Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([C:30]4[CH:35]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:33]=[C:32]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH:31]=4)=[O:29])[CH2:24][CH2:23]3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[C:42]1([C:32]2[CH:31]=[C:30]([C:28]([N:25]3[CH2:24][CH2:23][CH:22]([N:18]4[CH2:19][CH2:20][CH2:21][C@@H:16]([C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:15])[CH2:17]4)[CH2:27][CH2:26]3)=[O:29])[CH:35]=[C:34]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:33]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)[C@@H]2CCCN(C3CCN(C(=O)c4cc(-c5ccccc5)nc(-c5ccccc5)c4)CC3)C2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(c1cc(-c2ccccc2)nc(-c2ccccc2)c1)N1CCC(N2CCC[C@@H](C(=O)N3CCNCC3)C2)CC1
Temperature: -78 °C
Yield: 91.3 %

Procedure:
(3R)-4-[1′-(2,6-Diphenyl-pyridine-4-carbonyl)-[1,4′]bipiperidinyl-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (1.78 g, 2.79 mmol) was dissolved in ethyl acetate (25 mL) and cooled to −78° C. under nitrogen. Hydrogen chloride was passed in for several minutes and formation of a white precipitate was observed which redissolved almost immediately. When the solution was saturated with hydrogen chloride it was allowed to warmed to ambient temperature and after 1 h the solvent was evaporated in a stream of dry nitrogen, passing the evolved gasses to a water scrubber. A loose yellowish powder remained (2.02 g, >100% calculated as trishydrochloride). This was dissolved in water, basified by the addition of 2M sodium hydroxide (to pH 13.5) and extracted with dichloromethane (×3). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give the title compound as a powdery foam (1.37 g, 91%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CCO>[N+:8]([C:7]1[C:2]([NH:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Reaction time: 17 h
Yield: 59.3 %

Procedure:
A solution of 2-chloro-3-nitropyridine (290 mg, 1.83 mmol), triethylamine (0.26 mL) and 1-(4-pyridyl)-piperidine-4-methylamine (350 mg, 1.83 mmol) in EtOH (10 mL) was heated at reflux. After 17 h, the mixture was concentrated and the residue was purified by chromatography (SiO2, 2 to 4% (2 N NH3 in methanol) in chloroform) yielding 340 mg (60%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[C:16]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[N:8][C:7]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)c(-c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(-c2ccccc2)c(-c2ccccc2)c1
Reaction time: 16 h

Procedure:
A mixture of 5-nitro-2,3-diphenylpyridine (0.74 mmol, 0.21 g) and Pd/C 10% (0.02 g) in methanol (5 ml) was stirred for 16 hours under hydrogen atmosphere. The catalyst was filtered off and the solid thoughtfully washed with methanol. The solid residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 0.14 g (74% of yield) of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][N:9]2[C:12]([CH:30]=[O:31])=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[CH3:29])[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:7]=1[Cl:32])=[O:5])[CH3:2].C=C(C)C.C1C[O:40]CC1.P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.[Cl-].[Na+].O.C(Cl)Cl.CC(=O)OCC>[Cl:32][C:7]1[C:8]2[N:9]([C:12]([C:30]([OH:40])=[O:31])=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[CH3:29])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=[CH:11][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cnn2c(C=O)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1Cl
Agent: C=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cnn2c(C(=O)O)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
The compound of step 7 (5.15 g, 11.42 mmol) was suspended in tert-butanol (90 ml), and a 2 M solution of isobutene in THF (34.27 ml, 68.53 mmol), a solution of sodium dihydrogenphosphate (4.111 g, 34.27 mmol) in 25 ml of water and sodium chlorite (1.937 g, 17.13 mmol) were added. The mixture was stirred at room temperature for 2 h. Then brine (200 ml), water (50 ml), EA (400 ml) and DCM (100 ml) were added and the organic phase was separated, dried over magnesium sulfate, filtered and evaporated to dryness. The obtained solid was triturated several times with cyclohexane and dried in vacuo at 50° C. 5.23 g of the title compound were obtained as a yellow solid melting at 193-194° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29](Cl)=[O:30]>>[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(F)cccc4F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,6-difluorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1>C(O)(=O)C.[Pt]=O>[CH3:10][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1
Reactant: Cc1cccc(C(=O)O)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC1CCCC(C(=O)O)C1
Yield: 84.4 %

Procedure:
To a solution of m-toluic acid (13.6 g, 0.1 mole) in acetic acid was added platinum oxide (0.1 g) under nitrogen. The mixture was hydrogenated in a Parr shaker at 35 psi. Upon completion, the catalyst was removed by filtration and the filtrate was concentrated to dryness to give 12 g of the title compound. The NMR spectrum showed absorption at 0.84 (d, 3H), 0.90 (d, 3H), 0.99-1.13 (m, 1H), 2.21-1.46 (m, 3H), 1.54-1.65 (m, 3H), 1.70-1.98 (m, 2H) and 1.23-2.41 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH:16]([CH3:15])[C:17]#[CH:18])[N:3]=[CH:4][N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Reactant: C#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)Oc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 95.1 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 458 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 231 mg of 3-butyn-2-ol, to which 132 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 10 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 506 mg of 4-(2-fluorophenyl)-6-(1-methyl-2-propynyloxy)pyrimidine (the present compound (150)).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[C:14]1[S:18][C:17]([C:19](=[O:21])[CH3:20])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23]>O>[N+:22]([C:15]1[CH:16]=[C:17]([C:19](=[O:21])[CH3:20])[S:18][C:14]=1[S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc([N+](=O)[O-])cc2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.3 %

Procedure:
Anhydrous N,N-dimethylformide (5 mL) was degassed with nitrogen for 30 minutes then sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.75 mmol) was added. 4-Nitrobenzenethiol (0.38 g, 2.43 mmol) was added in portions at ambient temperature and the resulting mixture was stirred at ambient temperature under nitrogen for 20 minutes. Then 1-(5-chloro-4-nitro-2-thienyl)ethanone (0.5 g, 2.43 mmol) was added and the reaction mixture was stirred at ambient temperature overnight under nitrogen. The reaction mixture was diluted with water (40 mL) and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water (2×4 mL). The crude solid was recrystallised from acetonitrile (12 mL) to afford the title compound as a brown solid (0.302 g, 38% yield). 1H NMR (300 MHz, CDCl3) δ: 8.38 (2H, d, J=8.85 Hz), 8.09 (1H, s), 7.89 (2H, d, J=8.85 Hz), 2.50 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:27])[NH:9][N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(=O)O[CH2:31][CH2:30][O:29]1>CN(C)C=O>[OH:29][CH2:30][CH2:31][N:9]1[C:8](=[O:27])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[N:10]1
Reactant: Cc1ccc(-c2n[nH]c(=O)c(-c3ccccc3)c2-c2ccc(C)cc2)cc1
Reactant: O=C1OCCO1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nn(CCO)c(=O)c(-c3ccccc3)c2-c2ccc(C)cc2)cc1

Procedure:
4-Phenyl-5,6-bis(p-methylphenyl)-2H-pyridazin-3-one (1.8 g) and 0.88 g of ethylene carbonate were charged to a flask in 100 ml dimethylformamide. The flask was placed in an oil bath, preheated to 150° C. and the reaction was heated for 4 hours. The hot solution was quenched in an equal volume of 1 N HCl, causing a white solid to precipitate. The cooled solution was filtered and the solid recrystallized from ethyl acetate and dried for 5 hours, m.p. 192°-194° C.
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14](F)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][O:1][C:9]2=3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: OC1CNCc2ccoc21
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(OC2CNCc3ccoc32)cc1Cl

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([OH:14])(=[O:13])/[CH:10]=[CH:11]/[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][CH:11]([CH3:12])[CH2:10][C:9]([OH:14])=[O:13]
Reactant: C/C=C/C(=O)O
Reactant: Nc1cccc(Cl)c1
Product: CC(CC(=O)O)Nc1cccc(Cl)c1

Procedure:
3-(3-Chloroanilino)butanoic acid is prepared in a manner similar to that described in Example 1, but starting from 3-chloroaniline (65 cc; 0.5 mol), crotonic acid (11.20 g; 0.129 mol) and distilled water (31 cc). After purification, a product (14.66 g; 68.6 mmol) is thus obtained in the form of a white powder which melts at about 50° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[NH:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH3:2].C(OCC1NC(C(OCC)=O)=C(C(OCC)=O)N=1)(=[O:21])C.C[Mg]I>C(OCC)(=O)C>[C:1]([O:3][CH2:4][C:5]1[NH:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)(=[O:21])[CH3:2]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: CCOC(=O)c1nc(COC(C)=O)[nH]c1C(=O)OCC
Agent: C[Mg]I
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c(COC(C)=O)nc1C(C)(C)O
Reaction time: 8 h

Procedure:
Following a procedure similar to that described in Preparation 44(iii), 1.54 g of diethyl 2-acetoxymethyl-imidazole-4,5-dicarboxylate were reacted with 6.5 equivalents of methylmagnesium iodide. Ethyl acetate was then added to the reaction solution, whilst ice-cooling, and the reaction solution was concentrated by evaporation under reduced pressure. The resulting residue was mixed with 50 ml of pyridine and 25 ml of acetic anhydride, and left at room temperature overnight. At the end of this time, 10 ml of methanol were added to the reaction solution, which was then stirred for 30 minutes. The solution was then concentrated by evaporation under reduced pressure. The residue was mixed with water and ethyl acetate, and the ethyl acetate layer was separated, washed twice with a saturated aqueous solution of sodium hydrogencarbonate and then once with an aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:4 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.46 g of the title compound as a syrup.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:11]2[N:16]=[C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21](=[O:23])[N:22]=3)[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][S:10]([C:11]2[N:16]=[C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21](=[O:23])[N:22]=3)[CH:14]=[CH:13][CH:12]=2)=[O:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1nc(-c2cccc(SCCCc3ccccc3)n2)sc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2cccc(S(=O)CCCc3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
2-[6-(3-Phenylpropyl)thio-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.20 g, 0.50 mmol) was dissolved in chloroform (30 ml), and a solution of 3-chloroperbenzoic acid (ca. 70%, 0.11 g, 0.50 mmol) in chloroform (10 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.063 g, 31%) as pale yellow crystals.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:6][C:5]([CH2:10][C:11]#[N:12])([CH2:7][C:8]#[N:9])[CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O>[O:2]=[C:3]1[CH2:6][C:5]([CH2:7][C:8]#[N:9])([CH2:10][C:11]#[N:12])[CH2:4]1
Reactant: COC1(OC)CC(CC#N)(CC#N)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: N#CCC1(CC#N)CC(=O)C1
Temperature: 25 °C

Procedure:
To a mixture of 2,2′-(3,3-dimethoxycyclobutane-1,1-diyl)diacetonitrile (2 g, 0.01 mol) in acetone (5 mL) was added p-toluenesulfonic acid (1 g, 0.006 mol). The mixture was stirred at rt over weekend. The reaction was neutralized with aq. saturated NaHCO3 solution, extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give a crude product as brown oil.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[O:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1>C1COCC1>[CH3:1][Si:2]([C:5]#[C:6][C:15]1([OH:18])[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)([CH3:4])[CH3:3]
Reactant: O=C1CCOCC1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trimethylsilylacetylene (5 mL, 35.4 mmol) in THF (100 mL) cooled at −78° C., a 1.6M n-butyllithium in hexanes (22.1 mL, 35.4 mmol) was added dropwise. The solution was stirred for 30 min before tetrahydro-4H-pyran-4-one (3.47 mL, 37.2 mmol) was added. The temperature was slowly raised to room temperature and the reaction was stirred overnight. The reaction was quenched with a saturated ammonium chloride solution and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 4.60 (s, 1H), 3.85-3.75 (m, 2H), 3.61-3.51 (m, 2H), 1.98-1.87 (m, 2H), 1.74-1.66 (m, 2H), 0.16 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][CH2:7][N:8]1[C:13]([C:14](=[O:23])[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)=[C:12]([CH2:24][CH3:25])[C:11](=[O:26])[NH:10][C:9]1=[O:27])=[O:4].O.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:2][C:3]([CH:5]=[CH:6][CH2:7][N:8]1[C:13]([C:14](=[O:23])[C:15]2[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=2)=[C:12]([CH2:24][CH3:25])[C:11](=[O:26])[NH:10][C:9]1=[O:27])=[O:4])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC=CC(=O)OC)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C=CCn1c(C(=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Reaction time: 48 h
Yield: 148.4 %

Procedure:
To a solution of 100 mg (0.27 mmol) of the compound obtained from Example 8 in 10 ml of anhydrous ethanol was added 20 mg of p-toluenesulfonic acid monohydrate. The reaction mixture was refluxed with stirring for about 48 hours, neutralized with sodium bicarbonate, and evaporated under reduced pressure to give a light brown residue, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (1:2) as an eluent to afford 60 mg (yield 58%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:28]C=2C=1.C(N=C=NCCCN(C)C)C.[OH-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:19](=[O:21])[NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(N)=O)c1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 1.5 gm (5.2 mmol) of methyl 4-benzyloxy-3-carboxybenzoate in 8 mL of DMF is added 0.85 gm (6.2 mmol) of HOBT and 1.2 gm (6.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). After 1 hr, 0.86 mL of 30% ammonium hydroxide is added, and the solution stirred for an additional 2 hr. The reaction mixture is concentrated to remove most of the DMF, and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with brine and dried over Na2SO4. Removal of solvent by rotoevaporation gives 1.37 gm (4.8 mmol) of methyl 4-benzyloxy-3-carbamoylbenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][N:7]=1.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26]>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[NH:27][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N:26]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C=O)c2)cnc1N
Reactant: Nc1ccccc1N
Solvent: CN1CCCC1=O
Product: CNC(=O)c1nc(-c2cccc(-c3nc4ccccc4[nH]3)c2)cnc1N

Procedure:
A solution of 3-amino-6-(3-formylphenyl)-N-methylpyrazine-2-carboxamide (25.4 mg, 0.1 mmol) and 1,2-phenylendiamine in NMP (3 mL) was heated at 80° C. for 8 h. The solvent was removed and the residue was triturated with 0.1 M aquous hydrochloric acid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:10][O:11][CH2:12][C:13](Cl)=[O:14]>>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:3](=[O:4])[CH3:5])[C:13](=[O:14])[CH2:12][O:11][CH3:10])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: COCC(=O)Cl
Product: CCOC(=O)C(C(C)=O)C(=O)COC

Procedure:
In analogy to the procedure described in Intermediate 11A], ethyl acetoacetate and methoxyacetylchloride gave the crude title compound in quantitative yield as yellow oil. MS: 202.9 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[C:14]([CH3:19])[C:15]([C:16]([OH:18])=O)=[C:11]3[N:10]=[CH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O:64][C:65](=[O:80])[CH:66]([NH2:79])[CH2:67][C:68]1[CH:73]=[CH:72][C:71]([O:74]C(C)(C)C)=[CH:70][CH:69]=1)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O>[CH:1]1([C:7]2[N:12]3[N:13]=[C:14]([CH3:19])[C:15]([C:16]([NH:79][CH:66]([CH2:67][C:68]4[CH:69]=[CH:70][C:71]([OH:74])=[CH:72][CH:73]=4)[C:65]([OH:80])=[O:64])=[O:18])=[C:11]3[N:10]=[CH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc2c1C(=O)O
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc2c1C(=O)NC(Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A solution of 36 mg (0.1 mmol) 7-cyclohexyl-6-(4-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in 2 mL of dimethylformamide was cooled at 0° C. To the above cold solution was added 0.053 mL (0.3 mmol) of N,N-diisopropylethylamine (DIEA), followed by 38 mg (0.1 mmol) of HATU, and 37 mg (0.11 mmol) of 2-amino-3-(4-tert-butoxy-phenyl)-propionic acid tert-butyl ester, and a few crystals of 4-dimethylaminopyridine (DMAP), and the resulting mixture was allowed to warm up to rt, and stirred at rt overnight. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N NaOH solution, water, and brine, dried over sodium sulfate and evaporated to give a residue which was treated with 2 mL of 95:5 trifluoroacetic acid (TFA):water, and stirred at rt for 2.5 h. The mixture was quenched by the addition of 10 mL of 1:1 acetonitrile:water solution, and concentrated to give a residue which was purified via reverse-phase chromatography using Gilson to afford (after lyophilization) 8 mg (16% over 2 steps) of 2-{[7-Cyclohexyl-6-(4-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid as a white solid (92% purity, entry 517), as indicated by 1H-NMR. (LC-MS calcd for C29H29FN4O4 [M+H]+ 517.22; found 517.2).
Reaction SMILES: [F-:1].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[S:12](Cl)(=[O:14])=[O:13]>>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[S:12]([F:1])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: [F-]
Agent: [K+]
Product: O=S(=O)(F)c1cc(Cl)c(Cl)cc1Cl
Yield: 99 %

Procedure:
2,4,5-Trichlorobenzenesulfonyl fluoride was synthesized from potassium fluoride and 2,4,5-trichlorobenzenesulfonyl chloride using the procedure described in Example 1. A product with mp 80°-83° C was obtained in 99% yield. The chemical analysis, NMR and IR spectra were in agreement with the assigned structure.