Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]2[O:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)CC2C=CC=CC=2)[OH:10])=[CH:4][C:3]=1[Cl:38].Cl.C(O)C>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([Cl:38])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]2[O:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCc2nc3ccccc3o2)Cc2ccccc2)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2nc3ccccc3o2)cc1Cl

Procedure:
A solution of 4-amino-3,5-dichloro-α-[[[6-[2-(2-benzoxazolyl)ethoxy]hexyl](phenylmethyl)amino]methyl]benzenemethanol (1.09 g) in ethanol (25 ml) containing conc. hydrochloric acid-ethanol (1:9, 1.78 ml) was added to a pre-hydrogenated suspension of 10% palladium on carbon (50% aqueous paste, 0.65 g) and hydrogenated at room temperature and pressure, then filtered through hyflo and evaporated in vacuo. The residue was partitioned between 8% sodium bicarbonate (25 ml) and ethyl acetate (50 ml) and the organic phase dried and evaporated in vacuo to a semi solid. Purification by FCC over silica (Merck 60) eluting with System B (97:2:1→94:5:1) afforded the title compound as a gum, which crystallised after trituration with hexane to a white solid (613 mg) m.p. 85°-87°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][NH:4][C:3]1=[O:14]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][NH:4][C:3]1=[O:14]
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)NCC1C(=O)O
Yield: 100 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (801 mg, 4 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in TFA/DCM (trifluoroacetic acid/dichloromethane) (1:2, 9 ml) was stirred at room temperature for 6 hours. The solution was evaporated, the residue was co-evaporated with toluene and dried to give crude 3-methyl-2-oxo-4-imidazolidinecarboxylic acid (assume ˜4 mmol) which was used in the next step. LC/MS [M+H]+=145.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:13]=2[O:14][CH3:15])=[C:5]([CH3:25])[C:4]=1[F:26])#[N:2].C1C=C2N=NN(O)C2=CC=1.O.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C.[CH2:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH3:60]>CN(C=O)C>[CH2:59]([N:61]1[CH2:66][CH2:65][N:64]([C:20]([C:19]2[CH:23]=[CH:24][C:16]([N:12]3[C:13]([O:14][CH3:15])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:26])[C:5]=4[CH3:25])[CH:10]=[N:11]3)=[N:17][CH:18]=2)=[O:22])[CH2:63][CH2:62]1)[CH3:60]
Reactant: CCN1CCNCC1
Reactant: COc1c(-c2ccc(C#N)c(F)c2C)cnn1-c1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3OC)nc2)CC1
Yield: 52 %

Procedure:
Combined 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-methoxy-1H-pyrazol-1-yl)nicotinic acid (106 mg, 0.300 mmol), HOBT hydrate (68.9 mg, 0.450 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (86 mg, 0.450 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.157 mL) in DMF (1 mL) and stirred for 5 min. The mixture was then added to 1-ethylpiperazine (68.5, 0.600 mmol). After 18 hours the reaction mixture was purified via preparative HPLC (20-40% acetonitrile in water, with TFA) to give 4-(1-(5-(4-ethylpiperazine-1-carbonyl)pyridin-2-yl)-5-methoxy-1H-pyrazol-4-yl)-2-fluoro-3-methylbenzonitrile (70 mg, 0.156 mmol, 52%). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[F:7][C:8]([F:19])([F:18])[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.S(=O)(=O)(O)O.CCOCC>C1COCC1>[F:7][C:8]([F:18])([F:19])[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)[Mg]Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available t-butyl magnesium chloride in THF (1.0 mol) is added at 38°-40° C. a solution of 4-trifluoromethoxybenzaldehyde (56 g, 0.4 mol) in THF (50 ml) under nitrogen atmosphere. The reaction solution is stirred at room temperature overnight and cautiously acidified with dilute sulfuric acid at 15°-20° C. Ether is added and the organic phase is washed with water, dried (Na2SO4) and evaporated to a gummy solid. The crude material is purified by silica gel chromatography to give the alcohol which is used in Example 37.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[NH2:25][C:26]1[C:34]2[O:33][C:32]([F:36])([F:35])[O:31][C:30]=2[CH:29]=[CH:28][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:25][C:26]3[C:34]4[O:33][C:32]([F:36])([F:35])[O:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Nc1cccc2c1OC(F)(F)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2cccc3c2OC(F)(F)O3)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 815 mg, 2.19 mmol), 4-amino-2,2-difluoro-1,3-benzodioxole (950 mg, 5.49 mmol), p-toluenesulfonic acid monohydrate (416 mg, 2.19 mmol) and xylene (3.0 mL) was stirred at 150° C. for 2 hr. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound as a colorless powder (900 mg, 1.77 mmol, 81%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[S:2].[N:13]1[C:22]2[C:17](=CC(N)=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[N:8]([C:12]1[CH:11]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:13]=[CH:14][CH:15]=[CH:16]2)=[C:1]=[S:2]
Reactant: Nc1ccc2ncccc2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: S=C=Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
1,1′-Thiocarbonyldiimidazole (740 mg, 4.16 mmol) was added portion-wise to a solution of quinolin-6-amine (0.50 g, 3.47 mmol) in DCM (15 mL) at 0° C., and the mixture was stirred at rt for 1.5 hrs. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography eluted with DCM to give 0.60 g (93% yield) of the titled compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].C(OCC)C>C(Cl)Cl>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:29](=[O:31])[CH3:30])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCN1CCN(c2cccc3c2C[C@H](NC(C)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-butylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.35 mmol) and triethylamine (53 μL, 0.53 mmol) in methylene chloride (25 mL) was added dropwise acetyl chloride (25 ,μL, 0.35 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The methylene chloride phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave, after crystalization from diethyl ether, 100 mg (89% yield) of the title compound as white crystals: mp 118-120° C.; [α]21D +25° (c 0.54, chloroform); EIMS (70 eV) m/z (relative intensity) 329 (41, M+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([O-])=O.C(OCC)(=O)C>[Pd].CO>[NH2:1][C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1
Reactant: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc2c(cc1N)OCO2
Reaction time: 3 h

Procedure:
A mixture of the methyl 6-nitro-1,3-benzodioxole-5-carboxylate, 5% palladium on carbon (1.5 g), ethyl acetate (180 mL) and methanol (80 mL) was stirred 3 hours under a hydrogen atmosphere (15 psi). The mixture was filtered and concentrated and the residue was recrystallized from cyclohexane (200 mL) to give methyl 6-amino-1,3-benzodioxole-5-carboxylate (6.3 g, 32 mmol), m.p. 107°-108° C.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[NH:13][CH:14]=[C:15]([C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)=[O:11]>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10]([C:12]1[NH:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)Cc2ccccc2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(CCc2ccccc2)c[nH]1
Reaction time: 8 h
Yield: 50.3 %

Procedure:
Triethylsilane (0.323 mL, 2.03 mmol) was added to a stirring, room temperature solution of methyl-4-phenylacetyl-1H-pyrrole-2-carboxylate (0.1593 g, 0.655 mmol) in trifluoroacetic acid (TFA) (1.47 mL, 0.45 M) under N2. After stirring overnight, the reaction was complete by HPLC. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 95:5 Hexanes:EtOAc) to obtain pure 27 (0.0755 g, 50.3%): 1H (CDCl3, 400 MHz): δ 9.17 (1H, broad s), 7.32-7.25 (2H, m), 7.23-7.17 (3H, m), 6.80 (1H, s), 6.69 (1H, s), 3.85 (3H, s), 2.93-2.85 (2H, m), 2.84-2.75 (2H, m) ppm. 13C (CDCl3, 100 MHz): δ 161.97, 142.15, 128.70, 128.55, 126.13, 125.96, 122.40, 121.26, 115.28, 51.67, 37.57, 28.92 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 51.67; CH2 carbons: 37.57, 28.92; CH carbons: 128.70, 128.55, 126.13, 121.26, 115.28 ppm. HPLC: 10.033 min. (Starting material: 8.751 min.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.[NH:19]1[CH2:22][CH2:21][CH2:20]1>>[N:19]1([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:22][CH2:21][CH2:20]1
Reactant: C1CNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Yield: 83 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (100 mg, 0.47 mmole) by treatment with thionyl chloride followed by coupling with azetidine, in a manner as previously described for example 9d to afford 98 mg (83%) of a dark yellow solid. 1H NMR (DMSO-d6) δ 8.72 (1H, d, J=5.1 Hz), 7.96 (1H, s), 7.70 (1H, d, J=5.1 Hz), 4.62 (2H, t, J=7.4 Hz), 4.12 (2H, t, J=7.7 Hz), 2.34 (2H, tt, J=7.4, 7.7 Hz).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]([C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([NH:12][C@@H:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:14](OC)=[O:15])=[O:11])=[O:6])[CH2:2][CH3:3]>C1(C)C=CC=CC=1>[CH2:25]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([NH:12][C@@H:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]=[O:15])=[O:11])=[O:6])[CH2:26][CH3:27]
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@@H](CC(C)C)C(=O)OC)c1
Solvent: Cc1ccccc1
Product: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@H](C=O)CC(C)C)c1
Reaction time: 0.1 h
Yield: 52.3 %

Procedure:
Methyl(2S)-2-({3-[(dipropylamino)carbonyl]benzoyl}amino)-4-methylpentanoate (1.65 g, 4.4 mmol) in 20 mL of toluene under nitrogen is cooled to −78° C. To this is added, dropwise over 5 min, 11 mL of a 1 M solution of Dibal in toluene. The mixture is stirred an additional 6 minutes, and is then quenched by addition of 2 mL of methanol. The cold bath is removed and 20 mL of a Rochelle salt solution is added and vigorously stirred while the mixture warms to ambient temperature. The product is extracted into ether and the organic phase is washed successively with Rochelle salt solution, water, and brine. It is dried over Na2SO4, concentrated, and chromatographed over silica gel, eluting with 50% ethyl acetate in heptane, to afford the title compound as a colorless oil (0.79 g, 2.3 mmol, 52%). 1H NMR (CDCl3) δ 9.7 (s, 1H), 7.85 (m, 1H), 7.79 (s, 1H), 7.49 (m, 2H), 6.81 (d, J=7 Hz, 1H), 4.78 (m, 1H), 3.46 (br t, 2H), 3.15 (br t, 2H), 1.82 (m, 2H), 1.70 (m, 2H), 1.62-1.53 (m, 3H), 1.01 (m, 9H), 0.75 (br t, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1ccc(F)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cc(F)ccc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.50 g, 0.855 mmol) and (S)-(5-fluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.216 g, 1.027 mmol) in DMF (10 ml) was added sodium hydride (0.051 g, 1.283 mmol) and the resulting yellow mixture was stirred at rt. After 3 h, the mixture was diluted with EtOAc and washed with 1N HCl followed by water then brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 10 CV) to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.1481 g, 0.222 mmol, 26.0% yield) as a red oil. LCMS (M+H) calcd for C37H52FN4O6: 667.38. found: 667.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[F:26])([C:15]([F:18])([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1)#[N:29].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([NH:25][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:35][N:34]=3)=[O:37])[CH:22]=[CH:21][C:20]=2[F:26])([C:15]([F:16])([F:18])[F:17])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)(F)F)CCOC1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)(F)F)CCOC1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of [5-(5-amino-2-fluoro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamic acid tert-butyl ester (50 mg, 0.128 mmol), 5-cyano-2-pyridinecarboxylic acid (28.4 mg, 0.192 mmol) and HOAT (31.3 mg, 0.230 mmol) in 0.5 mL DMF was cooled to 0-5° C. EDC (36.7 mg, 0.192 mmol) and DIPEA (33 mg, 0.256 mmol) were added. The resulting solution was allowed to warm up to rt over night. The reaction mixture was then partitioned between saturated aqueous NaHCO3 solution and EtOAc. The layers were washed with saturated aqueous NaHCO3 solution, brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 4/1→3/1 to give 63.3 mg of the title compound as a white solid.
Reaction SMILES: C(Cl)Cl.Cl.[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1.C(N(CC)CC)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(OCC)C>[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH2:12][O:13][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cncc(Br)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a methylene chloride solution (20 mL) of 3-bromo-5-(hydroxymethyl)pyridine hydrochloride (described in example 69a) (1.00 g, 4.48 mmol) under nitrogen was added triethylamine (2.50 mL, 17.9 mmol, 4 eq) and tert-butyldimethylsilyl chloride (0.75 g, 5.0 mmol, 1.1 eq). The resulting solution was heated to reflux for 18 h, cooled to room temperature and diluted with diethyl ether (200 mL). The organic phase was washed with 2.5N NaOH (1×100 mL), water (3×100 mL) and saturated brine (1×100 mL). The ether solution was dried over anhydrous magnesium sulfate, filtered, and reduced to an colorless oil. The procedure resulted in 1.10 g (81%) of the title compound. The product required no additional purification. TLC analysis (Rf 0.19, ethyl acetate) MS (CI, CH4) m/z 302 (M+1,100), 304 (96), 330 (M+29,4), 332 (4)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[CH3:15].[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH:9]([O:8][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([CH3:15])=[C:2]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)[CH:7]=1)([CH3:11])[CH3:10]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1Br
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1-c1ccncc1
Temperature: 120 °C

Procedure:
To a mixture of 1-bromo-5-isopropoxy-2-methyl-4-nitrobenzene (Step 2, 1 g, 3.65 mmol), pyridine-4-boronic acid (490 mg, 4 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (300 mg, 0.73 mmol) and potassium phosphate (1.55 g, 7.3 mmol) in mixed solvent of dioxane (15 mL) and water (7.5 mL) was added tris(dibenzylidene-acetone)dipalladium (0) (334 mg, 0.36 mmol). This mixture was sealed and purged with nitrogen for 3 minutes and then heated at 120° C. for 5 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. After concentration, the crude product was purified with silica gel flash column chromatography (60% ethyl acetate in hexanes) to afford 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine a as yellow solid: ESMS m/z 273.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].COCCO[Al+]OCCOC.[Na+].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH:14]1([CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][OH:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CO)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (2R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid (30.4 g, 112 mmol) in toluene (300 mL) at 0° C. was treated with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al®) (115 mmol) over 45 minutes. The mixture was stirred for 30 minutes, warmed to room temperature, stirred for 1 hour, treated with aqueous Rochelle salt, and extracted with diethyl ether. The extract was washed with brine and aqueous NaHCO3, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[CH:25]=3)=[O:23])[CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[CH2:1]([N:3]([CH2:6][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:25]=3)=[O:23])[CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Solvent: O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCCC4)c3)ccc2C)cc1
Temperature: 80 °C

Procedure:
Using an analogous procedure to that described in Example 3, a mixture of N-[3-(4-diethylaminomethylbenzamido)-4-methylphenyl]-2-chloropyridine-4-carboxamide (0.5 g) and pyrrolidine (5 ml) was stirred and heated to 80° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water. The resultant solid was isolated, washed with diethyl ether and dried under vacuum at 40° C. There was thus obtained the title compound (0.021 g); NMR Spectrum: (DMSOd6) 1.0 (t, 6H), 1.95 (m, 4H), 2.2 (s, 3H), 2.44-2.49 (m, 4H), 3.42-3.5 (m, 4H), 3.6 (s, 2H), 6.86 (s, 1H), 6.96 (d, 1H), 7.22 (d, 1H), 7.58 (d, 1H), 7.79 (s, 1H), 7.92 (d, 2H), 8.18 (d, 1H), 9.83 (s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H+ 486.