Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.N1CCCCC1>C(OC(C)C)(=O)C>[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: O=Cc1ccccc1F
Solvent: C1CCNCC1
Solvent: CC(=O)OC(C)C
Product: N#CC(C#N)=Cc1ccccc1F
Yield: 28.3 %

Procedure:
Malononitrile (3.303 g, 50 mmol), 2-fluorobenzaldehyde (6.205 g, 50 mmol), 1 g of molecular sieves, and 500 mg of a resin bound piperidine (described in Tetrahedron Lett., 1999, 40, 7031-33) were placed in a vessel which was irradiated in a 300 W single mode microwave for 15 seconds. The reaction mixture was taken up in iso-propyl acetate, filtered, evaporated, taken up in dichloromethane, filtered through a pad of Magnasol, evaporated, and recrystallized from ethanol to yield 2.435 g of the title material as a crystalline solid,
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:37][CH2:38]OC(C)=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>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:37]=[CH2:38])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=O
Temperature: 90 °C

Procedure:
Intermediate (17a) (5.6 g, 11.5 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol), and (2-ethenyl)tri-n-butyltin (13.5 mL, 46.2 mmol) were dissolved in DMF (70 mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture was cooled to room temperature and 300 mL of EtOAc was added. The organic layer was washed using a 20% potassium fluoride solution (2×100 mL) and saturated aqueous NaCl. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to yield intermediate (17b) (4.3 g). MS m/z: [M+H+] calcd for C26H28N2O4, 433.2; found 433.4.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A suspension of 4-iodophenol (3 g, 13.64 mmol), 1-bromopropane (1.845 g, 15.00 mmol), and sodium carbonate (7.54 g, 54.5 mmol) in DMF (30 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with 0.5M NaOH (2×50 mL), and water (2×50 mL), and then dried over MgSO4. The solvent was removed. The crude product (3.11 g) was obtained, which was directly used for the next reaction without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.61-7.53 (m, 2H), 6.74-6.67 (m, 2H), 3.90 (t, J=6.5 Hz, 2H), 1.88-1.76 (m, 2H), 1.05 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-:6])O.[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:6][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(CC(=O)OCC)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(=O)OCC)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.20 g), sodium hydrogen carbonate (1.90 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, ethyl [4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]acetate (0.50 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.29 g, 51%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([Cl:17])[C:5]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:6]=2[N:7]=1.[O:18]([CH2:25][CH2:26][NH2:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O>[ClH:17].[CH3:1][C:2]1[NH:7][C:6]2[C:5]([N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=2)=[C:4]([NH:27][CH2:26][CH2:25][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: Cc1nc(Cl)c2[nH]c(-c3ccccc3)cc2n1
Reactant: NCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(NCCOc2ccccc2)c2nc(-c3ccccc3)cc-2[nH]1
Product: Cl
Yield: 19.7 %

Procedure:
This compound was prepared according to the method described in Example 2, by employing 2-methyl-4-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (Example 1(e)) (100 mg, 0.41 mmol), 2-phenoxyethylamine (Lancaster Synthesis Ltd.) (0.28 g, 2.05 mmol) and potassium carbonate (0.567 g, 4.1 mmol) in H2O (2.5 mL) to give 30.7 mg (22%) of the title compound as white crystals. MP: 266.9-267.4° C. (dec). 1H NMR (DMSO-d6; 400 MHz): δ 2.43 (s, 3), 3.91-3.93 (m, 2), 4.22 (t, 2, J=5.3), 6.74 (s, 1), 6.93-7.07 (m, 4), 7.29-7.40 (m, 3), 7.49-7.52 (m, 2), 7.79 (d, 2, J=7.79), 11.33 (br s, 1). MS m/z: 345 (M+1), 343 (M−1). Anal. Calcd for C19H24N4O: C, 70.34; H, 7.46; N, 17.27. Found: C, 70.14; H, 7.35; N, 17.13.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:35]N)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:30]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)c1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3ccc(OC(F)F)cc3)ccc2=O)c1

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and (3-methanesulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=459.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@@H:10]([CH3:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@H:10]([CH3:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethanol (1 ml) is added to a mixture of 100 mg (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) and 10% palladium on carbon (10 mg, 50% water wet, Degussa type E101 NE/W). Hydrogen gas is applied to the mixture. The mixture is stirred at ambient temperature and pressure for 24 h. The mixture is then filtered over Celites and washed with ethanol (2×0.5 ml). The mixture is then concentrated in vacuo to give (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 20:80 (3-a, R1=Boc: 3-b, R1=Boc) as determined by hplc. Spectroscopic data in described in WO/2008/083967, for example, Examples 14 and 18.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].C([O-])(=O)C.[K+].C(O)(=O)C.C(OC(=O)C)(=O)C.O1CCOCCOCCOCCOCCOCC1.[N:50](OCCC(C)C)=O>C(Cl)(Cl)Cl>[C:12]([N:11]1[C:10]2[CH:9]=[CH:8][C:7]3[C:6](=[O:15])[CH2:5][CH2:4][C:3]=3[C:2]=2[CH:1]=[N:50]1)(=[O:14])[CH3:13]
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1ccc2c(c1C)CCC2=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1ncc2c3c(ccc21)C(=O)CC3
Temperature: 65 °C
Reaction time: 23 h

Procedure:
A stirred mixture of N-(4-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)acetamide (20.00 g, 98.40 mmol), potassium acetate (19.32 g, 197 mmol), acetic acid (11.3 mL, 197 mmol), acetic anhydride (18.6 mL, 197 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (5.20 g, 19.7 mmol) in 600 mL of chloroform was heated at 65° C. and isopentyl nitrite (33.0 mL, 246 mmol) was added during 10 minutes. The mixture was stirred at 65° C. for 23 hours and was then allowed to cool to room temperature. The reaction mixture was diluted with chloroform and washed successively with saturated NaHCO3 (2×), water and brine. After drying over Na2SO4, the solution was concentrated to low volume under vacuum and flash chromatographed on silica gel eluting with EtOAc/dichloroethane (0:100 to 10:90) to give 3-acetyl-7,8-dihydrocyclopenta[e]indazol-6(3H)-one as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[S:27][C:26]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[K+].[Br-]>CCO>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:26]4[S:27][C:23]([Cl:22])=[CH:24][CH:25]=4)[CH2:30][CH2:31]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Clc1ccc(CN2CCNCC2)s1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(Cc2ccc(Cl)s2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-chloro-thiophen-2-ylmethyl)-piperazine, yield 48%. White crystals, m.p. 225-226° C. (from EtOH); 1H NMR (DMSO-d6): δ 12.00 (br, 1H), 8.60-8.55 (1H), 8.27-8.21 (dd-like, 1H), 7.33-7.20 (m, 6H), 7.20-7.15 (d, 1H), 4.55 (br s, 2H), 4.40-4.00 (br, 2H), 3.74-3.27 (br, 4H+H2O); 3.27-2.97 (br, 2H); IR (KBr): ν 1723 (C═O) cm1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[N:25]1[CH:29]=[CH:28][S:27][CH:26]1[Sn](CCCC)(CCCC)CCCC.O1CCOC[CH2:44]1>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>[F:23][C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][CH2:15][N:14]2[CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[N:7][C:2]([C:26]4[S:27][C:28]([CH3:44])=[CH:29][N:25]=4)=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1SC=CN1C
Reactant: C1COCCO1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1cnc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)s1
Temperature: 140 °C

Procedure:
To a mixture of 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline (100 mg, 0.3 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) was added 1,4-dioxane (2 mL) and then 3-methyl-2-tributylstannylthiazole (232 mg, 0.6 mmol). The resulting mixture was sealed and heated at 140° C. for 1.5 h. The resulting mixture was then absorbed on silica gel and purified by silica gel column using 40% EtOAc/hexane as the eluent to yield 2-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-5-methylthiazole.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[CH3:1][O:29][C:28](=[O:30])[C@H:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.6 %

Procedure:
Potassium carbonate (2.07 g), methyl iodide (1.25 mL) were added to a solution of N-tert-butoxycarbonyl-O-benzyl-L-homoserine (3.10 g) in DMF (15 mL). After stirring at room temperature for 5 hr, the solvent was removed in vacuo. Ethyl acetate and water were added to the residue. The separated organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the title compound (3.13 g) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.44 (m, 9H), 1.95-2.15 (m, 2H), 3.55 (m, 2H), 3.68 (s, 3H), 4.44 (m, 1H), 4.45 (d, J=11.6 Hz, 1H), 4.49 (d, J=11.7 Hz, 1H), 5.47 (m, 1H), and 7.27-7.37 (m, 5H).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([O:12][CH3:17])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
To a solution of (4R)-1-Boc-4-hydroxy-L-proline (8 g, 34.63 mmol) prepared in Step A in DMF was added K2CO3 (14 g, 101 mmol) and methyliodide (2.6 ml, 51.9 mmol). The reaction mixture was stirred at rt for 5 h, concentrated in vacuo, and extracted with EtOAc. The organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (8.0 g, 95%).
Reaction SMILES: C1C[O:4]CC1.[CH3:6][C:7]([CH3:40])([CH2:10][C@@:11]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:16][C:15](=[O:17])[N:14]([C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29](=[O:32])[N:28]([CH3:33])[CH:27]=3)=[CH:22][CH:21]=2)[CH3:19])[CH2:13][CH2:12]1)[C:8]#[N:9].C(N)(=O)C>Cl[Pd]Cl.O>[CH3:40][C:7]([CH3:6])([CH2:10][C@@:11]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:16][C:15](=[O:17])[N:14]([C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29](=[O:32])[N:28]([CH3:33])[CH:27]=3)=[CH:22][CH:21]=2)[CH3:19])[CH2:13][CH2:12]1)[C:8]([NH2:9])=[O:4]
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: C1CCOC1
Agent: Cl[Pd]Cl
Agent: CC(N)=O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C(N)=O)(c2ccccc2)OC1=O

Procedure:
A THF:H2O (2 mL, 3:1) solution of 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (55 mg, 0.12 mmol), acetamide (177 mg, 3 mmol) and PdCl2 (21 mg, 0.12 mmol) was stirred overnight. The solvent was removed and the crude material redissolved in CH3CN. The crude product was purified via prep HPLC to afford 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (28 mg). LC-MS Method 1 tR=1.25 min, m/z=488 (M+1); 1H NMR (CDCl3) 7.55 (dd, 1H, J=9 Hz, 3 Hz), 7.42 (d, 1H, J=3 Hz), 7.32 (d, 1H, J=4 Hz), 7.29 (m, 4H), 7.14 (d, 2H, 8 Hz), 7.00 (d, 2H, J=8 Hz), 6.79 (d, 1H, J=9 Hz), 5.66 (q, 1H, J=8 Hz), 3.62 (s, 3H), 2.95-2.89 (m, 1H), 2.5 (d, 1H, J=15 Hz), 2.26-2.1 (m, 3H), 2.2 (d, 1H, J=15 Hz), 2.5 (d, 1H, J=15 Hz), 2.26-2.10 (m, 3H), 2.2 (d, 1H, J=15 Hz), 1.53 (d, 3H, J=7 Hz), 1.22 (s, 3H), 1.20 (s, 3H)
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:9])([F:8])[C:4]([O:6][CH3:7])=[O:5].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O.CC(O)=O.C1COCC1>[CH:10]1([NH:1][CH2:2][C:3]([F:9])([F:8])[C:4]([O:6][CH3:7])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCC1
Reactant: COC(=O)C(F)(F)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(F)(F)CNC1CCCC1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a round bottom flask was added methyl 3-amino-2,2-difluoropropanoate (570 mg, 3.24 mmol), THF (20 mL), cyclopentanone (0.433 mL, 4.87 mmol), and HOAc (1 mL). To this mixture was added sodium triacetoxyborohydride (1.06 g, 5 mmol) portionwise. The reaction was left to stir overnight. It was then added slowly to a stirring solution of ice, NaHCO3 (sat.), and EtOAc. The aqueous layer was further extracted with EtOAc, the organic extracts combined, dried over MgSO4, filtered and concentrated to yield the desired product as clear syrup (400 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (td, J=13, 6 Hz, 2 H) 1.43 (d, J=8 Hz, 1 H) 1.47-1.70 (m, 4 H) 1.77 (dt, J=12, 6 Hz, 2 H) 3.12 (t, J=6 Hz, 1 H) 3.19 (t, J=14 Hz, 2 H) 3.88 (s, 3 H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[N:12]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:10]([Br:22])[C:8]=2[N:9]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>CN(C)C=O>[CH2:24]([O:23][C:6]1[C:7]2[N:12]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:10]([Br:22])[C:8]=2[N:9]=[C:4]([N:3]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[N:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1nc(OCc2ccccc2)c2c(n1)c(Br)cn2COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(OCc3ccccc3)c3c(n2)c(Br)cn3COCc2ccccc2)cc1

Procedure:
Sodium hydride (0.6 g, 50% dispersion) was added to a stirred solution of 2-amino-4-benzyloxy-5-N-benzyloxymethyl-7-bromopyrrolo[3,2-d]pyrimidine (1.2 g) in N,N-dimethylformamide (25 mL) followed by 4-methoxybenzyl chloride (1.1 mL). After 1 h the reaction was quenched carefully with water, chloroform was added and the solution was washed (×2) with water. Normal processing followed by chromatography afforded 4-benzyloxy-5-N-benzyloxymethyl-7-bromo-2-{N,N-bis-(4-methoxybenzyl)amino}pyrrolo[3,2-d]pyrimidine (1.7 g) as a white solid. 13C-NMR (CDCl3) δ 159.0, 158.5, 156.5, 151.5, 137.4, 137.0, 131.8, 131.6, 129.7, 128.9, 128.8, 128.4, 128.3, 128.0, 114.1, 110.5, 91.1, 77.8, 70.6, 68.0, 55.7, 49.4. Anal. calc. for C37H35BrN4O4: C, 65.39; H, 5.19; Br, 11.76; N, 8.24. Found: C, 65.47; H, 5.17; Br, 11.55; N, 8.42.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH3:5][P:6](=O)([O:10]CC)[O:7][CH2:8][CH3:9]>>[C:3]([CH2:2][P:6]([CH3:5])(=[O:10])[O:7][CH2:8][CH3:9])#[N:4]
Reactant: N#CCCl
Reactant: CCOP(C)(=O)OCC
Product: CCOP(C)(=O)CC#N
Temperature: 125 °C
Yield: 95 %

Procedure:
226.5 g (3 mol) of chloroacetonitrile were heated to 60° C. 470 g (3.53 mol) of diethyl methylphosphonate were added dropwise over a period of 3 hours at 70° to 80° C. During this step heating was not necessary; the reaction was exothermic. Ethyl chloride was collected in a down-stream cold trap. After the dropwise addition was finished, the mixture was slowly heated to 125° C. and kept at this temperature until no more waste gas (ethyl chloride) could be detected. The mixture was subsequently cooled and distilled through a column under an aspirator vacuum to give 418 g of ethyl cyanomethtylmethylphosphinate (b.p. 108°-109° C., 0.0133 kPa). This correspnds to a yield of 95% of theory, based on the amount of chloroacetonitrile used. ##STR4##
Reaction SMILES: CSC.B.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[CH3:26][C:27]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][C:30]2[N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:29]=2[CH:28]=1.CO>ClCCl>[OH:36][C@@H:35]1[CH2:34][CH2:33][CH2:32][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]2[CH:44]=[C:45]([C:46]([F:49])([F:47])[F:48])[C:27]([CH3:26])=[CH:28][C:29]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCCC2=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Add a solution of borane dimethylsulfide complex (3.8 mL, 7.58 mmol, 2 M in tetrahydrofuran) dropwise to a solution of (S)-2-methyl-CBS-oxazaborolidine (9.5 mL, 9.48 mmol, 1M in toluene) in dichloromethane (20 mL) at −30° C. under nitrogen. Stir the mixture for 30 min and add a solution of tert-butyl 7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.17 g, 6.32 mmol) in dichloromethane (20 mL) dropwise and warm the mixture slowly to 0° C. Pour the mixture into methanol (200 mL) at −20° C. and slowly warm the stirring mixture to room temperature over 1 h. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless oil (1.65 g, 76%). APCI MS m/z 345 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 102 mg of 4-ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.94 (t, 3H, J=7.6 Hz), 2.38 (q, 2H, J=15.2 Hz, 7.6 Hz), 6.94 (d, 2H, J=6.8 Hz), 7.16 (m, 2H), 7.23 (m, 1H), 7.30 (m, 4H), 8.60 (b, 2H), 9.73 (b, 1H). MS: m/z 401.1 (M++1).