Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:37])[NH:9][C:10]2[CH:15]=[C:14]([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)[CH:13]=[CH:12][C:11]=2[CH2:22][NH:23][C:24](=[O:36])[C:25]2[CH:30]=C(OC)[C:28]([CH3:33])=[C:27]([O:34][CH3:35])[CH:26]=2)C=CC=CC=1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl[C:46]([O:48][CH3:49])=O>C1COCC1>[CH3:49][O:48][C:46]1[CH:30]=[C:25]([CH:26]=[C:27]([O:34][CH3:35])[C:28]=1[CH3:33])[C:24]([NH:23][CH2:22][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:15][C:10]=1[NH:9][C:8]([NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37])=[O:36]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NC(=O)Oc2ccccc2)cc(OC)c1C
Reactant: Nc1ccccc1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NC(=O)Nc2ccccc2)cc(OC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
A solution of compound 19a (50 mg, 0.10 mmol) and aniline (0.010 mL, 0.11 mmol) in THF was heated at 60° C. for 5 h. Additional aniline (0.010 mL, 0.11 mmol) was added and the reaction was stirred at rt overnight. Additional methyl chloroformate (0.010 mL, 0.13 mmol) was added and the reaction was stirred at rt for 24 h. The solid precipitate was recovered by filtration and washed with ethyl acetate and MeOH to give compound 19b (13 mg, 26). ESI-MS m/e 502.4 (M+1).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:14][C:13]3[CH:15]=[C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:22])[CH:17]=[N:18][C:12]=3[NH:11][C:10](=[O:36])[CH2:9]2)=CC=1.[Cl:39]C(OC(Cl)C)=O>ClC(Cl)C.CO.C(Cl)Cl>[ClH:39].[CH3:35][N:23]([CH2:24][C:25]1[N:26]([CH3:34])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[N:18][C:12]2[NH:11][C:10](=[O:36])[CH2:9][NH:8][CH2:14][C:13]=2[CH:15]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)N(C)Cc4cc5ccccc5n4C)cc3C2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CNCC(=O)N2
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
A solution of (E)-3-[4-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (2.00 g, 3.92 mmol), from Example 65, in dichloroethane (80 mL) was cooled in an ice bath and treated with 1-chloroethyl chloroformate (0.47 mL, 4.31 mmol). After stirring at 0° C. under N2 for 30 min and then at room temperature for 30 min, the mixture was heated to reflux for 1.5 h. The mixture was allowed to cool and then concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3) gave a tan solid. The solid was suspended in methanol and heated to reflux for 2 h. The mixture was allowed to cool and the solid was isolated by filtration, dissolved in CH2Cl2, washed with 1 N NaOH, dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 95:5) gave the title compound (0.70 g, 49%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.38-8.33 (m, 2H), 7.72-7.67 (m, 1H), 7.60-7.57 (m, 2H), 7.32-7.20 (m, 3H), 7.14-7.09 (m, 1H), 6.90-6.80 (m, 1H), 6.49-6.38 (m, 1H), 4.93-4.78 (m, 2H), 4.08 (s, 2H), 3.95 (s, 2H), 3.71 (s, 3H), 3.13-3.07 (m, 3H); MS (ESI) m/e 390 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH3:8].[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][C:10]1[N:15]=[C:14]([S:16][CH2:2][C:3]2[S:7][CH:6]=[N:5][C:4]=2[CH3:8])[N:13]=[C:12]([OH:17])[CH:11]=1
Reactant: Cc1ncsc1CCl
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2scnc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 5-(chloromethyl)-4-methyl-1,3-thiazole (887 mg, 4.9 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (600 mg, 4.2 mmol), and potassium carbonate (2.1 g, 15 mmol) in acetone (30 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered and evaporated, co-evaporated with EtOAc (20 mL) and dried in vacuo. The solid residue was treated with diethyl ether (30 mL). The solid product was recovered by filtration, washed with diethyl ether (2×15 mL) and hexanes (1×15 mL), and dried in vacuo, affording 6-methyl-2-{[(4-methyl-1,3-thiazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol (1.0 g, 93% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.91 (s, 3H), 2.34 (s, 3H), 4.31 (s, 2H), 5.32 (s, 1H), 8.73 (s, 1H); M+ 254. The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:39].[F:40][C:41]1[CH:55]=[CH:54][CH:53]=[CH:52][C:42]=1[O:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(N(CC)CC)C>CN(C=O)C.O>[ClH:39].[F:40][C:41]1[CH:55]=[CH:54][CH:53]=[CH:52][C:42]=1[O:43][CH2:44][CH2:45][N:46]1[CH2:47][CH2:48][N:49]([C:15](=[O:17])[CH2:14][CH2:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:50][CH2:51]1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: Fc1ccccc1OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CCC(=O)N2CCN(CCOc3ccccc3F)CC2)cc(OC)c1OC
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a mixture of 3-(3,4,5-trimethoxyphenyl)propionic acid (0.36 g, 1.5 mmol), HOBt (0.24 g, 1.8 mmol), EDAC.HCl (0.34 g, 1.8 mmol) in DMF (4 mL) was added 1-[2-(2-fluoro-phenoxy)ethyl]piperazine (0.34 g, 1.5 mmol) and triethylamine (0.5 mL, 3.6 mmol). The mixture was then stirred at room temperature for a day, treated with water, and extracted with dichloromethane. The organic layer was washed with water and brine and then concentrated to dryness. The residue was dissolved in ethyl ether and was added with 2N HCl in ether (1 mL). The white solid was filtered and dried under vacuum to give the title compound (408 mg, 52%).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.I[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: O=C1NCCc2ccccc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccccc2C1=O
Yield: 35 %

Procedure:
Using analogous reaction conditions as described in Example 1, 3,4-dihydro-2H-isoquinolin-1-one (I-23b: 150 mg, 1.0204 mmol) was reacted with 3-iodo-4-methyl-pyridine (223.4 mg, 1.0204 mmol), 1,4-dioxane (3 mL), copper iodide (19.4 mg, 0.1020 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (48.1 mL, 0.3061 mmol) and potassium phosphate (540.8 mg, 2.551 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 85 mg of the product (35% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[C:23]([O:25]CC)=O)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[OH:25][CH:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:29])=[O:28]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CCOC(=O)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)C(O)C(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of ethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate (500 mg, 1.26 mmol) obtained in Example 15 in THF (10 mL) was added dropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride (2.0 M THF solution, 1.9 mL, 3.78 mmol) and the mixture was stirred for 30 minutes. After the reaction solution was warmed to room temperature and was stirred at the same temperature for 1 hour, the reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to obtain 194 mg (yield: 38%) of the title compound as a diastereomer mixture. Melting point: 165-166° C.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:22][CH:21]2[CH2:23][CH:14]1[CH:15]1[CH:20]2[CH:19]2[CH2:24][CH:16]1[CH:17]=[CH:18]2>>[CH:15]12[CH:16]3[CH2:24][CH:19]([CH:18]=[CH:17]3)[CH:20]1[CH:21]1[CH2:23][CH:14]2[CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:1]2([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:22]1
Reactant: O=C1CCCC1
Reactant: ClCCCCCC1CC2CC1C1C3C=CC(C3)C21
Product: OC1(CCCCCC2CC3CC2C2C4C=CC(C4)C32)CCCC1
Yield: 82 %

Procedure:
1-{5-(8-Tetracyclo[4.4.0.12,5.17,10]dodecen-3-yl)pentyl}-cyclopentanol (yield: 82%) was obtained in the same manner as in Synthesis Example 1, except that cyclopentanone and 1-chloro-5-(8-tetracyclo[4.4.0.12,5.17,10] dodecen-3-yl)pentane were used in place of acetone and 1-chloro-4-(5-norbornen-2-yl)butane, respectively.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:21])[CH2:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(OCC)C>C(Cl)Cl>[ClH:4].[Cl:4][CH:13]([C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)=[O:21])[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccn1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(Cl)C(=O)c1ccccn1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 182.2 %

Procedure:
A solution of sulfuryl chloride (2.84 g) in methylene chloride (5 ml) was dropwise added to a solution of ethyl 4-(2-pyridyl)-2,4-dioxobutyrate (4.42 g) in methylene chloride (60 ml) at 8° C. to 25° C. After the mixture was stirred for 30 minutes at ambient temperature, diethyl ether (60 ml) was added thereto. The precipitated crystals were collected by filtration, washed with diethyl ether and dried to give ethyl 3-chloro-4-(2-pyridyl)-2,4-dioxo-butyrate hydrochloride (5.6 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:35]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[S:35])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1c2cccnc2c(-c2cccc(Cl)c2)nn1Cc1ccccc1
Solvent: Cc1ccccc1
Product: S=c1c2cccnc2c(-c2cccc(Cl)c2)nn1Cc1ccccc1
Yield: 38.6 %

Procedure:
To a solution of 6-benzyl-8-(3-chlorophenyl)pyrido-[2,3-d]pyridazin-5-one (0.96 g, 2.76 mmoles) in toluene (100 mL) at room temperature under a nitrogen atmosphere was added solid 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) (0.67 g, 1.66 mmoles). The reaction mixture was heated under reflux for 18 hours, and then cooled and concentrated. Chromatography on silica gel using ethyl acetate/hexane (1:4) gave 0.233 g of 6-benzyl-8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-thione (23.2%), mp 132° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:14]2[CH:19]=C[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1OC.CO[N:22](C)C(=O)C1C=CC=NC=1.C([Mg]Cl)C1C=CC=CC=1>>[C:5]1([CH2:11][C:12]([C:14]2[CH:19]=[N:22][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: COc1ccc(CC(=O)c2ccccc2)cc1OC
Reactant: CON(C)C(=O)c1cccnc1
Agent: Cl[Mg]Cc1ccccc1
Product: O=C(Cc1ccccc1)c1cccnc1
Reaction time: 3 h
Yield: 19 %

Procedure:
Followed the procedure described in Step 2 of Intermediate 7 with N-methoxy-N-methylnicotinamide and benzylmagnesium chloride, where the mixture was stirred for 3 hours. Purification was achieved by column chromatography (PE:EtOAc=5:1) to give Intermediate 31 (110 mg, yield 19%).
Reaction SMILES: [CH:1]1([C:6]#[CH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.C([Li])CCC.CCCCCC.C1(C#C)CCCC1.[Li].O(C1C=CC=CC=1)[C:33]#[N:34]>>[CH:1]1([C:6]#[C:7][C:33]#[N:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CC1CCCC1
Reactant: N#COc1ccccc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CC#CC1CCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
To a oven dried 500 mL 3-neck round bottom flask equipped with a stir bar, a nitrogen inlet, a 125 mL addition funnel and a thermocouple, cyclopentylacetylene (7, 15.0 g, 0.143 mol) and anhydrous tetrahydrofuran (THF, 170 mL, 2.10 mol) were added at room temperature. The resulting solution was then cooled to −78° C. before a solution of 2.5 M n-butyllithium in hexane (63.1 mL, 0.158 mol, 1.1 equiv) was added dropwise over 25 min. The resulting lithium cyclopentylacetylene solution was stirred at −78° C. for 15 minutes before a solution of crude cyanatobenzene (6, 25.0 g, 0.210 mol, 1.5 equiv) in anhydrous tetrahydrofuran (THF, 30.0 mL, 0.400 mol) was added dropwise via a canula at −78° C. The resulting reaction mixture was stirred at −78° C. for an additional 10 min before the cooling batch was removed and the reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for 1-2 h. When the reaction was deemed complete, the reaction mixture was quenched with a 6 N aqueous sodium hydroxide solution (NaOH, 200 mL) and a 20% aqueous brine solution (200 mL). The aqueous solution was treated with ethyl acetate (EtOAc, 200 mL) before the two layers were separated. The organic layer was dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0 to 5% ethyl acetate/hexane gradient elution) to afford 3-cyclopentylpropiolonitrile (8, 14.3 g, 17.0 g theoretical, 84% yield for two steps) as a yellow to orange oil. For 8: 1H NMR (DMSO-d6, 400 MHz) δ 2.97 (m, 1H), 1.97 (m, 2H), 1.64 (m, 4H), 1.56 (m, 2H).
Reaction SMILES: F[C@@H:2]1C[N:5]([C:7](OC(C)(C)C)=O)[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=1.Br[C:37]1C=C(C(F)(F)F)C=CN=1>>[CH3:7][NH:5][C@H:4]([C:14]([NH:15][C@@H:16]1[C@@H:23]2[C@@H:19]([CH2:20][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=3)[CH2:22]2)[CH2:18][CH2:17]1)=[O:24])[CH:3]([CH3:2])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: FC(F)(F)c1ccnc(Br)c1
Product: CN[C@H](C(=O)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)C(C)C

Procedure:
The title compound was prepared by substituting tert-butyl methyl{(2S)-3-methyl-1-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylamino]-1-oxobutan-2-yl}carbamate from Example 733 for (2S,4S)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate and 2-bromo-6-(trifluoromethyl)pyridine for 2-bromo-4-(trifluoromethyl)pyridine in the procedure described in Example 637: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.28 (d, J=7.4, 1H), 7.53-7.46 (m, 1H), 6.98 (t, J=6.4, 1H), 6.52 (d, J=8.6, 1H), 4.47-4.36 (m, 1H), 3.72 (dd, J=10.9, 2.9, 1H), 3.65-3.58 (m, 1H), 3.53 (dd, J=10.8, 8.0, 1H), 3.29 (dd, J=11.0, 3.6, 1H), 2.93 (d, J=5.8, 1H), 2.73 (t, J=5.7, 2H), 2.42 (s, 3H), 2.18-2.09 (m, 2H), 1.97-1.88 (m, 1H), 1.67 (dq, J=12.8, 8.0, 1H), 1.38 (dtd, J=12.9, 7.9, 4.9, 1H), 1.07 (dd, J=6.8, 2.2, 6H); MS (ESI+) m/z 385 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]1([CH:14]([CH3:18])[C:15](O)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:16])[CH:14]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)N1CCCC1
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)Nc1ccc(Br)cc1)N1CCCC1
Reaction time: 8 h

Procedure:
4-Bromo aniline (0.25 g, 1.45 mmol), 2-pyrrolidin-1-ylpropanoic acid (0.25 g, 1.74 mmol) and diisopropylethylamine (0.3 ml, 1.74 mmol) were dissolved in dimethylacetamide (5 ml). HBTU (0.66 g, 1.74 mmol) was subsequently added and the mixture was stirred overnight. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined organics were washed several times with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield: 0.43 g, 100%. LCMS method: 2, RT: 2.73 min; MI: 297-299 [M+1].
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][S:10][C:4]=2[CH:3]=1.O.C(OCC)(=O)C.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:11]=[C:6]1[C:5]2[CH:12]=[CH:13][C:2]([C:21]#[N:22])=[CH:3][C:4]=2[S:10][CH2:9][CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: O=C1CCCSc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)SCCCC2=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of 8-bromo-5-oxo-2,3,4,5-tetrahydro-1-benzothiepine (5.00 g) synthesized according to a known method in N,N-dimethylformamide (50 ml) were added zinc cyanide (2.28 g) and tetrakis(triphenylphosphine)palladium(0) (1.13 g) and the mixture was stirred at 80-90° C. for 1 hr. The reaction mixture was allowed to warm to room temperature and water (500 ml) and ethyl acetate (100 ml) were added. The mixture was passed through celite. The filtrate was extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was recrystallized from ethyl acetate and hexane to give the objective 5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-8-carbonitrile (3.37 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].C(N(CC)CC)C.[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14]>C(O)C>[CH3:1][N:2]([O:3][CH3:4])[C:13](=[O:14])[C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:17]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CNOC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1N
Yield: 99.1 %

Procedure:
N,O-Dimethylhydroxylamine (102.5 g) was dissolved in 90% ethanol (40 ml). To the solution were added triethylamine (106 g) and isatoic anhydride (74 g). The mixture was heated for 1.5 hour under reflux. The reaction mixture was concentrated, to which was added a saturated aqueous saline solution, followed by extraction with ethyl acetate (500 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave N-methyl-N-methyloxy-2-aminobenzamide (81 g) as a yellow oily product. This compound (6.8 g) and 1-[(tert-butoxycarbonylamino-1-methyl)ethyl]-3-bromobenzene (10 g) were dissolved in tetrahydrofuran (200 ml). The solution was cooled to −80° C. or below, to which was added dropwise, while stirring, n-butyl lithium (1.6 mol/L) (128 ml) over 1.5 hour. To the reaction mixture was added water (200 ml), which was subjected to extraction with ethyl acetate (300 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-amino-3′-(1-tert-butoxycarbonylamino-1-methyl)ethyl-benzophenone (2.2 g) as a yellow oily product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][C:20]([C:24]([F:27])([F:26])[F:25])([OH:23])[CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:28][C:29]1[N:30]=[CH:31][N:32]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=2[O:41][CH3:42])[CH:33]=1>>[Cl:28][C:29]1[N:30]=[CH:31][N:32]([C:34]2[CH:40]=[CH:39][C:37]([NH:38][C:2]3[N:3]=[C:4]([N:18]4[CH2:22][CH2:21][C:20]([C:24]([F:26])([F:27])[F:25])([OH:23])[CH2:19]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:36][C:35]=2[O:41][CH3:42])[CH:33]=1.[C:20]([OH:41])([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: OC1(C(F)(F)F)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)C1
Product: COc1cc(Nc2nc3c(c(N4CCC(O)(C(F)(F)F)C4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Product: O=C(O)C(F)(F)F

Procedure:
1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol (Preparation Hi) (245 mg, 0.610 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (177 mg, 0.793 mmol) were combined and purified as per Example 16 to give 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol, TFA (first to elute, diastereomer A) (51.4 mg, 0.073 mmol) as a clear, colorless glass. LC-MS (M+H)+=589.1. 1H NMR (500 MHz, MeOD) δ ppm 7.97 (1H, s), 7.67 (1H, s), 7.17-7.26 (3H, m), 7.14 (1H, d, J=8.55 Hz), 7.04 (2H, t, J=8.70 Hz), 6.91 (1H, d, J=8.55 Hz), 4.14 (2H, t, J=8.85 Hz), 3.93-4.06 (3H, m), 3.58-3.68 (3H, m), 3.21-3.31 (1H, m), 3.09-3.21 (1H, m), 2.51-2.63 (1H, m), 2.28-2.41 (1H, m), 2.16 (1H, dd, J=12.82, 6.41 Hz), 1.95 (1H, dq, J=12.82, 8.55 Hz). The relative stereochemisty of Example 27 was not determined.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1.[C:18]1(C)[CH:23]=CC=C[CH:19]=1>>[C:13]([C:14]1[C:10](=[O:11])[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[C:18]([CH3:23])=[CH:19][C:15]=1[OH:16])(=[O:17])[CH3:12]
Reactant: Cc1ccccc1
Reactant: C=C1CC(=O)O1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Product: CC(=O)c1c(O)cc(C)n(-c2c(Cl)cccc2Cl)c1=O

Procedure:
A mixture of 2,6 dichlorophenylisocyanate (4.8 g, 0.025 mol), and diketene (4.3 g, 0.05 mol) in toluene (15.0 mL) was heated to reflux for 4 h under an atmosphere of argon. After removal of the solvent in vacuo, the residue was purified by silica gel flash chromatography using EtOAc/hexanes (1:3 v/v). The appropriate fractions, as monitored by ES mass spectrometry (MH+m/z=312) were combined and concentrated under reduced pressure. The resulting yellow solid (2.3 g) was further purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (45 min) at a flow rate of 100 mL/min. The appropriate fractions, as monitored by ES mass spectrometry (MH+ m/z=312) were combined and concentrated to half the volume. The solid that separated was extracted with EtOAc (2×25 mL). The combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated to dryness to give the title compound (0.77 g) as a pale yellow powder: 1H-NMR (CD3OD) δ: 7.62 (m, 2H), 7.52 (m, 1H), 6.19 (s, 1H), 2.59 (s, 3H), and 1.96 (s, 3H); ES-MS m/z=312 (MH+); HR-MS, m/z calc C14H12NO3Cl2 312.0189, found 312.0214.