Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43](O)=[O:44])[CH:38]=[CH:39][C:40]=1[CH3:41].Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43](=[O:44])[CH2:42][C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([F:34])[CH:36]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(CC(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ccc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1F
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotraiazole (0.4 g, 2.6 mmol) and 3-fluoro-4-methylphenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-fluoro-4-methyl-phenyl)-acetamide (0.7 g, 70%) as a white solid: mp 148-150° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.06 min. (98%); 1H NMR (DMSO-d6) δ 2.04-2.07 (m, 1H), 2.20 (s, 3H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.52 (s, 2H), 4.70 (d, J=5.7 Hz, 2H), 5.12-5.18 (dd, J=5.1 and 12.7 Hz, 1H), 6.99-7.07 (dd, J=11.2 and 14.7 hz, 2H), 7.21 (t, J=8.0 Hz, 1H), 7.63-7.76 (dd, J=3.3 and 7.5 Hz, 1H), 7.77-7.83 (dd, J=7.6 and 11.9 Hz, 2H), 8.65 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 13.74 (13.78), 21.95, 30.90, 37.84, 41.41, 48.83, 115.31, 115.60, 121.89, 124.84 (124.87), 127.12, 131.02 (131.28), 131.51, 133.20, 134.66, 135.87 (135.97), 139.09, 158.77 (161.98), 166.90, 167.42, 169.78, 170.26, 172.73; Anal. Calcd. for C23H20N3O5F: C, 63.15; H, 4.61; N, 9.61; F, 4.34. Found: C, 62.78; H, 4.45; N, 9.32; F, 4.47.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:12]=[CH:13][O:14][C:10]=2[C:9]([OH:15])=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6](C)[O:7]2.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][O:15][C:9]2[C:10]3[O:14][CH:13]=[CH:12][C:11]=3[C:2]([OH:1])=[C:3]3[C:8]=2[O:7][CH:6]=[CH:5][C:4]3=[O:17])=[CH:23][CH:24]=1
Reactant: Fc1ccc(CCCBr)cc1
Reactant: Cc1cc(=O)c2c(O)c3ccoc3c(O)c2o1
Product: O=c1ccoc2c(OCCCc3ccc(F)cc3)c3occc3c(O)c12

Procedure:
4,9-Dihydroxy-7-methyl-5H-furo[3,2-g]chromen-5-one was reacted with 1-bromo-3-(4-fluorophenyl)propane according to General Procedure A to give 9-(3-[4-fluorophenyl]propoxy)-4-hydroxy-5H-furo[3,2-g]chromen-5-one, that was further reacted according to General Procedure G step 1-3, to provide the title compound in 22% yield (over 4 steps). 1H NMR (300 MHz, CDCl3): δ 2.04-2.14 (m, 2H), 2.53 (s, 3H, CH3), 2.63 (s, 3H, CH3), 2.83 (t, J=7.8, 2H), 4.34 (t, J=6.3, 2H), 6.73 (d, J=2.1, 1H), 6.94 (t J=8.7 Hz, 2H), 7.13-7.18 (m, 2H), 7.50 (d, J=2.1 Hz, 1H), 8.98 (s, 1H, OH). MS (ES) m/z: 342.9 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=1>>[C:31]([C:27]1[CH:26]=[C:25]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C@@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]3[NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[CH2:19]2)[CH:30]=[CH:29][N:28]=1)#[N:32]
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Reactant: N#Cc1cc(Cl)ccn1
Product: N#Cc1cc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccccc3)C2)ccn1

Procedure:
1-((1R,2R)-2-((S)-1-(2-Cyanopyridin-4-yl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea was synthesized using 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (from intermediate C, Example 1) (100 mg, 0.32 mmol) and 4-chloropicolinonitrile (44 mg, 0.15 mmol) according to General Procedure A to give 29.3 mg (22.1%) of pale brown oil. Anal. Calcd. for C24H30N6O m/z 418.2, found: 419.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (d, J=6.5 Hz, 1H), 7.35 (d, J=2.7 Hz, 1H), 7.25 (m, 4H), 7.04 (m, 2H), 4.08 (m, 1H), 3.72 (m, 2H), 3.60 (m, 1H), 3.51 (m, 1H), 3.25 (m, 2H), 2.31 (m, 1H), 2.15-2.05 (m, 4H), 1.98-1.88 (m, 3H), 1.63-1.42 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[C:38]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[N:37][N:36]=[N:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH2:43][CH2:44][CH:39]([C:38]5[NH:37][N:36]=[N:35][N:34]=5)[CH2:40][CH2:41]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: C1CC(c2nnn[nH]2)CCN1
Product: O=C1N=C(N2CCC(c3nnn[nH]3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-(1H-tetrazol-5-yl)-piperidine following General Procedure B.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccc(I)cc1
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(Cc2ccc(I)cc2)c(C)c1CC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 60.2 %

Procedure:
To a stirred solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert.-butyl ester (10 g) in dimethylformamid (50 ml) at room temperature is added 1-bromomethyl-4-iodobenzene (15.5 g) and potassium carbonate (8.0 g). After 15 h of stirring, water is added and the reaction mixture is extracted twice with ethyl acetate. The organic layer is washed several times with water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (4:1 to 3:2 cyclohexane:ethyl acetate) to yield 1-(4-iodobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (12.2 g). [M+H]=427; HPLC retention time 1.57 min (Method E).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C([O-])([O-])=O.[K+].[K+].Br[C:30]1[C:31]([F:43])=[CH:32][C:33]([F:42])=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:35]=1>CN(C=O)C>[F:43][C:31]1[CH:32]=[C:33]([F:42])[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])=[CH:35][C:30]=1[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cc(Br)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1F
Temperature: 80 °C
Yield: 59 %

Procedure:
To a 250-mL RB flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (3.31 g, 10.7 mmol), K2CO3 (4.44 g, 32.1 mmol) and PdCl2dppf (870 mg, 1.07 mmol) was added a solution of N-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide (3.28 g, 11.8 mmol) in DMF (100 mL) at room temperature under argon. The mixture was heated to 80° C. under argon overnight, cooled to room temperature, filtered through celite and the celite was washed with EtOAc (3×20 mL). The filtrates were washed with H2O (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%–20% EtOAc/hexane) to give 2.4 g (6.31 mmol, 59%) of tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)-pyridine carboxylate: ESMS m/e: 379.3 (M−H)+.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C.O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1(c2ccc(C)cc2)CC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: COC(=O)C1(c2ccc(CBr)cc2)CC1
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
To a stirred solution of methyl 1-(p-tolyl)cyclopropanecarboxylate (3 g, 15.77 mmol) in acetonitrile (42 mL), was added N-bromosuccinimide (2.807 g, 15.77 mmol) followed by benzoyl peroxide (0.164 g, 0.473 mmol). The reaction was stirred at 80° C. for 2 hours 40 minutes and then allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with dichloromethane (×3). The combined organic extracts were washed with brine and dried (magnesium sulfate), filtered and concentrated under reduced pressure to afford a red oil. The crude material was purified by silica gel column chromatography eluting with 0-9% ethyl acetate in iso-hexane to afford the title compound (2.478 g, 58%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][CH:24](Br)[C:23](=[O:29])[C:22]=2[CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][CH:24]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:23](=[O:29])[C:22]=2[CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(OCc3ccccc3)ccc2OCCC1Oc1ccccc1
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 1.4 g of phenol in 50 ml of tetrahydrofuran was added 720 mg of 50% sodium hydride. After stirring for 30 minutes, a solution of 4.5 g of crude 7-benzyloxy-4-bromo-3,4-dihydro-1-benzoxepin-5(2H)-one was added. The reaction was allowed to stir at room temperature for 5 hours. The tetrahydrofuran was evaporated in vacuo, and the residue dissolved in ethyl acetate and washed with water. The ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified by recrystallization from methanol to give 2 g of title product, m.p. 112°-114° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=3)[N:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)ccc2c1
Reactant: C1CNCCN1
Product: FC(F)(F)Oc1ccc2nc(N3CCNCC3)ccc2c1

Procedure:
The title compound is being prepared in a manner analogous to Example 3, Step D from the 2-chloro-6-trifluoromethoxy-quinoline of Step D and piperazine.
Reaction SMILES: C(O)C.C(O[CH2:12][C:13]1([CH3:39])[CH2:17][C:16]2[C:18]([CH3:38])=[C:19]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1)C1C=CC=CC=1.[CH:40]([OH:42])=[O:41]>[C].[Pd]>[CH:40]([O:42][CH2:12][C:13]1([CH3:39])[CH2:17][C:16]2[C:18]([CH3:38])=[C:19]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1)=[O:41]
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(COCc3ccccc3)O4)CC2)cc1
Reactant: O=CO
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(COC=O)O4)CC2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 49 %

Procedure:
To a solution of ethanol (7.0 mL) containing 1-{2-[(benzyloxy)methyl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl}-4-(4-methoxyphenyl)piperazine (30 mg, 0.0628 mmol) synthesized in Example 134, 10% palladium carbon (500 mg) and formic acid (7.0 mL) were serially added, and the mixture was stirred at 100° C. for 15 hours. After cooled to room temperature, palladium carbon was removed by filtration, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 97:3-80:20) and crystallized from ethyl acetate-hexane to obtain 290 mg of the title compound (yield: 49%). Melting point was 120 to 124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-:17])=[O:16])[CH2:13][C:12]([CH2:18][NH2:19])=[CH:11][CH2:10]1.[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-:17])=[O:16])[CH2:13][C:12]([CH2:18][NH:19][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([O:21][CH3:20])=[O:32])=[CH:24][CH:25]=2)=[O:30])=[CH:11][CH2:10]1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of Example 12C (33 mg, 0.11 mmol) in CH2Cl2 (1 mL), 4-chlorocarbonyl-benzoic acid methyl ester (33 mg, 0.16 mmol) and diisopropylethyl amine (0.05 mL, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight. It was concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (41 mg, 81%). 1H NMR (500 MHz, CDCL3) δ ppm 8.06-8.10 (m, 2H), 7.86-7.92 (m, 2H), 7.37-7.41 (m, 1H), 7.15-7.26 (m, 2H), 5.73-5.82 (m, 1H), 5.02-5.13 (m, 1H), 4.01-4.13 (m, 3H), 2.50-2.95 (m, 3H). MS (ESI) m/z 463 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]([C:15]([O:17]C)=[O:16])[CH2:3]1.[OH-].[Na+]>CO>[C:11]([O:10][C:8]([N:6]1[CH2:7][C:2]([F:1])([F:19])[CH2:3][CH:4]([C:15]([OH:17])=[O:16])[CH2:5]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a solution of 1-tert-butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate (3.0 g, 10.74 mmol) in methanol (35 mL) was added a 1N aqueous solution of sodium hydroxide (20 mL) at below 5° C. The mixture was warmed to room temperature, and after 16 h, the mixture was concentrated under reduced pressure. The remaining aqueous layer was acidified with a 1N aqueous solution of hydrochloric acid (to pH˜4) and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-(tert-butoxycarbonyl)-5,5-difluoropiperidine-3-carboxylic acid (2.5 g) as a pale yellow solid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](C3N(C)C=CN=3)[S:17][C:10]=12.[CH2:39]([N:41]1[CH:45]=[C:44](C2SC3C(=NC=CC=3OC3C=CC(N)=CC=3F)C=2)[N:43]=[CH:42]1)[CH3:40]>>[CH2:39]([N:41]1[CH:45]=[C:44]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[O:28])=[CH:3][C:2]=3[F:1])[CH:15]=2)[N:43]=[CH:42]1)[CH3:40]
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Yield: 69 %

Procedure:
Following the procedure described above for the compound 28a (example 8, step 2) but replacing amine 9 for amine 15, title compound 28b was obtained in 69% yield. 1H NMR (DMSO-d6) δ (ppm): 10.78 (s, 1H), 9.62 (s, 1H), 8.66 (d, 1H), 8.37 (broad, s, 1H), 8.33 (s, 1H), 8.05 (dd, 1H), 7.94 (s, 1H), 7.92 (dd, 1H), 7.55 (t, 1H), 7.47 (dd, 1H), 7.07 (m, 2H), 6.96 (d, 1H), 6.89 (m, 1H), 4.13 (q, 2H), 3.84 (s, 2H), 1.42 (t, 3H). MS (m/z): 546.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][C:5]#[N:6].OCC(C)(C)C([NH:14][OH:15])=N>>[F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][C:5]([NH:14][OH:15])=[NH:6]
Reactant: CC(C)(CO)C(=N)NO
Reactant: N#CCCC(F)(F)F
Product: N=C(CCC(F)(F)F)NO

Procedure:
The title compound is prepared from 4,4,4-trifluoro-butyronitrile following a procedure analogous to that described in Intermediate 3. Mass spectrum (ESI+): m/z=157 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([NH2:15])[C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)[CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:21]([Cl:29])[CH:20]=1>N1C=CC=CC=1.ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:15][C:13]2[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[N:14]=2)(=[O:26])=[O:27])=[C:21]([Cl:29])[CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-[cis-3,5-dimethyl-1-piperazinyl]-3-(methyloxy)-2-pyridinamine (D7, Method C) (473 mg, 2 mmol) was dissolved in pyridine (5 ml) and dichloromethane (5 ml). 4-Bromo-2-chlorobenzene sulfonyl chloride (870 mg, 3 mmol) was added and the solution stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and azeotroped with methanol. The residue was loaded on to an SCX cartridge (Varian, 10 g) in methanol, washed with methanol and the basic products eluted with 2M ammonia/methanol. The product containing fractions were concentrated in vacuo and purified by flash chromatography (Biotage SP4, 40+S, 0-20% 2M ammonia/methanol in dichloromethane to afford the title product (D11), 478 mg, MS (ES+) m/e 489/491/493 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1.Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 103.9 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (16.3 mL of a 0.31 M stock solution, 5.04 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid methyl ester (1.0 g, 4.58 mmol) in tetrahydrofuran/hexamethylphosphoramide (8.6 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of bromomethylcyclohexane (1.92 mL, 13.76 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 3 h. The reaction was warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclohexyl-2-(3,4-dichloro-phenyl)-propionic acid methyl ester (1.5 g, quant.) as a clear oil: EI-HRMS m/e calcd for C16H20Cl2O2 (M+) 314.0840, found 314.0836.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([OH:14])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[H-].[Na+].[Cl:23][Ti:24](Cl)([Cl:35])[C:25]1([CH3:34])[C:29]([CH3:30])=[C:28]([CH3:31])[C:27]([CH3:32])=[C:26]1[CH3:33]>C1(C)C=CC=CC=1>[Cl:23][Ti:24]([Cl:35])([C:25]1([CH3:34])[C:26]([CH3:33])=[C:27]([CH3:32])[C:28]([CH3:31])=[C:29]1[CH3:30])[O:14][C:5]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Reactant: Cc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2c(-c3ccccc3)cc(C)cc2-c2ccccc2)C(C)=C1C
Reaction time: 24 h
Yield: 46.2 %

Procedure:
4-methyl-2,6-diphenylphenol (400 mg, 1.53 mmol) and sodium hydride (110 mg, 4.60 mmol) were dissolved in 10 mL of toluene, and then refluxed for 4 hours. Subsequently, cooling to normal temperature was conducted, a solution in which (trichloro)(pentamethylcyclopentadienyl)titanium(IV) (376 mg, 1.30 mmol) was dissolved in 5 mL of toluene was slowly dropped thereonto, and reflux was conducted for 24 hours. After the reaction finished, volatile materials were removed, washing was conducted using purified hexane, recrystallization was conducted using a mixed solution of toluene/hexane at −35° C., filtration was conducted, and drying was conducted at reduced pressure to produce 308 mg of red solid component.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (74 mg, 86%), MS (ISP) m/z=345.4 [(M+H)+], mp 236.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).