Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:10]1[C:11]([CH:16]=O)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][C:33]2[C:38]([CH3:39])=[CH:37][C:36]([Cl:40])=[CH:35][N:34]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][CH:28]([N:31]([CH2:32][C:33]2[C:38]([CH3:39])=[CH:37][C:36]([Cl:40])=[CH:35][N:34]=2)[CH2:16][C:11]2[C:10]([C:2]([CH3:1])([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:3])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc(Cl)cnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(c1ccccc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 3-(1-methyl-1-phenyl-ethyl)-pyridine-2-carbaldehyde, 4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave 4-{(5-Chloro-3-methyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid. 1H NMR (CDCl3): δ 1.13 (q, 2H, J=11.1 Hz), 1.44 (s, 9H), 1.50 (br, 2H), 1.62 (s, 6H), 2.28 (s, 3H), 2.43 (m, 3H), 3.34 (s, 2H), 3.61 (s, 2H), 3.98 (br, 2H), 6.98 (m, 2H), 7.17 (m, 4H), 7.35 (s, 1H), 7.85 (d, 1H, J=7.2 Hz), 8.20 (s, 1H), 8.48 (d, 1H, J=3.9 Hz). Deprotection with TFA using General Procedure F gave (5-Chloro-3-methyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][O:25][CH3:26]>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:23][CH2:24][O:25][CH3:26])[C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(C)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Reactant: COCCBr
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C)ccc(OC)c21

Procedure:
The title compound is prepared starting from 4-methyl-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole and (2-bromoethyl)-methyl ether using the same reaction conditions as described in Example 1. The title compound is obtained as a colorless oil.
Reaction SMILES: N[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].N(OC(C)(C)C)=O.[OH-].[Ca+2].[OH-].C1C=CN=CC=1.[FH:37]>O.N>[F:37][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: F
Agent: CC(C)(C)ON=O
Agent: N
Agent: [Ca+2]
Solvent: c1ccncc1
Solvent: O
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
0.282 g (1 mmol) of 2-aminoadenosine is suspended in a mixture of 7 ml of 50% HF-pyridine and 0.35 ml of H2O at -30° C. and within 30 minutes, 1.2 ml (~9 mol) of tert-butyl nitrite is instilled slowly with vigorous stirring at -30° C. After another 30 minutes at -25°→-30° C., the reaction mixture is instilled slowly in 120 ml of 33% aqueous ammonia at -10° C. with stirring and stirred for 1 hour at 0° C. After adding 7 g of solid calcium hydroxide, it is stirred for another 15 minutes at 0° C., filtered and washed with 40 ml of H2O. The light yellow filtrate is carefully concentrated by evaporation at about 25° C.-30° C. to about 15 ml and CO2 is introduced. After filtering off the small amount of precipitate and after washing the precipitate with 10 ml of H2O, the filtrate is concentrated by evaporation at a 10 mm vacuum. The yellowish-brown residue (0.39 g) is dissolved in 15 ml of methanol-H2O (1:1), mixed with 10 g of silica gel (40% H2O) and evaporated at a 10 mm vacuum. After feeding dry silica gel containing the substance on a column of 15 g of silica gel (40% H2O), which was taken up with isopropanol, elution with about 300 ml of isopropanol yields 0.261 g (~91%) of crude 2-fluoroadenosine, which still contains a little 2-aminoadenosine as well as isoguanosine.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(OOS([O-])(=O)=O)([O-])(=O)=[O:14].[K+].[K+]>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:9]([OH:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: COC(=O)c1cccc(Br)c1C
Agent: Cl[Ru]Cl
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(O)ccc(Br)c1C
Temperature: 85 °C
Yield: 75.4 %

Procedure:
A solution of methyl 3-bromo-2-methylbenzoate (Cpd FF, 2.40 g, 10.5 mmol) in trifluoroacetic acid (50 mL) and trifluoroacetic anhydride (20 mL) in a sealed tube was treated with potassium persulfate (3.12 g, 11.5 mmol) and dichloro(p-cymene)ruthenium(II) dimer (0.170 g, 0.278 mmol). The reaction mixture was heated at 85° C. overnight. The volatiles were removed under vacuum and the resulting residue was taken up in dichloromethane and water. The aqueous phase was brought to pH˜5 with K3PO4 (sat. aq.). The layers were separated and the organic layer purified by column chromatography (0-30% ethyl acetate/heptane) to give methyl 3-bromo-6-hydroxy-2-methylbenzoate (Cpd GG, 1.94 g, 75%) as a clear oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[NH2:18][CH2:19][CH2:20][OH:21].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[OH:21][CH2:20][CH2:19][NH:18][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: NCCO
Reactant: COC(=O)c1cc(C=O)cc(-n2cccc2)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(CNCCO)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 3-formyl-5-(pyrrol-1-yl)benzoate (1.66 g), 2-aminoethanol (0.88 ml) and molecular sieves 4A (1.7 g) in methanol (40 ml) was stirred for 6 hours at room temperature. Then, to the reaction mixture was added sodium borohydride (0.55 g). After stirring for 3 hours at room temperature, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(2-hydroxyethylaminomethyl)-5-(pyrrol-1-yl)benzoate (0.80 g).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1.N1CC[CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[N:4]1([N:5]2[NH:9][CH:8]=[C:7]([C:10]3[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=3)[S:6]2)[CH2:22][CH2:21][CH2:20][CH2:2][CH2:3]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCCO)S1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCCCC2)S1

Procedure:
A mixture composed of 7.4 g. of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole (Example 16), 6 g. of piperidine, and 200 ml. of dioxane is stirred at room temperture for 24 hours, and then taken to dryness under reduced pressure. The residue is shaken with 100 ml. of water and the insoluble portion collected and dried. Recrystallization from 150 ml. of 2-methoxyethanol gives 7.6 g. of the subject compound melting at 212°-213° C.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[CH:6]N=[C:4]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[S:14]1C=CN=C1>>[ClH:1].[S:14]1[CH:6]=[CH:7][N:3]=[C:4]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: c1cscn1
Reactant: c1c[nH]c(C2CCNCC2)n1
Agent: Cl
Product: c1csc(C2CCNCC2)n1

Procedure:
Prepared similarly as in the case of 4-(1H-imidazol-2-yl)piperidine dihydrochloride using 1,3-thiazole instead of 1-(diethoxymethyl)-1H-imidazole in Step A. 1H NMR (400 MHz, D2O): 8.24 (m, 1 H), 7.90(m, 1H), 3.77-3.68 (m, 1H), 3.57 (br. d, J=13 Hz, 2H), 3.19 (br. t, J=13 Hz, 2H), 2.42 (br. d, J=13 Hz, 21), 2.11-2.01 (m, 2H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:19][CH2:20]4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=3)(=[O:33])=[O:32])[CH:3]=2)[C:48]([CH3:61])=[N:47]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 90.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (intermediate 66G) (100 mg, 0.148 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (74 mg, 0.223 mmol) using Pd(PPh3)2Cl2 (6 mg, 0.007 mmol) and sodium carbonate (40 mg, 0.372 mmol) in toluene/ethanol/water (6/5/2 ml) to afford 100 mg (90.1% yield) of the titled compound after column purification using 50% ethyl acetate in hexane as eluent. MS: m/z=747.8 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:37])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[C:30](=[O:35])[C:29]2=[O:36])[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:37])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[C:30](=[O:35])[C:29]2=[O:36])[CH:23]=1
Reactant: CN1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C(=O)C1=O
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a suspension of 60% sodium hydride (192 mg, 4.8 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (466 mg, 4.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (200 mg, 1.2 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (51 mg, 20%) as a white solid: LC/MS m/e calcd for C24H28N4O5S (M+H)+: 485.58, observed: 485.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:38][CH2:37][CH:36]2[C:39]([O-])=[O:40])[CH2:31][CH2:30]1)=[O:28])[CH3:25].[Li+]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C@H:11]2[CH2:15][N:14]([C:39]([CH:36]3[CH2:37][CH2:38][N:35]3[CH:32]3[CH2:31][CH2:30][N:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:33]3)=[O:40])[C@H:13]([C:16](=[O:17])[NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)[CH2:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Cl)c3)CN2)CC1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3cccc(Cl)c3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(3-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7F and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(3-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (64%). MS ISP (m/e): 592.4/594.3 (100/41) [(M+H)]+.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)[NH2:2].[N:37]#[C:38]Br>C(O)C.CCOC(C)=O>[NH2:23][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:10]3[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:8][C:7]4[CH:6]=[CH:5][N:4]5[C:38]([NH2:37])=[N:2][N:1]=[C:3]5[C:12]=4[N:11]=3)=[CH:18][CH:17]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Reactant: N#CBr
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nnc2c3nc(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)cc3ccn12
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl {1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) (30 mg, 0.0620 mmol), cyanogen bromide (19.8 mg, 0187 mmol) in ethanol (2 mL) was stirred at 60° C. for 72 hours. The mixture was diluted with AcOEt, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel. The residue was treated with HCl in MeOH and the mixture was heated in a microwave reactor at 80° C. for 5 min. The solvent was evaporated and the residue was purified by reverse phase HPLC (H2O/0.1% TFA aq.-MeCN/0.1% TFA aq.) to give 9-[4-(1-aminocyclobutyl)phenyl]-8-phenyl[1,2,4]triazolo[4,3-h]-1,7-naphthyridin-3-amine (8-1) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](O)=[O:19])=[C:12]([C:21]([F:24])([F:23])[F:22])[C:11]=1[Cl:25].[NH:26]1[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:26]2[CH2:27][CH2:28][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][CH2:36]2)=[O:19])=[C:12]([C:21]([F:23])([F:22])[F:24])[C:11]=1[Cl:25]
Reactant: COc1ccccc1Sc1ccc(/C=C/C(=O)O)c(C(F)(F)F)c1Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccccc3OC)c(Cl)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To the acyl chloride (37 mg, 0.1 mmol) prepared from the compound of Example 351B, as a solution in CH2Cl2 was added 1.2 eq. of ethyl isonipecotate and 1.2 eq. of Hunig's base. The mixture was stirred at room temperature for 20 min., ˜90% of the solvent was removed in vacuo, and the resultant solution was loaded on a silica column to elute with hexane and EtOAc (3:2) to give 51 mg (98%) of the title compound. 1H-NMR (CDCl3, 300 MHz) δ 1.25 (t, J=7.5 Hz, 3H), 1.65-1.78 (m, 2H), 1.92-2.02 (br, 2H), 2.51-2.60 (m, 1H), 2.93-3.24 (br, 2H), 3.82 (s, 3H), 3.88-3.96 (m, 1H), 4.15 (q,J=7.5 Hz, 2H), 4.40-4.50 (br, 1H), 6.48 (d, J=l15 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 7.02 (d, J=7.5 Hz, 2H), 7.12 (d, J=9 Hz, 1H), 7.49 (t, J=9 Hz, (qq, J=4.5 Hz, 1H). MS (DCI/NH3) m/e 528 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[N:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccc(O)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and tyramine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>CN(C=O)C.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[CH:20]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[CH2:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cnnc(-c2cccc(C(F)(F)F)c2)c1Br
Agent: Cl[Pd+]
Agent: [CH2-]c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1c(OC)cnnc1-c1cccc(C(F)(F)F)c1
Yield: 41.6 %

Procedure:
4-Bromo-5-methoxy-3-[3-(trifluoromethyl)phenyl]pyridazine (1.0 g, 0.003 mole, Compound No. 57), vinyltributyltin (1.1 g, 0.0034 mole) and trans-benzyl(chloro)bis-(triphenylphosphine)-palladium(II) (20 mg) were heated to 110° C. in DMF (50 mL) under N2 for 4 h. The reaction was then cooled and partitioned between aqueous KF and ethyl acetate. The KF solution was extracted with additional ethyl acetate. The organic layers were washed with brine, dried (MgSO4), filtered through silica gel and then evaporated in vacuo. The crude oil was then chromatographed on a Prep-500 to give 4-ethenyl-5-methoxy-3-[3-(trifluoromethyl)phenyl]pyridazine (0.35 g, 42% yield, Compound No. 55) as a light brown solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:26])=[CH:20][C:21](OCC)=[O:22])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1COCC1>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:26])=[CH:20][CH2:21][OH:22])=[CH:17][CH:18]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C=C(C)c1ccc(C2CCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=CCO)c1ccc(C2CCCCC2)cc1

Procedure:
The LiAlH4 reduction of ethyl 3-(4′-cyclohexylphenyl)-but-2-enoate (3b) using THF as solvent under refluxing conditions did not provide the desired compound.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([C:46]#[N:47])[CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4([C:46]#[N:47])[CH2:45][CH2:44]4)=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N#CC1(c2ccc(Br)cn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C#N)CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 16 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclopropanecarbonitrile following a procedure analogous to that described in Example 1. Yield: 16% of theory; Mass spectrum (ESI+): m/z=496 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.81 (s, 3H), 1.18 (s, 3H), 1.47 (d, J=7.0 Hz, 3H), 1.70-1.74 (m, 2H), 1.81-1.85 (m, 2H), 2.02 (s, 2H), 2.11-2.20 (m, 1H), 2.38-ca. 2.50 (m, 2H) superimposed by D3CSOCHD2 signal, 3.03 (mc, 1H), 4.23 (s, 1H), 5.44 (q, J=7.0 Hz, 1H), 6.98 (d, J=8.3 Hz, 2H), 7.26-7.39 (m, 5H), 7.44 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 1H), 8.03 (dd, J=8.3, 2.4 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:35])[N:4]([C:18]2[C:32]([F:33])=[CH:31][C:21]([CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:20][C:19]=2[F:34])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Cl>O1CCCC1>[ClH:1].[NH2:23][CH2:22][C:21]1[CH:20]=[C:19]([F:34])[C:18]([N:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Cl:1])[C:3]2=[O:35])=[C:32]([F:33])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: NCc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1

Procedure:
tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzylcarbamate (from step 3) (1.39 g, 2.71 mmol) was dissolved in 20 ml tetrahydrofuran and treated with 4 ml concentrated hydrochloric acid. The solution was evaporated and dried in vacuo to a fine white solid (1.20 g, 99%). 1H-NMR (400 MHz, DMSO-d6) δ 8.54 (m, 2H), 7.86 (d, J=7.57 Hz, 1H), 7.65 (quartet, J=7.62, 1H), 7.50 (d, J=9.25 Hz, 2H), 7.34 (dt, J=10.50, 2.45 Hz, 1H), 7.16 (dt, J=8.38, 2.55 Hz, 1H), 6.78 (d, J=7.86 Hz, 1H), 5.37 (s, 2H), 4.10 (br s, 2H), 4.97-3.14 (v br s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ −109.21 (quintet, J=7.77 Hz, 1F), −113.51 (quartet, J=8.95 Hz, 1F), −119.56 (d, J=9.44 Hz, 2F). LC/MS tr=4.33 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 413 (M+H). ES-HRMS m/z 413.0712 (M+H calcd for C19H14ClF4N2O2 requires 413.0674).
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:8][NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH2:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][C:24]1[NH:25][CH2:26][CH2:27][CH2:28][N:29]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[CH2:35]([O:34][C:32]([NH:31][C@@H:7]([CH2:8][NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH2:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][C:24]1[NH:25][CH2:26][CH2:27][CH2:28][N:29]=1)[C:6]([OH:42])=[O:5])=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNc1ncnc2c1ncn2CCCC(=O)NC1=NCCCN1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCCn1cnc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)O)ncnc21)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70 mg (Q.12 mmol) of (2S)-2-benzyloxycarbonylamino-3-{9-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-9H-purin-6-ylamino}-propionic acid tert-butyl ester was dissolved in 3 ml of trifluoroacetic acid/water (95/5). The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water 1/1 and lyophilized. Yield: 51 mg (trifluoroacetate salt).