Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([OH:20])[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-(3-hydroxy-4-methoxyphenyl)benzamide (3.11 g, 10.1 mmol) and 2-chloro-5-nitropyridine (1.60 g, 10.1 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (4.24 g, 30.7 mmol), and the mixture was stirred at 60° C. for 16 hr. The reaction solution was cooled to room temperature, and diluted with a mixed solvent (250 mL) of ethyl acetate and hexane (1:1). The solution was washed with water (200 mL×3), and the combined m aqueous layer was extracted with a mixed solvent (100 mL×3) of ethyl acetate and hexane (1:1). The combined organic layer was washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (4.3 g, 99%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:4][N:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>C(#N)C>[CH3:21][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32]([NH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:4][N:3]=1)=[O:33])[CH3:20]
Reactant: CCCCCCCCCCCCc1cc(N)no1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CC#N
Product: CCCCCCCCCCCCc1cc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)no1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A slurry of 3-amino-5-dodecylisoxazole (2.20 g, 8.72 mmol) in acetonitrile (50 mL) was warmed until homogeneous. 2,6-Diisopropylphenyl-isocyanate (1.86 mL, 8.72 mmol) was then added in one portion and the resulting solution was heated under reflux for 6 hours. The resulting solution was cooled (25° C.), concentrated in vacuo, and chromatographed on silica (90:10 to 70;30 hexane:ethyl acetate). The product containing fractions were combined and concentrated to a solid which was washed with cold acetonitrile to yield 0.95 g (23.9%) of the title compound as a white solid, m.p. 101°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[OH-].[Na+]>Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
3-chloroaniline (K-IV) (1 eq., 50 g) was dissolved at −5 to 0° C. in concentrated HCl (300 ml) and stirred for 10 min. A mixture of NaNO2 (1.2 eq., 32.4 g), water (30 ml), SnCl2.2H2O (2.2 eq., 70.6 g) and concentrated HCl (100 ml) was added dropwise over a period of 3 h while maintaining the temperature. After stirring for a further 2 h at −5 to 0° C., the reaction mixture was set to pH 9 using NaOH solution and extracted with EE (250 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. The purification by column chromatography (SiO2, 8% EE/hexane) produced 40 g (72% yield) of (3-chlorophenyl)hydrazine (K-IV) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([O:16]C)=O)=[C:12]([CH2:18][O:19][CH3:20])[NH:11][C:10](=[O:21])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[CH:28]2.C(Cl)CCl.CCN(CC)CC>CO.O.CCOC(C)=O.CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]([C:14]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][N:29]=[CH:28]4)=[O:16])=[C:12]([CH2:18][O:19][CH3:20])[NH:11][C:10](=[O:21])[NH:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)cc2)NC(=O)N1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)cc2)NC(=O)N1
Temperature: 60 °C
Yield: 33.5 %

Procedure:
The product of step (a) (4.03 g, 13.69 mmol, 1 equiv) and NaOH (2.5 N, 20 mL) were dissolved in methanol (60 mL) and heated to 60° C. in a sealed tube for four hours. The reaction mixture was diluted with water (˜50 mL) and EtOAc (˜50 mL), stirred, and separated. The aqueous layer was brought to pH 1 with 2N HCl and extracted with EtOAc. The organic layer was concentrated en vacuo and the residue (650 mg, 2.32 mmol, 1 equiv) was dissolved in DMF (13 mL). 5-aminoindazole (376 mg, 2.78 mmol, 1.2 equiv), EDC (531 mg, 2.78 mmol, 1.2 equiv), Et3N (780 μL, 5.57 mmol, 2.4 equiv) and catalytic DMAP (5 mg) were added and the mixture was heated to 80° C. in a sealed tube for two hours. The residue was dissolved in EtOAc and water and extracted. The organic layer was washed with 1N HCl, satd. NaHCO3 and Brine. The organic layer was concentrated en vacuo and then triturated with CH2Cl2/Hexane to give 368 mg of the title compound as a beige powder (40%). MS (ES+) m/e 396 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:28]=[CH:27][C:16]([NH:17]CC4C=CC(OC)=CC=4)=[C:15]([N+:29]([O-:31])=[O:30])[CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:32]2[CH:47]=[CH:46][C:35]([NH:36]CC3C=CC(OC)=CC=3)=[C:34]([N+:48]([O-:50])=[O:49])[CH:33]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]([C:32]3[CH:47]=[CH:46][C:35]([NH2:36])=[C:34]([N+:48]([O-:50])=[O:49])[CH:33]=3)[CH2:10][CH2:11][CH:12]2[C:13]2[CH:28]=[CH:27][C:16]([NH2:17])=[C:15]([N+:29]([O-:31])=[O:30])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc(NCc5ccc(OC)cc5)c([N+](=O)[O-])c4)N3c3ccc(F)cc3)cc2[N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C2CCC(c3ccc(N)c([N+](=O)[O-])c3)N2c2ccc(F)cc2)cc1[N+](=O)[O-]

Procedure:
The product from Example 29B (0.78 g, 1.15 mmol) was dissolved in dichloromethane (10 mL) at room temperature and treated with TFA (1.8 mL, 23.0 mmol) for 3 h. The residue was concentrated and partitioned between dichloromethane and sodium bicarbonate solution. The organics were concentrated and purified by chromatography on silica gel with a 40 g column, eluting with dichloromethane to give 0.218 g (43%) of the trans isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][N:21]=[CH:22][C:14]=1[CH3:13]
Reactant: Cc1cnccc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: Cc1cnccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 60 °C
Yield: 36.6 %

Procedure:
A mixture of 0.62 g of 2-amino-4-(trifluoromethyl)phenol, 0.48 g of 3-methyl isonicotinic acid, 0.86 g of WSC and 5 ml of pyridine was stirred while heating at 60° C. for three hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated. Water was poured into the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 0.38 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-methylisonicotinamide.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[C:15]([C:18](O)=[O:19])[CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:21]([N:24]([CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C[CH2:56][N:57]=[C:58]=NCCCN(C)C.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([O:40][C:38](=[O:39])[NH:37][CH2:36][CH2:35][CH2:34][N:24]([CH:21]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2=[C:15]([C:18](=[O:19])[N:57]([CH3:58])[CH3:56])[CH:16]=[CH:17][N:11]2[N:10]=1)[CH2:22][CH3:23])[C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)([CH3:43])([CH3:42])[CH3:44]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCC(c1nn2ccc(C(=O)O)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(c1nn2ccc(C(=O)N(C)C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
A mixture of 3-benzyl-2-{1-[(3-tert-butoxycarbonylamino-propyl)-(4-methyl-benzoyl)-amino]-propyl}-4-oxo-3,4-dihydro-pyrrolo[2,1-f]-[1,2,4]triazine-5-carboxylic acid (0.0029 g, 0.0048 mmol), HOBt (0.0013 g, 0.0097 mmol), EDCI (0.002 g, 0.0097 mmol), dimethylamine (2 M in THF, 0.024 ml, 0.048 mmol) and DIPEA (0.003 mL, 0.019 mmol) in DMF (0.5 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum, dissolved in EtOAc (3 mL). The organic solution was washed with 10% LiCl (3×2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 3/1 hexane/EtOAc to afford title compound as a solid (0.001 g, 33%): MS (ESI+) 629 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Yield: 100.4 %

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)benzoic acid (15 g, 66.8 mmol) in methylene chloride (200 mL) was added oxalyl chloride (12.7 g, 100 mmol) drop wise followed by the addition of 5-6 drops of DMF. The reaction mixture was concentrated, the residue partitioned between methylene chloride and 5% aq. sodium carbonate. The organic layer was dried (MgSO4) and concentrated to give the title compound as a pale oil (16 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].C([O-])(=O)C.[NH4+:23].O>C1(C)C=CC=CC=1>[NH2:23]/[C:10](/[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[CH:11]/[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13]
Reactant: C=CCOC(=O)CC(=O)Cc1ccc(F)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)/C=C(/N)Cc1ccc(F)cc1F
Yield: 100.4 %

Procedure:
Allyl 4-(2,4-difluorophenyl)-3-oxobutanoate (5.0 g, 19.67 mmol) and ammonium acetate (7.58 g, 98.33 mmol) were refluxed in toluene (20 mL) for 2 h with azeotropic removal of H2O and then cooled and concentrated. The residue was redissolved in Et2O and the organics washed with 1N HCl (2×), H2O, brine, and then dried (Na2SO4), filtered and concentrated to give 5.0 g (100% yield) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.25–7.14 (m, 1H), 6.63 (dd, J=16.1, 7.9 Hz, 2H), 5.97–5.88 (m, 1H), 5.28 (dd, J=17.2, 1.5 Hz, 1H), 5.19 (dd, J=10.2, 1.1 Hz, 1H), 4.60 (s, 1H), 4.55 (d, J=5.7 Hz, 2H), 3.43 (s, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[O:35][C:34]([CH3:36])=[N:33][CH:32]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[O:35][C:34]([CH3:36])=[N:33][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: COC(=O)Cc1cnc(C)o1
Product: COc1ccc(N2CCN(C(=O)Cc3cnc(C)o3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 54 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (2-methyl-oxazol-5-yl)-acetic acid methyl ester with heating for 12 h to afford the title compound as tan solid (110 mg, 54%). LC/MS (Method B) 3.62 min, [M+1]+ 476.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13](=[O:16])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[CH:23]([Mg]Br)([CH3:25])[CH3:24].OC1(C)C2SC(C(N)=O)=NC=2C2C=C(C#CC(O)(C)C)C=CC=2OC1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:16])([CH:23]([CH3:25])[CH3:24])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: CCOC(=O)c1nc2c(s1)C(=O)COc1cc(F)c(Br)cc1-2
Reactant: CC(C)[Mg]Br
Agent: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(C)(O)CO2
Product: CCOC(=O)c1nc2c(s1)C(O)(C(C)C)COc1cc(F)c(Br)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (133 mg) was reacted with isopropylmagnesium bromide similarly to as described in the synthesis of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo {e}azulene-2-carboxylic amide with non-critical modifications to afford ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (80 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 12 mg and 13 mg (29% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCc1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCc1ccccn1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-[2-(t-butoxycarbonylamino)ethyl]pyridine (2 g) in dimethylformamide (10 ml) was added to a suspension of sodium hydride (0.54 g) in dimethylformamide (10 ml) at 0° C. The mixture was stirred at 0° C for 1 hour and at room temperature for 1 hour. Then a solution of ethyl bromoacetate (1.5 ml) in dimethylformamide (5 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The solution was poured into saturated ammonium chloride (50 ml) and the mixture was extracted with ethyl acetate (30 ml×2). The combined organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified with silica gel column chromatography (MeOH:CHCl3 =1:99 as an eluent) to give 2-[2-{N-(t-butoxycarbonyl)-N-(ethoxycarbonylmethyl)amino}ethyl]pyridine.
Reaction SMILES: C1([Mg]Br)C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14][NH2:15].C[O:20][C:21](=O)[CH:22]([CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[CH2:24].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][N:15]2[C:21](=[O:20])[C:22]([CH:36]([CH3:37])[CH3:38])=[C:23]([CH3:24])[N:25]=[C:26]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:16]=[CH:17][CH:18]=1
Reactant: NCCc1cccc(F)c1
Reactant: C=C(NC(=O)c1ccccc1OC)C(C(=O)OC)C(C)C
Agent: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1nc(C)c(C(C)C)c(=O)n1CCc1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Phenyl magnesium bromide (1M solution in THF, 0.0021 mol) was added to a solution of 3-fluoro-phenethyl amine (0.27 mL, 0.0021 mol) in anhydrous toluene (20 mL). After stirring the mixture at 20° C. for 10 min, 2-isopropyl-3-(2-methoxy-benzoylamino)-but-3-enoic acid methyl ester of step (b) above in this method (Method B of Example 13) (0.05 g, 0.0017 mol) was added. The mixture was refluxed for 10 hours, cooled and ethyl acetate (50 mL) was added followed by 1N HCl (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with 1N HCl (3×100 mL), water (100 mL), and brine (100 mL). After drying over sodium sulfate and concentration on a rotatory evaporator, the product was purified by column chromatography over silica gel (200-400 mesh) eluting with 12% EtOAc/hexanes to give 3-[2-(3-fluoro-phenyl)-ethyl]-5-isopropyl-2-(2-methoxy-phenyl)-6-methyl-3H-pyrimidin-4-one (0.3 g, 46%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Br[CH2:8][CH2:9][Cl:10].BrCCBr>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:8][CH2:9][Cl:10])[N:3]=1.[CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1
Reactant: ClCCBr
Agent: Cc1cc[nH]n1
Solvent: BrCCBr
Solvent: Cc1ccccc1
Product: Cc1ccn(CCCl)n1

Procedure:
When an equivalent amount of 3-methylpyrazole is substituted for 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane is substituted for 1,2-dibromoethane in the procedure of Example 19 using toluene as solvent, 2-(3-methyl-1H-pyrazol-1-yl)ethyl chloride is isolated after column chromatography (3-methylpyrazole, Aldrich, 36%, C).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22](I)=[CH:21][N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].C([Sn](CCCC)(CCCC)[C:37]1[O:38][CH:39]=[CH:40][N:41]=1)CCC>CC(N(C)C)=O.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.[Cu]I>[OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:37]4[O:38][CH:39]=[CH:40][N:41]=4)=[CH:21][N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CN(C)C(=O)C(O)c1cncc(-c2cnc3c(c2)c(I)cn3COCC[Si](C)(C)C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CN(C)C(=O)C(O)c1cncc(-c2cnc3c(c2)c(-c2ncco2)cn3COCC[Si](C)(C)C)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 22.5 %

Procedure:
A mixture of 2-hydroxy-2-{5-[3-iodo-1(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-acetamide (50 mg, 0.09 mmol), 2-tri-n-butylstannyloxazole (28 ul, 0.14 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), CuI (2 mg, 0.009 mmol) in DMA (1 ml) was stirred at 120° C. in a microwave for 20 minutes. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (2X). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-hydroxy-N,N-dimethyl-2-{5-[3-oxazol-2-yl-1(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-acetamide (10 mg, 22% yield).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][N:11]=1>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH3:7])=[CH:12][N:11]=1
Reactant: Cc1ccsc1Br
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2sccc2C)cn1

Procedure:
The title intermediate, MS: m/e 206.1 (MH+), was prepared analogously to Example 52 from 2-bromo-3-methyl-thiophene and 2-methoxy-5-pyridineboronic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[NH:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][C:38]=1[NH2:43].C(Cl)CCl>CN(C=O)C.O>[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[NH:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][C:38]=1[NH:43][C:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: O=C(O)c1cccnc1F
Reactant: Nc1cnccc1Nc1cccc(F)c1F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cnccc1Nc1cccc(F)c1F)c1cccnc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a solution of 2-fluoropyridine-3-carboxylic acid (1.41 g, 10.00 mmol) in anhydrous DMF (15 mL) was added HOBT (2.56 g, 16.74 mmol) and Et3N (2.0 g, 20.09 mmol) at RT. The mixture was cooled to 0° C., treated with a solution of N4-(2,3-difluorophenyl)pyridine-3,4-diamine in DMF (15 mL), stirred for 15 min at RT and EDC (3.2 g, 16.74 mmol) was added portion wise. The reaction mixture was warmed to RT and stirred for 16 hr. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (4×200 mL). The combined organics were washed with saturated aq. NaHCO3 solution (2×100 mL), water (2×100 mL), brine solution (100 mL), and dried (Na2SO4). Filtration and evaporation of the solvent in vacuo gave a brown solid. Chromatographic purification (silica gel, 1% methanol in chloroform) provided N-(4-(2,3-difluorophenylamino)pyridin-3-yl)-2-fluoropyridine-3-carboxamide (1.05 g, 45% yield) as yellow solid; LC-MS: 345.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:17][CH:16]([CH2:18][NH2:19])[CH2:15]1)=[N:9][C:8]([O:20][CH3:21])=[CH:7][CH:6]=2.[O:22]=[C:23]1[NH:28][C:27]2[N:29]=[C:30]([CH:33]=O)[CH:31]=[CH:32][C:26]=2[S:25][CH2:24]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:15][CH:16]([CH2:18][NH:19][CH2:33][C:30]3[CH:31]=[CH:32][C:26]4[S:25][CH2:24][C:23](=[O:22])[NH:28][C:27]=4[N:29]=3)[CH2:17]1)=[N:9][C:8]([O:20][CH3:21])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCN3CC(CN)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3CC(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 12 h
Yield: 109 %

Procedure:
To a stirred solution of [(1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azetidinyl)methyl]amine (138 mg, 0.47 mmole) in dry CH2Cl2 (40 mL) and dry EtOH (5 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (91 mg, 0.47 mmole). After 12 h, NaBH4 was added to the reaction solution. After 4 hrs, silica gel was added to the reaction contents and the slurry was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.24 g, 50%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.59 (1H, s), 8.17 (1H, d, J=9.0 Hz), 7.55 (1H, d, J=7.8 Hz), 7.04 (1H, d, J=9.0 Hz), 6.93 (1H, d, J=7.8 Hz), 4.08 (3H, s), 3.79 (2H, s), 3.51 (2H, t, J=7.4 Hz), 3.44 (2H, s), 3.22 (2H, app t), 2.95 (2H, t, J=6.7 Hz), 2.82 (4H, m), 2.65 (1H, m). LC-MS (ES) m/e 467 (M+H)+.