Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:13]([O:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=2)[N:24]=[C:23]([NH:35][NH2:36])[C:22]1=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCCC1>[CH2:13]([O:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=2)[N:24]=[C:23]([NH:35][NH:36][C:10](=[O:11])[CH2:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[C:22]1=[O:37])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNc1nc2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(=O)NNc1nc2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A solution of (diethoxyphosphoryl)acetyl chloride (5.8 g, 27 mmol) in 40 ml of dry tetrahydrofuran was added to a solution of 1-benzyloxy-3-hydrazino-7-trifluoromethylquinoxalin-2(1H)-one (8.75 g, 25 mmol) and dry triethylamine (3.6 ml, 27 mmol) in 200 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 3 h and filtered. The filtrate was evaporated to dryness, and the residue was crystallized by trituration with water (200 ml) to give 12.85 g (97%) of the title compound. M.p. 163°-166° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7](O)[CH2:8][CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=[O:15])C.[Cl-].[Na+]>O.C(O)(=O)C>[OH:15][CH:3]1[CH2:4][C:5](=[O:6])[C:7]([CH2:8][CH3:9])=[C:2]1[CH3:1]
Reactant: CC(=O)O
Reactant: CCC(O)c1ccc(C)o1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1=C(C)C(O)CC1=O
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixed solution of 28.97 g of the 1-(5-methyl-2-furyl)propanol thus obtained, 0.394 g of 50% aqueous acetic acid, 0.394 g of a 23% (w/v) sodium hydroxide solution in 579.4 g of water was heated and refluxed at the constant pH of 5.70 to 5.85 for 38 hours. After the mixed solution was cooled to the room temperature, a 23% (w/v) sodium hydroxide solution was added to the mixed solution to adjust the pH of the solution to 8.0 to 8.2, and then refluxed for three hours. A 50% acetic acid solution was added to the refluxing solution to adjust the pH to 6.0 to 6.5. The reaction solution was then cooled to the room temperature, mixed with 300 g of sodium chloride, and extracted three times with 500 ml of diethyl ether. The combined ether layer was washed twice with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was distilled, and a distillate fraction of 157° to 162° C. at 19 mmHg was collected to yield 15 g of (RS)-4-hydroxy-3-methyl-2-ethylcyclopent-2-en-1-one. Yield 52%
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>>[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: CN(C)CCCCCN
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Product: CN(C)CCCCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 26, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate 67) and 5-dimethylaminopentylamine.
Reaction SMILES: [CH2:1]([CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C.O>[CH2:1]([CH:16]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCC1CCCC(O)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCC1CCCC(=O)C1
Temperature: 60 °C

Procedure:
A solution of 25 g (80 mmol) of 3-pentadecylcyclohexanol in 190 ml of glacial acetic acid was cooled to about 0° C., with stirring, and a solution of 8.33 g (31.8 mmol) of sodium dichromate in 14 ml of glacial acetic acid and 5 ml of water was added dropwise over 4.5 hours at a temperature below 10° C. The reaction mixture was heated to 60° C. for one hour and vacuum stripped to remove acetic acid. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution and water and dried over sodium sulfate. Upon vacuum stripping of the solvent, the desired 3-pentadecylcyclohexanone was obtained as a waxy solid, m.p. 41° C. The yield was 23 g (92% of theoretical).
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:5](=O)[CH3:6].[NH:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][N:24]=1)[C:20]#[N:21])[NH2:16]>>[CH3:6][C:5]1[N:15]([C:17]2[CH:18]=[C:19]([C:20]#[N:21])[CH:22]=[CH:23][N:24]=2)[N:16]=[CH:3][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CC(=O)/C(=C/N(C)C)c1ccccc1
Product: Cc1c(-c2ccccc2)cnn1-c1cc(C#N)ccn1
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from (3E)-4-(dimethylamino)-3-phenylbut-3-en-2-one and 2-hydrazinylisonicotinonitrile (PREPARATION 2) according to the procedure for the preparation of Example 28, part D. [M+H] Calc'd for C16H12N4, 261. Found, 261.
Reaction SMILES: N[C@H:2]1[C@@H:5]([C:6]#[CH:7])[N:4]([S:8]([OH:11])(=[O:10])=[O:9])[C:3]1=[O:12].C(N(CC)CC)C>CC(C)=O.O>[C:6]([CH:5]1[N:4]([S:8]([OH:11])(=[O:10])=[O:9])[C:3](=[O:12])[CH2:2]1)#[CH:7]
Reactant: C#C[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C#CC1CC(=O)N1S(=O)(=O)O

Procedure:
190 mg (1 mmol) of (3S,4R)-3-amino-4-ethynyl-2-oxo-1-azetidinesulphonic acid, 526 mg (1.1 mmol) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]-imino]-acetic acid 2-benzthiazolyl thioester and 0.280 ml (2 mmol) of triethylamine are stirred at room temperature for 20 hours in 5 ml of acetone/water (4:1). Thereupon, the mixture is concentrated, the residue is taken up in 4 ml of methanol and filtered. The filtrate is chromatographed over reverse-phase silica gel using water/methanol (10:1). After lyophilization there are obtained 213 mg of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-tert-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-ethynyl-2-oxo-1-azetidinesulphonic acid as an amorphous powder.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:35])[CH:8]=1)[CH3:2].[OH-].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:35])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:33][CH:34]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(OCC(=O)OCC)cc3)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(OCC(=O)O)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of ethyl [4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenoxy]acetate (0.37 g, 0.77 mmol) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL) was added an aqueous solution (5 mL) of potassium hydroxide (0.26 g, 3.94 mmol), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether-hexane to give the title compound as colorless prism crystals. yield 91%.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27])(=[O:21])[C:18]([CH3:20])=[CH2:19]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(Cl)(Cl)Cl>[C:17]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: O=C(Oc1cccc(O)c1)c1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCNC(=O)Oc1cccc(OC(=O)c2ccccc2)c1
Yield: 90.7 %

Procedure:
A mixture of 65 grams (0.30 mol) of resorcinol monobenzoate, 50 grams (0.32 mol) of isocyanatoethyl methacrylate, 1.05 grams of dibutyltin dilaurate and 400 ml. of chloroform was heated under reflux for 4 hours. The solvent was then removed by vacuum stripping and the residue was recrystallized from a mixture of ethyl acetate and hexane. There was obtained 100.5 grams (87% of theoretical) of the desired 3-benzoyloxyphenyl 2-methacryloxyethylcarbamate having a melting point of 57.5°-61.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:14]([N:16]=[C:17](SC)SC)#[N:15].[CH2:22]([NH2:25])[C:23]#[CH:24]>>[C:14]([NH:16][C:17]([NH:25][CH2:22][C:23]#[CH:24])=[N:13][CH2:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:15]
Reactant: CSC(=NC#N)SC
Reactant: C#CCN
Reactant: NCCCSCc1ncccc1Cl
Product: C#CCNC(=NCCCSCc1ncccc1Cl)NC#N

Procedure:
Reaction of 3-[(3-chloro-2-pyridyl)methylthio]propylamine with dimethyl cyanodithioimidocarbonate and treatment of the resultant product with propargylamine according to the general procedure of Example 4 gives the title compound.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].C(O[C:8](=[O:24])[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)C.C(O)(=O)C>O>[O:1]=[C:2]1[NH:3][C:8](=[O:24])[CH2:9][N:10]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1
Reactant: N#C[O-]
Reactant: CCOC(=O)CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CC(=O)NC2=O)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
Potassium cyanate (31 mg, 0.384 mmol) was added to a solution of tert-butyl 4-[(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate (100 mg, 0.384 mmol) in water (2 mL). Acetic acid was then added to adjust pH of reaction to 4-5 and the mixture was heated at 40° C. After 16 h, the reaction was cooled to ambient temperature and purified by reverse phase HPLC(C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (33 mg).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>C(O)C>[C:37]1([NH:36][C:34]([CH2:33][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]3[S:23][C:22]4[N:24]5[C:15](=[CH:16][N:17]=[C:18]5[CH:19]=[CH:20][CH:21]=4)[CH:14]=3)=[O:12])[CH2:5][CH2:4]2)=[O:35])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: O=C(CCl)Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CN1CCC(CNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1)Nc1ccccc1

Procedure:
To a solution of 581 mg (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 759 mg (7.5 mM) of triethylamine in ethanol (30 ml) was added 254 mg (1.5 mM) of chloroacetylaniline at room temperature, and the mixture was refluxed for 18 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over Na2SO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate=½) to provide the title compound as red oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([NH:28][C:1](=[O:3])[CH3:2])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2nc3ccc(N)cc3s2)cn1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc3ccc(NC(C)=O)cc3s2)cn1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
Acetylchloride (3 μL, 0.037 mmol) and pyridine (3 μL, 0.037 mmol) was added to a sol. of 2-(6-methoxypyridin-3-yl)-1,3-benzothiazol-6-amine (9 mg, 0.034 mmol) in DCM (1 mL). The r.m. was stirred at r.t. o.n. Half of the solvent was distilled of in vacuo and a few drops of hexane were added. The precipitated solid was collected and dried in vacuo, to give the title compound (4 mg) as a white solid. 1H NMR δ 10.30 (s, 1 H) 8.91 (d, 1 H) 8.57 (d, 1H) 8.39 (dd, 1 H) 8.03 (d, 1 H) 7.63 (dd, 1 H) 7.08 (d, 1 H) 4.02 (s, 3 H) 2.16 (s, 3 H); MS m/z (M+H) 300, (M−H) 298.
Reaction SMILES: [C:1]([C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:10][CH2:11][C:12]([O:14]CC)=O)[CH2:4][C:5]([O:7]CC)=O)#[N:2].C(=O)([O-])[O-:24].[K+].[K+]>>[NH:2]1[C:12](=[O:14])[CH2:11][CH2:10][C:3]2([C:17]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:5](=[O:7])[C:4]2=[O:24])[CH2:1]1
Reactant: CCOC(=O)CCC(C#N)(CC(=O)OCC)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CCC2(CN1)C(=O)C(=O)c1ccccc12
Reaction time: 5 h
Yield: 4.4 %

Procedure:
A mixture of 310 grams of polyphosphoric acid and 30.24 grams (0.1 M) of diethyl β-cyano-β-phenyladipate, prepared by the general method of Branchini et al., Annali di Chimica, 51, 1382 (1961), Chem. Abstr., 56, 15362f (1962), were heated and stirred under nitrogen atmosphere on a steam bath for five hours. The reaction mixture was poured into an icewater slurry keeping the mixture temperature at about 10° C. by additions of crushed ice. Solid potassium carbonate was added to the reaction mixture until the pH was five. On cooling overnight, a precipitate formed. Careful crystallization from acetone and then from isopropyl alcohol gave 1.1 grams (4.4%) of spiro-[indane-1,3'-piperidine]-2,3,6'-trione, melting point 227°-228° C.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si](C(C)C)(C(C)C)C(C)C)=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2(O)[CH3:34])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[CH:8]2[CH3:34])=[CH:36][CH:37]=1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(C)O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 16 (52 mg, 0.099 mmol) in 1.4 mL of dry CH2Cl2 under a N2 atmosphere, was added BF3.OEt2 (49 μL, 0.397 mmol) followed by triethylsilane (63 μL, 0.397 mmol). The solution was allowed to stir at ambient temperature for 1 day when LCMS indicated a clean conversion of starting materials to the desired product. The reaction was worked up by removing the solvent and dissolving the residue in EtOAc. The organic layer was washed with water and the solvent removed under reduced pressure. The residue was dissolved in 1 mL of EtOAc and triturated by addition of hexanes to provide the product 18. 1H NMR (300 MHz, CDCl3) δ 1.60 (d, 3H, J=7 Hz), 3.93 (s, 3H), 4.28 (d, 1H), J=15 Hz), 4.65 (q, 1H, J=7 Hz), 5.25 (d, 1H, J=15 Hz), 7.06 (t, 2H, J=8 Hz), 7.32 (dd, 2H, J=6, 8 Hz), 7.67 (dd, 1H, J=4, 8 Hz), 8.59 (br s, 1H), 8.61 (d, 1H, J=8 Hz), 9.11 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 16.9,42.8, 54.5, 61.9, 113.9, 115.7, 116.0, 122.7, 126.6, 129.8, 129.9, 130.8, 132.1, 133.1, 136.7, 142.4, 147.8, 148.3, 162.3 (d, J=245 Hz), 168.1; 19F NMR (282.6 MHz, CDCl3) δ 62.5; EI MS (m/z) 353.5 [MH+], 385.4 [M+Na].
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14][O:15][CH2:16][CH3:17])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(O)C[OH:36]>>[NH:1]([C:8]1[C:13]([CH2:14][O:15][CH2:16][CH2:17][OH:36])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:23][CH:24]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Reactant: OCCO
Agent: Cl
Product: CN(C)CC(O)COc1ccc(Nc2ncc(COCCO)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86, 70 mg, 0. 16 mmol) was dissolved in ethylene glycol (2 ml). Ethereal hydrogen chloride (1.0M; 0.32 ml, 0.32 mmol) was added, and the solution was heated at 100° C. for 20 hours. Volatile material was removed by evaporation and the residue was triturated with diethyl ether, giving the product as a dihydrochloride salt (43 mg). NMR (CDCl3): 2.34 (s, 6H), 2.3-2.6 (m, 2H), 3.63 (t, 2H), 3.73 (s, 1H), 3.86 (t, 2H), 3.96 (d, 2H), 4.08 (m, 1H), 4.54 (s, 2H), 6.86 (d, 2H), 6.88 (s, 1H), 7.08 (t, 1H), 7.30 (dd, 2H), 7.43 (d, 2H), 7.58 (d, 2H), 7.88 (m, 2H); MS (MH+): 454.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.Cl.[NH2:24][CH2:25][C:26]1[C:27](=[O:37])[NH:28][C:29]([CH3:36])=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:24][CH2:25][C:26]1[C:27](=[O:37])[NH:28][C:29]([CH3:36])=[CH:30][C:31]=1[C:32]([F:33])([F:34])[F:35])=[O:9]
Reactant: Cc1cc(C(F)(F)F)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C(F)(F)F)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 23 °C
Reaction time: 7 h
Yield: 41.5 %

Procedure:
To a stirred solution of 5-chloro-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methylbenzoic acid (crude material, ˜0.7 mmol) and 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-1,2-dihydropyridin-2-one hydrochloride HCl salt (200 mg, 0.91 mmol) in DMSO (5.3 mL) was added PyBOP (550 mg, 1.05 mmol) and hunig base (366 ul, 2.10 mmol). The reaction mixture was stirred at 23° C. for 7 hours. The reaction mixture was quenched with water and diluted with ethylacetate. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (SiO2 Ethylacetate/MeOH=10/1+5% triethylamine). The crude compound was triturated with ethylacetate/hexane, and dried to give the titled compound as a white solid (145 mg, 42% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.08 (d, J=2.4 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.81-6.85 (m, 1H), 6.35 (s, 1H), 4.71 (d, J=5.2 Hz, 2H), 3.03 (q, J=6.8 Hz, 2H), 2.81-2.85 (m, 2H), 2.68-2.72 (m, 1H), 2.39 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H), 1.88-1.94 (m, 2H), 1.67-1.72 (m, 4H), 0.85 (t, J=6.8 Hz, 3H); MS (ES) [M+H] 499.1, [M+Na] 521.1; HPLC 96.0% purity.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(C([NH:13][C:14]1[N:22]=[C:21]([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]([NH:31][C@@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[O:30])[CH2:24]2)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C@@H:37]1[CH2:41][C@H:40]([NH:42][C:43](=[O:46])[CH2:44][CH3:45])[C@@H:39]([OH:47])[C@H:38]1[OH:48])CC)C.FC(F)(F)C(O)=O.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(N[CH2:79][C:80]2[C:89]3[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH:83]=[CH:82][CH:81]=2)N=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:47][C@H:39]1[C@@H:38]([OH:48])[C@H:37]([N:18]2[CH:17]=[N:16][C:15]3[C:19]2=[N:20][C:21]([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]([NH:31][C@@H:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)=[O:30])[CH2:24]2)=[N:22][C:14]=3[NH:13][CH2:79][C:80]2[C:89]3[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH:83]=[CH:82][CH:81]=2)[CH2:41][C@@H:40]1[NH:42][C:43](=[O:46])[CH2:44][CH3:45]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-((1S,2R,3S,4R)-4-{6-(1-Ethyl-propylamino)-2-[(R)-3-((R)-3-pyrrolidin-3-ylureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate by replacing N-{(1S,2R,3S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide with N-((1S,2R,3S,4R)-4-{2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])C=C.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:10]1[CH:9]=[CH:8][C:7]([Cl:11])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cccc(Cl)c1-c1ccccc1C
Product: C=CCc1ccc(Cl)c(-c2ccccc2C)c1O
Yield: 75 %

Procedure:
A solution of 2-allyloxy-6-chloro-2′-methylbiphenyl (4.0 g, 15.4 mmol) in mesitylene (100 mL) was refluxed for 24 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 3.0 g (75%) of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol as a light yellow oil.
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[CH3:20][C:21]1([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]1=O.Cl>CS(C)=O.CO.C(OCC)(=O)C>[CH3:20][C:21]1([CH3:27])[CH2:25][CH2:24][CH2:23][CH:22]1[C:11]#[N:12]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(C)CCCC1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CCCC1C#N
Temperature: 0 °C
Reaction time: 30 h
Yield: 31 %

Procedure:
Tosylmethyl isocyanide (3.76 g, 19.3 mmol) was dissolved in dimethylsulfoxide (15 mL) and cooled to 0° C. Solid potassium t-butoxide (6.3 g, 59.2 mmol) was added and a thick brown precipitate formed. The reaction mixture was warmed to room temperature and 2,2-dimethylcyclopentanone (2.0 mL, 16.0 mmol) was added in anhydrous methanol (680 μL) and the reaction mixture was stirred for 30 hours. It was diluted with ethyl acetate, acidified with hydrochloric acid and extracted with hexanes. The extracts were dried over magnesium sulfate, filtered and the solvent was removed to provide a brown oil which was purified by chromatography on silica gel eluted with 0-50% dichloromethane in hexanes to yield a yellow oil (612 mg, 31%).