Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si:3]1([C:16]2[CH:21]=CC=CC=2)[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)C.[F:22][C:23]1[CH:24]=[C:25]([Mg]Br)[CH:26]=[CH:27][C:28]=1[F:29]>>[CH2:16]([Si@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]2[CH:10]=[CH:11][C:12]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[C:28]([F:29])[CH:27]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:21]
Reactant: CC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Reactant: Fc1ccc([Mg]Br)cc1F
Product: CC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 12 was repeated using 30.2 g of 4-(4-ethyl-4-phenyl-4-silacyclohexyl)cyclohexanone and 3,4-difluorophenylmagnesium bromide, thereby obtaining the captioned compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([OH:15])=O)[N:7]2[CH3:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:40][C:41]1[C:42]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[CH:43][C:44]([O:48][CH3:49])=[C:45]([CH:47]=1)[NH2:46]>ClCCl.N1C=CC=CC=1>[F:40][C:41]1[C:42]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[CH:43][C:44]([O:48][CH3:49])=[C:45]([NH:46][C:13]([C:6]2[N:7]([CH3:12])[C:8]3[C:4]([CH:5]=2)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)=[O:15])[CH:47]=1
Reactant: COc1cccc2c1cc(C(=O)O)n2C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1NC(=O)c1cc2c(OC)cccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
4-Methoxy-1-methyl-1H-indole-2-carboxylic acid (0.225 mmol, 46.1 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.247 mmol, 94 mg) were added to a solution of 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.225 mmol, 60 mg) in dichloromethane (2.5 mL) and pyridine (0.5 mL) at 0° C. After stirring the reaction mixture overnight at room temperature it was concentrated in vacuo. Water was added to the residue and extracted with dichloromethane. The organic extracts were washed with water. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptanes/ethyl acetate) to give impure N-(5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (45 mg). The latter compound and 1-bromo-8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (35 mg) were reacted using the procedures described in example 4 step 4c and purification using column chromatography (silica gel, heptanes/ethyl acetate) gave N-(5-fluoro-2-methoxy-4-(8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (9.7 mg)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:30]=[C:31]([C:37]2[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=[CH:33][C:34]=1[CH2:35]Br>>[Br:28][C:29]1[CH:30]=[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]#[N:44])[CH:32]=[CH:33][C:34]=1[CH2:35][N:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH2:19][CH2:20][C@@H:14]([NH:13][C:11](=[O:12])[CH2:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:27])[CH3:26])[C:15]1=[O:25]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2Br)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) and 3'-bromo-4'-bromomethyl-1,1'-biphenyl-2-nitrile by the procedure described in Example 69, Step D. 1H NMR (200 MHz,CDCl3): 1.33 (s,3H), 1.34 (s,3H), 1.40 (s,9H), 1.91 (m,1H), 2.43 (d,14 Hz,1H), 2.55 (d,14 Hz,1H), 2.55-2.90 (m,3H), 4.62 (m,1H), 4.95 (d,16 Hz,1H), 5.28 (s,1H), 5.34 (d,16 Hz,1H), 6.63 (d,7 Hz,1H), 7.10-7.25 (m,4H), 7.45 (m,4H), 7.64 (m,1H), 7.75 (m,2H). FAB-MS (Li spike): calculated for C34H37BrN4O4 644, 646; found 651 (13%); 653 (15%).
Reaction SMILES: [Se](=O)=[O:2].[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=2>O1CCOCC1.O>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:2])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=[Se]=O
Reactant: Cc1c(Cl)cnc2ccccc12
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c(Cl)cnc2ccccc12
Temperature: 25 °C
Yield: 37.9 %

Procedure:
A solution of selenium dioxide (1.90 g) in 1,4-dioxan (5 ml) and water (1.2 ml) was added dropwise over 15 min to a stirred solution of 3-chloro-4-methylquinoline (2.91 g) in 1,4-dioxan (10 ml) at 60-70° C. The mixture was heated at reflux for 6 h, allowed to warm to room temperature, then concentrated in vacuo. The residue was purified by column chromatography (SiO2), eluting with dichloromethane to 5% methanol in dichloromethane by a stepwise gradient, to give the sub-title compound as a yellow solid (1.19 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH3:24][O:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][C:28]=1[F:37]>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:23])[CH2:18][CH2:19]2)(=[O:34])=[O:35])=[CH:29][C:28]=1[F:37]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Diisopropylethylamine (3.2 ml, 18.5 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.5 g, 2.5 mmol) in DCM (10 ml) at room temperature. To this mixture was added 4-chlorosulfonyl-2-fluoro-benzoic acid methyl ester (0.6 g, 2.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 98% DCM, 2% Methanol) to give the title compound (0.98 g, 87% yield) as a white solid. Tr=2.08 min m/z (ES+) (M+Na+) 439.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[N:8]=[C:7]([CH3:19])[C:6]=1[N+:20]([O-])=O)=[O:4].[Sn](Cl)Cl>C(=O)(O)[O-].[Na+]>[NH2:20][C:6]1[C:7]([CH3:19])=[N:8][N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[C:5]=1[C:3]([NH:2][CH3:1])=[O:4]
Reactant: CNC(=O)c1c([N+](=O)[O-])c(C)nn1-c1c(Cl)cc(Cl)cc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC(=O)c1c(N)c(C)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
A mixture of N,3-dimethyl-4-nitro-1-(2,4,6-trichlorophenyl)-1H-pyrazole-5-carboxamide (42 mg, 0.116 mmol) and tin (II) chloride (110 mg, 0.578 mmol) was stirred at 80° C. for 3 h and diluted with saturated sodium bicarbonate. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 50% ethyl acetate/hexane to give the title compound (20 mg, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12]C(=O)C1C=CC=CC=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: O=C(OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
A reaction vessel was charged with 11.6 g of 3,5-dichloro-4-(3-benzoyloxypropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 15.2 g of 10% aqueous potassium hydroxide solution and 30 ml of methanol. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. Water was poured into the concentrate, and the mixture was extracted twice with 150 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 7.41 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propanol (83% yield), m.p., 56.6° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:32])([F:31])[O:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][O:15][C:16]2[CH:28]=[CH:27][C:19]([CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl[C:34]1[S:35][C:36]2[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:37]=2[N:38]=1>CN(C)C=O>[F:32][C:8]([F:31])([F:7])[O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]2[CH:28]=[CH:27][C:19]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:34]4[S:35][C:36]5[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:37]=5[N:38]=4)[CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)Oc1ccc(COc2ccc(CC3CCNCC3)cc2)cc1
Reactant: Oc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc2nc(N3CCC(Cc4ccc(OCc5ccc(OC(F)(F)F)cc5)cc4)CC3)sc2c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Potassium carbonate (1.02 g) and 4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidine were added to an N,N-dimethylformamide solution (10 ml) of 2-chlorobenzothiazol-6-ol (1.37 g) and the mixture was stirred at 80° C. for 2 days. After being cooled to room temperature, the mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to afford the title compound as a white powder (2.1 g).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:15]=1.[NH2:29][C:30]1[CH:39]=[C:38]2[C:33]([CH2:34][CH2:35][C:36](=[O:41])[N:37]2[CH3:40])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:29][C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][C:36](=[O:41])[N:37]3[CH3:40])=[CH:32][CH:31]=2)=[O:20])=[C:16]([NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:15]=1
Reactant: CN1C(=O)CCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(Cl)cc1NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NC3CCCC3)cc21
Temperature: 25 °C
Reaction time: 26 h

Procedure:
Hydrochloride of 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide (250 mg) was added to a chloroform (15 mL) solution of 4-chloro-2-(cyclopentylamino)benzoic acid (250 mg) and 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (184 mg), followed by stirring at room temperature for 26 hours. The reaction liquid was concentrated under a reduced pressure. By purifying the residue by silica gel column chromatography (chloroform:methanol, 1:0 to 9:1), 4-chloro-2-(cyclopentylamino)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide was obtained. By treating this with 4 M hydrogen chloride/ethyl acetate solution, 4-chloro-2-(cyclopentylamino)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide hydrochloride (97 mg) was obtained as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1>O.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>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OB(O)c1cccc(F)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Yield: 97.8 %

Procedure:
3-Fluorophenylboronic acid (39.5 g, 0.282 mol), a solution of K2CO3 (150 g) in water (700 mL), [Bu4N]Br (3.5 g, 0.0107 mol), and Pd(PPh3)4 (12.4 g, 0.0107 mol) were added to a solution of 6-chloronicotinic acid (37.0 g, 0.235 mol) in toluene. The reaction mixture was stirred under reflux for 20 h. After cooling, the reaction mixture was filtered and acidified with 2 M HCl to pH 3. The formed precipitate was separated by filtration and dried to give 6-(3-fluorophenyl)nicotinic acid (yield 97%, 49.9 g). 1H NMR (400 MHz, DMSO-d6) □ ppm 7.29 (td, J=8.46, 2.42 Hz, 1H) 7.50-7.56 (m, 1H) 7.93 (dd, J=10.47, 2.15 Hz, 1H) 7.97 (d, J=7.79 Hz, 1H) 8.11 (d, J=8.06 Hz, 1H) 8.30 (dd, J=8.32, 2.15 Hz, 1H) 9.11 (d, J=1.88 Hz, 1H), 13.48 (bs, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1>C(O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(COC2CCCCO2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.8 %

Procedure:
To a solution of 4-(2-tetrahydropyranyloxymethyl)nitrobenzene (59.7 g, 0.256 mol) in ethanol (EtOH) (300 ml) was added under nitrogen atmosphere at room temperature 10% Pd/C (5.97 g), and catalytic hydrogenation was carried out. The mixture was stirred at room temperature for 24 hours. After the reaction completed, the catalyst was filtered off, and the organic layer was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 4-(2-tetrahydropyranyloxymethyl)aniline (39.7 g, 76%) as syrup.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[OH:25][CH2:26][CH2:27][NH:28][C:29]([CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)=[O:30].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[OH:25][CH2:26][CH2:27][NH:28][C:29]([CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[N:3]=[C:4]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][S:8][C:6]=3[N:7]=2)[CH2:32]1)=[O:30]
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reactant: O=C(NCCO)C1CCCNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)C1CCCN(c2nc(NCc3ccccn3)c3c(-c4ccccc4)csc3n2)C1
Temperature: 200 °C

Procedure:
(2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine (44 mg, 0.124 mmol), Piperidine-3-carboxylic acid(2-hydroxyethyl)amide (Fluorochem, 32 mg, 0.188 mmol, 1.5 eq) and N,N-diisopropylethylamine (Aldrich, 0.188 mmol) were dissolved in N-Methyl Pyrrolidinone (1.5 ml) in a Biotage microwave tube and heated to 200° C. and maintained at this temperature for 30 min. On cooling, the solvents were removed in vacuo. The residue was triturated with DCM (2×10 ml) and the extracts combined, concentrated and purified by prep TLC (eluent 10% MeOH/DCM) to give the product as a yellow oil, which slowly solidified on standing to a waxy solid. The waxy solid may be converted to a free-flowing powder by stirring in diethyl ether for 1-2 h (0.5 g in 10 ml). Yield=18.3 mg (30%)
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[C:31]([C:37](=[N:39]O)[NH2:38])=[N:32][CH:33]=[C:34]([F:36])[CH:35]=1>>[F:29][C:30]1[C:31]([C:37]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:39]=2)=[N:32][CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: NC(=NO)c1ncc(F)cc1F
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ncc(F)cc3F)no2)C1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 91 mg (0.56 mmol) of 3,5-difluoro-N′-hydroxypyridine-2-carboximidamide were reacted according to the General Method 2. Yield: 131 mg (63% of theory).
Reaction SMILES: CN(C)/C=[CH:4]/[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1.C1C[O:22]CC1.O>>[N+:15]([C:14]1[C:5]([CH:4]=[O:22])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:17])=[O:16]
Reactant: CN(C)/C=C/c1ccc2cccnc2c1[N+](=O)[O-]
Reactant: C1CCOC1
Solvent: O
Product: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
NalO4 (11.71 g, 54.76 mmol) was added portionwise to a solution of dimethyl-[(E)-2-(8-nitro-quinolin-7-yl)-vinyl]-amine (Intermediate 203) (4.44 g, 18.3 mmol) in THF/water (1:1, 70 ml). The mixture was stirred at room temperature for 16 h. The insoluble material was removed by filtration and washed with EtOAc (60 ml). The combined organic phases were washed with sat. sodium bicarbonate solution, brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (3.24 g, 71%).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].[O:31]=[C:32]1[CH:36]([CH2:37]OS(C)(=O)=O)[CH2:35][CH2:34][N:33]1[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[O:31]=[C:32]1[CH:36]([CH2:37][N:25]2[CH:26]=[C:22]([C:9]3[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]4[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:30])[N:6]([CH2:27][CH2:28][CH3:29])[C:7]=4[N:8]=3)[CH:23]=[N:24]2)[CH2:35][CH2:34][N:33]1[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:51])([F:50])[F:52])[CH:44]=1
Reactant: CS(=O)(=O)OCC1CCN(c2cccc(C(F)(F)F)c2)C1=O
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CCN(c5cccc(C(F)(F)F)c5)C4=O)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 77.5 °C
Yield: 64.5 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.23 mmol), methanesulfonic acid 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl ester (0.10 g, 0.32 mmol), K2CO3 (0.045 g, 0.32 mmol) and DMF (1 ml) was heated at 75-80° C. for 16 hrs. Reaction mixture was cooled to 20-25° C. and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate, washed with saturated brine solution. The organic layer was dried over Na2SO4 and evaporated to obtain crude product (0.2 g). The crude product was purified by preparative TLC to obtain pure 8-{1-[2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.10 g, 65%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[NH2:10][C:11]1[N:15]([C:16]2[CH:17]=[C:18]([S:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=2)[N:14]=[C:13]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:14]=[C:13]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(SCCO)c2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(SCCO)c2)n1
Reaction time: 3 h
Yield: 100 %

Procedure:
Trichloroethyl chloroformate (0.1 mL, 0.78 mmol) was added to a solution of Intermediate 3b (176 mg, 0.60 mmol) and DIPEA (0.31 mL, 1.81 mmol) in THF (10 mL), and the mixture stirred for 3 h. The mixture was then partitioned between water (15 mL) and EtOAc (3×20 mL), and the combined organic extracts dried (Na2SO4) and concentrated in vacuo. The residue was triturated (cyclohexane) and filtered to give the title compound as a yellow solid (280 mg, 100%). LCMS (Method 1): Rt 3.93 min, m/z 466/468 [MH+]
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22]>>[CH:1]([NH:4][CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:19]\[NH:20][C:21]([NH2:23])=[O:22])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)NCCN1C(=O)C(=O)c2ccccc21
Reactant: NNC(N)=O
Agent: Cl
Product: CC(C)NCCN1C(=O)/C(=N/NC(N)=O)c2ccccc21
Yield: 49.8 %

Procedure:
By using 1-(2-isopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 10 was carried out, and the reaction product was recrystallized from ethanol to obtain (E)-1-(2-isopropylaminoethyl)isatin 3-semicarbazone having a melting point of 169°-172° C. (decomposition) (yield: 49.8%).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:9]1)C1C=CC=CC=1.[CH3:32][O:33][C:34](Cl)=[O:35]>C1COCC1>[CH3:32][O:33][C:34]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([CH2:18][N:19]2[CH2:20][CH2:21][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)[CH2:9]1)=[O:35]
Reactant: COC(=O)Cl
Reactant: Fc1ccc(C2CCN(C[C@@H]3CN(Cc4ccccc4)C[C@H]3c3ccsc3)CC2)cc1
Solvent: C1CCOC1
Product: COC(=O)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 4.35 g (10 mmol) of 1-benzyl-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(R)-(3-thienyl)pyrrolidine in 20 mL of THF at 0° C. was added 3.7 mL (26 mmol) of methylchloroformate and the reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone: hexanes, 1:3) to give 3.5 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=1.[CH3:24][CH:25](O)[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[CH:25]([O:20][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:26])[CH3:24]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)OC(C)C)cn1
Reaction time: 15 h
Yield: 76.6 %

Procedure:
A solution of N,N-dicyclohexylcarbodiimide (258 mg, 1.25 mmol) and 4-dimethylaminopyridine (12 mg, 0.10 mmol) in dichloromethane (4 mL) was added dropwise to a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0 mmol) and 2-propanol (0.06 g, 1.0 mmol) in dichloromethane (4 mL) at room temperature. After 15 h, the mixture was filtered and the filtrate was concentrated and purified by chromatography (SiO2, heptane:ethyl acetate 100:0 to 8:2) to give the title compound (270 mg, 77%) as a colourless oil. MS: m/e=353.1 [M+H]+.