Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[Si:14]([O:13][CH2:12][CH2:11][NH2:10])([C:27]([CH3:29])([CH3:30])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](OCCNC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](OCCN)(c1ccccc1)c1ccccc1
Yield: 72.1 %

Procedure:
A solution of [2-(t-butyldiphenylsilyloxy)ethyl]carbamic acid benzyl ester (3.01 g, 6.9 mmol) (obtained as described in Reference Example 33(1)) in methanol (150 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (3.0 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (10:1) as the eluant to afford 2-(t-butyldiphenylsilyloxy)ethylamine (1.49 g, yield 72%) as a pale brown syrup.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)[CH2:3]P(=O)(OC)OC.C(N(CC)CC)C.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1>[Br:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[CH:3]/[C:2]([C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:1])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COP(=O)(CC(=O)c1ccnnc1)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Br)cc1)c1ccnnc1
Yield: 7 %

Procedure:
To a solution of dimethyl 2-oxo-2-(pyridazin-4-yl)ethylphosphonate (1.83 g, 7.95 mmol) in THF (18 mL) was added triethylamine (885 mg, 8.75 mmol) and 4-bromobenzaldehyde (1.49 g, 7.95 mmol) at 0° C. After 6 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was suspended in ethyl acetate and the title compound (824 mg, 36%) collected by filtration. Chromatography of the mother liquor (SiO2; ethyl acetate) produced a second crop of product (160 mg, 7%). Light yellow solid, MS: 288.9 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][NH2:25]>CN1CCCC1=O>[CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13]([NH:22][CH2:23][CH2:24][NH2:25])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(Cl)nc12
Solvent: CN1CCCC1=O
Product: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(NCCN)nc12
Yield: 56 %

Procedure:
The mixture 138 mg of 7-benzylamino-5-chloro-3-isopropylpyrazolo[4,3-d]pyrimidine (XVI), 0.62 mL of 2-aminoethylamine (20 eq.) and 0.6 mL of N-methyl-2-pyrrolidone was heated at 125° C. for 12 hours. The reaction mixture was evaporated to dryness in vacuo and then chromatographed over silica gel. The mixture of chloroform/methanol/NH4OH (91:9:1) was used as a mobile phase. Yield=56%; mp=145-147° C.; MS (ES+): 326.1 (100%, M+H+). 1H-NMR (300 MHz, CD3OD): 1.41 d (6H, J=6.9 Hz), 3.10 t (2H, J=5.8 Hz), 3.35 sept (1H, J=6.9 Hz), 3.73 t (2H, 5.8 Hz), 4.86 s (2H), 7.34 m (5H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3][CH2:5][CH2:6]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC1CCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCCC1
Yield: 85 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclopentylamine (0.080 ml, 0.81 mmol), and acetic acid (0.1 ml) were used to give 108.3 mg (0.37 mmol, 85% yield) of the title compound.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([NH:21][CH3:22])[CH:13]=1.[OH-].[Na+]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: O=CO
Reactant: CNc1cc(F)ccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1ccc(F)cc1N(C)C=O
Temperature: 25 °C
Reaction time: 1.83 h

Procedure:
A mixture of acetic anhydride (26.5 ml) and formic acid (98%, 17.4 ml) was stirred at 50°-60° for 110 minutes and then cooled to ambient temperature. 4'-Fluoro-2'-(methylamino)acetophenone (19.9 g) was added and the mixture stirred overnight at ambient temperature. Water (90 ml) was added and the mixture stirred in an ice/ salt bath. Aqueous sodium hydroxide (specific gravity 1.5, 50 ml) was added dropwise over a period of 30 minutes whilst maintaining the temperature below 30°. The mixture was extracted with dichloromethane (3×50 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-5'-fluoro-N-methylformanilide.
Reaction SMILES: CN1CCOCC1.Cl.[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]([C:16]([O:18][CH3:19])=[O:17])[NH2:15].[C:20]1(=[O:41])[N:24]([NH:25][C@H:26]([C:33](O)=[O:34])[CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:23](=[O:36])[C:22]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:21]12.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C=O>[C:23]1(=[O:36])[N:24]([NH:25][C@H:26]([C:33]([NH:15][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][OH:9])=[O:34])[CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:20](=[O:41])[C:21]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:22]12
Reactant: COC(=O)[C@@H](N)CCCCO
Reactant: O=C(O)[C@H](Cc1ccsc1)NN1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCCCO)NC(=O)[C@H](Cc1ccsc1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Methylmorpholine (1.89 ml., 18.12 mmol.) was added to a solution of 6-hydroxy-L-norleucine, methyl ester, hydrochloride (10.66 mmol.) in methylene chloride (41 ml.)/dimethylformamide (11 ml.) at room temperature under argon. The resulting mixture was cooled to 0° C. and N-phthalimido-3-(3-thienyl)-L-alanine (3.21 g., 10.66 mmol.), hydroxy-benzotriazole (1.48 g., 10.98 mmol.), and 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (2.25 g., 11.73 mmol.) were added sequentially. After stirring at 0° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 2 hours. The volatiles were evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with 0.5 N hydrochloric acid, water, saturated sodium bicarbonate, and brine, and the organic layer was dried (sodium sulfate), filtered, and concentrated. The residue was flash chromatographed (Merck silica gel) eluting with 4:1 ethyl acetate/hexane to give 3.8 g. of title compound as a white foam. TLC (ethyl acetate) Rf =0.56.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:21])[CH2:11]2)[CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=1[F:40])#[N:30].C([O-])(O)=O.[Na+]>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.O1CCOCC1>[C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[O:21])[CH2:11]3)[CH:3]=2)=[CH:33][C:32]=1[F:40])#[N:30]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To cis-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (204 mg, 0.486 mmol) and (4-cyano-3-fluorophenyl)boronic acid (104 mg, 0.632 mmol) were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL), and the resulting mixture was purged (“degassed”) with N2 into a sealable tube for 5 minutes. Pd(Ph3P)4 (28 mg, 0.024 mmol) was added, and N2 gas was bubbled through the mixture for an additional 5 minutes. The tube was sealed, and the reaction mixture was stirred overnight at 100° C. The reaction mixture was poured onto water. The precipitate formed was filtered. EtOAc was added to the solid in the filter, and the mixture was stirred gently with a spatula until the solid dissolved. The resulting solution was filtered, and the filtrate was dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc/Hexanes) afforded the title compound (152 mg) as a yellow foam. LC-MS (ES) m/z=505 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[C@@H:20]([OH:32])[CH2:19]1)=[O:17].C(N(CC)CC)C>CS(C)=O.C(Cl)Cl.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[C:20](=[O:32])[CH2:19]1)=[O:17]
Reactant: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a stirred solution of 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide (318 mg; example 1C) in DMSO/CH2Cl2 1:1 (6 ml) were added triethylamine (0.73 ml) and SO3-pyridine complex (638 mg). The mixture was stirred overnight at r.t. The clear brown solution was diluted with dichloromethane, washed with 0.5 N HCl, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 95:5) to give 5-chloro-thiophene-2-carboxylic acid {(1S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentyl}-amide (225 mg) as light yellow amorphous solid. MS 474.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:18]([CH3:19])=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1.[Li]CCCC.[C:33](C#N)(=[O:37])[O:34][CH2:35][CH3:36]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:18]([CH3:19])=[CH:17][C:16]2[C:12](=[C:13]([C:33]([O:34][CH2:35][CH3:36])=[O:37])[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1
Reactant: CCOC(=O)C#N
Reactant: COc1ccc(-c2cc3cn(COCC[Si](C)(C)C)nc3cc2C)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c2cc(-c3ccc(OC)cc3F)c(C)cc2nn1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a solution of 5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (650 mg, 1.68 mmol) in THF (10 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.74 mL, 1.85 mmol) dropwise via syringe. The reaction was stirred at −78° C. for 10 minutes, warmed to room temperature for 5 minutes, and cooled back to −78° C. A solution of ethyl cyanocarbonate (188 mg, 1.90 mmol) in THF (1 mL) was added via syringe. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with aqueous NH4Cl solution and diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc/heptane) to provide the title compound (448 mg, 58% yield). MS (ES+) 459.3 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.69 (s, 1H), 7.22 (t, J=8.54 Hz, 1H), 6.81 (dd, J=8.42, 2.32 Hz, 1H), 6.75 (dd, J=11.34, 2.32 Hz, 1H), 6.20 (s, 2H), 4.49 (q, J=7.07 Hz, 2H), 3.89 (s, 3H), 3.66-3.72 (m, 2H), 2.29 (s, 3H), 1.44 (t, J=7.07 Hz, 3H), 0.93-1.00 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[C:10]2[CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[S:20][C:9]1=2)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-].S1C2NC3C(C=2C=C1C(OC)=O)=CC=CC=3>>[Br:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][C:9]1[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:10]2=1
Reactant: COC(=O)c1cc2c3cc(Br)ccc3n(Cc3ccccc3)c2s1
Agent: COC(=O)c1cc2c([nH]c3ccccc32)s1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1cc2c([nH]c3ccc(Br)cc32)s1
Yield: 19.4 %

Procedure:
Prepared from (39) (1 g) by means of AlCl3 (2 g) as described for (19) gave 0.15 g of (41), m.p. 216°-218° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[Cl:39][C:40]1[CH:53]=[CH:52][C:43]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH:47]([NH2:51])[CH2:46]2)=[CH:42][CH:41]=1>C(Cl)(Cl)Cl.CCN(CC)CC>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH:47]([NH:51][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:12]=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)[CH2:46]2)=[CH:52][CH:53]=1
Reactant: NC1CCCN(Cc2ccc(Cl)cc2)C1
Reactant: Cc1cccc(C(=O)NCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=O)NCC(=O)NC2CCCN(Cc3ccc(Cl)cc3)C2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(3-Methylbenzoyl)glycine (10.6 mg, 0.055 mmol), EDCI (10.5 mg) and 1-hydroxybenzotriazole hydrate (7.4 mg) were added to a solution of 1-(4-chlorobenzyl)-3-aminopiperidine dihydrochloride (14.9 mg, 0.050 mmol) and Et3N (15.2 mg) in CHCl3 (2.5 mL). The reaction mixture was stirred at 25° C. for 16 h, washed with 2 N aqueous NaOH (2 mL×2) and brine (1 mL). After filtration through PTFE membrane filter, the solvent was removed under reduced pressure to afford 1-(4-chlorobenzyl)-3-[{N-(3-methylbenzoyl)glycyl}amino]piperidine (compound No. 355) as a pale yellow oil (17.4 mg, 87%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 400.0 (M++H, C22H26ClN3O2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([F:28])=[C:12]([C@H:17]([NH:20][CH:21]([CH:25]([CH3:27])[CH3:26])[CH2:22][C:23]#[N:24])[CH2:18][CH3:19])[CH:13]=[CH:14][C:15]=2[Cl:16])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:30].C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([F:28])=[C:12]([C@H:17]([NH:20][C@@H:21]([CH:25]([CH3:27])[CH3:26])[CH2:22][C:23]([NH2:24])=[O:30])[CH2:18][CH3:19])[CH:13]=[CH:14][C:15]=2[Cl:16])=[O:9])=[CH:4][CH:3]=1
Reactant: CC[C@@H](NC(CC#N)C(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@@H](N[C@H](CC(N)=O)C(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step 2 To a rapidly stirred solution of crude 3-{[(1R)-1-{3-[(6-aminopyridin-3-yl)carbonyl]-4-chloro-2-fluorophenyl}propyl]amino}-4-methylpentanenitrile (0.911 mmol) in toluene (2.91 mL) and water (0.145 mL) at 0° C. was added sulfuric acid (0.966 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was made neutral by the addition of saturated Na2CO3 solution followed by saturated NaHCO3 solution and was extracted into EtOAc (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by chiral preparative HPLC to give (3R)-3-{[(1R)-1-{3-[(6-aminopyridin-3-yl)carbonyl]-4-chloro-2-fluorophenyl}propyl]amino}-4-methylpentanamide which was converted to the HCl salt, 0.0656 g and (3S)-3-{[(1R)-1-{3-[(6-aminopyridin-3-yl)carbonyl]-4-chloro-2-fluorophenyl}propyl]-amino}-4-methylpentanamide which was also converted to the HCl salt, 0.0259 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])=[C:6]([CH:9]=1)[C:7]#[N:8].C([Li])CCC.[Li+].[C:22]([O-:30])(=[O:29])C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>O.C(O)(=O)C.C1COCC1>[C:7]([C:6]1[CH:9]=[C:2]([CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])[C:22]([OH:30])=[O:29])#[N:8]
Reactant: O=C([O-])c1ccccc1
Reactant: CC[C@H](C)COc1ccc(Br)cc1C#N
Agent: O=C(O)c1ccccc1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC[C@H](C)COc1ccc(C(=O)O)cc1C#N

Procedure:
Quantities: compound 41 (5.00 g, 0.016 mol), n-butyllithium (2.5 M, 7.2 ml, 0.018 mol), THF (100 ml). The experimental procedure was as described for compound 36 except that the n-butyllithium was added between −90° C. and −100° C. Acidification of the resultant benzoic acid lithium salt was achieved by boiling with glacial acetic acid. The benzoic acid was crashed out of solution by diluting with a large volume of water, the resultant product was washed with water (until acid-free) and then purified as described for compound 36 to leave an off-white semi-solid.
Reaction SMILES: CN(C)C(=N)N(C)C.[CH:9]([OH:11])=[O:10].[O:12]([CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([C:27](=[C:44]([CH3:47])[CH2:45]Br)[C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:24]1=[O:48])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[O:12]([CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([C:27](=[C:44]([CH3:47])[CH2:45][O:11][CH:9]=[O:10])[C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:24]1=[O:48])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(CBr)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reactant: O=CO
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Product: CC(COC=O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.65 ml (5 mmol) of tetramethyl guanidine and 0.15 ml (5 mmol) of formic acid in 20 ml of methylene chloride at 0° was added 563 mg (1 mmol) of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-4-bromo-2-butenoate. The reaction mixture was stirred for 15 minutes at 0° and 2 hours at room temperature. Methylene chloride (100 ml) was added. The resulting solution was washed with brine (3X), dried, and evaporated in vacuo to dryness to provide the title product: nmr (CDCl3) δ 2.17 and 2.05 (s, 3, CH3), 4.92 (m, 2, --CH2O--), 3.60 (m, 2, C4 --H), 4.98 (m, 1, C3 --H), 4.48 (s, 2, side chain CH2), 7.2 (b, ArH) and 8.03 (s, 1, --OCHO).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH3:9].[C:33](Cl)(=[O:36])[CH2:34][CH3:35].Cl>O>[C:33]([O:7][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:18][N:17]=2)=[CH:14][CH:15]=1)[CH3:9])(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OC(=O)CC)cc2)nc1
Yield: 97 %

Procedure:
Into 20 ml of pyridine were dissolved 1.78 g (5 millimole) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in the Preparation Example starting material compound (VI)] 70, and then 0.56 g (6 millimole) of propionic chloride was added thereto, to subject to reaction at 30 to 40° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, adjusted to pH 1 to 2 with 4N hydrochloric acid, and then extracted with 200 ml of toluene, followed by separation thereof. The organic phase was washed with water, 5% aqueous sodium hydrogen carbonate solution and water in this order. After drying over anhydrous magnesium sulfate, the residue obtained by distilling the organic solvent off under reduced pressure was purified by silica gel column chromatography (eluent; toluene: ethyl acetate) to obtain 2.00 g (yield: 97%) of (+)-2-(4-(1-Propanoyloxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:24])[NH:16][C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[O:7])=[CH:4][N:3]=1>C(N)CC>[CH2:2]([NH:3][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:24])[NH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:8][CH2:6][CH2:5][CH3:4])=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[O:7])=[CH:4][N:3]=1)[CH2:26][CH3:25]
Reactant: O=C(Nc1ccc(C(=O)Nc2ccc(Br)cn2)cn1)c1ccc(Br)nc1
Solvent: CCCN
Product: CCCNc1ccc(NC(=O)c2ccc(NC(=O)c3ccc(NCCC)nc3)nc2)nc1
Yield: 77.1 %

Procedure:
6-Bromo-N-(5-(5-bromopyridin-2-ylcarbamoyl)pyridin-2-yl)nicotinamide 6 (350 mg, 0.73 mmol) was dissolved in neat n-propylamine. The reaction mixture was heated for 3 days at reflux temperature. Then the solvent was evaporated to give a crude product, which was crystallized in EtOAc to give 6-(propylamino)-N-(5-(5-(propylamino)pyridin-2-ylcarbamoyl)pyridin-2-yl)nicotinamide 7 (122 mg, 38% yield) as a white solid. Mp. 249-250° C.
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[CH:14]=[C:13]([CH2:16][NH:17][C@@:18]([CH3:24])([C@@H:21]([OH:23])C)[CH2:19][OH:20])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C2C=[C:36]([CH:39]=[O:40])C3C(=CC=CC=3)C=2C=CC=1.Cl.NC(COCC)(CO)CO>>[ClH:1].[CH2:39]([O:40][CH2:24][C:18]([NH:17][CH2:16][C:13]1[C:12]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:15]=3[CH:14]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH2:21][OH:23])[CH2:19][OH:20])[CH3:36]
Reactant: O=Cc1cc2ccccc2c2ccccc12
Reactant: C[C@H](O)[C@@](C)(CO)NCc1cc2ccccc2c2ccccc12
Agent: CCOCC(N)(CO)CO
Agent: Cl
Product: CCOCC(CO)(CO)NCc1cc2ccccc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined for 7G, phenanthrene-9-carbaldehyde (Aldrich) and 2-amino-2-ethoxymethyl-1,3-propanediol hydrochloride.1/4H2O (8B) gave 2-ethoxymethyl-2-(((9-phenanthrenyl)methyl)amino)-1,3-propanediol hydrochloride mp 173°-175°, (EtOH/Et2O), (C,H,Cl,N).