Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2].N1C=CC=CC=1.C1(C)C=CC=CC=1.Cl[C:38]([O:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:39]>ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH:20][C:38]([O:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:39])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(NC(=O)OCC(C)(C)C)nc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5'-Deoxy-2',3'-di-O-acetyl-5-fluorocytidine (1.5 g) and dry pyridine (0.74 ml) were dissolved in dry dichloromethane (15 ml). To the mixture, toluene solution of neopentyl chloroformate (3 eq.) was added dropwise at 0° C., and stirred at room temperature for 1 hour. After the solvent was removed under reduced pressure, the residue was partitioned between ether and saturated aqueous solution of sodium carbonate. The organic layer was successively washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4 (neopentyloxycarbonyl)cytidine as pale yellow oil. This crude product was dissolved in ethanol (15 ml) and cooled on ice-bath. Then 1N aqueous sodium hydroxide solution was added dropwise while maintaining the temperature below 15° C. After the addition was completed, the reaction mixture was neutralized with concentrated. hydrochloric acid at 0° C. The solution was concentrated under reduced pressure, and the concentrate was partitioned between water and a mixed solution of CH2Cl 2 /MeOH (95:5). The aqueous layer was back-extracted with CH2Cl2 /MeOH (95:5) ten times (20 ml each). All organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH2Cl2 /MeOH (20:1) as an eluent to give 5'-deoxy-5-fluoro-N4 -(neopentyloxycarbonyl)cytidine (1.37 g: 84% yield) as amorphous powder: FAB-MS m/z 360 (MH+); 1H-NMR (d6 -DMSO) δ0.93 (9H, s), 1.31 (3H, d,J=6.3 Hz), 3.68 (1H,q,J=5.9 Hz), 3.81 (2H, br. s), 3.87-3.92 (1H, m), 4.04-4.09 (1H, m), 5.05 (1H,d,J=5.9 Hz), 5.41 (1H, br. d, J=5.3 Hz), 5.67 (1H,dd,J=1.3, 3.6 Hz), 8.04 (1H, br. s), 10.53 (~1H, br. s).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH:21]([C:23]3[C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[S:26][CH:27]=3)[OH:22])[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[S:26]1[CH:27]=[C:23]([C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:16][CH2:17]2)=[O:22])[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]1=2
Reactant: OC(c1csc2ccccc12)C1CCN(CCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(c1csc2ccccc12)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dissolve oxalyl chloride (4.22 g, 33.28 mmol) in methylene chloride (200 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, dimethylsulfoxide (5.42 g, 69.33 mmol) and stir at -78° C. for 15 minutes. Add, by dropwise addition, a solution of α-[1-(2-phenylethyl)-4piperidinyl]-3-benzo[b]thiophenemethanol (9.75 g, 27.73 mmol) in dimethylsulfoxide (150 mL). Stir at -78° C. for 30 minutes, add triethylamine (15.18 g, 0.150 mol) and stir at -78° C. for 1 hour. Remove the ice bath and stir for an additional 1.5 hours. Evaporate the solvent in vacuo and recrystallize (isopropanol) to give the title compound as a tan powder; mp 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1>C(O)CC(C)C>[ClH:12].[OH:23][CH:20]1[CH2:21][CH2:22][N:18]([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([Cl:12])[CH:10]=3)[N:5]=2)[CH2:19]1
Reactant: OC1CCNC1
Reactant: COc1c(Cl)cc2c(N)nc(Cl)nc2c1OC
Solvent: CC(C)CCO
Product: COc1c(Cl)cc2c(N)nc(N3CCC(O)C3)nc2c1OC
Product: Cl

Procedure:
A mixture of 4-amino-2,6-dichloro-7,8-dimethoxyquinazoline (5.48 g., 0.020 mole) and 3-pyrrolidinol (2.18 g., 0.025 mole) in 150 ml. of isoamyl alcohol is heated at reflux for five hours then cooled in ice. The precipitated product is collected by filtration and purified by recrystallization to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[N:7]3[C:18](=[O:20])[NH:19][C:5]([C:6]=23)=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[O:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[CH3:21][C:22]1[C:26]([C:2]2[C:11]3[O:10][CH2:9][CH:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]4)[N:7]4[C:18](=[O:20])[NH:19][C:5]([C:6]=34)=[CH:4][CH:3]=2)=[C:25]([CH3:30])[O:24][N:23]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=c1[nH]c2ccc(Br)c3c2n1C(C1CCCCN1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3C1CCCCN1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The 7-bromo-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.025 g, 0.074 mmol) of Step 2 was combined with (3,5-dimethylisoxazol-4-yl)boronic acid (0.016 g, 0.11 mmol) in 1,4-dioxane (3.0 mL) with potassium carbonate (0.02 g, 0.15 mmol) in water (0.38 mL) and was degassed with nitrogen. The catalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.006 g, 0.007 mmol) was added and the reaction was heated in a sealed tube to 100° C. After stirring for 2 h the reaction was allowed to cool to room temperature and was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give the crude product as a dark oil. The product was purified by prep HPLC on a C-18 column eluting a water:acetonitrile gradient buffered at pH 2 with TFA to give 7-(3,5-dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as two fractions.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)[CH2:5][C:6]([OH:8])=[O:7].[C:21](OC(=N)C(Cl)(Cl)Cl)([CH3:24])([CH3:23])[CH3:22].B(F)(F)F.CCOCC.C(Cl)Cl>O1CCCC1>[CH3:19][C:17]1[CH:18]=[C:10]([CH2:9][CH:4]([CH2:5][C:6]([O:8][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:7])[C:3]([O:2][CH3:1])=[O:20])[CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2
Reactant: COC(=O)C(CC(=O)O)Cc1cc(C)c2[nH]ncc2c1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(CC(=O)OC(C)(C)C)Cc1cc(C)c2[nH]ncc2c1
Reaction time: 3.5 h

Procedure:
To a solution of 4-methoxy-3-((7-methyl-1H-indazol-5-yl)methyl)-4-oxobutanoic acid (0.9764 g, 3.54 mmol) and t-butyl-2,2,2-trichloroacetoimidate (3.78 mL, 21.22 mmol) in tetrahydrofuran (25 mL) was added 1M boron trifluoride etherate (0.2 mL) at room temperature. Heat generation was observed and the reaction was stirred for 3.5 h before passing it through a pad of silica gel. Evaporation of the filtrate gave a white solid. Methylene chloride (20 mL) was added and the resulting white solid was removed by filtration. The filtrate was concentrated and the final product was obtained via silica gel chromatography eluting with 0% to 50% ethyl acetate/hexane. (0.605 g, 52%) HPLC tR=1.51 min, MS(ESI)[M+H]+=332.77.
Reaction SMILES: [C:1](O)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].ClCC(OC(=O)CCl)=O.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCC(Cl)(Cl)Cl>[C:1]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[Br:17])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: Brc1ccccc1
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(CCl)OC(=O)CCl
Product: CCCCC(=O)c1ccccc1Br
Temperature: 115 °C
Reaction time: 10 h
Yield: 56 %

Procedure:
In 50 ml of tetrachloroethane were dissolved 5.11 g (0.05 mole) of valeric acid and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 9.42 g (0.06 mole) of bromobenzene and 0.8 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 115° C. for 10 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 6.75 g of valerylbromobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.[W]>[Br:10][CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Cl)c1
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(CBr)c1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
The mixture of 1-Chloro-3,5-dimethyl-benzene (32 g, 0.23 mol) and N-bromosuccinimide (40.5 g, 0.23M) in carbon tetrachloride (400 ml) was refluxed for 3 hr under a light of 500 W tungsten light. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, hexane) to afford 33 g (68%) of a white solid. 1H NMR (200 MHz, CDCl3) δ: 2.32 (3H, s), 4.39 (2H, s), 7.10 (2H, s), 7.18 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=O)=[CH:21][CH:20]=1.NC1C(=S)NC=CC=1>>[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]2[S:17][C:3]3[C:2]([N:1]=2)=[CH:7][CH:6]=[C:5]([C:8]2([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:10][CH2:9]2)[N:4]=3)=[CH:21][CH:20]=1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Nc1ccc[nH]c1=S
Product: Ic1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1

Procedure:
Reaction of 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (503.8 mg, 2.079 mmol) and 4-iodobenzoyl chloride (554 mg, 2.079 mmol) according to Reference V and the general procedure for the condensation of 3-aminopyridine-2-thione with aryl acid chlorides gave 2-(4-iodophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 454.0; Observed: 454.9 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][S:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[S:14][CH2:13]1.C(N(CC)CC)C>O.C(Cl)Cl>[Cl:8][C:7]1[C:2]([NH:11][C@H:12]2[CH2:13][S:14][C@@H:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[S:16][CH2:17]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: Cc1ccc(C2SCC(N)CS2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ncnc(N[C@H]2CS[C@@H](c3ccc(C)cc3)SC2)c1Cl

Procedure:
1.77 g (10 mmol) of 4,5-dichloro-6-ethyl-pyrimidine and 2.2 g (10 mmol) of 5-amino-2-(4-methylphenyl)-1,3-dithian were stirred with 2.02 g of triethylamine at 80-90° C. for 6 hours. The mixture was taken up in water/methylene chloride and the organic phase was dried and concentrated. For purification, the residue was chromatographed over silica gel (eluting agent petroleum ether/ethyl acetate 4:1). This gave 1.0 g of colorless solid (27.3% of theory), melting point: 138-139° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:28])[NH2:27])[CH:21]=2)=[C:16]([F:29])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:31]>ClCCl.O1CCOCC1>[Cl-:31].[C:26]([C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][NH2+:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:15][C:16]=2[F:29])[CH:25]=[CH:24][CH:23]=1)(=[O:28])[NH2:27]
Reactant: CC(C)CCN(Cc1ccc(-c2cccc(C(N)=O)c2)c(F)c1)C(=O)OC(C)(C)C
Reactant: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CC[NH2+]Cc1ccc(-c2cccc(C(N)=O)c2)c(F)c1
Product: [Cl-]
Reaction time: 1 h

Procedure:
[(3′-Carbamoyl-2-fluoro-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-5d): 0.180 g, 0.434 mmol) was dissolved in dichloromethane (10 ml) and treated with 1 ml of a 4M hydrogen chloride solution in dioxane. After 1 hour, the reaction mixture was concentrated under reduced pressure to provide a solid that was titrated with hexanes to afford the title product (E5-01) after filtration.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([NH:20][CH:21]([CH2:26][N:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:22]([O:24][CH3:25])=O)=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1.[OH2:40].[NH2:41][NH2:42]>CO>[O:40]=[C:25]1[O:24][C:22]([C@@H:21]([NH:20][C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=2)=[CH:17]3)=[O:19])[CH2:26][N:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:42][NH:41]1
Reactant: NN
Reactant: O
Reactant: CNc1nccc(-c2cc3cc(C(=O)NC(CN(c4ccccc4)c4ccccn4)C(=O)OC)ccc3[nH]2)n1
Solvent: CO
Product: CNc1nccc(-c2cc3cc(C(=O)N[C@@H](CN(c4ccccc4)c4ccccn4)c4n[nH]c(=O)o4)ccc3[nH]2)n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
1.78 g (3.4 mmol) of ester 32 were dissolved in 30 ml of MeOH. 0.83 ml of hydrazine hydrate was added and the mixture was stirred at 40° C. for 5 h. After that, a further 1.6 ml of hydrazine hydrate were added and the mixture was stirred at RT for 15 h. The solvents were removed i.v. and the residue was taken up in 80 ml of dichloromethane. 3.2 ml of a 20% solution of phosgene in toluene were added and the mixture was stirred for 3 days. After that, the solvent was removed i.v. and the residue was partitioned between 80 ml of water and 80 ml of ethyl acetate. When this was done, a solid precipitated out and was filtered off with suction. The organic phase was evaporated and the residue was combined with the solid and chromatographed on silica gel using heptane/ethyl acetate 1:5. 390 mg (21%) of the oxadiazolone 33 were obtained. Empirical formula C29H25N9O3; M.W.=547.58; MS (M+H) 548.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([OH:18])[CH2:15][C:16]#[CH:17]>CCN(CC)CC.C(Cl)Cl.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.[Cu]I>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([C:17]#[C:16][CH2:15][CH2:14][OH:18])=[CH:3][CH:4]=1
Reactant: C#CCCO
Reactant: Ic1ccc(-c2ccccc2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1ccc(-c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
A sample of 4-iodobiphenyl (400 mg, 1.40 mmol) and (PPh3)4Pd (32 mg, 0.02 mmol) were dissolved in Et3N (6 mL) and stirred at 23° C. for 15 min before CuI (13.5 mg, 0.071 mmol) and but-3-yn-1-ol (0.129 mL, 1.71 mmol) were added. The reaction mixture was stirred at 23° C. for 3 h and then diluted with CH2Cl2, washed with saturated aqueous NH4Cl and saturated aqueous NaCl, and dried over Na2SO4. Evaporation in vacuo yielded the crude product. Flash chromatography (SiO2, 20% EtOAc-hexanes) afforded the title compound (270 mg, 85%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.59 (dd, 2H, J=8.5 Hz), 7.54 (dd, 4H, J=8.5 Hz), 7.44 (t, 2H, J=7.5 Hz), 7.36 (t, 1H, J=7.5 Hz), 3.84 (t, 2H, J=6.5 Hz), 2.73 (t, 2H, J=6.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 140.6, 140.2, 132.0, 128.7, 127.5, 126.9, 126.8, 122.2, 87.0, 82.2, 61.1, 23.9.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:17][C:18]1[CH:22]=[C:21]([NH2:23])[N:20]([CH:24]([CH3:26])[CH3:25])[N:19]=1>C1C=CC=CC=1>[CH3:17][C:18]1[C:22]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8][C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:23][C:21]=2[N:20]([CH:24]([CH3:26])[CH3:25])[N:19]=1
Reactant: Cc1cc(N)n(C(C)C)n1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccncc2)nc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 64 using ethyl 2,4-dioxo-4-(4-pyridinyl)butanoate (766 mg, 2.87 mmol), benzene (6 mL), and 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 2.87 mmol). The crude product was purified using column chromatography (Silica gel, eluent: 0 to 30% MeOH/DCM) to give 95 mg (10%) of product. LCMS E-S (M+H)=325.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.56 (m, 3H), 1.61-1.73 (m, 6H), 2.77 (s, 3H), 4.56 (q, J=7.2 Hz, 2H), 5.37-5.50 (m, 1H), 8.02-8.16 (m, 3H), 8.76-8.83 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=1[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21](OC)=[O:22].O>O1CCCC1>[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=1[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[CH2:21][OH:22]
Reactant: COC(=O)c1cccc(-c2c(F)c(F)c(F)c(F)c2F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(-c2c(F)c(F)c(F)c(F)c2F)c1
Temperature: 25 °C
Yield: 121.6 %

Procedure:
To a stirred suspension of 0.5 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran, cooled to -78°, was added dropwise methyl 3-(2,3,4,5,6-pentafluorophenyl)benzoate (2.6 g, 0.009 mole) in 50 ml of dry tetrahydrofuran. Upon complete addition, the reaction mixture was stirred while warming to room temperature. A solution of 10% water in tetrahydrofuran was then added dropwise to the reaction mixture to destroy excess lithium aluminum hydride. An additional 50 ml of water was then added, and the liquid phases separated. The aqueous layer was washed with two 50 ml portions of diethyl ether. The ether washes were combined with the organic layer from the reaction mixture and dried. The mixture was filtered and the filtrate evaporated under reduced pressure to give 3-(2,3,4,5,6-pentafluorophenyl)benzyl alcohol (3.0 g) as an oil, which solidified on standing. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]([OH:18])[C:19]#[N:20])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
A solution of 3-(4-(benzyloxy)phenyl)propanal (S49, 700 mg, 3.07 mmol, 1 equiv) in THF (13 mL) and H2O (18 mL) was treated with KCN (2.30 g, 35.3 mmol, 11.5 equiv). After stirring for 50 h at 25° C., the reaction was quenched with H2O and extracted with ether. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to afford S50 (755 mg, 2.96 mmol, 96%) as a white solid: 1H NMR (CDCl3, 400 MHz) 7.47-7.33 (m, 5H), 7.14 (d, 2H, J=8.8 Hz), 6.95 (d, 2H, J=8.8 Hz), 5.06 (s, 2H), 4.39 (t, 1H, J=6.9 Hz), 2.82-2.77 (m, 2H), 2.17-2.10 (m, 2H); 13C NMR (CDCl3, 100 MHz) 157.3, 136.9, 131.9, 129.4, 128.5, 127.9, 127.4, 119.9, 115.0, 70.0, 60.2, 36.6, 29.7; IR (film) νmax 3444, 2927, 2865, 2250, 1611, 1583, 1514, 1454, 1382, 1246, 1177, 1079, 1024, 912, 830, 738, 695 cm−1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CN(CCOCCN=[N+]=[N-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CCOCCN)C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
A solution of tert-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate (41.9 g, 170 mmol) in 600 mL of MeOH was treated with 2.5 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 37.2 g of crude tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate as a light yellow liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:21])=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[N:14]=1)=O)C.[NH3:22]>CO>[Cl:21][C:9]1[N:8]=[N:7][C:6]([C:4]([NH2:22])=[O:3])=[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[N:14]=2)[CH:10]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(CC)n1
Reactant: N
Solvent: CO
Product: CCc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reaction time: 3 h
Yield: 100 %

Procedure:
6-Chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (241 mg, 0.786 mmol) was suspended in 7M ammonia in methanol (9 mL). After 3 h, the reaction mixture was concentrated in vacuo to give 6-chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (218 mg, 100%) as an off-white solid which was used directly in the next step without purification. LCMS (EI/CI) m/z: 278 [M+H].
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=3)[C:11](=[O:22])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH3:29]O[Na].[C:32](OC)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[C:32]([C@@H:10]1[CH2:9][CH:8]([CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:2][CH:3]=2)[N:12](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:29]=2)[C:11]1=[O:22])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(CN2C(=O)CC[C@H]2Cc2ccc(-c3ccccc3)cc2)cc1
Reactant: COC(=O)c1ccccc1
Reactant: CO[Na]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-5-Biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (3a, R1=styryl) (10.0 g, 28.3 mmol) is heated to dissolve in 30 mL of anhydrous toluene under N2, add MeONa (1.99 g, 36.8 mmol) in one portion, stir at this temperature for 10 min, then add methyl benzoate dropwise, reflux overnight, cool to room temperature, quench with saturated NH4Cl aqueous solution, separate the organic phase, extract with toluene (15 mL*3), the combined organic extracts are washed with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4 and concentrate under vacuum. The residue is purified by silica gel column chromatography, eluting with 5:1 heptane/ethyl acetate to give (S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl), the ratio of (3S,5S) to (3R,5S) is 70:30 as determine by HPLC. Spectroscopic data as Example 8, Method 1.