Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.ON1C2C=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=N1.CN(C)CCCN=C=NCC.N1CCCC1>C(Cl)(Cl)Cl.ClCCl>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[C:9]([N:15]2[CH2:16][CH2:21][CH2:20][CH2:19]2)=[O:11])=[CH:5][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C=Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(/C=C/c1ccncc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a solution of 3-(4-pyridinyl)acrylic acid (1.01 g, 6.77 mmol) in CHCl3 (20 mL) in a 100 mL round bottom flask equipped with a magnetic stirrer and under nitrogen atmosphere was added 1-hydroxybenzotriazole (1.11 g, 8.21 mmol). The reaction mixture was stirred at RT for 10 min. Then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.56 g, 8.15 mmol) was added. The reaction mixture was stirred at 4° C. for 10 min. Then pyrrolidine (1.11 mL, 18.3 mmol) was added slowly and the reaction mixture was stirred for 15 h at +4° C. to RT. Dichloromethane (200 mL) was added and organic phase was washed with brine (100 mL), a solution of NaOH 0.5 N (100 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered, and evaporated to obtain (E)-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)prop-2-en-1-one (1.30 g, 94% yield). This free base (1.3 g, 6.40 mmol) was dissolved in MeOH (10 mL) at 4° C. and a solution of HCl 0.1 N in isopropanol (79 mL, 7.9 mmol) was added. After evaporation at 30° C. and drying, (E)-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)prop-2-en-1-one hydrochloride Compound 253 was obtained as a beige solid (1.40 g, 87% yield).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[CH:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH-:24].[Na+]>P(=O)(O)(O)O>[Cl:23][C:20]1[CH:21]=[CH:22][C:7]2[N:6]3[C:2](=[O:24])[NH:3][N:4]=[C:5]3[CH2:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:8]=2[CH:19]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=CCc1nnc(Br)n1-2
Reactant: [OH-]
Agent: O=P(O)(O)O
Agent: [Na+]
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=CC2
Temperature: 0 °C

Procedure:
9 g of 1-bromo-8-chloro-6-(2-chlorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine are stirred at 140° for 22 hours in 263 ml of 85% phosphoric acid. The mixture is poured on to 1.5 kg of ice water and neutralized with 28% sodium hydroxide solution. The product is extracted with chloroform. The residue from the chloroform extracts is chromatographed on 300 g of silica gel. Impurities are separated by elution with chloroform. By elution with chloroform which contains 2% or 4% ethanol, crystallization of the resulting material from diethyl ether/diisopropyl ether and recrystallization from ethyl acetate there is obtained 8-chloro-6-(2-chlorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 250°-251°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:5]=[C:4](Cl)[N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH2:29][CH3:30])=[C:23](B(O)O)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:21]2[CH:20]=[C:19]([Cl:18])[CH:24]=[CH:23][C:22]=2[O:28][CH2:29][CH3:30])[N:3]=1
Reactant: Nc1nc(Cl)cc(Nc2ccc(CO)cc2)n1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(CO)cc2)nc(N)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 61.8 %

Procedure:
To a mixture of [4-(2-amino-6-chloro-pyrimidin-4-yl-amino)-phenyl]-methanol (6.0 g, 24 mmol), 5-chloro-2-ethoxy-phenyl boronic acid (7.7 g, 38.4 mmol), palladium (II) acetate (0.54 g, 2.4 mmol) and triphenylphosphine (1.26 g, 4.8 mmol) was added a solution of sodium carbonate (12.7 g, 120 mmol) in water (80 ml) followed by glyme (300 ml). The mixture was stirred under an argon atmosphere at 95-105° C. for 18 hours. Filtration and concentration of the filtrate yielded a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide the title compound (5.5 g, 62% yield) as a white powder. 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=6.9 Hz, CH3), 4.13 (q, 2H, J=6.9 Hz, CH2), 4.45 (d, 2H, J=5.7 Hz, CH2), 5.07 (t, 1H, J=5.7 Hz, OH), 6.26 (s, 2H, NH2), 6.77 (s, 1H, Ar), 7.14 (d, 1H, J-8.9 Hz, Ar), 7.24 (d, 2H, J=8.4 Hz, Ar), 7.41 (dd, 1H, J=8.8, 2.8 Hz, Ar), 7.64 (d, 2H, J=8.3 Hz, Ar), 7.93 (d, 1H, J=2.8 Hz, Ar), 9.12 (s, 1H, NH).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:11](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=C(/C=C/C(OCC)=O)C(C2C=CC(F)=CC=2)=N1)C1C=CC=CC=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:11](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cnn(Cc2ccccc2)c1-c1ccc(F)cc1
Agent: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)/C=C/c1cnn(Cc2ccccc2)c1-c1ccc(F)cc1
Yield: 95.1 %

Procedure:
A mixture of the mixture (4.0 g) of ethyl (2E)-3-[1-benzyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]acrylate and ethyl (2E)-3-[1-benzyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl]acrylate produced in Reference Example 32, a 2N aqueous sodium hydroxide solution (11 ml) and methanol (20 ml) was stirred at 60° C. for 14 hrs. 1N Hydrochloric acid (22 ml) was poured into the reaction mixture. The precipitated solids were collected by filtration, washed with water and isopropyl ether and dried with airflow to give a mixture (3.5 g, 95%) of (2E)-3-[1-benzyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]acrylic acid and (2E)-3-[1-benzyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl]acrylic acid as a powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][C:26](=[O:28])[CH3:27])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([CH2:24][CH2:25][C:26](=[O:28])[CH3:27])=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(O)c1
Yield: 93 %

Procedure:
A mixture of 0.5 g. (1.31 mmols.) of 4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone, 360 mg. of solid sodium bicarbonate, 100 mg. of 10% palladium-on-carbon and 10 ml. of ethanol is stirred under one atmosphere of hydrogen pressure for one hour. The reaction mixture is filtered through diamtomaceous earth with ethyl acetate and the filtrate evaporated to an oil. The oil is purified via column chromatography on 100 g. of silica gel eluted with 50% ether-cyclohexane to yield 247 mg. (93%) of the title compound as an oil.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:9][CH2:8][C:7]2=[CH:10][C:11](=[O:22])[C:12](=[O:21])[C:13]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:6]2[CH2:5][CH2:4]1.Cl>CO>[Cl:1][C:10]1[C:7]2[CH2:8][CH2:9][N:3]([CH3:2])[CH2:4][CH2:5][C:6]=2[C:13]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:12]([OH:21])[C:11]=1[OH:22]
Reactant: CN1CCC2=CC(=O)C(=O)C(Sc3ccccc3)=C2CC1
Reactant: Cl
Solvent: CO
Product: CN1CCc2c(Cl)c(O)c(O)c(Sc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5 g. (0.0166 mole) of 7,8-dihydroxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine in 250 ml. of methanol was acidified with ethereal hydrogen chloride to yield the hydrochloride salt. The latter was dissolved in 300 ml. of methanol and 4.0 g. (0.0176 mole) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added portionwise under nitrogen and the mixture stirred at room temperature for 20 minutes. Ether was added to the reaction mixture and the solvents decanted to leave 3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrochloride. This hydrochloride was dissolved in a minimum amount of methanol and then added to a methanolic hydrogen chloride solution, portionwise. The mixture was stirred at room temperature for 1 hour, the solvent was evaporated and the residue triturated with acetonitrile. The separated solid was purified via conversion to its free base to give 9-chloro-7,8-dihydroxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 173°-174° C.
Reaction SMILES: OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)=O)=CC=1.[OH-].[Na+].[N+]([C:39]1[CH:40]=[C:41]([C:47]#[N:48])[C:42](=[CH:45][CH:46]=1)[C:43]#[N:44])([O-])=O.Cl>C1(C)C=CC=CC=1.CS(C)=O>[C:47](#[N:48])[C:41]1[C:42](=[CH:45][CH:46]=[CH:39][CH:40]=1)[C:43]#[N:44]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: N#Cc1ccccc1C#N
Temperature: 140 °C
Yield: 97 %

Procedure:
To a 2000 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added bisphenol A (100 g, 0.438 mol), 4,4′-dichlorobenzophenone (38.5 g, 0.153 mol), sodium hydroxide (38.5 g, 0.964 mol), toluene (25 mL), and dimethylsulfoxide (DMSO) (500 mL). Toluene was used to control the refluxing azeotropic removal of water and to control the temperature of the reaction content. The resulting mixture was degassed with nitrogen at ambient temperature and the Dean-Stark trap was filled with toluene. The mixture was refluxed at 135-145° C. under a nitrogen atmosphere for 6 h or until no more water was observed being collected in the Dean-Stark trap. The toluene was then slowly distilled off causing the temperature to rise in the reaction vessel to enhance the yield of the intermediate hydroxyl salt and high conversion to this intermediate. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (99.1 g, 0.573 mol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 h. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL portions of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL portions of water until neutral. The isolated solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile and the bisphenol A phthalonitrile composition (192 g, 97% yield). IR [cm−1]: ν 3077 (C═CH), 2232 (CN), 1586 (C═C), 1478 (aromatic), 1306 (aromatic), 1308 (C—O), 1245 (CH3), 1162 (C—O), 929 (C—O), 847 (aromatic).
Reaction SMILES: ClC[C:3]1[C:12]2[C:7](=[CH:8][C:9](OC)=[C:10](OC)[CH:11]=2)[C:6](CC2C=CC(OC)=C(OC)C=2)=[N:5][CH:4]=1.COC1C=CC=CC=1C1CCNCC1.C(N(CC)CC)C>CS(C)=O.O>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=[CH:4][N:5]=1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Agent: COc1ccccc1C1CCNCC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: c1ccc2cnccc2c1

Procedure:
A mixture of 5.0 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline, 2.49 g of 4-(2-methoxyphenyl)piperidine, and 2.63 g of triethylamine in 50 ml of dimethylsulfoxide was heated at 80° for one hour under argon and then the cooled solution was diluted with water and extracted with methylene chloride. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, charcoaled, and evaporated to give 7.0 g of 6,7-dimethoxy-1-}(3,4-dimethoxyphenyl)methyl}-4-[[4-(2-methoxyphenyl)-1-piperidinyl)-1-piperidinyl]methyl]isoquinoline as a yellow foam.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:23][CH3:24]>CN(C)C=O.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH2:23][CH3:24])=[O:8]
Reactant: CCI
Reactant: O=C(O)Cc1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccco1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.1 %

Procedure:
24.8 g of 2-(furan-2-yl)acetic acid was dissolved in 590 mL of N,N-dimethylformamide and mixed with 32.6 g (0.236 mol) of potassium carbonate and 6.42 g (19.7 mmol) cesium carbonate successively. The reaction mixture was further mixed with 19 mL (0.24 mol) of iodoethane under cooling with ice and stirred at room temperature for 14 hours. After completion of the reaction, the reaction mixture was diluted with distilled water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 17.0 g of the desired product as a brown liquid.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.[N:14]1(C(OCC2C=CC=CC=2)=O)[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16](O)=[O:17]>>[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([N:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4])=[O:17]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Yield: 99.4 %

Procedure:
A] Starting from H-Pro-OtBu.HCl (0.315 g, 1.5 mmoles) and Z-Pro-OH (0.397 g, 1.59 mmoles) the procedure of Example 1, C-D] was substantially applied. There was obtained 0.4 g of H-Pro-Pro-OtBu.
Reaction SMILES: [CH2:1]([OH:3])C.[S:4](=[O:8])(=[O:7])([OH:6])[OH:5].[CH:9]([Cl:12])([Cl:11])[Cl:10]>>[CH:9]([Cl:12])([Cl:11])[Cl:10].[CH3:1][OH:3].[S:4](=[O:6])(=[O:5])([OH:8])[OH:7]
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CO

Procedure:
A colorless solid (0.064 g, yield: 67.4%) was obtained through a reaction conducted as in example 2 except that the reactants were replaced by compound (117) prepared in example 17 (0.1 g), ethanol (83.3 mL), chloroform (83.3 mL), and sulfuric acid (36 N, 0.3 mL). IR analysis of the resulting product revealed the existence of an absorption band that suggested an acetoxy group at 1740 cm−1. 1H-NMR analysis revealed that the product consists of a compound (138) and the compound (117) (content of compound (138): 66.3 mol %).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C)C=O.O>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OC[C@H](CC3CCCCC3)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of methyl 4-(4-hydroxyphenyl)benzoate (0.94 g), (S)-(−)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-1-propanol (1.00 g) and triphenylphosphine (1.62 g) in N,N-dimethylformamide (20 ml) was added dropwise diisopropyl azodicarboxylate (1.21 ml) for 10 minutes under ice-cooling in a stream of nitrogen. The solution was stirred for 16 hours at ambient temperature, and then water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixed solvent of n-hexane-ethyl acetate (from 0% to 20% gradient elution) to give methyl (S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoate (290 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[CH:6][CH2:7]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Fc1cccc(C=CCCl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(F)c1)CC2
Yield: 44 %

Procedure:
Prepared from 3-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 44% of theory, Melting point: 128°-132° C. (ether).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[C:5]([CH3:15])=[CH:4][N:3]=1.O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH:11]([O:14][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]4)[CH2:12][CH2:13]2)[C:5]([CH3:15])=[CH:4][N:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: Cc1cnc(Cl)nc1N1CCC(O)CC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OC3CCN(c4nc(Cl)ncc4C)CC3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
To a solution of 1-(2-chloro-5-methyl-4-pyrimidinyl)-4-piperidinol (Example 458, 2.01 g, 8.81 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 970 mg, 4.40 mmol) in THF (35 mL) were added PPh3 (2.31 g, 8.81 mmol) and ADDP (2.22 g, 8.81 mmol). The reaction mixture was vigorously stirred at rt for 24 h. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (9:1 to 3:1 hexanes/EtOAc) to give the title product (1.54 g, 81%). 1H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H), 1.74-1.80 (m, 1H), 1.91-1.95 (m, 2H), 2.02-2.07 (m, 2H), 2.22 (s, 3H), 2.38-2.46 (m, 2H), 2.71-2.88 (m, 3H), 3.50-3.55 (m, 3H), 3.75-3.81 (m, 2H), 4.18 (q, 2H), 4.52-4.54 (m, 1H), 6.73 (d, 1H), 6.80 (s, 1H), 7.07 (d, 1H), 7.93 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:9]([N+:21]([O-:23])=[O:22])=[C:10]([CH:14](C(O)=O)[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1>S(=O)(=O)(O)O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:9]([N+:21]([O-:23])=[O:22])=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(C(C(=O)O)C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1[N+](=O)[O-]
Yield: 58.9 %

Procedure:
A solution of 6.9 g (0.017 mol) of 2-[3-(4-chlorobenzoyl)-2-nitrophenyl]propanedioic acid in 40 ml of 20% sulfuric acid and 40 ml of acetic acid was heated at reflux under a nitrogen atmosphere overnight. The reaction mixture was cooled, and the solid which precipitated was collected by filtration and stirred with 150 ml of 5% sodium bicarbonate. The mixture was filtered and the filtrate was made acidic with concentrated sulfuric acid. The resulting white solid was collected by filtration and recrystallized from aqueous isopropyl alcohol to yield 3.2 g (61%) of white needles, m.p. 164°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+]>C1OCCOC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:25][CH:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[CH2:27]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:11][CH2:12]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4F)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4F)C3)CC2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 41.8 %

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate (D169) (12 mg, 0.024 mmol) in a mixture 1-4 dioxane/water (3 ml/1 ml), 1N NaOH (0.036 ml) was added. The reaction mixture was stirred 12 h at 60° C. Organic solvent was evaporated in vacuo and the reaction mixture was acidified with 2N HCl (pH=2) and the resulting mixture was extracted with ethylacetate (3×5 ml). Combined organics were evaporated in vacuo and the residue was loaded on SNAP-C18 gold cartridge (15 g) eluting with H2O-AcOH (0.1%)/CH3CN—AcOH (0.1%) from 10/90 to 0/100. Collected fractions were evaporated in vacuo to afford the title (E35) (5 mg)
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([C:20]2([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:22][CH2:21]2)[N:14]=3)=[C:7]([F:29])[CH:6]=1)[OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:31][C:2]([F:1])([F:30])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([C:20]2([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:21][CH2:22]2)[N:14]=3)=[C:7]([F:29])[CH:6]=1)=[O:4]
Reactant: OC(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridine-2-yl)phenyl)ethanol (1.15 g, 2.6 mmol) in 25 mL DCM under nitrogen was added Dess-Martin Periodinane (2.0 g, 4.7 mmol) in one portion. The reaction mixture was allowed to stir for 3 h. The reaction mixture was quenched with sat'd aq. Sodium thiosulfate (2 mL) and 25 mL sat'd aq. Sodium bicarbonate and allowed to stir rapidly for 30 min. The organic layer was separated and the aq. Layer was extracted with DCM, combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow foam. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanone as a yellowish foam. The foam was treated with hexanes and concentrated in vacuo a few times to give a nice light yellow solid. MS (ESI) m/z: calculated: 442.1; Observed: 461.0 (M++H2O+1).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([NH:7][N:8]([CH3:26])[C:9](=[O:25])[C:10]([O:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:12])[CH3:11])=[O:6])[CH3:3].O.NN>ClCCl>[CH3:3][C:2]([CH3:27])([O:4][C:5]([NH:7][N:8]([CH3:26])[C:9](=[O:25])[C:10]([O:13][NH2:14])([CH3:11])[CH3:12])=[O:6])[CH3:1]
Reactant: CN(NC(=O)OC(C)(C)C)C(=O)C(C)(C)ON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CN(NC(=O)OC(C)(C)C)C(=O)C(C)(C)ON

Procedure:
A stirred solution of 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-2-methylpropanoic acid, 2-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazide (7.10 g, 19 mmole) in 50 ml of dichloromethane at 0° C. was treated dropwise with hydrazine hydrate (1.80 ml, 38 mmole). After 30 minutes the resulting slurry was filtered and the filtrate evaporated. The residue was crystallized from ether/petroleum ether to give the title compound as 3.3 g of a colorless solid, m.p. 85°-90° C.