Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[N:5]1)#[N:2].[H-].[Na+].[CH3:19][N:20]1[C:24]([Cl:25])=[C:23]([C:26](N2C=CC=N2)=[O:27])[C:22]([Cl:33])=[N:21]1.O>C1COCC1>[F:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([F:16])[C:9]=1[C:6]1[CH:7]=[CH:8][N:4]([C:3](=[C:26]([C:23]2[C:22]([Cl:33])=[N:21][N:20]([CH3:19])[C:24]=2[Cl:25])[OH:27])[C:1]#[N:2])[N:5]=1
Reactant: Cn1nc(Cl)c(C(=O)n2cccn2)c1Cl
Reactant: N#CCn1ccc(-c2c(F)cccc2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(Cl)c(C(O)=C(C#N)n2ccc(-c3c(F)cccc3F)n2)c1Cl
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A solution of 0.5 g of 1-cyanomethyl-3-(2,6-difluorophenyl)pyrazole dissolved in 10 ml of THF was dropwise added to a suspension of 0.15 g of 55% sodium hydride in 10 ml of THF, at 50° C. After the resulting product was stirred for 30 minutes, a solution of 0.67 g of 1-(1-methyl-3, 5-dichloropyrazole-4-carbonyl)pyrazole dissolved in 10 ml of THF was dropwise added thereto at 50° C. and then stirred overnight at room temperature. The reaction mixture was poured into water, then extracted with ethyl acetate and washed with a small amount of water. The resulting product was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was recrystallized from a mixed solvent of isopropyl ether/ethyl acetate=3/1 to obtain 0.52 g of 2-{3-(2,6-difluorophenyl)pyrazol-1-yl}-3-(l-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=4[O:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29].Cl[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][O:25][C:23]1[CH:22]=[CH:21][C:20]2[N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:28][CH3:29])[CH:4]=4)[CH2:13][CH2:12]3)=[O:27])[C:17](=[O:26])[O:18][C:19]=2[CH:24]=1)[CH3:36]
Reactant: CCOC(=O)CCl
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(O)ccc43)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)oc(=O)n2CC(=O)N1CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (44) (300 mg, 0.72 mmol, 1 eq), ethyl chloroacetate (132 mg, 1.08 mmol, 1.5 eq), cesium carbonate (467 mg, 1.43 mmol, 2 eq) in DMF (2 ml) was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and purified by flash chromatography to provide (3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid ethyl ester (45).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH:16]=O.CO[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)C(OC)=C[C:21]=1/[CH:32]=[C:33](\C)/[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:33](\[CH2:32][CH2:21][CH2:20][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])/[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COc1c(C)c(C=O)c(OC)c2ccccc12
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Product: CCCCCCCCC/C(=C\c1c(C)c(OC)c2ccccc2c1OC)C(=O)OCC

Procedure:
Compound 98c was prepared from 34 (0.479 g, 2.08 mmol) as described above for 28a to give 0.373 g (0.874 mmol, 41%) of the product as a yellow oil following flash chromatography (1:9 EtOAc:hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([O:20]C)=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.O.[OH-].[Li+].C1COCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([OH:20])=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: COC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1nc2n(c1C(=O)O)CCOc1ccc(Br)cc1-2
Yield: 88 %

Procedure:
10-Bromo-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (5 g) was subjected similar to as described in Example 6 to yield 4.2 g of methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate. Methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (0.52 g) was subjected to lithium hydroxide water/THF to give 0.44 g of 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid. 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.44 g) was reacted with Methylamine hydrochloride similar to as described in Example 2 to afford 314 mg 10-bromo-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following triteration from water. 10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.1 g) was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 43.9 mg of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 436 (M)+. 1H NMR (400 MHz, DMSO) δ 11.06 (q, J=4.3 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.40 (dd, J=8.5, 2.0 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.47 (s, 1H), 6.36 (s, 1H), 5.04-4.91 (m, 2H), 4.57-4.44 (m, 2H), 2.81 (d, J=4.5 Hz, 3H), 2.41 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[N:11]([C:12]([C:14]2[N:15]=[C:16]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)[CH:18]=2)=[O:13])[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([O:4][CH2:5][C@H:6]1[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[C:12]([C:14]1[N:15]=[C:16]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=2)[CH:18]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1cccc(-n2cc(C(=O)N3CCNC[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Reaction time: 2 h

Procedure:
((2R)-1-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl-1H-imidazol-4-yl]carbonyl}piperazin-2-yl)methyl acetate To 350 mg (0.330 mmol) of 10% palladium on carbon was added a solution of 3.55 g (5.95 mmol) of benzyl (3R)-3-[(acetyloxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate from Step C in 50 mL of anhydrous methanol. The resulting suspension was agitated under an atmosphere of hydrogen at 40 psi for 2 hours then filtered through a plug of Celite®. The plug was washed with methanol (75 mL), and the combined filtrates were concentrated in vacuo to yield the title compound as a colorless foam, which was used without further purification. 1H NMR (DMSO-d6): δ 7.85 (s, 1 H), 7.33 (t, J=8.2 Hz, 1 H), 7.21 (d, J=8.5 Hz, 2 H), 7.13 (d, J=8.5 Hz, 2 H), 6.98-7.00 (m, 1 H), 6.92 (s, 1 H), 6.77-6.79 (m, 1 H), 4.68-5.81 (m, 2 H), 4.18-4.59 (m, 3 H), 4.00 (q, J=6.8 Hz, 2 H), 2.72-3.02 (m, 4 H), 2.57-2.62 (m, 1 H), 2.27 (s, 3 H), 1.78-2.00 (m, 3 H), 1.27 (t, J=6.8 Hz, 3 H). LC/MS 463.5 (M+1).
Reaction SMILES: [CH3:1][C:2]12[C:13]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:12]=3[CH2:11][CH:9]([NH:10]1)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CN([CH:25]=[O:26])C.O>[Cu].CCOCC>[CH3:1][C:2]12[C:13]3[CH:14]=[C:15]([O:26][CH3:25])[CH:16]=[CH:17][C:12]=3[CH2:11][CH:9]([NH:10]1)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC12NC(Cc3ccc(Br)cc31)c1ccccc12
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)C1(C)NC(C2)c2ccccc21

Procedure:
A mixture of 0.00905 mol of 3-bromo-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, 0.181 mol of sodium methoxide, 5.56 g of electrolytic copper dust, and 87 ml of DMF is stirred and heated on a steam bath for 2.5 hours. After cooling, 150 ml of water and 150 ml of ether is added to the mixture, and, after stirring, the mixture is filtered through a pad of celite. The ether phase is separated, washed with water, dried over magnesium sulfate, filtered, and the ether is removed on a rotary evaporator. The residue is dissolved in warm acetonitrile. On standing, the solution deposits crystals. The supernatant, containing the desired product, is decanted from the crystals. Evaporation of the solvent gives 3-methoxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]1([CH2:19][NH2:20])[CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH2:19][CH:16]2[CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: NCC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)cc1C(F)(F)F
Yield: 90.6 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and cyclopropylmethylamine (0.34 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethyl)-benzenesulfonamide (0.50 g, 91%) was provided after purification. MS (ESI) m/z 358. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® 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: I[CH2:2][CH2:3][CH3:4].[CH:5]1([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH:5]1([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH3:4])[CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1
Reactant: CCCI
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCCNCC3)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCN1CCCN(c2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Iodopropane (0.039 ml) was added to a stirred mixture of N-cyclopropyl-3-[6-(1,4-diazepan-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzamide (0.150 g) and potassium carbonate (0.199 g) in DMA (0.50 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 ml), the resulting solid was filtered and dried (magnesium sulphate) under vacuum at 40° C. There was thus obtained the title compound (0.098 g); NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.68 (m, 2H), 0.80 (t, 3H), 1.39 (m, 2H), 1.87 (m, 2H), 2.11 (s, 3H), 2.36 (t, 2H), 2.49 (m, 2H), 2.72 (m, 2H), 2.84 (m, 1H), 3.56 (m, 4H), 7.23 (d, 1H), 7.36 (d, 1H), 7.50 (d, 1H), 7.58 (d, 1H), 7.79 (s, 1H), 7.87 (d, 1H), 7.95 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:29]>C(O)C>[NH2:29]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)=[O:6]
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: N
Solvent: CCO
Product: C/C(N)=C/C(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
To a solution of 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate (3.21 g) in ethanol (5 ml), 20% ethanolic ammonia (15 ml) was added, and the mixture was allowed to stand in a refrigerator overnight. The solvent and ammonia were distilled off to give crude 2-(4-benzhydryl-1-piperazinyl)ethyl 3-aminocrotonate as an oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.O[NH:9][C:10](=[NH:19])[C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1>CN(C=O)C>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[N:9]=[C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[O:7][N:19]=2)=[CH:16][CH:15]=1
Reactant: CSc1ccc(C(=N)NO)cc1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: CSc1ccc(-c2noc(CCC(=O)O)n2)cc1
Temperature: 120 °C

Procedure:
Succinic anhydride (112 mg, 1.12 mmol) and N-hydroxy-4-methylsulfanyl-benzamidine (203 mg, 1.12 mmol) were dissolved in 2.0 mL of DMF and heated at 120° C. overnight. The cooled solution was evaporated and dried to give 3-[3-(4-methylsulfanyl-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid which was used without further purification.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1>CO.O=[Pt]=O>[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NCc1cccnc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCCNC1
Reaction time: 16 h
Yield: 93.5 %

Procedure:
A cold solution of HCl in MeOH (prepared by adding acetyl chloride (13.5 mL, 14.9 g, 0.19 mol) to 1 L of MeOH) was added to a cold solution of tert-butyl pyridin-3-ylmethylcarbamate (41.0 grams, 0.20 mol) in MeOH (100 mL). The solution was transferred to a Parr hydrogenation apparatus at 12° C. PtO2 (3 g) was added, and 12 bar pressure of H2 was applied. After 16 hours 1H NMR of a concentrated sample indicated the reaction to be complete. The catalyst was filtered, and conc. aq. NaOH (20 mL) was added to neutralize the HCl. The solution was concentrated to remove the bulk of the MeOH and extracted with tert-butyl methyl ether (4×200 mL). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated to give the product (40.16 g, 0.187 mol, 95%) as a yellow oil that crystallized upon standing. 1H NMR (300 MHz, CDCl3): δ 4.62 (bs. s, 1H), 3.06-2.94 (m, 4H), 2.52 (dt, J=12 Hz, 3 Hz, 1H), 2.28 (dd, J=12 Hz, 10 Hz, 1H), 1.82-1.72 (m, 1H), 1.70-1.51 (m, 3H), 1.49-1.34 (m, 1H), 1.42 (s, 9H), 1.06 (dq, J=12 Hz, 4 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[C:32]([O:34][CH3:35])=[O:33].[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:48][CH3:49])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:48][CH3:49])[C:45]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C@H:24]1[C:32]([O:34][CH3:35])=[O:33])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)C1Cc2ccccc2N1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OC
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Triethylamine (3.15 ml) and bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (5.75 g, 22.6 mmol) were added to a solution of methyl indoline-2-carboxylate (2 g, 11.3 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (2.6 g, 13.6 mmol) in methylene chloride (15 ml), at 0° C. under nitrogen. The reaction was stirred for 2 h at 5° C. and then at room temperature overnight. The mixture was filtered, the filtrate was washed with water (2×40 ml) and the combined aqueous fractions were extracted with methylene chloride. The combined organic fractions were dried and concentrated to give a residue, which was purified by chromatography on a column of silica gel, using a 7/3 petroleum ether/ethyl acetate mixture as eluent. The product was obtained in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:38])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=3)[CH2:25][CH2:24]2)[CH:18]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C)C=O>[C:12]([O:11][C:9]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:38])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[C:37][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:31]=3)[CH2:25][CH2:24]2)[CH:18]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: Ic1ccccc1
Reactant: C#Cc1cccc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cccc(C#Cc4ccccc4)c3)CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A mixture of N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-ethynyl-benzoyl)-piperidin-4-yl]-benzylamine (0.24 g, 0.46 mmol), iodobenzene (95 mg, 0.46 mmol), dichlorobis(triphenylphosphine)palladium (II) (35 mg, 0.05 mmol), copper (I) iodide (26 mg, 0.14 mmol), triethylamine (0.57 ml, 4.1 mmol) and anhydrous dimethylformamide (8 ml) was stirred at ambient temperature under nitrogen for 18 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (3 lots of 50 ml) and water (20 ml). The combined organic layers were washed with brine (50 ml), then dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (3:2, v/v) to give N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-phenylethynyl-benzoyl)-piperidin-4-yl]-benzylamine as a yellow oil (0.23 g). 1H NMR (CDCl3, 500 MHz): δ 7.58 (m, 4H), 7.40 (m, 5H), 7.25 (m, (m, 1H), 7.10 (m, 3H), 4.90 (br m, 1H), 4.79 (s, 2H), 3.80 (br m, 1H), 3.15 (br m, 1H), 2.84 (br, m, 1H), 2.78 (br m, 1H), 1.95 (m, 1H), 1.80 (m, 3H), 1.42 (s, 18H). MS(EI): 617(M++Na).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](B1OC(C)(C)C(C)(C)O1)[CH:27]=[CH2:28]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:27]=[CH2:26]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1sc2c(c1Br)c(=O)n(C)c(=O)n2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1c(C(=O)OCC)sc2c1c(=O)n(C)c(=O)n2C

Procedure:
To a stirred solution of Step 5 intermediate (24.5 g, 70.60 mmol) in dry THF (350 ml) was added cesium carbonate (46.0 g, 141.20 mmol) and allyl boronic acid pinacol ester (23.8 ml, 127.08 mmol) under nitrogen atmosphere and the mixture was degassed for 10 min. Tetrakis(triphenylphosphine)palladium(0) (8.1 g, 7.06 mmol) was added and the reaction was refluxed for 24 h under nitrogen atmosphere. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were concentrated and the residue obtained was purified by silica gel column chromatography using 5% ethyl acetate in pet ether to give 4.62 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=7.2 Hz, 3H), 3.41 (s, 3H), 3.56 (s, 3H), 4.18-4.24 (m, 2H), 4.31-4.40 (m, 2H), 4.99-5.15 (m, 2H), 5.95-6.03 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N-]C(NC(OC(C)(C)C)=O)CCCCCCCCCCC)(=O)[CH3:26]>C(Cl)(Cl)Cl.CO>[OH:12][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCCCCCC([N-][C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCC(CO)NC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
Procedure as for 44, Method C (using 42 in place of 41). RF=0.72 chloroform:methanol 10:0.7 (v/v); yield 82%; 1H NMR δ 3.69-3.45 (m, 2H, αCH, CH2a), 2.97 (m, 1H, CH2b), 1.41 (s, 9H, 3×Boc CH3), 1.25 (m, 18H, 13CH2), 0.88 (t, 3H, CH3); FAB MS C21H43NO3 (357.32) m/z (%) 380 [M+Na]+ (15), 258 [M−Boc+H]+ (100).
Reaction SMILES: [C:1]([NH:11][C:12]([CH2:26][CH2:27][CH2:28][CH:29]1OCC[O:30]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([O-])(O)=O.[Na+]>Cl>[C:1]([NH:11][C:12]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(NC(CCCC1OCCO1)(Cc1ccccn1)c1ccccc1)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=CCCCC(Cc1ccccn1)(NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.8 %

Procedure:
The amine of step (b) (25 g) was dissolved in 1N HCl (300 ml) and stirred at room temperature overnight to hydrolyze the acetal group. The solution was neutralized with NaHCO3 and the amine was extracted into chloroform. Concentration of the chloroform afforded the subtitle compound (27 g) as a yellow solid.
Reaction SMILES: Cl.CNC.C=O.[C:7]([O:10][C:11](=O)[CH3:12])(=O)[CH3:8].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[N:27]3[N:28]=[CH:29]C=[C:26]3[N:25]=[CH:24][CH:23]=2)[CH:17]=1>>[CH2:7]([O:10][CH2:11][C:12]1[CH:29]=[N:28][N:27]2[C:22]([C:18]3[CH:17]=[C:16]([C:15]([F:32])([F:14])[F:31])[CH:21]=[CH:20][CH:19]=3)=[CH:23][CH:24]=[N:25][C:26]=12)[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Agent: C=O
Agent: CNC
Agent: Cl
Product: CCOCc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 2.15 g. of dimethylamine hydrochloride, 1.5 ml. of 37% formalin, and 10.5 ml. of acetic anhydride is swirled and heated gently until the reaction mixture becomes homogeneous. To the mixture is added 2.63 g. of 7-(α,α,α-trifluoro-m-tolyl) pyrazolo[1,5-a]pyrimidine and the reaction mixture is heated for 2 hours on a steam bath. The reaction mixture is evaporated to dryness and acetone is added and briefly refluxed and evaporated to dryness again. Water is added and the mixture extracted with methylene chloride. The residue, on evaporation of the solvent, when recrystallized from ethanol gave the product, m.p. 110°-111° C.