Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:22])[C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)[CH3:2].C(OCC)(=O)C.[ClH:29]>>[ClH:29].[ClH:29].[CH2:1]([N:3]([CH3:22])[C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCN(C)c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN(C)c1ccc2c(c1)OCCNC2
Yield: 68.1 %

Procedure:
A solution of tert-butyl 8-[ethyl(methyl)amino]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (230 mg, 0.751 mmol) in 4N hydrogen chloride-ethyl acetate (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (143 mg, 68.1%) as a solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1>N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([O:19][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 51 %

Procedure:
A 2.93 g quantity of nicotinoyl chloride hydrochloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 100 ml of pyridine, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was concentrated and the concentrate was washed with ethyl acetate and water, thereby producing 1.77 g of the title compound in a yield of 51%.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:23][CH2:22]4)[CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:28])[N:11]3[C:24]([O:26][CH3:27])=[O:25])[CH2:2]1.[CH:29](=O)[CH3:30]>>[CH:21]1([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:3]4[CH2:2][N:1]([CH2:29][CH3:30])[CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:24]([O:26][CH3:27])=[O:25])[C@@H:10]([CH3:28])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH2:22][CH2:23]1
Reactant: CC=O
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C
Product: CCN1CC(Oc2c(-c3cnn(C4CC4)c3)ccc3c2CC[C@H](C)N3C(=O)OC)C1

Procedure:
(S)-Methyl 6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-ethylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from (S)-methyl 5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate and acetaldehyde according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 0.96 (t, J=7.20 Hz, 3H), 1.05-1.20 (m, 7H), 1.42-1.55 (m, 1H), 2.15-2.25 (m, 1H), 2.40-2.52 (m, 3H), 2.81-2.95 (m, 1H), 3.01-3.15 (m, 2H), 3.41-3.52 (m, 2H), 3.68-3.71 (m, 1H), 3.78 (s, 3H), 4.21-4.28 (m, 1H), 4.51-4.61 (m, 1H), 7.20-7.32 (m, 2H), 7.76 (s, 1H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z 411 [M+H]+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[I:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH2:21]Br>O>[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH2:21][O:15][C:12]1[CH:13]=[CH:14][C:9]([I:8])=[CH:10][CH:11]=1
Reactant: BrCC1OCCO1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccc(OCC2OCCO2)cc1
Reaction time: 3 h
Yield: 46.5 %

Procedure:
A suspension of 65% sodium hydride (9.3 g)/dimethylformamide (100 ml) was ice-cooled, followed by the addition of 4-iodophenol (50.5 g)/dimethylformamide (200 ml) solution, and the mixture was stirred for 3 hr. To the mixture solution was added (1,3-dioxolan-2-yl)methylbromide (46.0 g), and the mixture was reacted at 60° C. for 1 day. The reaction solution was poured into water, and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and then dried (over magnesium sulfate). The solvent was removed, and the resulting residue was purified by NH silica gel column chromatography (chloroform), and then recrystallized from ethyl acetate/hexane, to give 32.7 g of the title compound as pale yellow prisms.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13]>C(O)C>[F:13][C:12]([F:15])([F:14])[C:11]1[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:10]=1
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1nc(C(F)(F)F)cs1

Procedure:
A solution of ethyl amino(thioxo)acetate (4 g) and 3-bromo-1,1,1-trifluoroacetone (3.1 ml) in ethanol (150 ml) was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (3.56 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1.[NH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.[H][H]>[Pd].CO>[NH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: NCn1cnc2ccccc21
Solvent: CO
Product: COC(=O)c1ccc(N)cc1
Reaction time: 16 h
Yield: 96 %

Procedure:
To a parr shaker under nitrogen atmosphere was charged 3-aminomethylbenzimidazole-4 nitro benzoic acid methylester (10 g, 0.037 mol, 1.0 eq) and 180 ml of methanol. To the slurry was charged 1 g of 10% Palladium on carbon This was placed under 55 psi hydrogen atmosphere and shaken for 16 hours. The reaction was removed under nitrogen atmosphere and filtered over a bed of celite under an atmosphere of nitrogen and the celite/Pd/c washed with 500 ml of methanol (degassed with nitrogen) and the combined organics concentrated to an off white solid. Yield 96%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.CN(C)C(=O)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>O>[SH:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc2nc(S)[nH]c2c1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: O=C(Nc1ccc2nc(S)[nH]c2c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
36.6 g of 5-amino-2-mercaptobenzimidazole and 17.1 g of pyridine were added to 250 ml of N,N-dimethylacetamide, and thereto was added dropwise 34.4 g of phenyl chloroformate at room temperature. After the resulting solution as such was stirred for 1.5 hours at room temperature, 1.5 liters of ice cooled water was added to deposit crystals, which were filtered off and recrystallized from acetonitrile, whereby 47.7 g of 2-mercapto-5-phenoxycarbonylaminobenzimidazole was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[C:35]([CH:39]=1)[C:36](O)=[O:37]>CN(C)C=O>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[C:35]([CH:39]=1)[C:36]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:37]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1F
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Pyridinamine (0.21 g, 2.19 mmol), EDC (0.34 g, 1.75 mmol), HOBT (0.36 g, 2.33 mmol) and N-ethylmorpholine (0.37 ml, 2.91 mmol) were added to a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}benzoic acid (may be prepared by Description 103; 0.5 g, 1.46 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 hours. The N,N-dimethylformamide was removed on a buchi and the residue was diluted with ethyl acetate (50 ml) washed with saturated aqueous sodium hydrogencarbonate (1×25 ml) and water (1×25 ml) and dried (MgSO4), filtered and evaporated to yield the title compound as a white solid. 0.6 g.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1.CCO.[NH4+].[Cl-]>[Fe].O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1
Reactant: COc1ccc(Cn2nc(I)c3cc([N+](=O)[O-])cnc32)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2nc(I)c3cc(N)cnc32)cc1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
3-Iodo-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (3.5 g, 8.5 mmol), EtOH (70 mL), water (30 mL), Fe (0) (1.9 g, 34 mmol), and NH4Cl (4.6 g, 85 mmol) were charged to a 250 mL round-bottomed flask. This mixture was warmed to 80° C. for 4 hours, and then allowed to cool to room temperature. The mixture was filtered through GF/F filter paper and concentrated to remove EtOH. The organic layers were extracted with EtOAc (2×100 mL), dried over Na2SO4, and concentrated to get 3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (2.7 g, 74%) of crude product as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][N:29]1[C:33]([NH2:34])=[CH:32][C:31]([CH3:35])=[N:30]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:34][C:33]3[N:29]([CH3:28])[N:30]=[C:31]([CH3:35])[CH:32]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: Cc1cc(N)n(C)n1
Product: Cc1cc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)n(C)n1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 2,5-dimethyl-2H-pyrazol-3-ylamine according to procedure B followed by deprotection yielded the title compound as a black waxy solid. MS (ESI): m/z=373.2 [M+H]+.
Reaction SMILES: [Na].CO.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:15]=[N:14][C:13]([OH:16])=[N:12]1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CS(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:15]=[N:14][C:13]([O:16][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:24])=[N:12]1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2ccccc2Cl)n1
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccccc2Cl)n1
Yield: 92.6 %

Procedure:
The process was carried out essentially according to that of Example 2 above, starting with 1.2 g of sodium, 30 ml of methanol, 10 g of 1-(2-chlorophenyl)-3-hydroxy-1,2,4-1H-triazole and 9.3 g of ethyl 2-bromopropionate. The solvent was 100 ml of dimethylsulfoxide. The product obtained was 14 g of the desired product, an oil.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:27])[C:8]1=[O:28])=O.[F:29][C:30]([F:43])([F:42])[O:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[CH2:35]B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[F:29][C:30]([F:42])([F:43])[O:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[CH2:35][C:15]1[CH:16]=[N:17][C:10]2[N:9]([CH3:27])[C:8](=[O:28])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=2[C:14]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Br)cnc21
Reactant: OB(O)Cc1cccc(OC(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Cc3cccc(OC(F)(F)F)c3)cnc21
Temperature: 85 °C
Yield: 16.4 %

Procedure:
To a mixture of 3-(6-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (See Compound 34, step 2, 80 mg, 0.171 mmol) and 3-(trifluoromethoxy) benzylboronic acid (103 mg, 0.342 mmol) in dioxane (4 mL) was added aq. 2 M K3PO4 (0.8 mL) and Pd(dppf)Cl2 (10 mg). The reaction was degassed with nitrogen (3×) and heated at 85° C. for 3 h, cooled to RT, diluted with water (10 mL) then extracted with EA (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(3-(trifluoromethoxy)benzyl)-5-(4-chlorobenzyl)-3-(3-hydroxy propyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 16.5% yield) as a white solid. 1H NMR (CDCl3) δ: 8.63 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.98-6.92 (m, 3H), 4.70 (s, 2H), 4.42-4.40 (m, 1H), 4.05 (s, 2H), 3.94-3.90 (m, 2H), 3.60 (s, 3H), 3.42-3.40 (m, 2H), 1.69-1.64 (m, 2H). LCMS: MH+ 534 and TR=3.262 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[N:23](COCC[Si](C)(C)C)[C:22]5[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=5[N:20]=4)=[CH:14][CH:13]=3)[C:9](=[O:11])[NH:10][C:3]=12.[ClH:36]>CCO>[ClH:36].[ClH:36].[NH:20]1[C:21]2[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=2[N:23]=[C:19]1[O:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[NH:10][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of 7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.053 g) and 2N HCl in EtOH (5.0 mL) was stirred at 60° C. for 10 h. After cooling to room temperature, the solvent was removed. The residue was recrystallized from EtOH-AcOEt to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride (0.030 g).
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH3:21].C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].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>[CH:20]([C:23]1[CH:28]=[C:27]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=4[O:8][CH2:7][CH2:6][N:5]3[CH:19]=2)[CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
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: CC#N
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3cccc(C(C)C)c3)nc1-2
Yield: 5.1 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 3-isopropylphenylboronic acid (65 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 296 (4 mg). ESI-MS: 363.1 (M)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=3)[N:7]=2)=[CH:9]1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: Clc1nccc(-c2ccsc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CNc2nccc(-c3ccsc3)n2)cc1
Temperature: 130 °C
Yield: 48 %

Procedure:
To a solution of 14 (680 mg, 3.46 mmol) and methyl 4-(aminomethyl)benzoate (686 mg, 4.51 mmol) in dry 1,4-dioxane (10 mL) was added DIPEA (1.50 mL, 8.65 mmol) and the mixture was heated for 48 h at 130° C. in a sealed tube. Solvents were removed under vacuum and the residue was triturated with a mixture of EtOAc/Et2O, to form a solid, which was collected by filtration and dried. This material was purified by flash chromatography on silica gel (EtOAc/CH2Cl2: 30/70) to afford the title compound 15 (540 mg, 1.66 mmol, 48% yield). 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 8.29-8.23 (m, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.84-7.77 (m, 1H), 7.69-7.59 (m, 2H), 7.52-7.43 (m, 2H), 7.03 (d, J=5.2 Hz, 1H), 4.60 (d, J=6.4 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(Br)cn1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Nc1ccc(-c2ccc(Cl)cc2)cn1

Procedure:
Prepared from commercially available 2-amino-5-bromopyridine (8.65 g, 50 mmol) and commercially available 4-chlorophenylboronic acid (12.08 g, 77 mmol) as described in example C.20 step 2. Obtained the crude 5-(4-chloro-phenyl)-pyridin-2-ylamine as an orange solid (89% pure).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cccnc1F

Procedure:
A solution of 2-fluoropyridine-3-carboxaldehyde (400 mg, 3.2 mmol) and sodium borohydride (121 mg, 3.2 mmol) in methanol (8 mL) was stirred at rt for 16 h. The mixture was then diluted with EtOAc and washed with H2O, then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give (2-fluoropyridin-3-yl)methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:15][C:8]3([CH2:13][CH2:12][N:11](C)[CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:15][C:8]3([CH2:13][CH2:12][N:11]([C:24]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:25])[CH2:10][CH2:9]3)[C:6]=2[CH:7]=1
Reactant: CN1CCC2(CC1)SC(c1ccccc1)c1ccc(F)cc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1ccccc1)c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.3 g of 6-fluoro-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine] and 0.3 g of phenyl chloroformate in 10 ml of methylene chloride which was previously stirred at ambient temperature for 16 hours is sequentially quenched with water, washed with 10% sodium hydroxide and dried. The reaction mixture is concentrated under vacuum leaving a viscous oil which crystallized with standing. The solid product is recrystallized from an ether-pentane mixture to give prisms, m.p. 156°-158° C. of 6-fluoro-1,3-dihydro-3-phenyl-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH2:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>[Pd].C(O)C.O.[Pt]=O>[NH:1]1[C:5]([CH:6]2[C:14]3[C:9](=[CH:10][C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH2:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1
Reactant: COc1cc2c(cc1C)CC=C2c1cnc[nH]1
Agent: O=[Pt]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1C)CCC2c1cnc[nH]1

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, by the hydrogenation of 0.5 gram (0.0022 mole) of 3-(imidazol-5-yl)-5-methoxy-6-methylindene (viii) in the presence of 0.1 gram (catalyst) of 10% palladium on carbon and 0.1 gram (catalyst) of platinum oxide hydrate in 40 mL of ethanol. The yield of subject compound was 0.42 gram, mp 68-70° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1.[CH3:16][O:17][P:18]([O:21]C)[O:19][CH3:20]>>[N+:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH2:2][P:18](=[O:21])([O:19][CH3:20])[O:17][CH3:16])=[CH:4][CH:5]=1)([O-:15])=[O:14]
Reactant: COP(OC)OC
Reactant: O=[N+]([O-])c1ccc(CBr)c2ccccc12
Product: COP(=O)(Cc1ccc([N+](=O)[O-])c2ccccc12)OC

Procedure:
1-Bromomethyl-4-nitronaphthalene and trimethylphosphite ((CH3O)3P) were treated in the same manner as in Reference Example 43 to yield dimethyl (4-nitro-1-naphthyl)methylphosphonate, which was then recrystallized from ethanol-hexane to yield yellow prisms having a melting point of 128°-129° C.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][CH:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N(C)C)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.26 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 481 [M+H]
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([O-])(=O)C.[Na+].CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[N:7]1([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[CH:16]=[CH:20][CH:19]=[CH:18]1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1cccc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
Glycine ethyl ester hydrochloride (1.0 g, 7.2 mmol) and sodium acetate (960 mg, 12 mmol) were dissolved in water (5 mL). Acetic acid (10 mL) was then added. The solution was heated to reflux and 2,5-dimethoxytetrahydrofuran (0.95 mL, 7.3 mmol) was added. The mixture was heated at reflux for 4 hours before being allowed to cool to room temperature. The dark brown solution was diluted with water (40 mL), neutralised with solid NaHCO3 (16 g) and extracted with CH2Cl2 (3×40 mL). The organic layers were dried (MgSO4), filtered, concentrated in vacuo to give a dark brown liquid. The material was purified by flash chromatography (Biotage SP4, 40 g cartridge, gradient 0-60% gradient EtOAc in hexanes) to give ethyl 1H-pyrrol-1-ylacetate as a colourless liquid (720 mg, yield 65%). 1H-NMR (400 MHz, CDCl3): δ 1.28 (t, 3H, J 7.1 Hz), 4.22 (q, 2H, J 7.2 Hz), 4.62 (s, 2H), 6.20-6.22 (m, 2H), 6.65-6.67 (m, 2H).