Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:4]#[N:5].[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1(C)C(C)=CC=CC=1>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([O:1]/[C:2](/[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])=[C:3](\[C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][CH:11]=1)/[C:4]#[N:5])=[O:29]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Solvent: Cc1ccccc1C
Product: Cc1nn(C)c(/C(OC(=O)C(C)(C)C)=C(\C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 70 °C
Yield: 95.9 %

Procedure:
In a 10 L-reaction flask, 456 g (1.47 mol) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile and 2738 g of xylene were added, the temperature was raised to 70° C., and 534 g (4.43 mol) of pivaloyl chloride was added dropwise under reflux over 10 hours while removing hydrogen chloride under a reduced pressure at 68 to 71° C./10 to 13 kPa. After reacting as such for 3 hours, 2181 g of a mixture of pivaloyl chloride and xylene was distilled off at 70° C. under a reduced pressure in order to remove excess pivaloyl chloride. After adding 456 g of warm water of 70° C., 228 g of 2.7% sodium hydrogen carbonate aqueous solution was added dropwise. After separating the resulting aqueous phase, the resulting organic phase was washed with 456 g of warm water of 70° C., the resulting aqueous phase was separated to obtain a xylene solution. A quantitative analysis with liquid chromatography showed that the xylene solution contained 555 g (yield 95.6%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) acrylonitrile. After distilling off xylene at 90° C., 1141 g of heptane was added, and crystallization was carried out by gradually cooling from 70° C. After aging at 0° C. for 1 hour, the resulting crystal was filtered, and dried to obtain 533 g (yield 91.9%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) acrylonitrile (melting point: 110° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:26][C:25]([O:27][CH:28]3[CH:32]4[O:33][CH2:34][C@H:35]([OH:36])[CH:31]4[O:30][CH2:29]3)=[N:24][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[O:22]C)=[CH:10][CH:9]=1.[Cl-].[Li+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:26][C:25]([O:27][CH:28]3[CH:32]4[O:33][CH2:34][C@H:35]([OH:36])[CH:31]4[O:30][CH2:29]3)=[N:24][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[OH:22])=[CH:10][CH:9]=1
Reactant: COc1c(F)cc(F)cc1-c1ccc(-c2nc3nc(OC4COC5C4OC[C@@H]5O)[nH]c3cc2Cl)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1c(F)cc(F)cc1-c1ccc(-c2nc3nc(OC4COC5C4OC[C@@H]5O)[nH]c3cc2Cl)cc1
Temperature: 140 °C

Procedure:
A mixture of (3S)-6-[[6-chloro-5-[4-(3,5-difluoro-2-methoxy-phenyl)phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (5.2 mg, 0.01 mmol), and lithium chloride (45.0 mg, 1.06 mmol) in DMF (0.5 mL) was heated in a 140° C. oil bath for 20 hours and then 3.5 additional hours at 150° C. The reaction mixture was cooled to room temperature and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile/water+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a light yellow solid. LC-MS: calculated for C24H18ClF2N3O5 501.09 observed m/e: 502.13 (M+H)+ (Rt 1.16/2 min); 1H NMR δ (ppm) (CD3OD): 7.83 (s, 1H), 7.66-7.74 (m, 4H), 6.93-6.98 (m, 2H), 5.55 (qt, 1H), 4.97 (t, 1H), 4.47 (t, 1H), 4.26-4.30 (m, 1H), 4.17 (dd, 1H), 4.11 (dd, 1H), 3.90 (t, 1H), 3.60 (t, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:39]1[CH:44]=[CH:43][C:42]([C@@H:45]([NH2:48])[CH2:46][OH:47])=[CH:41][CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:48][C@H:45]([C:42]3[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=3)[CH2:46][OH:47])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](CO)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 70 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and R-(−)-2-phenylglycinol: yield 70%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[O:24][C:18]=2[CH2:17]1.CCOCC>C1COCC1.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[O:24][C:18]=2[CH2:17]1)=[O:1]
Reactant: OCc1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Agent: O=[Mn]=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1

Procedure:
37.4 g of 2-[4-(5-hydroxymethyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine are dissolved in 1.6 l of THF, and 300 ml of ether are added. While stirring, 55 g of MnO2 are added. The mixture is stirred at 20° for 16 hours, a further 100 g of MnO2 are added in portions, and the mixture is stirred at 20° for a further 100 hours. After filtration and the usual working up, 2-[4-(5-formyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCN(CC)S(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 16 h
Yield: 21.3 %

Procedure:
According to general procedure B, 4-bromo-N,N-diethylbenzenesulfonamide (117 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethylbenzenesulfonamide (27 mg, 21%) was provided after purification. MS (ESI) m/z 317. HPLC purity 100.0% at 210-370 nm, 10.8 min.; the Xterr® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:12]=1[O:13][CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])([O-:10])=[O:9]>C(Cl)Cl>[CH2:1]([NH:7][C:15](=[O:16])[CH:14]([O:13][C:12]1[CH:20]=[C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])[CH:22]=[CH:23][C:11]=1[N+:8]([O-:10])=[O:9])[CH2:18][CH3:19])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: CCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Product: CCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)NCc1ccco1
Temperature: -15 °C

Procedure:
Furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]butyryl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-furfuryl-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]butyramide.
Reaction SMILES: C([NH:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C(C)(C)NCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)N

Procedure:
To the solution of tert-butyl 2-(benzylamino)-2-methylpropanoate (20 g, 0.08 mol) in ethyl acetate (1 L), was added the catalyst Palladium-carbon (10%, 2.2 g). The resulting mixture was put under the hydrogen pressure of 5 Kg/cm2, at RT for 18 h. The reaction mixture was filtered. The filtrate was concentrated affording the title compound as pale green liquid. 1H NMR (DMSO-d6, 400 MHz) δ 1.38 (brs, 2H), 1.14 (s, 9H), 1.14-1.11 (d, J=10.7 Hz, 6H).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[F:11][C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([F:19])[N:13]=1.C(=O)(O)[O-].[Na+]>COC(C)(C)C.C(OCC)(=O)C>[F:11][C:12]1[C:17]([NH:18][CH:5]=[O:7])=[CH:16][CH:15]=[C:14]([F:19])[N:13]=1
Reactant: Nc1ccc(F)nc1F
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: O=CO
Product: O=CNc1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Acetic anhydride (6 ml) was added to formic acid (6 ml), followed by stirring at room temperature for 20 minutes. Then, a solution of 2,6-difluoro-3-aminopyridine (2.06 g) in tert-butyl methyl ether (7 ml) was added so that the reaction solution was maintained at room temperature. The reaction solution was further stirred at room temperature for four hours. Ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.42 g). The property values of the compound are as follows.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][N:16]4[C:20]([C:23]5[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=5)=[N:21][N:22]=[C:15]34)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N>[N:26]1[CH:27]=[CH:28][C:23]([C:20]2[N:16]3[CH2:17][CH2:18][CH2:19][N:14]([CH2:13][C:10]4[N:11]=[N:12][N:8]([C:4]5[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=5)[C:29]#[N:30])[N:9]=4)[C:15]3=[N:22][N:21]=2)=[CH:24][CH:25]=1
Reactant: Ic1cccc(-n2nnc(CN3CCCn4c(-c5ccncc5)nnc43)n2)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(-n2nnc(CN3CCCn4c(-c5ccncc5)nnc43)n2)c1

Procedure:
The title compound is prepared from 8-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [N:1]1([CH:7]=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CO>[OH:13][CH2:12][CH2:11][CH2:10][N:4]1[CH2:5][CH2:6][N:1]([CH:7]=[O:8])[CH2:2][CH2:3]1
Reactant: OCCCBr
Reactant: O=CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=CN1CCN(CCCO)CC1
Yield: 11.9 %

Procedure:
A solution of 1-piperazinecarboxaldehyde (25 g, 0.219 mol), 3-bromo-1-propanol (33.5 g, 0.241 mol) and potassium carbonate (38 g, 0.273 mol) in methanol (33 ml) was heated at reflux for 5 hours. After cooling, the solid was filtered, washed with methanol and the filtrate was evaporated. The residue was dissolved in methylene chloride and washed with a small amount of water. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (90/10 followed by 80/20) to give 4-(3-hydroxypropyl)-1-piperazinecarboxaldehyde (4.5 g, 12%).
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:21]1([C:24]([NH2:32])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([NH:32][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][O:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)COC2)cn1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3(F)COC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 131b) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (45 mg, 39%); MS (ESI, m/z): 445.5 (M+H+).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C)C=O>[NH2:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([C:5]([OH:4])=[O:15])=[C:7]([O:14][CH2:18][CH:17]=[CH2:16])[CH:8]=1
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (1.52 g, 38 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 30 mmol), stirred at room temperature for 30 minutes, and treated with allyl bromide (4.60 g, 38 mmol). The mixture was stirred at 95°±5° C. for one hour, cooled to room temperature, and added to water (250 mL). The solid was removed by filtration and saved, and the filtrate was extracted with ether (2×100 mL). The concentrated ethereal extracts were combined with the filtered solid, taken up in 20% aqueous ethanol (100 mL), treated with potassium hydroxide (10 g), and refluxed for 45 minutes. The ethanol was removed in vacuo and the aqueous solution was extracted with ether (50 mL) and petroleum ethers (30°-60°, 50 mL), cooled (0° C.), and acidified to pH 4 with concentrated hydrochloric acid (17 mL). The suspension was filtered and the solid was air dried, dissolved in methylene chloride (150 mL) containing a little methanol, dried (Na2SO4), and concentrated in vacuo. Trituration from cold ether/petroleum ethers (30°-60°) and recrystallization from ethyl acetate/hexane (2 crops) afforded 4.25 g (62.2%) of a pale tan solid; mp 136°-137° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([N:19]([CH3:30])[CH:20]4[CH2:29][CH2:28][C:23]5([CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[CH:16]=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([N:19]([CH3:30])[CH:20]4[CH2:29][CH2:28][C:23]5([CH2:27][N:26]([C:34](=[O:35])[CH2:33][C:31]#[N:32])[CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[CH:16]=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: N#CCC(=O)O
Reactant: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CCNC5)CC4)n3)cc2nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CC4)CCN(C(=O)CC#N)C5)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of N2-(2,3-dimethyl-2H-indazol-6-yl)-N4-methyl-N4-(2-azaspiro[4.5]decan-8-yl)pyrimidine-2,4-diamine (300 mg, 0.74 mmol), 2-cyanoacetic acid (156 mg, 1.83 mmol) in a mixture of DCM and DMF (4/1 (v/v), 35 mL) were added HATU (925.8 mg, 2.44 mmol) and Et3N (0.49 g, 4.84 mmol). After addition, the reaction mixture was stirred at rt for 0.5 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), and dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as a beige solid (210 mg, 60.0%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)=[CH:10][N:9]2CC)[CH:5]=[CH:6][CH:7]=1.Cl.[F:24][C:25]([F:35])([F:34])C1C=C(NN)C=CC=1>CO>[Cl:20][C:16]1[CH:15]=[C:14]([C:11]2[C:12](=[O:13])[N:8]([C:4]3[CH:3]=[C:2]([C:25]([F:35])([F:34])[F:24])[CH:7]=[CH:6][CH:5]=3)[NH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCn1cc(-c2cccc(Cl)c2)c(=O)n1-c1cccc(Cl)c1
Reactant: NNc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: O=c1c(-c2cccc(Cl)c2)c[nH]n1-c1cccc(C(F)(F)F)c1
Yield: 37.7 %

Procedure:
A mixture of 12 grams of the 3-chloroatropic acid, methyl ester (prepared in Example 9 above), 13 grams 3-(trifluoromethyl)phenylhydrazine hydrochloride and 100 ml. methanol was refluxed overnight to yield 4.6 grams of 4-(3-chlorophenyl)-1-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 190°-192° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22].[C:23](=O)([O-])[O-].[K+].[K+].CBr.Cl>CN(C=O)C.O>[Br:1][C:2]1[C:10]([O:11][CH3:23])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(O)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: CBr
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.2 g (0.49 mmol) of 4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-hydroxy-benzoic acid was dissolved in 5 ml DMF and 0.272 mg (1.97 mmol) of potassium carbonate was added. The solution was cooled to 0° C. and 0.699 g (4.9 mmol) methyl bromide was added. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/1). The resulting compound was dissolved in 10 ml dioxan and 1 ml water. 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h. 5 ml water was added, followed by concentrated hydrochloric acid to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20]([CH:28]3[CH2:31][C:30](=[CH:32][O:33]C)[CH2:29]3)[N:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=23)[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(C(O)=O)(F)(F)F.C([O-])([O-])=O.[K+].[K+]>O>[NH2:27][C:23]1[C:22]2[N:21]([C:20]([CH:28]3[CH2:31][CH:30]([CH:32]=[O:33])[CH2:29]3)=[N:19][C:18]=2[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:13]=2)[CH:26]=[CH:25][N:24]=1
Reactant: COC=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccn2c(C3CC(C=O)C3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a methylene chloride solution (6.0 mL) of 1-(3-Benzyloxy-phenyl)-3-(3-methoxymethylene-cyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine (287.0 mg, 0.696 mmol), CF3CO2H (0.11 mL, 1.392 mmol) was added, followed by H2O (0.5 mL). The reaction mixture was allowed to react for 1 h at rt. After which an ethanolic solution (5.0 mL) of K2CO3 (192.3 mg, 1.392 mmol) was added to the reaction and allowed to stir at rt for an additional 2 h. The reaction mixture extracted between water and EtOAc. The organic layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo to yield the desired product as a brown solid; 1H NMR (CDCl3, 400 MHz) (mixture of cis and trans isomers) δ 2.45-2.84 (m, 4H), 3.25-3.32 (m, 1H), 3.74-3.79 (m, 1H), 5.22 (s, 2H), 6.84-6.85 (m, 1H), 7.00-7.17 (m, 5H), 7.27-7.39 (m, 6H), 9.69 (s, 1H), 9.88 (s, 1H); MS (ES) 399.07 (M+1), 400.0 (M+2), 401.0 (M+3).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>CCO>[OH:12][CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=Cc1cnc2ccccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cnc2ccccc2c1
Reaction time: 1 h

Procedure:
Quinoline 3-carboxaldehyde (1.0 g, 6.37 mmol) was dissolved in 20 mL of EtOH and treated with NaBH4 (70 mg). After stirring for 1 hour, the solution was treated with 2 mL of 1N HCl, and after stirring for 10 min the reaction mixture was treated with enough 1N NaOH to make the solution basic. The reaction temperature was extracted with Et2O and the organic portion was washed with H2O and brine. The organic portion was dried over Na2SO4 and concentrated under reduced pressur to give the title compound. MS(CI) m/e 160 (M+H)+.