Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:35])[N:27]([CH2:31][CH2:32][O:33][NH2:34])[CH:28]([CH3:30])[CH3:29])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:35])[N:27]([CH2:31][CH2:32][O:33][NH:34][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])[CH:28]([CH3:30])[CH3:29])([CH3:22])([CH3:24])[CH3:23]
Reactant: CC(C)N(CCON)C(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)N(CCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 80.9 %

Procedure:
Following a procedure analogous to Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) of Example 9 or 16 and tert-butyl(2-(aminooxy)ethyl)(isopropyl)carbamate (596 mg) described in Reference Example 17, 578.4 mg of the title compound was afforded (yield 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>O1CCCC1>[F:30][C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:39])[NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (220 mg, 0.74 mmol) in tetrahydrofuran (5 mL) and triethyl-amine (0.2 mL, 1.48 mmol) was added 3-fluorophenyl isocyanate (0.1 mL, 0.89 mmol) dropwise. The reaction mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-{3-[3-(3-fluoro-phenyl)-ureido]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (67 mg, 20%) as a white solid: LC/MS m/e calcd for C25H24FN3O3 (M+H)+: 434.49, observed: 434.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[O:30]=[S:31]1(=[O:45])[CH2:36][CH2:35][N:34]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:33][CH2:32][S:31](=[O:45])(=[O:30])[CH2:36][CH2:35]4)=[CH:44][CH:43]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(N2CCS(=O)(=O)CC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(N5CCS(=O)(=O)CC5)cc4)nc23)CC1)Nc1nccs1
Temperature: 85 °C
Yield: 13.1 %

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.050 g, 0.13 mmol, 1 eq), EtOH (2.2 mL) and DMF (0.29 mL), 4-(1,1-dioxothiomorpholino)benzaldehyde (0.033 g, 0.14 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 mL, 0.38 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v, 92:8) and washed with DCM/MeOH (1 mL, 1/1) to give the title compound as a pale yellow solid (0.010 g, 13%); 1H-NMR (500 Mz, DMSO-d6): 2.72-2.83 (m, 4H, piperazine N(CH2)2), 3.08-3.17 (m, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CO), 3.66-3.77 (m, 4H, dithioxomorpholino SO2(CH2)2), 3.85-3.95 (m, 4H, dithioxomorpholino SO2(CH2)2), 7.17 (d, J=8.5 Hz, 2H, ArH C6H4), 7.23 (d, J=3.5 Hz, 1H) and 7.49 (d, J=3.5 Hz, 1H) (thiazole H-4, H-5), 8.08 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.12 (d, J=8.5 Hz, 1H, ArH, C6H4), 11.88 (br s, 1H, NHCO), 13.31 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.47 min—541/543 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[N:13]=1.O>CN(C=O)C>[C:29]([C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([NH:18][C:14]3[N:15]=[C:16]([N:4]4[CH:5]=[C:6]([CH:7]=[O:8])[C:2]([CH3:1])=[N:3]4)[CH:17]=[CH:12][N:13]=3)[CH:20]=2)[N:24]([CH3:28])[CH:23]=1)(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)C(=O)c1cn(C)c2ccc(Nc3nccc(Cl)n3)cc12
Reactant: Cc1n[nH]cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(C(=O)C(C)C)cn4C)n2)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 3-methyl-1H-pyrazole-4-carbaldehyde (273 mg, 2.48 mmol) in anhydrous DMF (5 mL) was added 60% NaH (130 mg, 3.25 mmol) at 0° C. After being stirred for 30 min at room temperature, it was cooled to 0° C. To this, was added intermediate 5 (542 mg, 1.65 mmol) and then stirred for 6 hours at 60° C. Quenching the reaction by addition of ice and 20 mL of water resulted precipitation of brown solids. The resulted solids were collected by filtration, rinsed with water and the dried in vacuo to provide the desired intermediate 6 as a brown solid (424 mg, 80%); MS (ESI) m/z 403 [M+H]+.
Reaction SMILES: [ClH:1].NC(=O)[C@@H]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])C1C=CC=CC=1.[CH:34]1(N)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: NC1CCCCC1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Agent: Cl
Product: Nc1cc(Oc2ccc(NC(=O)CC(=O)NC3CCCCC3)cc2F)ccn1
Yield: 52 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with cyclohexanamine (Aldrich, 20 mg, 0.2 mmol) in a manner similar to that which is described in Step C of Example 1 to give N1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N3-cyclohexylmalonamide, hydrochloride salt (22 mg, 52% yield). 1H NMR (DMSO-d6) δ 14.00 (s, 1H), 10.72 (s, 1H), 8.10 (d, 1H, J=7.0 Hz), 7.97 (d, 1H, J=7.0 Hz), 7.88 (m, 3H), 7.44 (m, 2H), 6.70 (m, 1H), 6.14 (d, 1H, J=2.0 Hz), 3.54 (m, 1H), 3.27 (s, 2H), 1.66-1.75 (m, 4H), 1.52 (m, 1H), 1.15-1.25 (m, 5H); MS(ESI+) m/z 387.32 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([OH:22])[CH2:7]1)=[O:5])[CH3:2].[Na].[H-].[Na+].[CH3:26]I>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([O:22][CH3:26])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(OC)C1

Procedure:
2 gm (6.65 millimols) of 5-hydroxy-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester were converted into the sodium salt in 50 ml of absolute tetrahydrofuran with 0.32 gm (7 millimols) of 50% sodium hydride, and the salt was methylated with 0.43 ml (7 millimols) of methyl iodide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[O:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:16]1=2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:16]2[O:15][CH2:20][CH2:19][O:18][C:17]=2[CH:21]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc4c(c3)OCCO4)cc12
Temperature: 100 °C
Yield: 10.2 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (40.0 mg, 0.14 mmol), (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (27.4 mg, 0.152 mmol) and 2 N aqueous potassium carbonate solution (0.2 mL, 0.4 mmol) in toluene (0.3 mL) and EtOH (0.7 mL) was purged with N2, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under N2. The reaction mixture was heated to 100° C. for 48 hours, cooled to room temperature and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 10.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to afford the title compound (4.7 mg, 10% yield). MS (ES+) 331.1 (M+H)+. Retention time=2.62 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26]OC)[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C3C(C)=C(C)SC=3NC(=O)[C@]3(C[C@@H]3C)N=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@:10]3([CH2:25][C@@H:24]3[CH3:26])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Agent: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@]1(C[C@@H]1C)C(=O)N2
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@]1(C[C@@H]1C)c1nnc(C)n1-2

Procedure:
A procedure analogous to that set forth for Compound 202 was followed, with the exception that (1R,2S)-5′-(4-chlorophenyl)-2,6′,7′-trimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one (Compound 218) was used as starting material. LRMS (M+H)+: 383 m/z. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 4H), 2.56-2.62 (m, 3H), 2.39 (s, 3H), 1.94-2.05 (m, 1H), 1.58 (s, 3H), 1.39 (d, J=6.18 Hz, 1H), 1.10 (s, 1H), 0.79 (d, J=5.49 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[O:43][CH:40]1[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:36])[CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc(O)cc(Br)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C

Procedure:
3-Bromo-5-methoxyphenol (0.18 g, 0.89 mmol) and triphenylphosphine (0.284, 1.07 mmol) were taken into THF (5 mL) and the resulting mixture cooled to 0° C. 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.89 mmol), and DIAD (0.207 mL, 1.07 mmol) were taken up into THF (5 mL) and added slowly to the mixture, which was then stirred at room temperature over night. The resulting mixture was taken into EtOAc and washed with saturated NaHCO3 and brine. The solvent was dried over sodium sulfate and removed in vacuo. The resulting residue was purified on normal phase chromatography (EtOAc/heptane) to yield tert-butyl 4-(3-bromo-5-methoxyphenoxy)piperidine-1-carboxylate. MH+ 386.2, 388.2
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:25])[C@@H:12]3[C@H:15]([O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:16])[C:9]=2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])=[CH:4][CH:3]=1.N1C=CC=CC=1.ClC(Cl)(Cl)[C:47]([N:49]=C=O)=[O:48].C(OCC)(=O)C>ClCCl>[NH2:49][C:47]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:25])[C@@H:12]3[C@H:15]([O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:16])[C:9]=2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])=[CH:4][CH:3]=1)=[O:48]
Reactant: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3ccc(O)cc3)C[C@H]12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3ccc(OC(N)=O)cc3)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
4-Nitrobenzyl (5R,6S)-3-(4-hydroxyphenyl)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200 mg) prepared in the above step was dissolved in dichloromethane (4.5 ml). Thereto were added under ice cooling pyridine in a catalytic amount and trichloroacetyl isocyanate (106 mg), and the mixture was stirred for 1 hour. The reaction mixture was poured into a mixture of ice water and ethyl acetate. The mixture was extracted and separated with a separating funnel. The organic layer was washed with cold water (twice) and a cold saturated aqueous sodium chloride solution in the order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in methanol (13.5 ml) and thereto silica gel (2.7 g) was added. The mixture was stirred for 1.5 hours and then, kept in a refrigerator overnight. After the reaction mixture was diluted with chloroform, silica gel was removed by filtration. The solution was washed with chloroform/methanol (=4/1) and the solvent was removed under reduced pressure. The residue was purified by silica gel thin layer chromatography (chloroform/acetone=9/1) to give 4-nitrobenzyl (5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (113 mg).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][S:13][C:7]=3[CH2:6][C:5]=12.[CH2:14](O)[CH3:15]>C(O)(=O)C.[Pd]>[CH3:3][N:4]1[CH2:15][CH2:14][CH:7]([CH:6]2[C:7]3[S:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][N:1]3[N:2]=[CH:3][N:4]=[C:5]23)[CH2:6][CH2:5]1
Reactant: CCO
Reactant: C1=Cn2cnnc2Cc2sccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CCC(C2c3sccc3CCn3ncnc32)CC1
Yield: 76 %

Procedure:
A mixture of compound (10) (0.00342 mol) and compound (9) (0.00342 mol) was hydrogenated in acetic acid (1.65 ml) and ethanol (150 ml) with palladium on activated carbon (2 g) as a catalyst at 50° C. overnight under a 3 bar pressure in a Parr apparatus. The catalyst was filtered through celite and the filtrate was evaporated till dryness. The residue was taken up in dichloromethane and washed with potassium carbonate 10%. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 90/10/1) (15-40 μm). The pure fractions were collected and evaporated. The residue (1.5 g) was crystallized from 2,2'-oxybispropane, yielding 0.92 g (76%) of (±)-6,10-dihydro-10-(1-methyl-4-piperidinyl)-5H-thieno[2,3-d][1,2,4]triazolo[1,5-a]azepine; mp. 123.4° C. (comp. 11).
Reaction SMILES: CO[C:3](=O)[C:4]1[C:9]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26].[Al+3].[Cl-].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C>C1COCC1>[CH3:3][C:4]1[C:5]([O:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[N:6][C:7]([CH3:16])=[CH:8][C:9]=1[NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reaction time: 0.17 h
Yield: 102.1 %

Procedure:
To a mixture of 4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester (prepared as described in Preparation F, 29 mg, 0.078 mmol) and AlCl3 (10 mg,0.078 mmol) in dry THF was added 1 M LiAlH4 in diethyl ether (0.31 ml, 0.31 mmol) at room temperature. After stirring for 10 min, the mixture was heated under reflux for 2 hr. The mixture was quenched with 0.2 ml of water, 0.2 ml of 1N NaOH and 0.4 ml of water and 10 ml of dry THF and stirred for 15 min. The mixture was filtered through Celite® and washed with chloroform. The filtrate was dried over dry sodium sulfate, filtered and concentrated to dryness to give 26 mg (93%) of white solid. 1H NMR (CDC13) δ 6.85(s,2H), 6.08(s,1H), 3.72(d,NH, 1H), 3.35(m,1H), 2.30(s,3H), 2.16(s,3H), 2.13 (s,3H), 2.05(s, 6H), 1.45-1.75(m,4H), 0.98(t,6H) ppm. The corresponding HCl salt was prepared and triturated with diethyl ether to give white solid, mp.212-215° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][O:8][N:9]1C(=O)C2=CC=CC=C2C1=O.NN>C(O)C>[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][O:8][NH2:9]
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccsc1Cl
Agent: NN
Solvent: CCO
Product: NOCc1ccsc1Cl
Temperature: 25 °C

Procedure:
44 gms (0.15 mol) of N-(2-chlorothien-3-yl)methoxyphthalimide was mixed with 5.8 gms (0.17 mol) of 95% hydrazine in 600 mls of ethanol and refluxed for 2 hours. After cooling to room temperature, the solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was treated with methylene chloride, filtered, and concentrated again under reduced pressure, affording O-[(2-chlorothien-3-yl)methyl]hydroxylamine.
Reaction SMILES: C(CC[O:12][C:13]([CH2:15][NH:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[NH:19][C:18]=1[C:28]([O:30]CC)=[O:29])=[O:14])C(C1C=CC=CC=1)=O.[OH2:33].[OH-].[Li+]>O1CCCC1.O>[CH2:18]([N:16]([CH2:15][C:13]([OH:12])=[O:14])[C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[NH:19][C:18]=1[C:28]([OH:30])=[O:29])[C:17]([C:25]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:33]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)OCCCC(=O)c1ccccc1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CN(CC(=O)c1ccccc1)c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12
Yield: 113.8 %

Procedure:
Dissolve 3-[(phenacyl)carbethoxymethyl-amino]-2-carbethoxy-4,6-dichloroindole (0.29g, 0.626 mmol) in tetrahydrofuran (27 mL) and water (13 mL). Add lithium hydroxide monohydrate (0.158 g, 3.76 mmol) and stir overnight. Pour into 1N hydrchloric acid (100 mL) and extract into ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the title compound (0.15 g, 59%); mp 235°-7° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[NH2:30]>CN1C(=O)CCC1>[NH2:30][C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[NH:31][C:16]1[S:17][C:13]2[CH:12]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=3)[CH:22]=[CH:21][C:14]=2[N:15]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4N)sc3c2)ccn1
Temperature: 105 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15 mg, 43 μmole) in 400 μL of NMP was added (1R,2R)-cyclohexane-1,2-diamine (17 mg, 150 μmole). The reaction solution was stirred at 105° C. for 24 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give 4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (12 mg, 30 μmole) as white powder. ES/MS m/z 398.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.[I:12][C:13]1[CH:14]=[C:15]([CH2:19]O)[CH:16]=[CH:17][CH:18]=1>>[I:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][N:8]1[C:6]2=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[O:10][C:9]1=[O:11]
Reactant: OCc1cccc(I)c1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Product: Cc1ccc2oc(=O)n(Cc3cccc(I)c3)c2n1

Procedure:
Reaction of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one with (3-iodophenyl)methanol under Mitsunobu conditions gives 3-(3-iodobenzyl)-5-methyl-3H-oxazolo[4,5-b]pyridin-2-one; ESI: 367 (M+H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:21][C:22]1[C:28]([OH:29])=[CH:27][C:25]([NH2:26])=[C:24]([F:30])[CH:23]=1>>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:26][C:25]3[CH:27]=[C:28]([OH:29])[C:22]([Cl:21])=[CH:23][C:24]=3[F:30])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Agent: Cl
Product: Oc1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)c(F)cc1Cl
Yield: 94.2 %

Procedure:
Using an analogous procedure to that described in Example 70, 7-benzyloxy-4-chloroquinazoline hydrochloride (307 mg, 1 mmol), (prepared as described for the starting material in Example 70), was treated with 4-chloro-2-fluoro-5-hydroxyaniline (193 mg, 1.2 mmol), (EP 061741 A2), to give 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinazoline hydrochloride (407 mg, 94%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20].S(=O)(=O)(O)O.[CH3:33]O>>[CH3:33][O:26][C:25](=[O:27])[CH2:24][CH2:23][CH2:22][NH:21][C:19]([C:3]1[N:4]=[CH:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[C:8]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:7]=2)=[O:20]
Reactant: CO
Reactant: O=C(O)CCCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: O=S(=O)(O)O
Product: COC(=O)CCCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C

Procedure:
To a solution of 4-[(4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-butyric acid (1.32 g, 3.6 mmol) in MeOH (7.2 mL) was added 10% sulfuric acid. The reaction mixture was stirred at reflux for 20 hours. After cooled to rt, the solvent was concentrated in vacuo as a oil and purified by silica gel chromatography over silica gel, eluting with 15-75% EtOAc/hexanes to give product (900 mg) as a colorless oil: MS (m/z) 381.0 (M+1)+.