Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])/[C:24]#[N:25])=[C:19]([F:36])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:36])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C1C(C(=O)OC(C)(C)C)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Yield: 14 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1.1 g, 5 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-acrylonitrile (1.28 g, 4 mmol) prepared in Example 85a, AgF (0.76 g, 6 mmol), and triethylamine (1.38 mL, 10 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.3 g, 14%).
Reaction SMILES: [OH:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.[NH2:29]C(C)(CC(C)C)C(O)=O>CN(C=O)C.O1CCOCC1.Cl>[NH2:29][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([C:9]2[C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][C:6]3[C:5]4=[N:4][N:3]=[C:2]([OH:1])[N:14]4[CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(-c2nc3ccn4c(O)nnc4c3cc2-c2ccccc2)cc1
Reactant: CC(C)CC(C)(N)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NCc1ccc(-c2nc3ccn4c(O)nnc4c3cc2-c2ccccc2)cc1
Temperature: 150 °C

Procedure:
A suspension of 4-(3-hydroxy-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)-benzaldehyde (3-6, 2.4 g, 6.6 mmol) and 2-amino-2,4-dimethylpentanoic acid (3-7, 1.9 g, 13.1 mmol) in DMF (25 mL) was heated at 150° C. for 20 min. The reaction mixture was cooled, diluted with dioxane (50 mL) and 2N HCl (50 mL) and heated at 100° C. for 30 min. The mixture was cooled and purified via reverse phase HPLC (0-60% acetonitrile/water) to give, upon evaporation of the solvent, the title compound as a yellow solid. HRMS m/z (M+1) Calcd: 368.1506. Found 368.1504.
Reaction SMILES: [F:1][C:2]([F:26])([C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH:24]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C:3]([OH:5])=[O:4].[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([C:2]([F:26])([F:1])[C:3]([OH:5])=[O:4])[CH:7]=1)[CH3:28]
Reactant: COc1ccc(C(F)(F)C(=O)O)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)C(=O)O)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: difluoro-(2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid and ethylamine (2M in THF).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[S:27][CH3:28])[C:21](Cl)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C)C=O>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([S:27][CH3:28])=[C:18]([O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:19]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CSc1ccc(C(=O)Cl)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reaction time: 0.33 h

Procedure:
A solution of 4-amino-3,5-dichloropyridine (0.46 g) in dry dimethylformamide (20 mL) is treated with sodium hydride (0.23 g of a 60% dispersion in mineral oil; 2.8 mmol) and the mixture is stirred for 20 minutes. It is then treated with a solution of 3-cyclopentyloxy-4-(methylthio)benzoyl chloride (0.76 g; that is prepared as described in Reference Example 20 in dimethylformamide (10 mL) and stirred at 60° C. for 2 hours. The solution is then concentrated and the resulting residue is partitioned between water (30 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (50 mL) and the combined organic layers are dried, concentrated, and subjected to flash chromatography on silica gel, eluting with a mixture of diethyl ether and pentane (1:1 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (0.7 g) in the form of a white crystalline solid, m.p. 157°-159° C. [NMR (CDCl3):8.57 (s,2H), 7.69 (bs,1H), 7.47 (dd,1H,J=8Hz,J=2Hz), 7.43 (d,1 H,J=2Hz), 7.17 (d,1H,J=8Hz), 4.95 (m,1H), 2.46 (s,3H), 1.98-1.6(m,8H); Elemental analysis: C,54.0; H,4.5; N,7.0; Cl,17.8%; calculated: C,54.4; H,4.6; N,7.05; Cl,17.85%].
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][CH2:24][CH2:25][CH:26]4[NH:29][C:30]([C:32]4[C:33](=[O:47])[N:34]([CH2:38][C:39]5[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=5)[CH:35]=[CH:36][CH:37]=4)=[O:31])=[CH:21][CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(Cl)Cl>C[O-].[Na+].CO>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH:26]3[NH:29][C:30]([C:32]3[C:33](=[O:47])[N:34]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=4)[CH:35]=[CH:36][CH:37]=3)=[O:31])=[CH:21][CH:20]=2)=[CH:11]1
Reactant: O=C(NC1CCCc2ccc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)cc21)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1CCCc2ccc(-c3c[nH]c4ncccc34)cc21)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [7-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amide (0.063 g, 0.000097 mol;) was dissolved in 0.5 M of Sodium methoxide in methanol (3 mL) and Methylene chloride (3 g, 0.04 mol;) and heated at 75 C for 1 hour. LC-MS showed the disappearance of starting material and the appearance of product. The reaction was concentrated and dissolved in DMSO and methanol 1:1 for purification by Gilson Preparative HPLC. Pure fractions were combined and concentrated to give the pure product. ES (+) MS m/e=511.37; (400 MHz, DMSO-d6) δ ppm 1.84 (m, 3H), 2.07 (m, 1H), 2.80 (m, 2H), 5.22 (d, 2H, 5 Hz), 5.25 (m, 1H), 6.62 (t, 1H, J=8 Hz), 6.99 (m, 1H), 7.12 (m, 1H), 7.20 (d, 1H, J=8 Hz), 7.30-7.45 (m, 2H), 7.52 (m, ′H), 7.60 (s, 1H), 7.78 (s, 1H), 8.16 (d, 1H, J=8 Hz), 8.22 (m, 2H), 8.46 (m, 1H), 10.10 (d. 1H, J=8 Hz), 12.55 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]3([CH3:18])[CH3:17])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13][C:12]3([CH3:18])[CH3:17])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1
Reactant: CC1(C)CNCCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CN(S(C)(=O)=O)CCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a cloudy solution of (+/−)-6-bromo-4-(3,3-dimethylpiperidin-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 3 of Example 1 (300 mg, 0.625 mmol) and DIPEA (0.436 mL, 2.499 mmol) in dichloromethane (10 mL) at 0° C. was added methanesulfonyl chloride (0.058 mL, 0.750 mmol) and the resulting mixture was stirred at rt for 3 h. Reaction was diluted with dichloromethane (150 mL), washed with water and brine, dried over MgSO4, filtered and concentrated to afford the title compound as a tan solid (94% yield). HPLC (condition B): retention time=3.11 min. LCMS (condition H): m/z 444, 446 +ve.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([CH:26]([C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)[NH2:27])[N:22]=1>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:27][CH:26]([C:23]3[N:22]=[C:21]([CH3:20])[O:25][N:24]=3)[C:28]3([CH3:32])[CH2:31][O:30][CH2:29]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: Cc1nc(C(N)C2(C)COC2)no1
Product: Cc1nc(C(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)C2(C)COC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (example 68a) and (5-methyl-1,2,4-oxadiazol-3-yl)-(3-methyloxetan-3-yl)methanamine (example 254b) as starting materials and isolated (47 mg, 55%); MS (ESI, m/z): 441.3 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=2)=[CH:14][N:13]=1>CN(C=O)C>[CH2:7]([S:8][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=2)=[CH:14][N:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCc1ccccc1
Reactant: CC(C)c1cccc(-c2ccc(Cl)nc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc(-c2ccc(SCc3ccccc3)nc2)c1
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
A solution of phenyl-methanethiol (0.8 mL, 5.84 mmol) in DMF (5 mL) was treated with NaH (0.140 g, 5.84 mmol) at room temperature under argon. After 15 min of stirring, the reaction mixture was treated with a solution of 2-chloro-5-(3-isopropyl-phenyl)-pyridine (0.900 g, 3.90 mmol) in DMF (15 mL). After 2 h of additional stirring at room temperature (reaction was monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4, and concentrated in vacuo to obtain a crude product, which was purified over silica gel (Biotage column chromatography, gradient elution using 0-1% ethyl acetate in hexane) to furnish 2-benzylsulfanyl-5-(3-isopropyl-phenyl)-pyridine (0.680 g, 54.71%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[C:4]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=2)[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.[H-].[Na+].Br[CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1>CN(C=O)C>[CH2:26]([O:25][C:18]1[CH:17]=[C:16]([C:4]2[C:5]3[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=3[N:15]=[C:2]([NH:1][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)[C:3]=2[C:28]#[N:29])[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=1)[CH3:27]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOc1cc(OCC)cc(-c2c(C#N)c(N)nc3c2c(=O)n(C)c(=O)n3C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)cc(-c2c(C#N)c(NCc3ccc4ccccc4c3)nc3c2c(=O)n(C)c(=O)n3C)c1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 56d (100 mg, 0.25 mmol) in DMF (3 mL) was treated with 60% NaH (12 mg, 0.3 mmol). After the mixture was vigorously stirred for 30 min, a solution of 2-(bromomethyl)naphthalene (55 mg, 0.25 mmol) was added. The mixture was stirred at rt for 20 min, and 50° C. for 2 h. After which the solution was suspended in 200 mL of EtoAce and was washed with brine, 3×200 mL. The organic layer was dried over Na2SO4 and evaporated in vacuuo. The residue was purified by prep HPLC to give 5-(3,5-diethoxyphenyl)-1,3-dimethyl-7-(naphthalene-2-ylmethylamino)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (56e, 87 mg). MS [m+H] calc'd for C31H29N5O4, 536.22; found 536.22
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.[H-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([Br:24])[C:21]([OH:25])=[C:20]([Br:26])[CH:19]=1)=[O:17]>CN(C)C=O>[Br:24][C:22]1[CH:23]=[C:18]([C:16](=[O:17])[CH2:15][N:4]2[C:5](=[O:7])[CH2:6][O:1][C:2]3[CH:11]=[CH:10][N:9]=[CH:8][C:3]2=3)[CH:19]=[C:20]([Br:26])[C:21]=1[OH:25]
Reactant: O=C1COc2ccncc2N1
Reactant: O=C(CBr)c1cc(Br)c(O)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)COc2ccncc21)c1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 10 ml flask, 4H-pyrido[4,3-b][1,4]oxazin-3-one (50 mg, 0.33 mmol) was dissolved in N,N-dimethyl formamide (2.0 ml) and then cooled to 0□. Sodium hydride (15 mg, 0.37 mmol) was added thereto at 0□ and then stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0□, 2-bromo-1-(3,5-dibromo-4-hydroxy-phenyl)-ethanone (124 mg, 0.33 mmol) was added thereto dropwise and stirred at 0□ for 30 minutes, and then the mixture was stirred at room temperature for 1 hour. The precipitates formed were filtered and washed with acetonitrile. The resulting solid was recrystallized from methanol to obtain the target compound 56, i.e., 4-[2-(3,5-dibromo-4-hydroxy-phenyl)-2-oxo-ethyl]-4H-pyrido[4,3-b][1,4]oxazin-3-one, as white solid (48 mg, 33%).
Reaction SMILES: C(OC([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=1)CN>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([NH:8][CH2:39][C:54]3[CH:53]=[CH:50][CH:49]=[C:48]([O:47][CH3:46])[CH:55]=3)=[O:38])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2cc(N3CCCC3=O)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (187 mg) described in Example 769 and 3-methoxybenzylamine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (120 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([N:26]1[C:34]2[C:29](=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[N:28]([CH3:44])[C:27]1=[O:45])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:34]6[N:26]([CH2:24][CH3:25])[C:27](=[O:45])[N:28]([CH3:44])[C:29]6=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCn1c(=O)n(C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Product: CCn1c(=O)n(C)c2ncc(-c3ccc4ncc5c(c4c3)n(-c3cn(C)nc3C)c(=O)n5C)cc21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1-ethyl-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Stage 68.1.1) to give the title compound as a white solid. (HPLC: tR 2.47 min (Method A); M+H=469 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.14-8.08 (m, 3H), 8.01-7.94 (m, 1H), 7.62-7.58 (m, 1H), 7.58-7.54 (m, 1H), 3.94 (q, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 3.37 (s, 3H), 1.97 (s, 3H), 1.28 (t, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH3:18])[NH:11][C:10]2=[N:19][NH:20][C:21]([OH:22])=[C:9]12.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:39]([O:43][C:44](=O)[O:45]C(C)(C)C)([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44]([O:22][C:21]1[C:9]2[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH3:18])[NH:11][C:10]=2[NH:19][N:20]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCCC1=C(C#N)C(c2ccccc2Cl)c2c(n[nH]c2O)N1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC1=C(C#N)C(c2ccccc2Cl)c2c(OC(=O)OC(C)(C)C)n[nH]c2N1
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-3-hydroxy-6-propyl-2H-pyrazolo[3,4-b]pyridine (12.5 g) in THF (400 mL) was added triethylamine (4.5 g), dimethylaminopyridine (0.5 g) and di-t-butylcarbonate (9.6 g) and the mixture was stirred for 3 hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (12 g) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[NH:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[CH:13][C:12]=1[Cl:24])[C:6](=O)[CH2:7][CH3:8])C.[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([NH2:39])[CH:33]=1)[CH3:30]>>[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]2[C:33]=1[C:4](=[O:3])[C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[NH:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)=[CH:13][C:12]=1[Cl:24])=[C:6]([CH2:7][CH3:8])[NH:39]2)[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(C(=O)NC2CCC2)cc1Cl)C(=O)CC
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c(N)c1
Product: CCc1[nH]c2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(=O)c1Cc1ccc(C(=O)NC2CCC2)cc1Cl

Procedure:
The title compound was prepared by the method of Preparation 65c using 2-(2-chloro-4-cyclobutylcarbamoylbenzyl)-3-oxopentanoic acid ethyl ester and (S)-2-(3-amino-4-fluorophenoxy)propionic acid methyl ester.
Reaction SMILES: [CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[CH:1]1([C:4](=[O:11])[C:5](=[CH:12][O:13][CH2:14][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C1CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Ethyl β-cyclopropyl-β-ketopropionate (247.0 g, 1.58 mole) [prepared according to the procedure described in J. Am. Chem. Soc., 70, 497 (1948)], triethyl orthoformate (468.3 g, 3.16 mole) and acetic anhydride (484.0 g, 4.74 mole) were combined and the solution was stirred at reflux for 4 h and at ambient temperature for 17 h. The excess reagents were distilled at water aspirator pressure (maximum head temperature permitted was 72° C.) and the oily pot residue was stirred at 10° C. with a mixture of ether and water. The ether layer was separated, washed once with cold water and dried over Na2SO4. Removal of the solvent gave 321.5 g (96%) of an orange-red liquid that was used directly in the next step.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:15]([NH:21][NH2:22])=[N:16][CH:17]=[CH:18][C:19]=1[Cl:20]>C1COCC1>[Br:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:22][N:21]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: NNc1nccc(Cl)c1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Br)c(Cl)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a stirring solution of triphosgene (5.766 g, 19.43 mmol) in anhydrous THF (50 mL) at room temperature was added 1-(3-bromo-4-chloropyridin-2-yl)hydrazine (1.438 g, 70% pure) portion-wise over 15 min. The resulting suspension was stirred under argon at room temperature overnight, then cooled at 0° C. and quenched carefully by slow addition of water (30 mL). The resulting yellowish suspension was filtered, and the solid collected was washed with water (20 mL×3), then diethyl ether (5 mL), and dried in a 60° C. vacuum oven to obtain 0.525 g of the title compound, 8-bromo-7-chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as an off-white solid. HPLC/MS: retention time=1.93 min, [M+H]+=248.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15].Cl.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N+:14]([O-:16])=[O:15])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc2ncnc(Nc3ccccc3[N+](=O)[O-])c2cn1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 33.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (220 mg, 1.15 mmole) and 2-nitroaniline (2.00 g, 14.5 mmole) is heated to 100° C., then excess dry HCl gas is added to the hot stirred solution, and the mixture stirred at 160° C. for 20 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto silica gel and chromatographed over silica gel (2-4% MeOH/CH2Cl2) to give 7-amino-4-(2-nitroanilino)pyrido[4,3-d]pyrimidine (108 mg, 33%) as a yellow brown solid. 1H NMR (DMSO) δ 10.40 (1H, brs), 9.24 (1H, brs), 8.20 (1H, brs), 8.12 (1H, brs), 8.01 (2H, brs), 7.75 (1H, brs), 6.70 (2H, brs), 6.43 (1H, brs)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=1)[OH:5].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[F:13][C:14]([F:21])([F:20])[C:15]([NH:1][CH2:2][CH2:3][CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=1)=[O:16]
Reactant: NCCC(O)c1cccc(I)c1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC(O)c1cccc(I)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-amino-1-(3-iodophenyl)propan-1-ol (105) (3.9 g, 14 mmol) in DCM (50 mL) were added ethyl trifluoroacetate (2 mL, 17 mmol) and triethylamine (2.95 mL, 21 mmol) and the mixture was stirred at RT for 4 h during which the reaction was found to be complete. Concentration under reduce pressure gave (2,2,2-trifluoro-N-(3-hydroxy-3-(3-iodophenyl)propyl)acetamide) as a yellow oil. The product was pure enough to be used as such for the next transformation. Yield (4.9 g, 93%): 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 4.79-4.82 (m, 1H), 3.67-3.72 (m, 1H), 3.37-3.42 (m, 1H), 2.96 (bs, 1H), 1.87-1.99 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[C:36]([NH:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1)(=[O:38])[CH3:37]
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 28 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.83 (br s, 1H), 7.41–7.85 (m, 12H), 4.90 (s, 1H), 3.36 (dd, 2H, J=5.6, 12.0 Hz), 3.18 (d, 2H, J=11.6 Hz), 2.69 (t, 2H, J=6.4 Hz), 2.53 (m, 1H), 2.34 (m, 2H), 2.15 (s, 3H), 1.96–1.79 (m, 6H); ESMS m/e: 506.4 (M+H)+.