Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4]Br.[CH3:13][C:14]1([CH3:20])[CH2:18][O:17][NH:16][C:15]1=[O:19].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O1CCOCCOCCOCCOCCOCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4][N:16]1[C:15](=[O:19])[C:14]([CH3:20])([CH3:13])[CH2:18][O:17]1
Reactant: O=[N+]([O-])c1cccc(Cl)c1CBr
Reactant: CC1(C)CONC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CON(Cc2c(Cl)cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of 2-chloro-6-nitrobenzyl bromide (17.5 g, 0.07 mole), 4,4-dimethyl-3-isoxazolidinone (11.5 g, 0.1 mole), potassium carbonate (13.8 g, 0.1 mole), and 1,4,7,10,13,16-hexaoxacyclooctadecane (0.5 g, 0.002 mole) in acetonitrile (500 ml) was stirred at ambient temperature overnight. The reaction mixture was poured into ethyl acetate (500 ml) and the mixture washed with water (3×200 ml). The dried (magnesium sulfate) ethyl acetate layer was concentrated under reduced pressure to yield a liquid. The liquid product was subjected to chromatography on silica gel, eluting with 1:9 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield a white solid. The solid was recrystallized from ethyl acetate to yield 10.5 g of 2-[(2-chloro-6-nitrophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone, m.p. 86°-88° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:36])[CH2:9]1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:36][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A solution of acryloyl chloride (49 μL, 0.60 mmol) in CH2Cl2 (2.77 mL) was added dropwise over 5 minutes to 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 156, 246 mg, 0.57 mmol) in CH2Cl2 (8.3 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h asn was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (182 mg, 66%) as a yellow solid after trituration with diethyl ether; 1H NMR: 2.09 (6H, s), 3.04-3.12 (1H, m), 3.55-3.60 (2H, m), 3.83 (3H, s), 3.96 (2H, t), 5.67 (1H, dd), 6.18 (1H, dd), 6.26 (1H, s), 6.48 (1H, dd), 7.05 (1H, td), 7.20 (1H, d), 7.41-7.46 (1H, m), 7.71 (1H, s), 8.00 (1H, s), 8.29 (1H, d), 8.43 (1H, br d), 8.75 (1H, s), 8.77 (1H, d), 9.29 (1H, s); m/z: ES+ MH+ 485.69.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]([O:15]C)=[O:14].O.[OH-].[Li+].O>CO>[Cl:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccc2scc(OC)c2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1csc2ccc(C(=O)O)c(Cl)c12
Yield: 92.2 %

Procedure:
A mixture of methyl 4-chloro-3-methoxybenzo[b]thiophene-5-carboxylate (8.35 g) and lithium hydroxide hydrate (1.37 g) was stirred in methanol (75 ml) and water (25 ml) at room temperature for 4 days. The methanol was evaporated in vacuo and the mixture poured onto excess cold dilute hydrochloric acid. The solid was filtered, washed with cold cyclohexane and dried to give 4-chloro-3-methoxybenzo[b]thiophene-5-carboxylic acid (7.28 g) as a white solid, NMR (d6DMSO) δ3.9(3H,s), 7.0(1H,s), 7.6(1H,d), 7.95(1H,d), 13.3(1H,brs).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9]4=[C:10]([C:17](=[O:20])[C:18](=[O:19])[N:8]24)[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]N1C(=O)CCC1=O>CN(C)C=O>[Cl:21][C:12]1[CH:13]=[C:14]2[C:9]3=[C:10]([C:17](=[O:20])[C:18](=[O:19])[N:8]3[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:16][CH2:15]2)[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1C(=O)N2c3c(cccc31)CCC2c1ccccc1
Solvent: CN(C)C=O
Product: O=C1C(=O)N2c3c(cc(Cl)cc31)CCC2c1ccccc1
Temperature: 80 °C
Yield: 97 %

Procedure:
A mixture of 5,6-dihydro-4-phenyl-4H-pyrrolo[3,2,1-ij]-quinoline-1,2-dione (3.1 g) and N-chlorosuccinimide (1.89 g) in dimethylformamide (DMF; 50 ml) was stirred at 80 ° C. for an hour. After cooling, the mixture was concentrated under reduced pressure and to the resulting residue was added chloroform (500 ml). The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3.4 g, 96.8%). This crystals was recrystallized from acetonitrile to give dark reddish crystals, mp 173°-174 ° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=O)[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][NH2:27]>CO>[CH3:1][C:2]1([CH3:18])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]/[C:6]/1=[N:27]\[O:26][CH3:25]
Reactant: CON
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CO/N=C1\CN(C(=O)OCc2ccccc2)CC1(C)C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of phenylmethyl 3,3-dimethyl-4-oxo-1-pyrrolidinecarboxylate (0.9135 g, 3.694 mmol) in MeOH (37 mL) was added sodium acetate (0.606 g, 7.387 mmol) and O-methylhydroxylamine hydrochloride (0.620 g, 7.397 mmol). The solution was stirred for 3 h, and then concentrated in vacuo. The residue was partitioned between DCM (100 mL), water (5 mL), and sat. aq. NaHCO3 (30 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide phenylmethyl (4Z)-3,3-dimethyl-4-[(methyloxy)imino]-1-pyrrolidinecarboxylate (0.9124 g, 89% yield) as a pale yellow oil. LCMS: (M+H)+: 277.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[S:12])=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[S:12])=[N:8][CH:9]=1
Reactant: COC(=S)Cc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=S)Cc1ccc(N)cn1
Yield: 55.5 %

Procedure:
A mixture of methyl 5-nitro-(pyrid-2-yl)-thioacetate (6.3 g, Reference Example 2) iron powder (12 g), ammonium chloride (1 g), ethanol (150 ml) and water (150 ml) was heated at reflux for 2 hours. The reaction mixture was cooled and then filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue was subjected to flash chromatography on silica gel eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound as a yellow oil (3.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:20]=[C:21]2[NH:27]C(=O)O[C:23](=[O:24])[C:22]2=[CH:29][CH:30]=1)([O-:18])=[O:17]>>[NH2:27][C:21]1[CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:30]=[CH:29][C:22]=1[C:23]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:24]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)Nc1cccc(OCc2ccccc2)c1
Yield: 75.1 %

Procedure:
Using the procedure described in Example 91, Part B, 3-benzyloxyaniline (4.4 mmol) and 4-nitroisatoic anhydride (4.8 mmol) yielded 1.2 g (81%) of the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34]CC4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[C:39](N)([CH3:42])([CH3:41])[CH3:40]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][C:39]([CH3:42])([CH3:41])[CH3:40])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)N
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Product: CC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using tert-butylamine instead of cyclopropylmethylamine. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: [OH:1][CH:2]1[CH2:25][CH2:24][C:5]2([C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1>[F:22][C:19]([F:20])([F:21])[C@H:18]([CH3:23])[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:4][CH2:3][C:2](=[O:1])[CH2:25][CH2:24]3)[C:9]2=[O:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1)C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: C[C@H](Oc1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of 8-hydroxy-2-[4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2-aza-spiro[4.5]decan-1-one (5.79 g) and 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) (506 mg) in CH2Cl2 (85 mL) was added a solution of potassium bromide (482 mg) in water (16 mL). Then, sodiumhypochlorite (13%, 42.5 mL) was added dropwise over a period of 10 minutes, followed by sodium bicarbonate (NaHCO3) (4.08 g). The mixture was stirred for 1.5 hours at RT. TLC showed a remainder of starting material. More TEMPO (125 mg) and sodiumhypochlorite solution (10 mL) were added and the mixture was stirred for an additional 2 hours at RT. The reaction was poured into ice/water and was extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the crude material was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to provide the title compound as a light brown solid (5.47 g). MS (m/e): 356.1 (MH+).
Reaction SMILES: CC(C)([O-])C.[Na+].[O:7]=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[NH:9]1.Cl[C:22]1[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[N:25]=[CH:24][N:23]=1>>[CH3:20][O:19][C:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([OH:7])=[C:16]2[C:22]1[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[N:25]=[CH:24][N:23]=1)=[O:18]
Reactant: Clc1ncnc2c1CCCC2
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COC(=O)c1ccc2[nH]c(O)c(-c3ncnc4c3CCCC4)c2c1

Procedure:
The title compound was synthesized according to the procedure described for Example 9 using sodium tert-butoxide (48 mg, 0.5 mmol), methyl 2-oxo-5-indolinecarboxylate (21 mg, 0.11 mmol) and 4-chloro-5,6,7,8-tetrahydroquinazoline solution (0.1 mL, 1 M in N-methylpyrrolidinone, corresponding to 17 mg, 0.1 mmol; described in: Budesinsky Z., Roubinek F. Collect. Czech. Chem. Commun., 1964, 29, 2341). The crude oil was purified on SCX-column pre-rinsed with methanol using ethyl acetate, methylene chloride, methylene chloride/methanol 1:1, and methanol/ammonia (2 M, aq) as elution solvents.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:20]([O-:22])=[O:21])[C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1ccc(Cl)c(C2CCCCC2)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)c(C2CCCCC2)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,4-dichloro-2-cyclohexylbenzene (12.0 g) in conc.sulfuric acid (15 ml) was added dropwise a mixture of nitric acid (d=1.42, 4 ml) and conc.sulfuric acid (6 ml) with stirring under ice-cooling. After the stirring was continued for 10 minutes, ice-water was added to the reaction mixture to give an oily residue, which was extracted with ether, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resultant oily residue was distilled under reduced pressure to give 1,4-dichloro-2-cyclohexyl-5-nitrobenzene (10.0 g).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12]([CH:15]=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([NH2:23])([CH2:21][OH:22])[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH3-]C#N.[Na+].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.[ClH:70]>CCO.CCOCC.O.C1(C)C=CC=CC=1>[ClH:70].[CH3:17][C:18]([NH:23][CH2:15][C:12]1[C:11]2[C:6]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=3[CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)([CH2:21][OH:22])[CH2:19][OH:20]
Reactant: CC(N)(CO)CO
Reactant: O=Cc1cc2ccccc2c2ccccc12
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: CC(CO)(CO)NCc1cc2ccccc2c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a 2 L Erlenmeyer flask was added 9-phenanthrenecarbaldehyde (Aldrich Chemical Co., Milwaukee, WI, 53201, 20.63 g, 0.1 mol), 2-methyl-2-amino-1,3-propanediol (Aldrich, 9.13 g, 86.8 mmol), p-toluenesulfonic acid.H2O (Eastman Kodak Co., Rochester, NY, 14650, 0.1 g, 0.5 mmol), and PhCH3 (500 mL). The mixture was warmed to reflux for a few minutes and H2O (2-3 mL) was driven off. The resulting golden colored solution was allowed to cool to RT, diluted with absolute EtOH (500 mL) and stirred overnight. NaBH3CN (Aldrich, 95%, 4.40 g, 70 mmol) was added to the reaction. After the NaBH3CN dissolved, an indicator (bromocresol green, Eastman, 5 mg) was added. To the resulting blue solution was added 5 drops of 1M solution of HCl gas in absolute EtOH every 15 minutes. After 3 days the indicator turned green then yellow and voluminous white precipitate was present in the flask. To the flask was then added 1M HCl gas (10 mL) in absolute EtOH. The reaction was diluted to 4 L with absolute ether and stirred for 1 h. The precipitate was then collected by filtration using a medium porosity glass fritted funnel and pressed dry. The filter cake was washed thoroughly with CH2Cl2 (4×500 mL), pressed, sucked dry, and dried overnight (100°). Recrystallization from EtOH/Et2O (3×) gave 11.84 g (36%) of 2-methyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediol hydrochloride mp 144°-146°, (C,H,Cl,N).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>CC(O)(C)C.CC(O)(C)C.CO>[C:12]([C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[CH2:15][C:14]([O:18][CH3:19])=[O:17])#[N:13]
Reactant: C=CC(=O)OC
Reactant: N#CCc1ccc2ccccc2c1
Solvent: CC(C)(C)O
Solvent: CO
Product: COC(=O)CCC(C#N)(CC(=O)OC)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
2-naphthylacetonitrile (3.45 g, 20.6 mmol) and methyl acrylate (9.7 ml, 107 mmol) were suspended in 2-methyl-2-propanol (10 ml). Heat was applied to the reaction vessel until the solution became clear. The mixture was cooled to room temperature, at which time (Bu)4NOH (6.9 mmol, 0.33 equiv.) was added as a solution in 2-methyl-2-propanol:methanol (1:2). The combined reaction mixture was heated to reflux for 4 h under vigorous stirring at which time the reaction appeared complete by GC-MS. After allowing the reaction to cool the mixture was partitioned between H2O (75 ml) and EtOAc (50 ml). The aqueous layer was removed and washed with EtOAc (2×50 ml). The combined organic phases were washed with NaHCO3 (sat. aq.) and brine and dried over MgSO4. After filtration the solvent was removed in vacuo. The crude product was purified by flash column chromatography (25% EtOAc in hexanes) to isolate the title compound as a light yellow oil (5.75 g, 82%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:25][CH3:26])[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:3]=1.[F:37][C:38]1[CH:39]=[C:40]([CH:58]=[C:59]([F:61])[CH:60]=1)[CH2:41][N:42]1[C:46]([CH3:47])=[C:45](B2OC(C)(C)C(C)(C)O2)[C:44]([CH3:57])=[N:43]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:37][C:38]1[CH:39]=[C:40]([CH:58]=[C:59]([F:61])[CH:60]=1)[CH2:41][N:42]1[C:46]([CH3:47])=[C:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:25][CH3:26])[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:3]=2)[C:44]([CH3:57])=[N:43]1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)cc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(C)C
Yield: 86.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl (5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)carbamate (intermediate 66B) (200 mg, 0.322 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (169 mg, 0.483 mmol) using Pd(dppf)Cl2 (12 mg, 0.016 mol) and sodium carbonate (103 mg, 0.967 mmol) in toluene/ethanol/water (5/2/1 ml) to afford 200 mg (86.9% yield) of the titled compound after column purification using 2% methanol in DCM as eluent. MS: m/z=615.2 (M-Boc+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CS(C)=O.Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[N:3]=2)=[CH:14][CH:13]=1
Reactant: COc1nccc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CS(C)=O
Product: O=c1nc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Temperature: 95 °C
Reaction time: 20 h
Yield: 22.2 %

Procedure:
A suspension of 4-chloro-2-methoxypyrimidine (500 mg, 3.47 mmol), 4-(trifluoromethyl)phenylboronic acid (788 mg, 4.17 mmol), PdCl2(dppf) (283 mg, 0.347 mmol) and K2CO3 (958 mg, 6.94 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 95° C. for 20 h. The suspension was cooled, H2O was added and the suspension was filtered to afford a light colored solid. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. The white solid was diluted with concentrated HCl solution (10 mL) and stirred at reflux for 4 h. The reaction was cooled, and the solution was neutralized with saturated NaHCO3 solution. The resulting suspension was filtered to afford 185 mg (22%) of the title compound as a white solid: ESI MS m/z 241 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([OH:33])([CH3:32])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27](Cl)[CH:26]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.NC1C(C2C=CC([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=CC=2)=NC(Br)=C(C(F)(F)F)N=1>>[CH:1]1([C:4]([OH:33])([CH3:32])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:11]([C:25]3[CH:30]=[CH:29][C:28]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[CH:27][CH:26]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Nc1ccc(-c2nc(Br)c(C(F)(F)F)nc2N)cc1
Reactant: CC(O)(CNC(=O)c1nc(-c2cccc(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Product: CC(O)(CNC(=O)c1nc(-c2ccc(NS(C)(=O)=O)cc2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
This compound was prepared in analogy to example 5 (6-(3-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide) by substituting 5-bromo-3-(3-chloro-phenyl)-6-trifluoromethyl-pyrazin-2-ylamine by N-[4-(3-amino-6-bromo-5-trifluoromethyl-pyrazin-2-yl)-phenyl]-methanesulfonamide.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[N:7][N:6]=[C:5]1[CH:19]([OH:21])[CH3:20].CN(C=O)C.Cl[C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][N:29]=1>C(Cl)(Cl)Cl.O>[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:16])([F:18])[F:17])=[N:7][N:6]=[C:5]1[CH:19]([O:21][C:28]1[N:29]=[CH:30][CH:31]=[CH:32][C:33]=1[C:34]#[N:35])[CH3:20]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(O)c1nnc(-c2ccccc2C(F)(F)F)n1C
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ncccc1C#N)c1nnc(-c2ccccc2C(F)(F)F)n1C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
Sodium hydride (53 mg) was added to a mixture of 1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethanol (300 mg) and DMF (10 ml) at room temperature, followed by stirring for 10 minutes, and 2-chloro-3-cyanopyridine (153 mg) was added thereto, followed by stirring at room temperature for 13 hours. Water and chloroform were added to the reaction solution, followed by separation operation, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain, as a light yellow amorphous product, 2-(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)nicotinonitrile (306 mg).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1
Reactant: CCOC(=O)c1cc(O)n2nc(-c3ccc(OC)cc3)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Cl)n2nc(-c3ccc(OC)cc3)cc2n1
Temperature: 115 °C
Yield: 60.4 %

Procedure:
Ethyl 7-hydroxy-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (1.26 g; 4.03 mmol) was suspended in phosphoryl chloride (8 mL; 88 mmol) and the mixture was heated to 115° C. for 1 h. The reaction mixture was allowed to cool to room temperature and then carefully quenched into a cold mixture of methylene chloride and saturated sodium bicarbonate. The basic aqueous layer was back extracted once with methylene chloride and the combined organic phases were washed with brine. Concentration afforded a crude solid which was triturated in methanol (15 mL) at 60° C. for 5 min. and then at room temperature for an hour. Filtration afforded 808 mg (60%) of the title compound. LCMS m/z 332.1 (M+H)+, ret. time=2.77 min.