Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:16][C:17]1[C:18]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=2)=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([NH:22][CH3:23])=[O:21]>>[Cl:16][C:17]1[C:18]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:1][C:2]3[CH:15]=[CH:14][C:5]4[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:29]=2)=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([NH:22][CH3:23])=[O:21]
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCC(=O)NC3(C)C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1826d, 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one and 3-chloro-2-(2,5-dichloropyrimidin-4-ylamino)-N-methylbenzamide were converted to 3-chloro-2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-N-methylbenzamide, TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.3 (s, 1H), 7.9 (dd, 1H), 7.75 (dd, 1H), 7.65 (t, 1H), 7.4 (d, 1H), 7.3 (d, 2H), 7.2 (dd, 1H), 3.1 (m, 2H), 3.0 (s, 3H), 2.7 (m, 2H), 1.8 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])[C:3]=1[C:20]([O:22]C)=O.[O:24]1[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.Cl>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:10])[C:3]=1[C:20](=[O:22])[NH:30][CH:26]1[CH2:27][CH2:28][CH2:29][O:24][CH2:25]1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: NC1CCCOC1
Agent: Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)NC1CCCOC1

Procedure:
Same procedure as described in preparation 137a was used from (S)-methyl 3-bromo-1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (4.00 g, 10.25 mmols) and tetrahydro-2H-pyran-3-amine.HCl (2.12 g, 15.41 mmols). The title compound was obtained (2.24 g, 48%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([Sn](CCCC)(CCCC)CCCC)[S:5][CH:6]=1.[CH3:20][N:21]1[C:33](=[O:34])[N:32]([CH3:35])[C:31]2[C:23](=[C:24]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:25]3[C:30]=2[C:29](OS(C(F)(F)F)(=O)=O)=[CH:28][CH2:27][CH2:26]3)[C:22]1=[O:50].[Cl-].[Li+]>C1COCC1.CCOC(C)=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:35][N:32]1[C:31]2=[C:30]3[N:25]([C:24]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[C:23]2[C:22](=[O:50])[N:21]([CH3:20])[C:33]1=[O:34])[CH2:26][CH2:27][CH:28]=[C:29]3[C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CCC3
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1csc(C2=CCCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)n1
Temperature: 25 °C

Procedure:
4-Methyl-2-tributylstannanyl-thiazole (Intermediate J) (491 mg, 1.265 mmol) was added to a suspension of trifluoro-methanesulfonic acid 2,4-dimethyl-1,3-dioxo-9-phenyl-1,2,3,4,7,8-hexahydro-2,4,8a-triaza-fluoren-5-yl ester (Intermediate K) (480 mg, 1.054 mmol), lithium chloride (4.47 mg, 0.105 mmol), copper(I) iodide (20.07 mg, 0.105 mmol) and PdCl2(dppf) (77 mg, 0.105 mmol) in THF (12 ml) and the mixture heated at reflux under nitrogen for 2 h. Further 4-methyl-2-tributylstannanyl-thiazole (Intermediate J) (491 mg, 1.265 mmol) was added and the mixture continued at reflux for 2 h, then further 4-methyl-2-tributylstannanyl-thiazole (Intermediate J) (491 mg, 1.265 mmol) was added and the mixture stirred at reflux for 1 h. The mixture was cooled to RT, diluted with EtOAc and washed with dilute aqueous NH4OH, water and brine. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. The residue was triturated with MeOH/Et2O and the precipitate collected by filtration. The precipitate was purified by chromatography on silica, eluting with 50% EtOAc in hexane. Trituration with Et2O and collection by filtration afforded 1,3-dimethyl-10-(4-methylthiazol-2-yl)-5-phenyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione as a pale yellow solid
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]3[CH:27]=[C:28](/[CH:30]=[CH:31]/[C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=[C:25]3[C:24]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[N:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]3[CH:27]=[C:28](/[CH:30]=[CH:31]/[C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=[C:25]3[C:24]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[N:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)[Si](C)(C)OCCNS(=O)(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 33a (135 mg, 0.201 mmol) in THF (5 mL), TBAF (112 mg, 0.402 mmol) was added. The resulting mixture was stirred at rt for 2 h and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexanes, 0-100%). The solid obtained was suspended in 50% diethyl ether/hexanes, sonicated, and collected by filtration to obtain the title compound 73. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.48-7.52 (m, 2H), 7.06-7.13 (m, 6H), 6.99-7.04 (m, 2H), 6.87-6.92 (m, 1H), 6.78-6.84 (m, 1H), 6.67-6.73 (m, 2H), 3.90-3.95 (m, 1H), 3.44-3.50 (m, 4H), 2.94-2.99 (m, 4H), 2.54-2.61 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H28N6O4S: 557.2 (M+H). Found 557.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[C:10]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[C:10]2([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)C12CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CN(Cc2ccccc2)CC12CCCC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a cooled to 0° C. solution of 2-benzyl-2-azaspiro[4.4]nonane-1,4-dione (20.00 g, 82.2 mmol) in THF (150 mL) was added LiAlH4 (20.93 g, 550.8 mmol) portionwise. After addition, the reaction mixture was stirred at 80° C. overnight, cooled down to rt and quenched carefully with sequential addition of EtOAc (200 mL), 15% KOH aqueous solution (40 mL) and water (100 mL). After addition, the resulting mixture was stirred at rt for 3 h, and filtered through a Celite pad, then washed with EtOAc (1 L). The filtrate was concentrated in vacuo to give the product as yellow oil (19.02 g, 100%).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[NH2:20][CH:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[CH:16]=[C:15]([OH:18])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1CCc2ccc(O)cc2C1Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine (2.56 g, 9.57 mmol) in dry dichloromethane (47.4 mL) under Argon at 0° C. 1M BBr3 in dichloromethane (23.93 mL, 23.93 mmol) was added. The cooling bath was removed and the reaction was allowed to reach room temperature overnight. The reaction was quenched with water, and 1 M NaOH was added to alkalinity. The organic layer was separated and the aqueous phase was extracted with dichloromethane (4×50 mL). The collected organic extracts were concentrated until the product precipitated as a green solid. The solid was collected via filtration and washed with cold dichloromethane (ca. 10 mL). The solid obtained was dried to a gray-greenish powder (2.233 g, 8.81 mmol, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH2:20].Cl>CC(O)CCC>[ClH:1].[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH:20][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COCCOc1ccc2c(Cl)cnnc2c1
Agent: Cl
Solvent: CCCC(C)O
Product: COCCOc1ccc2c(Nc3cc(O)c(C)cc3F)cnnc2c1
Yield: 83.8 %

Procedure:
A solution of 4-chloro-7-(2-methoxyethoxy)cinnoline (156 mg, 0.65 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (111 mg, 0.78 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (8 ml) and 5M isopropanolic hydrogen chloride (1 ml) was heated at 120° C. for 2.5 hours. The solid was filtered off, washed with isopropanol and then ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)cinnoline hydrochloride (207 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[S:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:20][C:19]2[CH:21]=[CH:22][C:16]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: CCOc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-ethoxybenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 76%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:5](=[O:26])[C:4]=2[CH:3]=1.[Li]CCCC.[C:32]1(=[O:38])[O:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1>[OH:38][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:5](=[O:26])[C:4]=2[CH:3]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(Br)cc3C2=O)CC1
Reactant: O=C1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(C(=O)CCCCO)cc3C2=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of 3-1 (0.66 g, 1.5 mmoles) in THF (30 ml) was cooled to -78° and treated with n-BuLi (3.0 mmoles) and the resulting yellow brown solution was stirred for 30 minutes. Then, valerolactone (0.16 g, 1.65 mmoles) was added and this was stirred at -70° for 6 hours and then overnight at ambient temperature. The reaction mixture was cooled to -10°, quenched with 10% KHSO4 and concentrated. The residue was taken up in H2O/EtOAc and the organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane (3)/acetone(2) to give 4-1, Rf 0.35.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:47]=[CH:46][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:26]=4)=[CH:20][C:19]=3[N:37](C)[C:38](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:48].O1CCOCC1>>[ClH:48].[CH3:38][N:37]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:46]=[CH:47][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(-c4ccccc4)c3)cc21
Temperature: 25 °C
Reaction time: 63 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3-phenylphenoxy)phenyl}-N-methylcarbamate (2.57 g) and 4N hydrogen chloride/dioxane (30 ml) was stirred at room temperature for 63 hours. The solvent of the reaction mixture was evaporated to dryness and to the residue was added ethyl acetate and insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (2.01 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:32]([OH:34])[CH3:33]>>[CH2:32]([O:34][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1)[CH3:33]
Reactant: CCO
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1

Procedure:
A portion of 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (5 g) was refluxed in ethanol in presence of K2CO3 (3.2 g) for about 8–10 h. TLC was monitored. After the completion of the reaction, the reaction mass was filtered through vacuum and the filtrate was evaporated to yield the title compound. (Wt. 4.6 g Y: 90%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:25]([C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:15][CH:25]([C:29]3[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1
Reactant: CCCC(OS(C)(=O)=O)c1ccc(C(=O)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (140 mg, 0.585 mmol) in N,N-dimethylformamide (2 mL) was added to a suspension of 60% sodium hydride (27.2 mg, 0.679 mmol) in N,N-dimethylformamide (2 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. A mixture of ethyl 4-(1-(methylsulfonyloxy)butyl)benzoate (0.170 g, 0.566 mmol) in N,N-dimethylformamide (3 mL) was then added at room temperature. The reaction was stirred for 2 hours. The reaction was diluted with ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-15% ethyl acetate in heptanes) gave ethyl 4-(1-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-ylamino)butyl)benzoate (25.0 mg, 10%) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.98-8.05 (m, 4 H), 7.67 (d, J=8.19 Hz, 2 H), 7.53 (d, J=9.36 Hz, 1 H), 7.44 (d, J=8.19 Hz, 2 H), 6.57 (d, J=9.36 Hz, 1 H), 5.56-5.67 (m, 1 H), 4.82-4.93 (m, 1 H), 4.34 (q, J=7.22 Hz, 2 H), 1.79-2.01 (m, 2 H), 1.36 (t, J=7.22 Hz, 3 H), 1.28-1.54 (m, 2 H), 0.96 (t, J=7.32 Hz, 3 H). MS (M+1): 444.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[CH2:25][NH:26][C:14]([C:10]1[S:9][C:8]([N:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]2=[O:17])=[N:12][C:11]=1[CH3:13])=[O:16]
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Reactant: NCc1cccc(F)c1
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1cccc(F)c1
Yield: 44 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with (3-fluorophenyl)methanamine, the title compound was obtained as a colorless solid in 44% yield: mp 250-252° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.50 (br s, 1H), 8.78 (t, J=6.0 Hz, 1H), 8.59 (d, J=8.0 Hz, 1H), 7.39-7.30 (m, 1H), 7.13-7.00 (m, 3H), 6.26 (dd, J=8.0, 2.5 Hz, 1H), 5.82 (d, J=2.5 Hz, 1H), 4.39 (d, J=5.9 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 164.2, 162.1, 161.6, 154.2, 142.9, 142.8, 132.6, 130.7, 123.7, 123.4, 114.5, 114.1, 104.4, 98.0, 42.6, 17.5; MS (ES+) m/z: 360.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[Br:16][C:17]1[C:18](F)=[C:19]2[O:23][C:22]([CH:24]3[CH2:26][CH2:25]3)=[N:21][C:20]2=[C:27]([C:30]#[N:31])[C:28]=1[CH3:29]>CS(C)=O>[Br:16][C:17]1[C:18]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:19]2[O:23][C:22]([CH:24]3[CH2:25][CH2:26]3)=[N:21][C:20]2=[C:27]([C:30]#[N:31])[C:28]=1[CH3:29]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(Br)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 90 °C
Yield: 26.4 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (157 μl, 1.24 mmol) and triethylamine (348 μl, 2.50 mmol), were added to a dimethyl sulfoxide (5 ml) solution of 6-bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (304 mg, 1.03 mmol). The system was purged with nitrogen and then sealed up and heated at 90° C. for 2 hours. After cooling, the solvent was evaporated away under reduced pressure, then the resulting residue was dissolved in chloroform, washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, the resulting residue was washed with a mixed solvent of isopropyl ether and ethanol. The crystal was collected by filtration to obtain the entitled compound (106 mg, 26%) as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8]([CH2:18][NH:19][C:20](=[O:30])[CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)([C:11]3[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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.O>[C:31]([C:33]1[CH:38]=[C:37]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3([CH2:18][NH:19][C:20](=[O:30])[CH2:21][C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=4)[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)[CH:36]=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(Cc1cc(F)cc(F)c1)NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(-c2ccc(C3(CNC(=O)Cc4cc(F)cc(F)c4)CCN(CC4CC4)CC3)cc2)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a flask containing 1 N-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-2-(3,5-difluoro-phenyl)-acetamide (0.040 g, 0.76 mmol) was added Pd(PPh3)4 (0.01 g, 0.008 mmol, 10 mol %), 3-cyanophenylboronic acid (0.020 g, 0.12 mmol, 1.5 eq.) and Na2CO3 (0.106 g, 1 mmol). The mixture was suspended in toluene (1.5 mL), EtOH (0.75 mL) and H2O (0.5 mL) and heated to 80° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (5 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), saturated brine (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a brown solid which was purified by HPLC to give the title compound N-[4-(3′-cyano-biphenyl-4-yl)-1-cyclopropylmethyl-piperidin-4-ylmethyl]-2-(3,5-difluoro-phenyl)-acetamide (0.036 g, 0.072 mmol, 10%). MS(ESI): 500.3/501.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4]1.[CH3:16]O>S(=O)(=O)(O)O>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4]1
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)CCC(CO)O2
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)CCC(CO)O2
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a stirred solution of 40 parts of 3,4-dihydro-2-(hydroxymethyl)-2H-1-benzopyran-6-carboxylic acid in 400 parts of methanol were added a few drops of sulfuric acid. Stirring was continued overnight at reflux. The reaction mixture was evaporated. The residue was taken up in 1,1'-oxybisethane. The whole was washed with a sodium hydroxide solution 10% and with water, dried, filtered and evaporated, yielding 24 parts (53.9%) of methyl 3,4-dihydro-2-(hydroxymethyl)-2H-1-benzopyran-6-carboxylate as a residue (intermediate 4).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.CCN(C(C)C)C(C)C.[NH2:26][CH:27]([C:29]1[CH:36]=[C:35]([CH3:37])[C:32]([C:33]#[N:34])=[C:31]([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:43]=2)[C:30]=1[O:48][CH2:49][CH3:50])[CH3:28]>C(O)C>[CH2:49]([O:48][C:30]1[C:31]([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([S:44]([CH3:47])(=[O:45])=[O:46])[CH:43]=2)=[C:32]([C:35]([CH3:37])=[CH:36][C:29]=1[CH:27]([NH:26][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:28])[C:33]#[N:34])[CH3:50]
Reactant: CCOc1c(C(C)N)cc(C)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(C)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (35 mg, 0.15 mmol, from Example 176, Step 4) and DIPEA (0.04 mL, 0.2 mmol) were added to 4-(1-aminoethyl)-3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile in ethanol (2 mL). The reaction was heated to 120° C. overnight. The reaction was allowed to cool to room temperature and was concentrated in vacuo to give 3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)benzonitrile as a solid residue. This intermediate was dissolved in 4.0 M HCl in dioxane (1 mL) and was stirred for 10 minutes. The reaction was concentrated and was purified on prep HPLC on a C-18 column eluting with water:acetonitrile gradient buffered with TFA to give 3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile as a white solid (0.010 g, 16%). LCMS calculated for C23H24N7O3S (M+H)+: m/z=478.1. found: 478.1. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (d, J=2.2 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H), 8.75 (m, 1H), 8.54 (t, J=2.1 Hz, 1H), 8.33 (m, 2H), 7.68 (s, 1H), 5.80 (m, 1H), 3.99-3.79 (m, 1H), 3.40 (s, 3H), 3.34 (m, 1H), 2.47 (s, 3H), 1.58 (d, J=6.9 Hz, 3H), 0.98 (t, J=6.9 Hz, 3H).