cl.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[F:22][C:19]([F:20])([F:21])[C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C:10]1[CH:9]=[C:8]([O:23][C:24]2[CH:25]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:28][CH:29]=2)[N:7]=[CH:6][N:11]=1
Reactant: CCS(=O)(=O)c1nc(Cc2cccc(C(F)(F)F)c2)cc(Oc2cccc(C(F)(F)F)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(Cc2cc(Oc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 93.1 %

Procedure:
2-(Ethylsulfonyl)-4-[m-(trifluoromethyl)benzyl] -6-[(α,α,α-trifluoro-m-tolyl)oxy]pyrimidine (1.17 g, 2.4 mmol) is added to chloroform (10 ml) and ethanol (10 ml). sodium borohydride (0.3 g, 7.9 mmol) is added portionwise over 15 minutes and the reaction is stirred at room temperature for 80 mins. The mixture is taken up in ethyl acetate and is washed with water, brine and dried over magnesium sulfate. The solvent is evaporated to give 1.05 g of a cloudy oil which is chromatographed to yield 0.89 g 4-[m-(trifluoromethyl)benzyl]-6-[(α,α,α-trifluoro-m-tolyl)oxy]pyrimidine as a water white oil. 1H NMR CDCl3 4.17 (2H, s) 6.75 (1H,s) 7.3-7.6 (8H, m) 8.71 (1H, s)
Reaction SMILES: [CH2:1]1[CH2:6][CH:5]([NH2:7])[CH:4]([NH2:8])[CH2:3][CH2:2]1.[Cl-].[Cl-].[Pt+2:11]>[N+]([O-])([O-])=O.[Ag+]>[Pt+2:11].[NH2:7][C@@H:5]1[CH2:6][CH2:1][CH2:2][CH2:3][C@H:4]1[NH2:8]
Reactant: NC1CCCCC1N
Agent: [Ag+]
Agent: [Pt+2]
Agent: O=[N+]([O-])[O-]
Product: N[C@@H]1CCCC[C@H]1N
Temperature: 60 °C
Yield: 56.6 %

Procedure:
Dichloro(1,2-diaminocyclohexane)platinum(II) (760 mg) and silver nitrate (680 mg) were stirred in the dark at 50° C. for 3 hours. The reaction mixture was chilled for 24 hours and filtered. An excess of sodium heptafluorobutyrate was added to the filtrate and the reaction mixture was heated at 60° C. A precipitate appeared and this was filtered and washed with water to give the title product (350 mg). The product is insoluble in water but soluble in alcohol (ethanol) to 50 mg/ml. In the TLC system n-butanol:acetic acid:H2O (12:3:5) on cellulose, the product gave an Rf of 0.83 (spotting solvent-ethanol with heptafluorobutyric acid). The IR was consistent for the indicated structure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Li+].[C:14](#[N:17])[CH:15]=[CH2:16]>C(O)(=O)C>[C:14]([CH2:15][CH2:16][O:1][CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:17]
Reactant: CN(CCO)c1ccccc1
Reactant: C=CC#N
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(CCOCCC#N)c1ccccc1
Temperature: 50 °C

Procedure:
In a one-gallon autoclave was charged 1019 gm (6.75 moles) of hydroxyethylmethylaniline, 3 gm of anhydrous lithium hydroxide, and 532 gm (10 moles) of acrylonitrile. The autoclave was sealed and slowly heated to 50° C. until the initial exotherm was over. The reaction was then heated to 65°-70° C. for 6 hours. The reaction contents were cooled to room temperature and made slightly acidic with acetic acid. The reaction contents were then filtered. The crude filtered reaction product was stripped of all excess acrylonitrile under vacuum (15-30 mm Hg) at a temperature not exceeding 80° C. to give the orange liquid, 2-cyanoethoxyethylmethylaniline. Liquid chromatography showed the product to be about 97.4% purity. The IR, NMR, and GC mass spectra of the product were consistent with 2-cyanoethoxyethylmethylaniline.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10]>>[OH:4][CH2:3][C:2]([NH:1][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])([CH3:6])[CH3:5]
Reactant: CCCC(=O)Cl
Reactant: CC(C)(N)CO
Product: CCCC(=O)NC(C)(C)CO
Yield: 32 %

Procedure:
Prepared according to the literature (Boyd, R. N.; Hansen, R. H. J. Am. Chem. Soc. 1953, 75, 5896) from 2-amino-2-methylpropan-1-ol and butyryl chloride in 32% yield. MS 160 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1.C(N(CC)CC)C.C(Cl)Cl.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>>[CH3:40][S:41]([O:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1)(=[O:43])=[O:42]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (1.00 g, 0.00247 mol) and triethylamine (0.412 mL, 0.00296 mol) in methylene chloride (20.00 mL, 0.3120 mol) was added methanesulfonyl chloride (0.210 mL, 0.00271 mol). The mixture was stirred at rt overnight. After quenched with MeOH, the mixture was evaporated to dry in vacuo and diluted with ethyl acetate. The organic layers were washed with water, brine and dried, concentrated to dry. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexane, to generate the mesylate compound (0.98 g, 82%). MS (ESI): (M+H)+=484.1.
Reaction SMILES: C([N:8]([CH2:14][C:15]1[C:19]2[N:20]=[CH:21][N:22]=[C:23]([OH:24])[C:18]=2[NH:17][CH:16]=1)[CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12])C1C=CC=CC=1.[H][H]>O.[Pd]>[OH:24][C:23]1[C:18]2[NH:17][CH:16]=[C:15]([CH2:14][NH:8][CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12])[C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: OC[C@H](O)CN(Cc1ccccc1)Cc1c[nH]c2c(O)ncnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: OC[C@H](O)CNCc1c[nH]c2c(O)ncnc12
Temperature: 25 °C
Yield: 99.1 %

Procedure:
(R)-3-(Benzyl((4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)amino)propane-1,2-diol (0.1 g, 0.305 mmol) was dissolved in hot water (20 ml), cooled to rt and 10% Pd—C (50 mg) added. Hydrogen was added from a balloon and the mixture stirred at rt. After 4 h tlc (CH2Cl2-MeOH-cNH3, 5:4.5:0.5) showed reaction over. The hydrogen was replaced with Ar and the mixture heated to 80° C. to ensure product was in solution then the mixture filtered through Celite and the solvent evaporated to give (R)-3-((4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)propane-1,2-diol as a colourless solid (0.072 g, 99%). The product was converted to its hydrochloride salt with 5% HCl. 1H NMR (D2O+DCl, 300 MHz), δ ppm, 9.07 (s, 1H), 7.91 (s, 1H), 4.53 (s, 2H), 4.06 (m, 1H), 3.69-3.57 (m, 2H), 3.33 (dd, 1H, J 12.9, 2.9 Hz), 3.17 (dd, 1H, J 12.9, 9.8 Hz). 13C NMR (D2O+DCl, 75.5 MHz), δ ppm, 153.8 (C), 146.1 (CH), 134.1 (C), 133.1 (CH), 119.6 (C), 104.1 (C), 68.5 (CH), 64.5 (CH2), 50.2 (CH2), 41.8 (CH2). [α]D18 +12.6 (c, 0.565, H2O). +ESMS Found 261.0952 (M+Na)+ C10H14N4O3Na requires 261.0964.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:13][NH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:10])[N:14]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH3:13])=[CH:11][CH:12]=1
Reactant: CNc1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Reactant: O=C=NCCc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(-c2cccc(N(C)C(=O)NCCc3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.3 %

Procedure:
340 μL (1.84 mmol, 2 eq) of 4-fluorophenethyl isocyanate are added to a solution of 250 mg (0.92 mmol, 1 eq) of methyl 3-(3′-methylaminobiphenyl-4-yl)propanoate in 8 mL of a 4/1 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 24 hours at room temperature. The reaction is stopped by addition of 10 mL of saturated ammonium chloride solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 221 mg of methyl 3-(3′-{3-[2-(4-fluorophenyl)ethyl]-1-methylureido}biphenyl-4-yl)propanoate are obtained. Yield=55%
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:5])[OH:4].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO>[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][NH:1][CH2:2][CH:3]([CH3:5])[OH:4]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(O)CN
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CNCc1ccccc1Cl
Temperature: 10 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A mixture of 2-amino-1-methylethanol (25.0 g), 2-chlorobenzaldehyde (51.5 g), sodium bicarbonate (33.6 g), and methanol (1000 ml) is refluxed with stirring for 4 hours. After the reaction mixture is cooled to 10° C., sodium borohydride (13.9 g) is added in small portions, and the resulting mixture is stirred at 25° C. for 1 hour. The solvent is removed under reduced pressure, and the residue is diluted with water and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give the title compound (55.0 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)[CH3:2].C([OH:15])C.[OH-].[K+]>O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:5]([CH2:6][C:7]([OH:12])=[O:15])[CH:4]=1)[CH3:2]
Reactant: CCO
Reactant: CCc1ccc2c(c1)CC(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(N)c(CC(=O)O)c1

Procedure:
5-Ethyloxindole (˜54 g, ˜335 mmol), ethanol (750 ml), water (150 ml) and potassium hydroxide (65 g, 1.62 mol) are combined and heated at reflux for 3 days. The mixture is allowed to cool and then filtered through a bed of Celite. The filtrate is concentrated under reduced pressure, water is added and the pH adjusted to 6.5. The precipitate is filtered off, washed with water and dried in an oven overnight to yield 5-ethyl-2-aminophenylacetic acid. A mixture of water (405 ml) and concentrated HCl (48 ml) is stirred and cooled to 0°. 5-Ethyl-2-aminophenylacetic acid (53.7 g, 300 mmol) is slowly added while maintaining the temperature at 0-2°. After this addition a solution of sodium nitrite (22.2 g, 322 mmol) in 60 ml water is added dropwise over 30 minutes keeping the temperature at 0-2°. After a further 20 minutes a solution of potassium iodide (48 g, 290 mmol) in 18 ml conc HCl and 130 ml water is added dropwise while keeping the temperature below 10° C. The reaction mixture is allowed to warm to room temperature and then heated to reflux for 2 hours. The mixture is extracted with ethyl acetate and ether (1:1 mixture, 4×300 ml), the organic layer is then washed first with a 30% aqueous solution of sodium thiosulfite and then with a sodium hydroxide solution (0.1 M) before being acidified to pH 6 and extracted with ethyl acetate. This solution is washed with saturated brine, dried (magnesium sulfate), filtered, and the solvent removed under reduced pressure. The residue is treated with hexane to yield 5-ethyl-2-iodophenylacetic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]([Cl:14])([Cl:13])[CH:10]1[O:12][CH2:11]1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:11][CH:10]([OH:12])[C:9]([Cl:14])([Cl:13])[Cl:8])[CH2:4][CH2:3]1
Reactant: ClC(Cl)(Cl)C1CO1
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(CC(O)C(Cl)(Cl)Cl)CC1
Reaction time: 144 h

Procedure:
N-methyl piperazine (2 g) is dissolved in 80 ml chloroform, and mixed with a solution of 3.22 g 3,3,3-trichloropropylene oxide in 20 ml chloroform. The mixture is allowed to stand at room temperature for 6 days. The chloroform is removed by evaporation, and ether is added to the residue, which is then collected by filtration, washed with ether and dried at room temperature under water pump vacuum, to give the heading compound, m.p. 165°-167° C.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)=[O:5])C.[CH3:15][CH2:16][O:17][C:18]([CH3:20])=[O:19].C(O[K])(C)(C)C>C1(C)C=CC=CC=1>[O:5]=[C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:10]=1)[CH2:20][C:18]([O:17][CH2:16][CH3:15])=[O:19]
Reactant: CCOC(=O)c1nc(C(F)(F)F)cs1
Reactant: CCOC(C)=O
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1nc(C(F)(F)F)cs1
Temperature: 100 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 4-trifluoromethylthiazole-2-carboxylic acid ethylester (8.88 mmol) in toluene (50 mL) were added successively EtOAc (13.32 mmol) and tBuOK (17.76 mmol). The resulting mixture was stirred at 100° C. for 1 hr. The solvent was removed by evaporation and water and Et2O were added. The solution was neutralized with acetic acid. The extract was washed with water and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 28 as a yellow oil in 45% yield. MS (ESI, EI−): m/z=266 (MH−).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.[CH2:23]1[O:26][CH:24]1[CH3:25]>C1COCC1>[O:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH2:1][CH2:23][CH:24]([OH:26])[CH3:25])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)CCS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of 4-phenoxyphenyl methyl sulfone (1.0 g, 4.0 mmol) in 40 mL of THF at −78° C. was treated with n-butyllithium (1.6 mL, 2.5 M in hexanes), stirred 15 minutes at −78° C., treated with propylene oxide (257 μL), stirred from −78° C. to 23° C. over 16 hours, quenched with H2O, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. Purification on silica gel with 1:1 hexanes/ethyl acetate provided 1.1 g (100%) of the desired product.