Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22](O)=O)[CH2:18][CH2:17]3)[S:13][C:14]=2[CH3:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].CC(O)=O.C(O[Na])(C)=O.C=O.[BH3-]C#N.[Na+]>Cl.O1CCOCC1>[CH3:15][C:14]1[S:13][C:12]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[N:11][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1sc(N2CCN(C(=O)O)CC2)nc1-c1ccc(C(=O)O)cc1
Agent: C=O
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1sc(N2CCN(C)CC2)nc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
4-[4-(4-Carboxyphenyl)-5-methylthiazol-2-yl]-piperazine-1-carboxylic acid tort-butyl ester (0.421 mmol) was dissolved in 4M HCl in 1,4-dioxane, and stirred at room temperature for 1 h. The solvent was then removed in vacuo, and the residue 4-(5-methyl-2-piperazin-1-yl-thiazol-4-yl)-benzoic acid was suspended in methanol (10 mL) and treated with AcOH/AcONa buffer (pH ˜5.5, 5 mL), and formaldehyde (0.547 mmol). The reaction mixture was stirred at room temperature for 1 h, then treated with NaCNBH3 (0.547 mmol) and stirred at room temperature overnight. The solvent was then removed under vacuum, and the residue was purified by column chromatography to afford the title compound (0.403 mmol, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([OH:24])[N:9]=1.[CH2:25]([N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][C:29]1=[O:38])[C:26]#[CH:27].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[C:26][CH2:25][N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:29]3=[O:38])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([OH:24])[N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2O
Reactant: C#CCN1C(=O)CCc2ccccc21
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CCc4ccccc43)cc1C(c1ccccc1F)=NC2O

Procedure:
The title compound was obtained by reacting rac-6-(2-fluorophenyl)-4-hydroxy-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with 3,4-dihydro-1(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined good fractions were evaporated and the residue was crystallized from methanol/ethyl acetate to give colorless crystals of rac-1-{3-[6-(2-fluorophenyl)-4-hydroxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-propynyl}-3,4-dihydro-2(1H)-quinolinone with m.p. 253°-255° with decomposition. These crystals contained molar equivalents of water.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=O.O=P(Cl)(Cl)[Cl:15]>CN(C=O)C>[Cl:15][C:7]1[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2c(I)cccc12
Solvent: CN(C)C=O
Product: Clc1ccnc2c(I)cccc12
Yield: 97.8 %

Procedure:
8-Iodo-1H-quinolin-4-one (3.36 g, 8.72 mmol) was suspended in POCl3 (8 mL, 87.2 mmol) and catalytic anhydrous DMF (6.72 μL) was added. The mixture was refluxed for 1 h. The hot crude was poured over ice and the mixture stirred until ice was completely melted. Solid was filtered off, thoroughly washed with water and kept in the vacuum oven overnight to afford 4-chloro-8-iodo-quinoline as a grayish solid (2.47 g, 98%). 1H NMR (DMSO-d6, 400MHz) δ 7.45 (t, 1H), 7.81 (d, 1H), 8.19 (dd, 1H), 8.45 (dd, 1H), 8.87 (d, 1H). Exact mass calculated for C9H5ClIN 288.92, found 289.9 (MH+).
Reaction SMILES: [H-].[Na+].COCCOC.COP([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:17])(=O)OC.[CH2:31]([O:33][C:34](=[O:49])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C@@H:42]1[CH:47]=O)[CH3:32]>C(OCC)(=O)C>[CH2:31]([O:33][C:34](=[O:49])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C@@H:42]1/[CH:47]=[CH:15]/[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)[OH:17])[CH3:32]
Reactant: COP(=O)(CC(=O)c1cccc(Cc2ccccc2)c1)OC
Reactant: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.1 %

Procedure:
To 60% sodium hydride in mineral oil (20 mg, 0.51 mmol) was added a DME solution (5 mL) of [2-(3-benzyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (164 mg, 0.51 mmol). After 1.5 h a DME solution (5 mL) of 7-((R)-2-formyl-5-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester (126 mg, 0.47 mmol) was added. The reaction mixture was stirred for 45 min. at room temperature then diluted with ethyl acetate and washed with an aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The residue was subjected to column chromatography (2.5 ethyl acetate: 1 hexanes) to provide 7-{(R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxy-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (112 mg, 0.24 mmol) as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:31][Mg]Br>O1CCCC1.C(OCC)C>[CH3:31][C:2]1([OH:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(C)(O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Oxo-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) is suspended in tetrahydrofuran (20 ml), and thereto is added dropwise a 3.0M solution of methyl magnesium bromide in diethyl ether (1.5 ml) at room temperature. The mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice-water (20 ml), and extracted with ethyl acetate. The extract is dried over magnesium sulfate, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=2:3→1:1), and recrystallized from ethyl acetate/n-hexane to give 5-methyl-5-hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as white powder, m.p. 204°-205° C.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>N1C=CC=CC=1>[C:17]1([O:16][C:14](=[O:15])[NH:12][C:9]2[CH:10]=[N:11][C:6]([N:1]3[CH:5]=[N:4][N:3]=[N:2]3)=[CH:7][CH:8]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(-n2cnnn2)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-n2cnnn2)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(1H-Tetrazol-1-yl)pyridin-3-amine (50 mg, 0.308 mmol) was dissolved in pyridine (1.5 mL), followed by addition of phenyl chloroformate (53.1 mg, 0.339 mmol). The mixture was stirred at RT overnight, and was concentrated to give crude title compound. LC/MS: [(M+1]+=283.14, [(M+1-28)]+=255.13.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]([NH2:12])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:10][N:12]=1
Reactant: NC=O
Reactant: N#Cc1ccccc1N
Product: Nc1ncnc2ccccc12
Temperature: 220 °C

Procedure:
A mixture of o-aminobenzonitrile (22.58 g) and formamide (96 ml) was refluxed for 2 hours at 220° C. After the resultant mixture was cooled to ambient temperature, precipitated crystals were separated by filtration, washed twice with a small volume of water and dried under reduced pressure to give crystalline 4-aminoquinazoline (17.0 g).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])(C)C.[Cl-].[Na+].[C:9]([O:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]1)(=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]1)=[O:19]>CCCCCCCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[C:9]([O:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([O:5][CH2:1][CH2:4][CH2:27][CH2:25][CH2:26][CH2:21][CH2:22][CH2:23][CH3:29])[C:35]([CH3:42])([CH3:41])[CH2:34]1)(=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]1[CH2:26][C:25]([CH3:27])([CH3:28])[N:24]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[C:23]([CH3:29])([CH3:30])[CH2:22]1)=[O:19]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Ti+4]
Agent: CCCC[O-]
Agent: [Cl-]
Solvent: CCCCCCCCC
Product: CCCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 151 °C
Yield: 6 %

Procedure:
A 2-phase mixture of 85.7 g (0.666 mol) of 70% aqueous tert-butyl hydroperoxide, 200 ml of n-nonane and 15 g of sodium chloride is agitated in a separatory funnel. The organic layer is dried over anhydrous magnesium sulfate. A mixture of 40.0 g (0.0832 mol) of bis-(2,2,6,6-tetramethylpiperidin-4-yl) sebacate and the tert-butyl hydroperoxidenonane solution is heated to reflux (151° C.) under a nitrogen atmosphere. To this mixture is added over a 10-minute period, a solution of 5.0 g of titanium tetrabutoxide in 50 ml of nonane. The reaction mixture turns red. Water is collected in a Dean Stark trap. The reaction mixture is heated at reflux for 17 hours. Another 5.0 g of titanium tetrabutoxide is added, and the reaction mixture is heated at reflux for an additional 7 hours. Solids are removed by filtration, and the filtrate is concentrated under reduced pressure. The crude red oil obtained is purified by chromatography (Waters Prep 500A HPLC; 29:1 heptane:ethyl acetate) to give 3.6 g (6% yield) or the title compound as a light yellow oil.
Reaction SMILES: CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+:23]([CH3:25])[CH3:24].[CH3:26][O:27][C:28](=[O:59])[N:29]=[C:30]([S:57][CH3:58])[C:31]([C:45]1[CH:46]=[C:47]([O:55][CH3:56])[C:48]2[O:52][CH2:51]C(O)[C:49]=2[CH:54]=1)=[N:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]=[C:42]([CH3:44])[O:41][N:40]=2)=[CH:35][CH:34]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:26][O:27][C:28](=[O:59])[N:29]=[C:30]([S:57][CH3:58])[C:31]([C:45]1[CH:46]=[C:47]([O:55][CH3:56])[C:48]2[O:52][CH2:51][CH:24]([O:23][CH3:25])[C:49]=2[CH:54]=1)=[N:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]=[C:42]([CH3:44])[O:41][N:40]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)C(O)CO2
Reactant: C[O+](C)C
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)C(OC)CO2
Reaction time: 2 h
Yield: 51.8 %

Procedure:
After adding 201 mg of 1,8-bis(dimethylamino)naphthalene and 138 mg of trimethyloxonium tetrafluoroborate to a solution of 150 mg of {2-(3-hydroxy -7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 3 ml of acetonitrile at 0° C., the mixture was stirred for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (80 mg) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([NH2:21])=[C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33](OCC)(OCC)OCC>C(OC(=O)C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]3[C:20]=2[N:21]=[CH:33][N:22]3[C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2N)CC1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2ncn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 140 °C

Procedure:
4-[5-Amino-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.6 mmol) was dissolved in mixture of triethyl orthoformate (4 mL) and acetic anhydride (4 mL), and then the mixture was refluxed at 140° C. for 15 hours. The crude product was quenched with saturated sodium bicarbonate and extracted with ethyl acetate, then dried in vacuo. Solid was precipitated out in acetonitrile/water and provided Compound B4 as a peach solid (205 mg, 67%). 1H NMR (CDCl3, 400 MHz) δ 1.48 (s, 9H), 1.95–1.91 (m, 2H), 2.14–2.11 (m, 2H), 3.12 (s, 3H), 3.34–3.27 (m, 2H), 3.94–3.91 (m, 2H), 5.61 (m, 1H), 8.06 (d, 2H), 8.19 (d, 2H), 8.29 (s, 1H), 8.61 (s, 1H). Exact mass calculated for C22H27N5O5S 473.17, found 474.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:45])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4C(OC(C)(C)C)=O)[NH:16][C:15]=3[CH:14]=[C:13]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])=[O:34])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[ClH:46].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:1].[ClH:46].[Cl:1][C:2]1[C:3]([CH3:45])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([C@@H:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)[NH:16][C:15]=3[CH:14]=[C:13]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:42])[F:43])=[O:34])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c([C@@H]3CCCN3C(=O)OC(C)(C)C)nc12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c([C@@H]3CCCN3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2S)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-2-yl}pyrrolidine-1-carboxylate (26 mg) (Example 69) in ethyl acetate (2 mL), was added 4N hydrogen chloride/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hours. N-hexane was added to the reaction mixture, the precipitate was collected, and dried to obtain the titled compound (20 mg) as pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].OCC[C:19]#[N:20]>>[F:1][C:2]([F:14])([F:15])[CH2:3][O:4][CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH2:12][C:19]#[N:20])=[O:9]
Reactant: CCOC(=O)CC(=O)COCC(F)(F)F
Reactant: N#CCCO
Product: N#CCCOC(=O)CC(=O)COCC(F)(F)F
Yield: 95.1 %

Procedure:
A mixture of 4.04 g of ethyl 4-(2,2,2-trifluoroethyl)oxy-3-oxobutanoate (17.7 mmol) and 2.55 g of 3-hydroxypropionitrile (35.9 mmol) was heated at reflux temperature at a bath temperature of 135°-150° C. at 10 torr for 6 hrs. The reflux condenser was replaced with a distillation head and the product was distilled under reduced pressure to give 4.26 g (96%) of the desired product as a viscous oil: bp 155°-158° C. (1.5). The product was used in the next step after spectral characterization.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Cl:40][C:41]1[C:42]([C:51]([F:53])([F:52])[F:54])=[N:43][N:44]([CH2:47][C:48]([N:37]2[CH2:38][CH2:39][N:34]([C:28]3[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[CH2:35][CH2:36]2)=[O:49])[C:45]=1[CH3:46]
Reactant: COc1ccc(F)cc1N1CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(F)cc1N1CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Methoxy-5-fluorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 6.93 (m, 1H), 6.77 (m, 3H), 5.36 (s, 2H), 3.77 (s, 3H), 3.59 (m, 4H), 3.07 (m, 2H), 2.98 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expect 435.1, found 435.0.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].FC(F)(F)C(O)=O.[CH2:15]([O:17][C:18]1[CH:39]=[CH:38][C:21]([O:22][C:23]2[N:28]=[CH:27][N:26]=[C:25]3[N:29]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[N:30]=[CH:31][C:24]=23)=[C:20]([F:40])[CH:19]=1)[CH3:16].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH:5]([O:4][C:2]([N:35]1[CH2:36][CH2:37][CH:32]([N:29]2[C:25]3=[N:26][CH:27]=[N:28][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:18]([O:17][CH2:15][CH3:16])=[CH:19][C:20]=4[F:40])=[C:24]3[CH:31]=[N:30]2)[CH2:33][CH2:34]1)=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Isopropyl chloroformate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 1 M in toluene; 0.079 ml, 0.079 mol) was added to a mixture of 4-(4-ethoxy-2-fluoro-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 29; 28 mg, 0.078 mmol), and diisopropylethylamine (30 mg, 0.235 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give 4-[4-(4-ethoxy-2-fluoro-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (27 mg, 80%) as a white solid. Mass spectrum MH+=444.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH2:13][OH:14])=[CH:4]2.CN(C)C=O>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH:13]=[O:14])=[CH:4]2
Reactant: OCC1=Cc2cnc3cccc(n23)S1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=CC1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7.777 g (38.076 mM) of 5-thia-1,8b-diazaacenaphthylene-4-methanol in ethyl acetate (50 ml)-N,N-dimethylformamide (50 ml) was added 23 g of active manganese dioxide and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the precipitate was washed with N,N-dimethylformamide. The pooled filtrate was distilled under reduced pressure to remove the solvent. The crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde thus obtained was not purified but used as it was in the next reaction. To a solution of 9.39 g (41.9 mM) of ethyl diethylphosphonoacetate in 50 ml of toluene was added 1.68 g (41.9 mM) of a 60% suspension of sodium hydride in liquid paraffin at room temperature and the mixture was stirred for 0.5 hour. This mixture was added to a solution of the above crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde in N,N-dimethylformamide (50 ml)-toluene (200 ml) under ice cooling and the mixture was stirred at room temperature for one hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The resulting crude ethyl 3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylate was not purified but used as it was in the next reaction. To a solution of the above crude ethyl 3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylate in 300 ml of ethanol was added 60 ml (120 mM) of 2N-aqueous solution of sodium hydroxide and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added concentrated hydrochloric acid (ca 10 ml) with stirring to bring the pH into the range of 4-5 and the resulting precipitate was recovered by filtration and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8](I)[C:9](=[O:10])[N:4]2[CH:3]=1.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]([C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=3)[C:9](=[O:10])[N:4]2[CH:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(/C=C/c2nc3sc(Cl)cn3c(=O)c2I)c1OCC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2nc3sc(Cl)cn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC(C)(C)C
Yield: 108.8 %

Procedure:
The title compound was prepared from Intermediate 19 (65 mg, 0.122 mmol) and 4-trifluoromethoxyphenyl boronic acid (27 mg, 0.132 mmol) using Pd[(C6H5)3P]4 (5 mg, 0.004 mmol) in toluene (10 ml) and ethanol (5 ml) followed by sodium carbonate (77 mg, 0.734 mmol) in water (5 ml) according to the procedure outlined in Example 1 to afford 75 mg of the desired compound; 1H NMR (300 MHz, DMSO-d6) δ 0.99 (s, 9H), 3.50 (s, 2H), 3.76 (s, 3H), 6.81 (d, J=16.2 Hz, 1H), 6.88-6.94 (m, 1H), 6.99 (d, J=4.2 Hz, 2H), 7.42-7.48 (m, 4H), 8.18 (d, J=15.6 Hz, 1H), 8.26 (s, 1H); ESI-MS (m/z) 565.55, 567 (M+H)+.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.C(N(CC)C(C)C)(C)C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2C(=O)[CH2:46][CH2:45][CH2:44][C:43]=2[OH:49])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>ClCCl>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2[C:43](=[O:49])[CH2:44][CH2:45][CH2:46][C:6]=2[O:7][CH3:9])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: C[O+](C)C
Reactant: N#Cc1ccc(C(NC(=O)Nc2ccnc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2ccnc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethyloxonium tetrafluoroborate (47 mg, 0.318 mmol) is added to a solution of N,N-diisopropylethylamine (72 μL, 0.412 mmol) and 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea (intermediate 26, 90 mg, 0.209 mmol) in dichloromethane (10 mL). The mixture is stirred at room temperature for 1 h and extracted three times with water. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 100 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.05 min (V012_S01).