Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:17][CH2:18][C:19]1[N:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[K+]>CO>[OH:17][CH2:18][C:19]1[N:24]=[CH:23][C:22]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:21][CH:20]=1
Reactant: CC(=O)OCc1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(CO)nc1
Yield: 13 %

Procedure:
A sample of (S)-1-t-butoxycarbonyl-2-azetidinemethanol (1.64 g, 8.18 mmol) and 1.05 g (6.29 mmol) of 6-acetyloxymethyl-3-hydroxypyridine, prepared as described by Deady and Dayhe, Aust. J. Chem., 2565:36 (1983), were reacted with triphenylphosphine (540 mg, 2.06 mmol) and DEAD (0.33 mL, 2.06 mmol) in TBF (25 mL) according to the procedure of Example 2a. The product was stirred in methanol (4 mL) containing KOH (450 mg) at room temperature for 4 hours, then neutralized and concentrated. The residue was purified by chromatography (silica gel; 1:1 ether: hexane and ethyl acetate) to give title compound (240 mg, 41% for two steps). MS (DCI/NH3) m/e: 295 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.42 (s, 9H), 2.24-2.48 (m, 2H), 3.84-3.96 (m, 2H), 4.18 (dd, J=2.6, 11 Hz, 1H), 4.40 (m, 1H), 4.53 (m, 1H), 4.82 (s, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.51 (m 1H), 8.31 (d, J=3.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=O)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:28]([NH2:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([NH:30][CH2:28][CH3:29])=[O:24])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN
Reactant: Cc1c(C(=O)Nc2cccc(C(=O)O)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1cccc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)c1
Temperature: 40 °C

Procedure:
A mixture of 3-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]benzoic acid (Example 63) (0.143 g, 0.35 mmol), ethylamine in THF, 2M solution (1.75 mL, 0.35 mmol), HATU (0.199 g, 0.52 mmol) and DIPEA (0.09 mL, 0.52 mmol) in DMF was stirred at 40° C. for 1 week. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated. The title compound was obtained after recrystallisation from acetonitrile as white solid (49 mg, 32%). HRMS calculated for C20H19Cl2N5O2 (M+H)+ 432.0994. found: 432.0957, Rt: 2.82 min. MP: 192.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:10][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH3:9])=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: C[C@H](O)c1cccc(Cl)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(F)c(C#N)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of (S)-1-(3-chlorophenyl)ethanol (20.4 g, 130.26 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (5.73 g, 143.29 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (19.93 g, 143.29 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice-water, stirred, extracted with ether, dried, filtered and concentrated to afford 30.0 g of 2-fluoro-5-[(S)-1-(3-chlorophenyl)ethoxy]benzonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1cccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1
Reactant: CI
Product: Cc1cccc(CN(C)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
2′-Methyl-N-methyl-N-(3-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-N-(3-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, s), 7.55-7.48,(5H, m), 7.27,(1H, t), 7.16-7.10,(2H, m), 7.00,(1H, b), 4.66-4.50,(2H, m), 2.89,(3H, m), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.52 min, MH+ 412.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:10]([NH2:13])[NH:11][N:12]=1.[C:21](OCC)(=[O:26])[CH2:22][C:23]([CH3:25])=O.C(OCC)C>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:12][N:11]3[C:21]([OH:26])=[CH:22][C:23]([CH3:25])=[N:13][C:10]=23)=[CH:19][CH:18]=1
Reactant: Nc1[nH]nc(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 100 °C

Procedure:
To a mixture of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-1b; 3.00 g, 9.86 mmol) in acetic acid (12 ml) was added ethyl acetoacetate (1.63 ml, 12.8 mmol). The reaction was heated at 100° C. for 16 hours. After cooling to room temperature, the precipitated solid was isolated by vacuum filtration and then repulped from diethyl ether to afford I-3A-4a (1.1 g, 30%) as a colorless solid: +ESI MS (M+1) 370.0; 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.45–7.33 (m, 6H), 7.13 (d, J=8.7 Hz, 2H), 5.70 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH:38]([Sn](CCCC)(CCCC)CCCC)=[CH2:39]>>[CH2:38]([C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:22])([CH3:23])[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1)[CH3:39]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: CCc1ccc(N(CCc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and vinyltributyltin. 1H NMR (CDCl3) δ 8.02 (d, 1H, J=2.0), 7.32 (dd, 1H, J=8.8; 2.0), 7.12 (d, 2H, J=8.6), 7.07 (d, 2H, J=8.5), 7.0 (d, 2H, J=8.4), 6.82 (d, 2H, J=8.4), 6.42 (d, 1H, J=8.8), 4.50 (s, 2H), 3.67 (t, 2H, J=7.4), 2.80 (t, 2H, J=7.4), 2.49 (q, 2H, J=7.6), 1.55 (s, 6H), 1.19 (t, 3H, J=7.6). MS: m/z 503 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:17]=1)[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH2:39][S:40][CH3:41])[NH2:37].C1C=C2C(N(O)N=NC2=CC=1)=O.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.O>[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH2:39][S:40][CH3:41])[NH:37][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH2:15][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: Cc1ccccc1-c1cc(CN(Cc2ccccc2)c2cccnc2)ccc1C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CN(Cc2ccccc2)c2cccnc2)cc1-c1ccccc1C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a stirred solution of product of Example 407B (12.34 g, 29 mmol) in DMF (80 mL) was added successively methionine methyl ester hydrochloride (7.53 g, 37.7 mmol, 1.3 eq), HOOBt (5.21 g, 31.9 mmol, 1.1 eq), EDCI (6.11 g, 31.9 mmol, 1.1 eq) and 4-methylmorpholine (5.1 mL, 46.4 mmol, 1.6 eq). The mixture was stirred overnight, then poured into water and extracted with ethyl acetate. The organic solution was washed successively with water, sodium carbonate and sodium chloride, dried (Na2SO4), concentrated in vacuo, and the residue purified by flash chromatography on silica gel eluting with 70% ethyl acetate—hexanes changing to 100% ethyl acetate to yield the title compound (15.51 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[Br-:15].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:15][C:10]1[C:9](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: [Br-]
Reactant: O=c1ccccn1-c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClC(Cl)Cl
Product: O=c1c(Br)cccn1-c1ccc(Cl)cc1

Procedure:
A solution 1-(4-chlorophenyl)pyridin-2(1H)-one (1 eq) and tetrabutylammonium tribromide (1.2 eq) in chloroform (0.1M) was stirred 6 h at reflux. The reaction mixture was diluted with aqueous NaHCO3 solution and aqueous Na2S2O3 solution. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Hexane:EtOAc, 80:20) to afforded the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([F:13])=[CH:11][C:10]([CH:14]2[CH2:19][CH2:18][Si:17]([CH2:26][CH2:27][CH2:28][CH2:29]CCC)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:9][C:8]=1[F:33])(=O)=O.[Cl-].[Li+].CN(C)C=O>C1COCC1.[Cl-].[Zn+2].[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>[CH2:26]([Si:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15][CH:14]([C:10]2[CH:11]=[C:12]([F:13])[C:7]([CH2:11][CH:10]([CH3:14])[CH2:9][CH3:8])=[C:8]([F:33])[CH:9]=2)[CH2:19][CH2:18]1)[CH2:27][CH2:28][CH2:29][CH2:21][CH2:20][CH3:25]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(c2cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCC[Si]1(c2ccccc2)CCC(c2cc(F)c(CC(C)CC)c(F)c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 140.1 %

Procedure:
3.0 g (20 mmols) of (S)-1-bromo-2-methylbutane was dropped in a mixture of 0.5 g (21 mmols) of magnesium and 50 ml of THF to obtain a Grignard reagent. This reagent was dropped in 20 ml of a THF solution of 2.8 g (20 mmols) of zinc chloride to obtain an organizing reagent. Subsequently, the solution was dropped in a mixture of 10.7 g (20 mmols) of (2,6-difluoro-4-(4-n-heptyl-4-phenyl-4-silacyclohexyl)phenyl) trifluoromethanesulfonate, 100 mg of tetrakis(triphenylphosphine)palladium (0), 500 mg of lithium chloride and 50 ml of N,N-dimethylformamide, and agitated at 50° C. for 8 hours. The reaction mixture was after-treated by a usual manner and purified through chromatography to obtain 6.4 g (yield: 70%) of 4-(4-n-heptyl-4-phenyl-4-silacyclohexyl)-1-(2-methylbutyl)-2,6-difluorobenzene.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:18][NH:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:18][N:19]([CH3:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[CH:4]=1
Reactant: CC1(C)OB(c2cccc(CBr)c2)OC1(C)C
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of 3-bromomethylphenyl boronic acid pinacol ester (Combi Block Inc., 297 mg, 1.0 mmol) in acetonitrile (5 mL) was added dimethylamine (2M solution in methanol, 2.0 mmol) followed by the addition of K2CO3 (691 mg, 5.0 mmol). The reaction mixture was stirred at room temperature for 16 h. Acetonitrile was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3, dried (MgSO4), filtered and the filtrate concentrated in vacuo to give dimethyl-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]amine (INTERMEDIATE XI.1) as a viscous oil (200 mg, 0.77 mmol, 77%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:32])=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=O)=[CH:20][CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1[C:3]([CH3:32])=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[CH:22][CH:23]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N)cccc1-c1cn2ccnc2c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(N)cccc1-c1cn2ccnc2c(Nc2ccc(CN3CCOCC3)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
{4-[6-(3-Amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-morpholin-4-yl-methanone (350 mg; 0.82 mmol) is dissolved in anhydrous THF (5 mL) under nitrogen at rt. Solid lithium aluminum hydride (0.5 g) is added portion-wise to the stirring reaction, and the reaction refluxed under nitrogen for 2 hr. The reaction is cooled to 0° C. in an ice bath and quenched carefully by the dropwise addition of water (0.5 mL), then 15% NaOH(aq) (0.5 mL), and finally by more water (5 mL). The reaction is stirred at 0° C. for 15 minutes then the slurry is filtered through celite to remove the aluminum salts. The filtrate is partitioned between water and ethyl acetate, and the ethyl acetate layer is washed with water (1×50 mL), and brine (1×50 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo to provide [6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(4-morpholin-4-ylmethyl-phenyl)-amine as a tan solid (300 mg), which is pure enough to use in further steps.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([NH:4][C:5](=[O:25])[C:6]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C=C(C(=O)NC2CC2)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=Cc2ccc(C(=O)O)cc2)C(=O)NC2CC2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of methyl 4-(3-(cyclopropylamino)-2-(4-methylphenyl)-3-oxoprop-1-en-1-yl)benzoate (4 g, 12 mmol) in methanol (10 mL), a solution of NaOH (1.4 g, 36 mmol) in water (1 mL) was added. The reaction mixture was refluxed for two hours at 70° C. The solvent was removed by evaporation, poured to ice cold water. The aqueous layer was acidified to pH 3 with citric acid and allowed to stand at 4° C. for 30 minutes the solid precipitated out was filtered and dried under vacuum to get a pale yellow solid (3.2 g, 83% yield).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH2:6]CCC[CH2:2]1.CC(C[C@H](NC(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)C=O)C>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([NH:12][CH:8]([CH2:7][CH:1]([CH3:6])[CH3:2])[C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Agent: CC(C)C[C@@H](C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: CC(C)CC(NC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1)C(=O)O
Yield: 14 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Leu Wang resin (111 mg, 0.9 mmol/g), producing 8.1 mg of the title compound (14% yield). MS: 560.25 (M−H+) HPLC Procedure A, retention time=17.17 min.
Reaction SMILES: OS([O-])=O.[Na+].[OH-:6].[Na+].[CH3:8][N:9]1[C@@H:25]2[CH2:26][C:14]3[CH:15]=[CH:16][C:17]([OH:29])=[C:18]4[O:19][C@H:20]5[C:21]([O:27]C)=[CH:22][CH:23]=[C:24]2[C@:12]5([C:13]=34)[CH2:11][CH2:10]1.[OH-].[NH4+]>CC(O)=O>[CH3:8][N:9]1[C@@H:25]2[CH2:26][C:14]3=[CH:15][CH:16]=[C:17]([OH:29])[C:18]4[O:19][C@H:20]5[C:21]([CH2:22][CH2:23][C@:24]2([OH:6])[C@:12]5([C:13]=43)[CH2:11][CH2:10]1)=[O:27]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: [OH-]
Agent: O=S([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 38 °C
Reaction time: 0.07 h

Procedure:
To the above filtrate, NaHSO3 (0.1 g per g of oripavine) was added and nitrogen sweep was initiated. 50% Sodium Hydroxide, NaOH, (1.33 g per g of oripavine) was charged (pH=about 6.6). Temperature reached 35° C. during charging. The pH was adjusted with additional 50% NaOH (˜0.15 mL per g of oripavine) to 7.0. Note: The pH value would take 3 to 5 minutes to become steady. The pH adjustment was repeated until the pH change was within +/−0.2 over 5 minutes. The pH was adjusted to 6.6 to 7.0 with 50% NaOH or HOAc if necessary. The solution was heated and stirred at 38° C. (35° C. to 80° C.) for 2 hours to form a light brown solution (pH changed within +/−0.2). The solution was cooled to room temperature (20° C.). Concentrated ammonium hydroxide, c-NH4OH, (0.5 mL per g of oripavine) was added to form a precipitate (pH=9.0 to 10.0). The mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the resulting solid was washed with water (3×1 mL per g of oripavine). The solid was dried under flowing air at room temperature for 1 hour to give product as a tan solid.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(OCC)(=O)C(OCC)=[O:13]>>[O:13]=[C:2]([CH2:3][CH2:4][CH2:5][CH3:6])[C:1]([OH:8])=[O:7]
Reactant: CCCCCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Product: CCCCC(=O)C(=O)O

Procedure:
Ethyl n-hexanoate and diethyl oxalate were subjected to Claisen condensation, and then hydrolyzed to form 2-oxo-n-hexanoic acid. This product was then condensed with diaminomaleonitrile to form 9.1 g (0.042 mole) of 2,3-dicyano-5-hydroxy-6-n-pentylpyrazine (m.p. 61°-64° C.). The product was dissolved in 120 g of phosphorus oxychloride, and 3.32 g (0.042 mole) of pyridine was added. The mixture was refluxed for 5 hours, and then worked up in the same way as in Example 3 and the resulting oily product was concentrated under reduced pressure. The resulting product was chromatographed on a silica gel column with benzene as an eluent to afford 6.0 g (yield 61%) of 2,3-dicyano-5-chloro-6-n-pentylpyrazine as a yellow liquid.
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C4CCCCO4)=[CH:19][CH:18]=3)[CH:12]=[C:13]2[NH2:16])=[N:8]1.[Br:30][C:31]1[N:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:30][C:31]1[N:36]=[C:35]([C:37]([NH:16][C:13]2[CH:12]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:10]=[C:9]3[C:14]=2[CH:15]=[N:7][NH:8]3)=[O:38])[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cc(-c2ccc(OC3CCCCO3)cc2)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2ccc(O)cc2)cc2[nH]ncc12)c1cccc(Br)n1
Temperature: 70 °C
Reaction time: 120 h

Procedure:
2-(Tetrahydro-2H-pyran-2-yl)-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazol-4-amine (500 mg, 1.27 mmol), 6-bromo-2-pyridinecarboxylic acid (272 mg, 1.35 mmol), HATU (531 mg, 1.35 mmol) and DIPEA (0.442 ml, 2.54 mmol) were combined in DMF (10 ml) and heated at 70° C. overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with DCM:MeOH:ammonia. Appropriate fractions were combined and the solvent was removed in vacuo. The residue was dissolved in Methanol (20 ml) and 4 M HCl in dioxane (2 ml) and stirred at RT for 5 days. A small amount of the reaction mixture was removed (2 ml), the solvent was removed in vacuo and the residue purified by MDAP (Method B) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][CH3:19])[C:14]=1[OH:15])[CH:10]=O)([CH3:6])[CH2:3][CH2:4][CH3:5].[C:22]([CH2:24]C(O)=O)#[N:23].N1CCCCC1.Cl>O.N1C=CC=CC=1>[CH3:1][C:2]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][CH3:19])[C:14]=1[OH:15])[CH:10]=[CH:24][C:22]#[N:23])([CH3:6])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)(C)c1cc(C=O)cc(C(C)(C)CCC)c1O
Reactant: N#CCC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: CCCC(C)(C)c1cc(C=CC#N)cc(C(C)(C)CCC)c1O

Procedure:
3,5-bis(1,1-dimethylbutyl)-4-hydroxycinnamonitrile was prepared by heating a mixture of 29 grams of 3,5-bis(1,1-dimethylbutyl)-4-hydroxybenzaldehyde, 25.5 grams of cyanoacetic acid, 75 milliliters of pyridine, and 3 milliliters of piperidine at 95° to 100° C. for 7 hours. The reaction mixture was poured into a solution of 50 milliliters of concentrated hydrochloric acid in 100 milliliters of water. The oil which precipitated was separated by extraction with petroleum ether and the extract was stripped under vacuum to a pot temperature of 50° C./13 mm. The residue, which weighed 32 grams, was a viscous liquid which crystallized slowly on standing.