Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1>CN(C)C=O>[N:30]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[C:4]([C:24]([F:27])([F:25])[F:26])[CH:3]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: c1cn[nH]c1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cccn2)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Yield: 54.9 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)-(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), pyrazole (0.25 g) and dimethylformamide (35 ml). The product (0.62 g) was obtained as a colorless amorphous solid, MS, m/z: 423.2 (M+H)+, 445.2 (M+Na)+, 845.3 (2M+H)+.
Reaction SMILES: CS(C)=O.C(=O)([O-])O.[K+].Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15].[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18]>CC1(C)N(O)C(C)(C)CC(O)C1.O>[C:16]([O:20][CH2:11][CH2:12][CH2:13][C:14]#[N:15])(=[O:19])[CH:17]=[CH2:18]
Reactant: N#CCCCBr
Reactant: C=CC(=O)O
Agent: CC1(C)CC(O)CC(C)(C)N1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CC(=O)OCCCC#N
Temperature: 80 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a 200 mL three-necked flask, 33 g of dimethyl sulfoxide, 33 g of water, 14.8 g of potassium hydrogencarbonate, 10 g of 4-bromobutyronitrile, and 10 mg of 4-hydroxy TEMPO (4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl free radical) were added. Thereafter, 9.8 g of acrylic acid were added thereto dropwise. Then, the contents of the flask were heated to 80° C., and stirred at 80° C. for 4 hours. The resulting reaction liquid was cooled to room temperature. After cooling, the reaction liquid was washed with water, and was purified by column chromatography, to obtain 9 g of 3-cyanopropyl acrylate.
Reaction SMILES: N[C@H](C(O)=O)C.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O.[CH2:15]([NH2:18])[CH:16]=[CH2:17].S([O-])([O-])(=O)=O.[Mg+2]>O.ClCCl.CO.C(N(CC)CC)C.C(O)=O>[CH2:15]([NH:18][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]1[CH3:7])[CH:16]=[CH2:17]
Reactant: CC1CCCCC1=O
Reactant: C=CCN
Agent: C[C@H](N)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=CO
Product: C=CCN[C@@H]1CCCC[C@@H]1C
Reaction time: 168 h
Yield: 77 %

Procedure:
A solution of 22.5 mg (35 μmol) of the catalyst from example Ala in 3.2 ml of a mixture of formic acid and triethylamine (5:2 v/v) is added dropwise to a mixture of 676 mg (6 mmol) of 2-methylcyclohexanone, 2.74 g (48 mmol of allylamine and 100 mg of magnesium sulfate, and stirred. After 7 days at room temperature, the reaction mixture is diluted with 20 ml of water and extracted three times with 15 ml of dichloromethane. The organic phase is dried over sodium sulfate. After removal of the solvent and column chromatography (silica gel, 10:1 dichloromethane/methanol), 708 mg (77% yield) of (1R,2S)-N-allyl-(2-methylcyclohexyl)amine are obtained.
Reaction SMILES: [CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13]1[C:22]([O:23][CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=2[CH:14]=1)=[CH:3]\[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.C(O)C>[CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13]1[C:22]([O:23][CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:32])[C:15]=2[CH:14]=1)=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: CCC#CCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)OCC)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC#CCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
1.02 g of ethyl (2E,4E,6E)3-methyl-7-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-hepta-2,4,6-trienoate were placed in 8 ml of abs. THF/ethanol (1/1) and treated under argon with 3.9 ml of 3N NaOH. The mixture was stirred at room temperature for 2 days and at 400 for 3 h. Then, the mixture was poured on to ice/HCl, extracted with diethyl ether, washed with water, dried and evaporated. Crystallization from diethyl ether yielded 644 mg of (2E,4E,6E)-3-methyl-7-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-hepta-2,4,6-trienoic acid as yellow crystals of m.p. 208°-209°.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[C:10]([C:20]([O:22]CC)=[O:21])[C:9]=2[CH2:25][CH3:26])=[O:7])=[CH:4][CH:3]=1.[Na].[OH-].Cl>O>[C:20]([C:10]1[C:9]([CH2:25][CH3:26])=[C:8]([C:6](=[O:7])[C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([CH3:13])[C:11]=1[CH2:14][C:15]([OH:17])=[O:16])([OH:22])=[O:21]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(CC)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CCc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 18.2 g. (0.044 mole) of ethyl 5-(ρ-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate in 170 ml. of 25% aquous sodium, hydroxide solution is heated under reflux for 3 hrs. It is cooled, diluted with water and acidified with dilute hydrochloric acid. The precipitated solid is collected by filtration and air dried. It is recrystallized from acetone-water to give 3-carboxy-5-(ρ-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid, M.P. 211°-212.5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:5][N:6]=1.[C:13]([C:20](OCC)=[O:21])#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[O:10]1[CH2:9][CH2:8][N:7]([C:4]2[S:3][C:2]3=[N:1][C:20](=[O:21])[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]3[N:5]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Nc1nnc(N2CCOCC2)s1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(N3CCOCC3)nn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3.5 g of the 2-amino-5-morpholino-1,3,4-thiadiazole obtained in Example 1 were mixed with 40 ml of absolute ethanol and then 3.2 g of diethyl acetylendicarboxylate was added. The reaction mixture was heated on a water bath to about 60° C. until a clear solution was formed. This was stored overnight at room temperature and then evaporated in vacuo to dryness. The residue was triturated with a small amount of cold ethanol, filtered off, washed with ether and finally dried. Thus 3.8 g, corresponding to 65.2% of the theoretical yield, of ethyl 2-morpholino-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylate, melting at 151° to 153° C., was obtained.
Reaction SMILES: Cl[C:2]1([Cl:8])[NH:7][CH:6]=[N:5][CH:4]=[CH:3]1.CN(C)C=O.[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:8][C:2]1[CH:3]=[C:4]([O:24][C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[F:14])[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: ClC1(Cl)C=CN=CN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)c(F)c1
Yield: 85.7 %

Procedure:
6,6-dichloropyrimidine (1.000 g, 7 mmol) was dissolved in N,N-dimethylformamide (5 ml, 7 mmol), then 2-fluoro-4-nitrophenol (1 g, 7 mmol) was added into the mixture. Then Cesium Carbonate (2 g, 10 mmol) was added into the mixture with stirring. The mixture was stirred at ambient temperature under nitrogen overnight. The progress of the reaction was monitored by LC/MS, which had confirmed completion. Then diluted the mixture with water was stirred an additional 3 hours. The precipitate was collected by filtration and washed with hexanes. The solid was dried in a reduced-pressure oven overnight to give the desired product 4-chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine (1.500 g, 6 mmol, 83% yield) as a yellow solid. MS (ESI pos. ion) m/z: 270 (MH+). Calc'd exact mass for C10H5ClFN3O3: 269. 1HNMR (300 MHz, CDCl3): 7.14 (s, 1H), 7.43 (s, 1H), 8.14 (s, 2H), 8.55 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=1[Cl:8].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:22]1([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]3[CH2:14][CH2:13][N:12]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=2[Cl:8])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Yield: 74.7 %

Procedure:
5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 66a (375 mg, 1 mmol), phenylboronic acid (146 mg, 1.2 mmol) and Pd(0) (35 mg) were mixed together in toluene (2 mL), and the mixture was heated at reflux for 16 hours. NaHCO3 solution (2%, 1 mL) was added, and the mixture was extracted with chloroform. The CHCl3 was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane 1:1 to afford the title compound (280 mg). MS (DCI/NH3) m/z 375 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.40 (s, 9H), 2.33-2.43 (m, 2H), 3.29 (t, J=7.5 Hz, 2H), 4.15 (dd, J=2.5, 7.5 Hz, 1H), 4.32-4.42 (m, 1H), 4.48-4.57 (m, 1H), 7.25-7.29 (m, 4H), 7.28 (d, J=2 Hz, 1H), 7.42-7.48 (m, 5H), 8.12 (d, J=3 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccccn4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and pyridine-2-carbaldehyde. MS (ESI) m/z 470.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH2:11][OH:12])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([O-:24])=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][C:5]([Si:2]([O:1][CH2:9][CH2:10][CH2:11][O:12][S:31]([C:28]1[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=1)(=[O:32])=[O:33])([CH3:4])[CH3:3])([CH3:6])[CH3:7]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
A solution of 3-t-butlydimethylsiloxy-1-propanol, prepared by the method of McDougal, et al. JOC, 1986, 51, 3388, which is incorporated herein by reference, (7.6 g, 40 mmol) and diisopropylethylamine (10.4 mL, 60 mmol) in methylene chloride (200 mL) at 0° C. was treated with p-nitrophenylsulfonyl chloride (9.7 g, 44 mmol), stirred for 3 h, poured into saturated NaHCO3 and extracted with diethyl ether. The extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with 5% ethyl acetate/hexanes to provide 6.00 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:26])(=[O:25])[NH2:24])=[CH:13][C:12]=2[F:27])=[C:8]([C:28]#[N:29])[N:7]([C:30]2[CH:35]=[C:34]([C:36](OCC)=[O:37])[CH:33]=[CH:32][C:31]=2[C:41]([F:44])([F:43])[F:42])[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(N)CCC>[CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:25])(=[O:26])[NH2:24])=[CH:13][C:12]=2[F:27])=[C:8]([C:28]#[N:29])[N:7]([C:30]2[CH:35]=[C:34]([C:36](=[O:37])[NH:6][CH2:5][CH2:1][CH2:2][CH3:3])[CH:33]=[CH:32][C:31]=2[C:41]([F:42])([F:44])[F:43])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(C(=O)OCC)ccc2C(F)(F)F)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc(C(F)(F)F)c(-n2nc(CCCC)c(Cc3ccc(-c4ccccc4S(N)(=O)=O)cc3F)c2C#N)c1

Procedure:
A solution of 3-n-butyl-1-[5-(ethoxycarbonyl)-2-(trifluoromethyl)phenyl]-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-1H-pyrazole-5-carbonitrile (from Step K) in n-butylamine (approximately 10 mL of amine per mmole of ester) is heated in a sealed tube at 120° C. overnight. Volatiles are removed by evaporation, and the residue is chromatographed on silica gel (elution with CH2Cl2 --MeOH) to provide the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl>O1CCCC1.O>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CCc1cccc(O)c1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
1.0M Lithium aluminum hydride in tetrahydrofuran (35.07 mL, 35.07 mmol) was added to a solution of 3-(3-hydroxyphenyl)propionic acid methyl ester (3.16 g, 17.5 mmol) in tetrahydrofuran (30 mL) at 0-5° C. under an argon atmosphere. The mixture was stirred at room temperature for 6 hours, and sodium sulfate decahydrate (15 g) was added to the mixture, followed by cooling to 0-5° C., and a dropwise addition of water (about 10 mL) and concentrated hydrochloric acid to pH 2-3. The mixture was extracted with ethyl acetate, and the extract was washed with water, brine, dried over magnesium sulfate, and concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave 3-(3-hydroxypropyl)phenol as a clear oil (2.34 g, 88%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I.O>[NH2:18][C:19]1[CH:24]=[CH:23][N:22]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[C:12]([CH3:17])[N:13]=2)[C:21](=[O:25])[CH:20]=1
Reactant: Nc1cc[nH]c(=O)c1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(-n2ccc(N)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.4 %

Procedure:
To a degassed solution of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide (1.58 g, 5.00 mmol), 4-aminopyridin-2(1H)-one (0.72 g, 6.50 mmol), potassium carbonate (2.00 g, 14.40 mmol) and 8-hydroxyquinoline (0.08 g, 0.50 mmol) in dimethyl sulfoxide (30 mL) was added copper(I) iodide (0.10 g, 0.50 mmol). The reaction mixture was heated at 75-80 C. for 16 hours, then cooled to ambient temperature. Water (300 mL) was added to the mixture and the crude product was precipitated and collected by filtration. The crude product was subjected to column chromatography to afford the title compound as a white solid (0.84 g, 49%): mp 171-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J=5.7 Hz, 1H), 8.40 (d, J=7.8 Hz, 1H), 7.32-7.19 (m, 5H), 6.80 (s, 2H), 6.07 (dd, J=7.8, 1.8, Hz, 1H), 5.38 (d, J=1.8 Hz, 1H), 4.37 (d, J=5.7 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.2, 160.8, 157.7, 154.6, 150.0, 140.0, 131.5, 128.7, 127.7, 127.1, 122.9, 103.4, 90.5, 43.0, 17.5; MS (ES+) m/z 341.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:1][C:2]2[C:7]3[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Product: CC1(C)OC(=O)c2c(OCc3ccc(F)cc3)cccc2O1

Procedure:
5-(4-Fluoro-benzyloxy)-2,2-dimethyl-benzo[1,3]dioxin-4-one was prepared from 5-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and 4-fluorobenzyl bromide under conditions analogous to example 46-a. Crude product was purified by silica gel chromatography (eluting with 40%-100% CH2Cl2 in hexanes) to provide the title compound. MS ESI(+) m/e: 303.06 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:16][NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNc1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 10.0 g. of 6-(p-chlorophenyl)-3-chloropyridazine, 6.6 g. of hydrazine hydrate and 150 ml. of butanol is heated at reflux overnight. The reaction mixture is cooled and the precipitate is collected by filtration, washed with butanol and water and then dried yielding 6-(p-chlorophenyl)-3-hydrazinopyridazine.
Reaction SMILES: [CH2:1]([P:3]([O:10]CCCC)([CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])[CH3:2].O>C(O)CCC.O>[CH2:1]([P:3]([OH:10])([CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCC(=O)O
Solvent: CCCCO
Solvent: O
Product: CCP(=O)(O)CCC(=O)O
Reaction time: 4 h
Yield: 93 %

Procedure:
444 g (2 mol) of 3-(ethylbutoxyphosphinyl)propionic acid (produced as in Example 13) are initially charged in a 1 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. At 160° C., during 4 h, 500 ml of water are metered in and a butanol-water mixture is distilled off. The solid residue is recrystallized from acetone to obtain 309 g (93% of theory) of 3-(ethylhydroxyphosphinyl)propionic acid as colorless solid.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:14][N:13](C(OC(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25].[C:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)#[N:27]>CN(C=O)C>[ClH:25].[C:1]([NH:9][C@@H:10]1[CH2:14][NH:13][C@H:12]([C:22]([N:29]2[CH2:30][CH2:31][CH2:32][C@H:28]2[C:26]#[N:27])=[O:24])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@H](NC(=O)c2ccccc2)CN1

Procedure:
(2S,4S)-4-Benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (title compound of Reference Example 7, 1.1 g) and (S)-2-cyanopyrrolidine hydrochloride (0.44 g) were dissolved in DMF (10 mL), and triethylamine (0.98 mL), HOBT (0.54 g) and EDC hydrochloride (0.67 g) were successively added. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-((2S,4R)-4-benzoylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine (1.0 g) as a white solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](=[O:26])[NH:14][C:13]1=[O:27])=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](=[O:26])[NH:14][C:13]1=[O:27])([OH:5])=[O:3]
Reactant: CCCCCC(=O)CCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(=O)CCN1C(=O)NC(=O)C1CCCCCCC(=O)O

Procedure:
Diethyl 2-(3-oxooctylamino)nonanedioate (7.7 g) prepared by the method described in Example 1B was treated with potassium cyanate and hydrochloric acid to give 5-(6-ethoxycarbonylhexyl)-1-(3-oxo-octyl)hydantoin. Hydrolysis of this ester using sodium hydroxide solution gave 5-(6-carboxyhexyl)-1-(3-oxooctyl)hydantoin as a viscous oil, which crystallised to a low-melting solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([CH3:22])=[C:12]([CH3:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]=[C:5]([O:6][CH3:7])[CH:4]=1>C(O)C.[Pd]>[CH3:7][O:6][C:5]1[CH:8]=[C:9]([CH:11]([CH3:22])[CH:12]([CH3:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CCCCCCCCC(C)=C(C)c1cc(OC)cc(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC(C)C(C)c1cc(OC)cc(OC)c1

Procedure:
Dehydration by distillation from a few drops of 20% aqueous sulfuric acid gives a mixture of 5-(1,2-dimethyldec-1-enyl)resorcinol dimethyl ether and 5-(1-methylenyl-2-methyldecyl)resorcinol dimethyl ether which is hydrogenated over 10% palladium-on-carbon in absolute ethanol at 50 p.s.i. and 25° to give 5-(1,2-dimethyldecyl)-resorcinol dimethyl ether.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=O)[CH2:12][C:13]#[N:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>CCO.O.CCOC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[C:13]([NH2:14])[O:23][N:22]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: NO
Reactant: N#CCC(=O)c1ccc2cnccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccc3cnccc3c2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a solution of 3-(isoquinolin-6-yl)-3-oxopropanenitrile (2.1 g, 11 mmol) in 60 mL of EtOH was added sodium acetate (5.3 g, 64 mmol) and hydroxylamine hydrochloride (3.7 g, 54 mmol) in 60 mL of water. The mixture was heated to reflux. After 3 hours, the reaction mixture was cooled to room temperature and diluted with 300 mL of EtOAc. The mixture was transferred to a separatory funnel and washed three times with 50 mL of water and once with 50 mL of brine. The remaining liquid was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1 to 5% MeOH/CH2Cl2), affording 3-(isoquinolin-6-yl)isoxazol-5-amine (0.96 g, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.35 (s, 1H), 8.56 (d, J=6.5 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.04 (dd, J=1.4 Hz, 8.5 Hz, 1H), 7.91 (d, J=5.9 Hz, 1H), 6.92 (s, 2H), 5.60 (s, 1H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH2:14]1CCN2C(=NCCC2)CC1.CI>C(#N)C.CCOC(C)=O>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([C:7]2([C:10]([O:12][CH3:14])=[O:11])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2(C(=O)O)CC2)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CC#N
Product: COC(=O)C1(c2ccc(C)cc2)CC1
Yield: 64 %

Procedure:
To a solution of 1-(p-tolyl)cyclopropanecarboxylic acid (900 mg, 5.1 mmol) in acetonitrile (20 mL) was added DBU (917 μL) followed by methyl iodide (1.91 mL). The resulting solution was heated at reflux overnight, and then diluted with AcOEt. The mixture was washed with a 0.5 N HCl solution, a saturated solution of NaHCO3, and brine, dried on MgSO4, and concentrated. The resulting colorless oil was purified by chromatography on silica gel (Hexane/ethyl acetate 9/1) to afford the title compound as a colorless oil (622 mg, 64%).