Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:3]=1[CH:4]1[CH:9]([C:10]2=[O:16])[CH2:8][CH2:7][CH2:6][CH2:5]1.C(OC(=O)C)(=O)C.[CH3:24][N:25]([CH2:27]N(C)C)[CH3:26].[Cl-].[Na+]>>[CH3:24][N:25]([CH2:27][C:13]1[C:12]([OH:15])=[C:11]2[C:3]([CH:4]3[CH:9]([C:10]2=[O:16])[CH2:8][CH2:7][CH2:6][CH2:5]3)=[C:2]([CH3:1])[CH:14]=1)[CH3:26]
Reactant: CN(C)CN(C)C
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(CN(C)C)c(O)c2c1C1CCCCC1C2=O
Temperature: 90 °C

Procedure:
A mixture of 25 g of 5-methyl-8-hydroxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone, 62.5 ml of acetic anhydride and 18.88 ml of bisdimethylaminomethane was stirred with heating at 90° C. for 2 hours. The reaction mixture was left to stand for cooling and then to the reaction mixture was added saturated aqueous sodium chloride solution, followed by extraction with dichloromethane. The organic layer was dried with magnesium sulfate and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) to obtain 14.37 g of 7-dimethylaminomethyl-8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]Br>CN(C)C=O>[Br-:20].[Br-:20].[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: [Br-]

Procedure:
To a solution of 9.13 g (0.035 mole) of triphenylphosphine in 70 ml of dimethylformamide at 5°-10° C. was slowly added 1.93 ml (0.035 mole) of bromine to form triphenylphosphine dibromide. The yellow-orange mixture was then treated with 1.91 g (0.01 mole) of 2,4-diamino-6-hydroxymethylpyrido[2,3-d]pyrimidine at 10° C. The mixture was stirred for 45 minutes at ambient temperature. The red solution was cooled to 10° C., treated with 1 ml of ethanol (dropwise) and stirred for an hour at ambient temperature. The solution was concentrated to a volume of 10 ml in vacuo and washed thrice with 90-ml portions of warm (40° C.) benzene. The residual liquid was treated with 30 ml of hot acetic acid. The hot solution was filtered and the filtrate chilled to afford 2.44 g of crystalline precipitate; UV λ pH 1 248 nm (ε 20, 200), 320 (8,780), 333 (7,030); λ pH 13 270 (11,050), 342 (6,300 ). Calc'd for C8H8N5Br.HBr: C, 28.7; H, 2.7; N, 20.9; Br, 47.7. Found: C, 28.9; H, 2.85; N, 21.1; Br, 47.4.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:12]([NH:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:13])[CH2:10][OH:11])=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])C(O)=O.FC(F)(F)C(OCC)=O>C(N(CC)CC)C>[F:21][C:22]([F:27])([F:26])[C:6]([NH:8][C@H:9]([C:12]([NH:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:13])[CH2:10][OH:11])=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)NCc1nccs1
Reactant: O=C(O)C(F)(F)F
Agent: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(NCc1nccs1)[C@H](CO)NC(=O)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A 1.540 g portion of 2-[(N-tert-butoxycarbonyl-L-seryl)amino]methylthiazole and 15 ml of trifluoroacetic acid were added, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure. To the solution of (L-seryl)aminomethylthiazole trifluoroacetatate salt thus obtained in 50 ml of methylene chloride were added with stirring 2.73 g of triethylamine and 3.84 g of ethyl trifluoroacetate. The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure and subjected to flash column chromatography on silica gel (eluted with ethyl acetate) to give 1.519 g of 2-[(N-trifluoroacetyl-L-seryl)amino]methylthiazole. Quantitative yield. NMR (CDCl3) δ: 1.5-1.75 (1H, br), 3.69 (1H, dd, J=11.5 Hz, 6.7 Hz), 4.18 (1H, dd, J=11.5 Hz, 3.5 Hz), 4.58 (1H, td, J=11.5 Hz, 3.5 Hz), 4.75 (1H, dd, J=16.7 Hz, 5.5 Hz), 4.96 (1H, dd, J=16.7 Hz, 6.9 Hz), 7.01-7.07 (1H, br), 7.31 (1H, d, J=3.3 Hz), 7.60-7.70 (1H, br), 7.68 (1H, d, J=3.3 Hz).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[CH3:18][N:19]=[C:20]=[O:21]>C1C=CC=CC=1>[CH3:18][NH:19][C:20]([N:8]1[CH2:9][CH2:10][CH2:11][CH:6]([N:5]2[C:4](=[O:12])[C:3]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]3[C:1]2=[O:17])[CH2:7]1)=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1C1CCCNC1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CCCC(N2C(=O)c3ccccc3C2=O)C1

Procedure:
A mixture of 11.5 g. of 3-phthalimidopiperidine and 2.85 g. of methyl isocyanate in 100 ml. of dry benzene is stirred at 25° C. for 2 hours. The resulting mixture is concentrated in vacuo and filtered to give 1-(N-methylcarbamoyl)-3 -phthalimidopiperidine. Treating this phthalimidopiperidine with hydrazine hydrate by the procedure of Example 17 gives 1-(N-methylcarbamoyl)-3-aminopiperidine.
Reaction SMILES: CC([NH:9][S:10](/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:12])=[O:11])(C)CC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15](/[CH:14]=[CH:13]/[S:10]([NH2:9])(=[O:11])=[O:12])[CH:16]=1
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)/C=C/c1cccnc1
Yield: 72.8 %

Procedure:
(E)-2-pyridin-3-yl-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (3.63 g, 12.3 mmol) was stirred for 3 hours in a 1:1 mixture of trifluoroacetic acid and dichloromethane (40 mL). The solvent was concentrated in vacuo to afford a yellow oil. The oil was dissolved in dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL), dried over MgSO4, filtered and concentrated in vacuo to afford (E)-2-pyridin-3-yl-ethenesulfonic acid amide as a pale yellow solid (1.65 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:25])[CH2:18][N:19]4[CH:23]=[C:22](I)[CH:21]=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].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].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.[Fe+2]>[C:26]([C:22]1[CH:21]=[N:20][N:19]([CH2:18][C:17]([N:12]2[CH2:13][CH2:14][CH2:15][C:16]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]2=3)=[O:25])[CH:23]=1)#[N:27]
Reactant: CN(C)C=O
Reactant: O=C(Cn1cc(I)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Temperature: 90 °C
Yield: 68 %

Procedure:
A mixture of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-(4-iodopyrazol-1-yl)ethanone (0.388 g, 0.86 mmol), Zn(CN)2 (0.151 g, 1.29 mmol), Pd2(dba)3 (0.079 g, 0.086 mmol) and dppf (0.072 g, 0.13 mmol) in DMF (10 mL) was heated at 90° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (10 mL) and sat. NaHCO3 (50 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography with a gradient elution of 0-100% EtOAc/CH2Cl2 to afford 2-(4-cyanopyrazol-1-yl)-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (0.205 g, 68%).
Reaction SMILES: C[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][CH:9]=1)=[C:3]([CH3:7])[C:4]([OH:6])=[O:5].[OH-].[K+].Cl>CO>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:2]=[C:3]([CH3:7])[C:4]([OH:6])=[O:5])=[CH:13][CH:12]=1
Reactant: CC(C(=O)O)=C(C)c1ccc(OCCCCO)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=Cc1ccc(OCCCCO)cc1)C(=O)O
Yield: 57.2 %

Procedure:
In a 300 ml three neck distillation flask, the compound prepared above in (7b) (13.6 g, 48.9 mmol) and methanol (50 ml) were placed. To the flask, aqueous solution (30 ml) of potassium hydroxide (5.5 g, 98 mmol) was dropwise added. After the mixture was refluxed for 2 hours, dilute hydrochloric acid was added to precipitate crystalline product. The product was collected by filtration, and recrystallized from acetonitrile to obtain the titled compounds (7.0 g, yield: 57%).
Reaction SMILES: O=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH2:5][O:4][CH2:3]1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[C:19]1([CH2:18][NH:17][CH2:15][C@H:6]2[CH2:5][O:4][CH2:3][CH2:2][N:7]2[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(NCc1ccccc1)[C@H]1COCC(=O)N1Cc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(CNC[C@H]2COCCN2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of (3R)-5-oxo-N,4-bis(phenylmethyl)-3-morpholinecarboxamide (assumed 96.07 g, 296.2 mmol) in PhMe (750 mL) was added Red-Al (65% w/w in PhMe, 645 mL) via addition funnel. After approximately 50 mL of Re-Al had been added, the resulting mixture was warmed to room temperature, and the remainder of the Red-Al was then added over 30 min. The mixture was then heated at 50° C. and stirred overnight. The solution was cooled to 0° C., and the reaction was quenched by the slow dropwise addition of 1 N aqueous NaOH (50 mL). An additional portion of 1 N aqueous NaOH (500 mL) was then added, followed by Et2O (200 mL). The phases were separated, and the organic phase was washed with fresh 1 N aqueous NaOH (400 mL). The combined aqueous phase was extracted with fresh 4:1 PhMe-Et2O (250 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1-phenyl-N-{[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine as a yellow oil that was used without further purification. LCMS: (M+H)+: 297.1.
Reaction SMILES: [CH3:1][CH:2]([C:4]([CH3:8])([OH:7])[CH2:5][CH3:6])[CH3:3].C[Li].Cl[C:12]([O:14][CH2:15][C:16](=[CH2:18])[CH3:17])=[O:13].O>O1CCCC1.C(OCC)C>[C:12](=[O:13])([O:14][CH2:15][C:16](=[CH2:17])[CH3:18])[O:7][C:4]([CH3:8])([CH2:5][CH3:6])[CH:2]([CH3:3])[CH3:1]
Reactant: C=C(C)COC(=O)Cl
Reactant: CCC(C)(O)C(C)C
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=C(C)COC(=O)OC(C)(CC)C(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a solution of 13.94 grams (0.12 mole) of 2,3-dimethylpentan-3-ol in 75 milliliters of anhydrous tetrahydrofuran at 0° C under a nitrogen atmosphere was added with stirring one equivalent of methyllithium in diethyl ether. Then 19.31 grams (0.14 mole) of methallyl chloroformate in 25 milliliters of anhydrous tetrahydrofuran was added. During additions the temperature was maintained at 0° C. Cooling was discontinued and the reaction mixture was stirred for about 18 hours. The reaction mixture was poured into water, and then extracted with ether. The ether layer was separated and washed with water, and then dried over magnesium sulfate. Removal of solvent under reduced pressure yielded 24.32 grams (94.6%) of a yellow oil. A pure sample was obtained by vacuum distillation (Fraction 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]3)(=[O:13])=[O:12])[CH2:6][CH2:5]2.[N:24]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36]([CH:41]=O)=[CH:35]3)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]3=[CH:41][C:36]1[NH:37][C:38]3[C:34]([CH:35]=1)=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:40][CH:39]=3)(=[O:12])=[O:13])[CH2:6][CH2:5]2
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4cc(Br)ccc43)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4cc(Br)ccc43)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
5-(5-Bromo-2,3-dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]([S:8][C:9]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:7]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:11](=[O:13])[C:10]3[C:9](=[CH:17][CH:16]=[C:15]([O:18][CH3:19])[CH:14]=3)[S:8][C:6]=2[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2sc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Reaction time: 8 h

Procedure:
The requisite 1-chloro-7-methoxy-4-nitrothioxanthone was prepared as follows: A mixture of 118.5 g (0.35 mole) of 2-(5-chloro-2-nitrophenylthio)-5-methoxybenzoic acid and 131 ml of thionyl chloride in 600 ml of toluene was heated under reflux for 1.5 hours. The mixture was concentrated in vacuo, and the resulting solid was dissolved in 950 ml of nitrobenzene with heating and then cooled to 0° in an ice bath. Aluminum chloride (44.2 g) was added in portions over 0.5 hour with cooling, and the mixture was then allowed to come to room temperature and stirred overnight. The mixture was poured into 5 l of cold water. As much of the water layer as possible was decanted. The residue was triturated twice with 1 l portions of methanol and then twice with 2 l portions of methanol. The oil was triturated with 4 l of methanol and a solid resulted. This was washed with methanol and dried in vacuo at 75° to give 72.7 g of the product as a brownish-yellow solid, mp 235°-240°.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1NC.I/C=C/CCCC>[Cu]I.C1(C)C=CC=CC=1>[CH:25](/[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: NC(=O)c1ccccc1
Agent: [Cu]I
Agent: CCCC/C=C/I
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCC/C=C/NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 675.2 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), benzamide (145 mg, 1.20 mmol), K3PO4 (430 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %), trans-1-iodo-1-hexene (143 μL, 1.00 mmol), and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 25° C. for 24 h. The resulting light blue suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated, the residue was dissolved in 5 mL of dichloromethane and purified by flash chromatography on silica gel (2×15 cm, hexane-ethyl acetate, 15 mL fractions). Fractions 12–19 provided 140 mg (69% yield) of the desired product as white needles.
Reaction SMILES: B1([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(C)C=CC=CC=1.[CH2:50]([O:57][C:58]1[CH:73]=[C:72](Cl)[CH:71]=[CH:70][C:59]=1[C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)(O)[O-].[Na+]>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(OCC)(=O)C.O1CCOCC1>[CH2:50]([O:57][C:58]1[CH:73]=[C:72]([B:10]2[O:11][C:12]([CH3:17])([CH3:18])[C:13]([CH3:15])([CH3:16])[O:14]2)[CH:71]=[CH:70][C:59]=1[C:60]([O:62][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)=[O:61])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(Cl)cc1OCc1ccccc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bis(pinacolato)diboron (0.41 g), potassium acetate (0.25 g), tris(dibenzylideneacetone)dipalladium(0) (46 mg), and a 15% tricyclohexylphosphine-toluene solution (0.25 mL) were added to a dioxane (3.5 mL) solution of benzyl 2-(benzyloxy)-4-chlorobenzoate (0.35 g), followed by stirring under a nitrogen atmosphere at room temperature for 30 minutes and then at 80° C. for 5 hours and 30 minutes. After cooling the reaction mixture to room temperature, tris(dibenzylideneacetone)dipalladium(0) (46 mg) and a 15% tricyclohexylphosphine-toluene solution (0.25 mL) were added thereto, followed by stirring under a nitrogen atmosphere at 90° C. for 8 hours. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-75% hexane/ethyl acetate] to obtain benzyl 2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:9]2[C:4]([CH2:5][N:6]([C:17]([O:19]C(C)(C)C)=O)[CH2:7][CH2:8]2)=[N:3]1.Cl.O1CCOCC1.[Cl:31][C:32]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:33]=1C(O)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CO>[Cl:31][C:32]1[C:40]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:38]=[CH:37][C:33]=1[C:17]([N:6]1[CH2:7][CH2:8][C:9]2=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:2]([CH3:1])[N:3]=[C:4]2[CH2:5]1)=[O:19]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: Cn1nc2c(c1-c1ccccn1)CCN(C(=O)OC(C)(C)C)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1nc2c(c1-c1ccccn1)CCN(C(=O)c1cccc(C(F)(F)F)c1Cl)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-methyl-3-(pyridin-2-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (135 mg, 0.429 mmol) in CH2Cl2 (5 mL) was added 4 M HCl in dioxane (0.43 mL, 1.72 mmol). The reaction was allowed to stir at rt for 1 h, then 1 mL MeOH was added and the reaction was stirred overnight. The reaction was concentrated to a yellow gum. It was combined with 2-chloro-3-(trifluoromethyl)benzoic acid (155 mg, 0.690 mmol), BOP (305 mg, 0.690 mmol) and triethylamine (0.37 mL, 2.65 mmol). After stirring overnight at rt, the reaction was filtered and purified by HPLC (Agilent prep system, Waters XBridge C18 5 μm 50×100 mm column, 5-99% MeOH/20 nM NH4OH over 18 min at 80 mL/min). The desired product was isolated as a white solid (56 mg, 31%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]#[CH:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:26])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]#[CH:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:26])=[O:7])#[N:2]
Reactant: C#Cc1cc(C(=O)O)cc(C#N)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#Cc1cc(C(=O)Cl)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 3-cyano-5-ethynyl-4-methoxybenzoic acid (610 mg), toluene (6 mL), N,N-dimethylformamide (1 droplet) and oxalyl chloride (0.32 mL) were added to the solution under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (c).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][Mg]Cl>>[F:11][C:12]1[CH:13]=[C:14]([CH2:15][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Fc1cccc(C[Mg]Cl)c1
Product: O=C(CCC1CCC(=O)N1)Cc1cccc(F)c1
Yield: 62.3 %

Procedure:
Analogous to the procedure described for Compound 1A, Step A, tetrahydro-pyrrolizine-3,5-dione (2 g, 14 mmol) was reacted with 3-fluorobenzylmagnesium chloride (0.25M in Et2O, 62 mL, 15.5 mmol) over 2.5 h. Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to 2:1 EtOAc:hexanes to EtOAc to 2% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) provided 5-[4-(3-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.1730 g). 1 H NMR (CDCl3) δ 7.32-7.27 (m, 1H), 7.00-6.90 (m, 3H), 6.12 (bs, 1H), 3.69 (s, 2H), 3.59 (m, 1H), 2.52 (t, 2H), 2.30 (m, 2H), 2.19 (m, 1H), 1.75 (m, 2H), 1.65 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2N=N[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1.[CH:28](N1CCCC1)=[CH2:29]>C(Cl)(Cl)Cl>[C:20]1([C:10]2[N:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:29]=[CH:28][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=CN1CCCC1
Reactant: CCOC(=O)c1nnc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure D, ethyl 6-(4-trifluoromethylphenyl)-5-phenyl-1,2,4-triazine-3-carboxylate (Compound 15), (378 mg, 1.01 mmol) and crude 1-vinylpyrrolidine (Compound 38, 780 mg) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O>O1CCCC1>[Br:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Solvent: C1CCOC1
Product: CCc1sc(C(=O)OC)cc1-c1c(Br)cnn1C
Yield: 88.7 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1 g, 3.99 mmol)[prepared in Example 98] and N-bromosuccinimide (0.711 g, 3.99 mmol) in tetrahydrofuran (8 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (10-50% EtOAc in hexanes yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (1.2 g, 3.54 mmol, 89% yield) as an orange oil: LCMS (ES) m/e 329, 331 (M, M+2)+.