Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:29][CH:28]=1
Reactant: Oc1ccc(S)cc1
Reactant: CCCCCCCCC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N(CCCCCCCCCCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-[(2-Bromo-decyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03008, 607 mg, 1.5 mmol), 4-hydroxy-thiophenol (378 mg, 3.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) in DMF (10 mL) was stirred for 12 hours at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.71). The resulting yellow solid was dissolved in acetone and precipitated by addition of hexane to give a light yellow powder. Yield: 401 mg (59%). 1H-NMR (400 MHz, d6-DMSO) δ=1.16-1.52 (m, 16H), 2.76 (t, J=7.2 Hz, 2H), 3.80 (t, J=7.2 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.72 (d, J=9.0 Hz, 2H), 8.97 (s, 2H), 9.53 (s, 1H, —OH). LRMS (FAB+): 450.2 (100, [M+H]+). HRMS (FAB+) 450.23208 C25H32N5OS requires 450.232758.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#CC1CCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(F)cc2)CCC1

Procedure:
4-Fluoro-aniline (Aldrich Chemicals) (2.3 g, 21 mmol), cyano-ketone (Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) and T.H.F. (30 ml) were heated under reflux for 21 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (160° C., 0.4 mm Hg) gave the product as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH:15]2[CH2:17][CH2:16]2)=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[N:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[N:26][C:21]2=[C:20]([C:27](Cl)=[O:28])[CH:19]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH:15]2[CH2:17][CH2:16]2)=[C:6]([C:8]2[C:12]([NH:13][C:27]([C:20]3[CH:19]=[N:18][N:22]4[CH:23]=[CH:24][CH:25]=[N:26][C:21]=34)=[O:28])=[CH:11][NH:10][N:9]=2)[CH:7]=1
Reactant: O=C(Cl)c1cnn2cccnc12
Reactant: Nc1c[nH]nc1-c1cc(Cl)ccc1OC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC1CC1)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazol-4-amine (0.2 g, 0.8 mmol) was dissolved in 15 mL of anhydrous THF. Pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.17 g, 0.96 mmol) was added followed by DIPEA (0.2 g, 1.6 mmol). The mixture was stirred at room temperature for 2 h, then evaporated to dryness. The residue was purified by silica gel chromatography (EtOAc as eluant) to afford 0.3 g of the title compound. Yield: 95%. 1H NMR (DMSO-d6, 400 MHz) δ: 12.93 (d, 1H), 9.56 (d, J=5.2 Hz, 1H), 9.34 (d, J=7.2 Hz, 1H), 8.75-8.74 (m, 1H), 8.65 (s, 1H), 8.22 (s, 0.5H), 8.05 (s, 0.5H), 7.55-7.25 (m, 4H), 3.97-3.94 (m, 1H), 0.70-0.44 (m, 4H).
Reaction SMILES: O=C(C(OCC)=O)C(OCC)=O.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[Br:24])[N:20]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18](=[O:30])[NH:17]2>C(O)C>[Br:13][C:14]1[C:23]([Br:24])=[CH:22][C:21]2[C:16](=[N:17][C:18](=[O:30])[CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc2cc(Br)c(Br)cc2[nH]c1=O
Agent: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1N=c2cc(Br)c(Br)cc2=NC1=O

Procedure:
4,5-Dibromo-o-phenylaminediamine was cyclized to the corresponding quinoxaline carboxylic acid ester by the procedure of Example 1 utilizing 4.1 g. of the diamine and 2.7 g. of diethyl ketomalonate in 75 ml. of anhydrous ethanol. Ethyl 6,7-dibromo-3,4-dihydro-3-oxo-2-quinoxaline carboxylate thus prepared melted at 235°-236° C. (yield=3.9 g.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)[C:14]=2C)=[CH:8][CH:7]=1.[C:30](Cl)(=[O:32])[CH3:31].[CH2:34](N(CC)CC)C>ClCCl>[C:30]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH3:34])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)[CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)(=[O:32])[CH3:31]
Reactant: CCN(CC)CC
Reactant: Cc1cc(OCCCO)ccc1-c1cccc(COc2ccc(C=O)cc2)c1C
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OCCCOc1cc(C)c(-c2cccc(COc3ccc(C=O)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 4-{[4′-(3-hydroxypropoxy)-2,6′-dimethylbiphenyl-3-yl]methoxy}benzaldehyde, acetyl chloride, triethylamine and dichloromethane was stirred at room temperature for 3.5 hours to obtain 3-({3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)propyl acetate.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([OH:6])=O.[NH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>>[C:14]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:17][CH:16]=1)#[N:13]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccccn1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccccn1

Procedure:
(RS)-Methoxy-pyridin-2-yl-acetic acid was reacted with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-pyridin-2-yl-acetamide. Brown oil. MS 282.2 ([M+H]+)
Reaction SMILES: [CH2:1]([S:5]([OH:8])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].N1C=CC=C[CH:10]=1.C(S([O-])(=O)=O)CCC.[NH+]1C=CC=CC=1.S(OC)(OC)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([S:5]([O:8][CH3:10])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)O
Reactant: c1ccncc1
Agent: CCCCS(=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Solvent: C1CCCCC1
Product: CCCCS(=O)(=O)OC

Procedure:
After 1-butanesulfonic acid (10 g, 0.072 mol) was dissolved in methylene chloride (50 mL), pyridine (11 g, 0.14 mol) was added dropwise thereto, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under the reduced pressure to dryness to obtain a crude product containing pyridinium 1-butanesulfonate salt. To a suspension of this crude product (5 g, 0.023 mol) in cyclohexane (50 mL), dimethyl sulfate (15 g, 0.12 mol) was added, and the mixture was reacted at 80° C. for 2 hours. The resultant reaction liquid was condensed under the reduced pressure to obtain the desired product of methyl 1-butanesulfonate. Quantitative analysis by 1H-NMR showed a conversion rate of 77%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].C(Br)[C:26]1[CH:31]=CC=CC=1.O.[CH3:34][N:35](C=O)[CH3:36]>>[C:1]([O:5][C:6]([N:8]([CH2:26][CH2:31][N:35]([CH3:36])[CH3:34])[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(trans-4-(tert-butoxycarbonylamino)cyclohexyl)acetic acid (1.47 g) in DMF (10 mL) was added Na2CO3 (0.907 g) and benzyl bromide (0.75 mL). The resultant reaction mixture was stirred at RT for overnight. Water was then added and extracted with EtOAc. The organic phase was dried and concentrated to afford the desired product as white solid (1.60 g). To this solid was added 4N HCl (10 mL) and the reaction mixture was stirred at RT for 1 hr. Diethyl ether was then added to the reaction mixture to precipitate out the benzyl 2-(trans-4-aminocyclohexyl)acetate HCl salt as white solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cc1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methoxybenzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-[(4-methoxyphenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=1)[CH2:18][N:19]1[CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:18][C@@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1ccc([C@H](N)CN2CCC2)cc1Cl
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: N#Cc1ccc([C@@H](CN2CCC2)Nc2ncnc3c(C(N)=O)ccnc23)cc1Cl

Procedure:
Compound 47 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with 4-((S)-1-Amino-2-azetidin-1-yl-ethyl)-2-chloro-benzonitrile hydrochloride to give the title compound as a white solid. LC/MS [409 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.16 (d, 1H), 9.03 (d, 1H), 8.56 (s, 1H), 8.40 (d, 1H), 8.18 (s, 1H), 7.93 (d, 1H), 7.66 (d, 1H), 5.35 (s, 1H), 3.27-2.97 (m, 2H), 2.88 (d, 2H), 2.01-1.83 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=CC=1.[C:16]([CH:19]1[CH2:24][CH2:23][O:22][C:20]1=[O:21])(=O)[CH3:17]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[OH:8][C:7]1[C:2]2=[N:1][C:16]([CH3:17])=[C:19]([CH2:24][CH2:23][OH:22])[C:20](=[O:21])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: Nc1ncccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1nc2c(O)cccn2c(=O)c1CCO
Temperature: 125 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
In a reaction vessel equipped with a dropping funnel and a reverse water-separator, 2-amino-3-hydroxypyridine (110.12 g; 1 mol) was added to chlorobenzene (1500 ml) at room temperature. 2-Acetylbutyrolactone (134.53 g; 1.05 mol) was added dropwise to this mixture from the dropping funnel while stirring. The dropping funnel was rinsed with chlorobenzene (250 ml) and the resulting solution was added dropwise to the previously obtained mixture. Next, p-toluenesulfonic acid monohydrate (5.7 g; 0.03 mol) was added, and the resulting mixture was heated to reflux temperature (refluxing starting at 125° C.). The reaction mixture was refluxed for 19 hours, while the water liberated during the course of the reaction was collected in the reverse water-separator. The mixture was allowed to cool to about 80° C. and then there were added 2-propanol (250 ml), activated carbon (Norit A™ supra, 25 g) and filter agent (dicalite speed plus; 2.5 g). The mixture was heated to reflux (100° C.) during 30 minutes. The reaction mixture was filtered at a temperature of 90 to 95° C. and the filter cake was washed with chlorobenzene (100 ml; 80° C.). The combined filtrate was allowed to cool to room temperature. Crystallization of the reaction product started at about 40-45° C. and was left to continue for 18 hours at room temperature. The crystals were collected and washed with chlorobenzene (100 ml) and dried in vacuo at 50-60° C. for 24 hours, yielding 164.2 g (73.6%) 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp 150° C.; purity >97% (LC % w/w); residual 2-amino-3-hydropyridine: 0.85%; sum of other impurities <0.52%; residual 2-acetylbutyrolactone was 0% (GC % w/w).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.Br[CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1.C(N(CC)CC)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:14]1[CH2:15][C@H:16]2[C@:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])([CH2:17]2)[CH2:13]1
Reactant: Fc1cc(C(F)(F)F)ccc1[C@@]12CNC[C@@H]1C2
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1cc(C(F)(F)F)ccc1[C@]12C[C@H]1CN(CCCCl)C2
Temperature: 25 °C

Procedure:
To a solution of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (P13, 426 mg) in dry tetrahydrofuran (9 mL), triethylamine (0.79 mL) and 1-bromo-3-chloropropane (0.37 mL) were added and the resulting mixture was refluxed for 16 hours. After cooling at room temperature it was concentrated in vacuo, diluted with ethyl acetate, washed with a saturated solution of NaHCO3 in water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel) eluting with cyclohexane/EtOAc 8:2 to give the title compound as yellow oil (582 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+]>CO.ClCCl>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: N=C(N)CC1(c2ccc(Br)cc2)CCCC1
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a mixture of the HCl-salt of 2-[1-(4-bromophenyl)-cyclopentyl]-acetamidine (229) (6.5 g, 20.47 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (9.47 g, 30.71 mmol) in methanol (100 mL) was added sodium methoxide (3.32 g, 23.73 mmol, 25% in methanol) at 0° C. Then the reaction mixture was allowed to warm to room temperature and was stirred for 16 h. After completion of the reaction, solvent was reduced and the crude product was dissolved in dichloromethane (150 mL). The organic part was washed with 1N HCl, separated and dried over Na2SO4. After evaporation, the crude product was purified by 100-200 silica gel column chromatography using 20% ethyl acetate in hexane as the eluent to give 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (230) (7.9 g, 71%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:14]([O:16]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:7])([CH3:4])[CH3:3].[CH3:37][O:38][C:39]([C@@H:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40].Cl.C(N(CC)CC)C>CN(C)C=O>[NH:26]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C@H:13]([C:14]([NH:49][C@H:41]([C:39]([O:38][CH3:37])=[O:40])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
25.0 g of Z-Lys(BOC)-ONP and 10.7 g of H-Phe-OMe. HCl in 70 ml of dimethylformamide are mixed with 6.9 ml of triethylamine at room temperature whilst stirring and the mixture stirred for a further 18 hours. After dilution with ethyl acetate the mixture is washed with potassium carbonate solution until free of nitrophenol, extracted by shaking with 0.1 M citric acid and water, dried over sodium sulphate and evaporated to dryness in vacuo. The protected dipeptide of melting point 78°-80°C crystallises from ethyl acetate-hexane. Rf = 0.45 in a thin layer chromatogram on silica gel in the system chloroform-acetone (8:2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:24]CC1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C=CC1(C)C
Reactant: C1CCOC1
Agent: O=[Cr](=O)([O-])Cl
Agent: B
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g, 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of Celite™. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1-butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1=H, R2-3=methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL) was treated with 1.0 M BH3-THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3 M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5 mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d, J=7.8, 1H), 7.42 (t, J=7.8, 1H), 7.31 (d, J=7.8, 1H), 7.02 (t, J=7.8, 1H), 2.73 (s, 2H), 1.56 (s, 9H), 1.49 (s, 6H).
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[N:13][C:6]2[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>C(#N)CC.O>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[CH2:41][CH2:42][N:43]([CH2:2][C:3]3[CH:14]=[N:13][C:6]4[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:44][CH2:45]2)=[CH:36][CH:35]=1
Reactant: CN1CC(=O)Nc2cc(CO)cnc21
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: O
Product: CN1CC(=O)Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (85.0 mg, 0.44 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (18.1 mg, 11%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.30-7.36 (m, 2H), 7.23-7.29 (m, 2H), 6.95 (d, J=2.0 Hz, 1H), 3.92 (s, 2H), 3.32 (s, 3H), 2.84-2.92 (m, 5H), 1.98 (t, J=10.7 Hz, 2H), 1.66-1.75 (m, 2H), 1.50-1.64 (m, 2H). [M+H] calc'd for C20H23ClN4O, 371; found, 371.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])[C:2]=1[Cl:1])[C:13]#[N:14]
Reactant: CC(CCO)c1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CCO)c1cc(C#N)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.4 %

Procedure:
Tert-butyl (2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)carbamate (184 mg, 0.566 mmol) was taken up in DCM (6 mL) and TFA (1.746 mL, 22.66 mmol) was added. The reaction was stirred at room temperature for 1 h. LCMS indicates a mixture of the alcohol and the TFA ester. The solvent was removed in vacuo and the material dissolved in 2N NH3 in MeOH. The solution was stirred at room temperature for 10 min and the solvent removed in vacuo. 3-amino-4-chloro-5-(4-hydroxybutan-2-yl)benzonitrile (162 mg) was obtained. The crude material was taken forward without purification.