Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:30])[N:6]=1.[H-].[Na+].Cl[C:34]1[N:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=1>C1COCC1.CC(N(C)C)=O>[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:8]2[N:7]([CH3:30])[N:6]=[C:5]([O:4][CH2:3][CH2:2][O:1][C:34]3[N:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:19])=[O:20])=[N:22][CH:23]=1)([CH3:28])[CH3:29]
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(S(C)(=O)=O)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 0.08 h
Yield: 20.4 %

Procedure:
To a solution of N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 40) (112 mg) in anhydrous THF (5 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 21.8 mg) and the mixture was stirred for 5 minutes. To the mixture was added 2-chloro-5-(methylsulfonyl)pyrimidine (50 mg) in dimethylacetamide (1 ml). After stirring for 150 min, the reaction mixture was partitioned between ethyl acetate (50 ml) and saturated ammonium chloride solution (50 ml). The ethyl acetate layer was washed with brine (50 ml), dried (MgSO4), filtered and evaporated to dryness. Purification of the residue on a Phenomenex Magellen™ column using a 0.1M NH4OAc:MeCN gradient (95;5 to 60:40) over 5 min. and then an isocratic flow (60:40) for 15 minutes gave the title compound as a white solid (31 mg).
Reaction SMILES: FC1C([O:8][C:9](=O)[C@H:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=C(F)C(F)=C(F)C=1F.Cl.[C:43]1([CH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:58])[C@@H:54]([CH2:56][OH:57])[NH2:55])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:55][C@@H:54]([C:53]([NH:52][CH2:51][CH2:50][CH2:49][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:58])[CH2:56][OH:57])=[O:8])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:28]=1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@H](CO)C(=O)NCCCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@H](CO)C(=O)NCCCc1ccccc1)OCc1ccccc1
Yield: 57.3 %

Procedure:
A solution of N-benzyloxycarbonyl-O-benzyl-L-tyrosine pentafluorophenyl ester (2.34 g.), N-(3-phenylpropyl)-D-serinamide hydrochloride (1.00 g.) and diisopropylethylamine (0.71 ml.) in tetrahydrofuran (25 ml.) was stirred at room temperature for one hour. The mixture was triturated with water, and the product was precipitated with hot ethyl acetate and recrystallized from ethyl acetate, affording (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-N-(3-phenylpropyl)-D-serinamide (1.35 g., m.r. 175°-177° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[N:17]=[CH:16][C:15]([C:22]([NH2:24])=[O:23])=[C:14]3[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([C:11]3[CH:12]=[C:13]4[C:18](=[C:19]([CH3:21])[CH:20]=3)[N:17]=[CH:16][C:15]([C:22]([NH2:24])=[O:23])=[C:14]4[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)(=[O:10])=[O:9])[CH:3]=2)=[CH:38][CH:37]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(Br)c4)cc23)c1
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a suspension of Intermediate 62 (0.95 mmol) and 4-(hydroxymethyl)phenylboronic acid (290 mg, 1.90 mmol) in DME (10 mL) at room temperature was added 2 M Na2CO3 (1.4 mL, 2.85 mmol) and PdCl2(PPh3)2 (33 mg, 0.005 mmol). The reaction mixture was stirred at reflux for 2 h and then cooled to room temperature. After the addition of 60 mL of chloroform, a white precipitate formed which was collected by filtration. The crude product was purified by flash column chromatography (0-15% MeOH in dichloromethane) to give the title compound (357 mg, 68% for 3 steps). ES/MS calcd. for C31H28N3O5S+ 554.2. Found m/z=554.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9]
Reactant: CC1(CC(=O)O)CCCCCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CC1(C)CCCCCC1=O
Reaction time: 3 h

Procedure:
A mixture of 1-methyl-2-oxocycloheptaneacetic acid (3.0 g, 0.0163 mole, obtained as described above), anhydrous potassium carbonate (2.76 g, 0.020 mole) and methyl iodide (8 ml) in acetone (50 ml) is stirred and heated to reflux for 2 hrs. Methyl iodide (3ml) is added and heating to reflux is continued for another 3 hrs. The solvent is evaporated, the residue taken up in water (50 ml), saturated with sodium chloride, and extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to yield 1-methyl-2-oxocycloheptaneacetic acid methyl ester as an oil, νmaxCHCl3 1730, 1700 cm-1, nmr (CDCl3) δ1.2 (s), 3.67 (s).
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O>[NH:16]([C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)cc1Nc1ccccc1

Procedure:
3-Methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.0 g) and aniline (10 mL) were heated to reflux for 5 hours and diluted with water. Hydrochloric acid (2N) was added and the mixture extracted with ethyl acetate. The organic extracts were washed (acid, brine), dried and evaporated to give a solid which was purified by chromatography, with ethyl acetate:toluene (1:4) as the eluent. Recrystallization from ethyl acetate gave the title compound (0.405 g); mp 227°-228° C.: NMR: 6.28 (s,1); MS(EI): m/z=264(M). Analysis for C16H12N2O2.0.1 H2O : Calculated: C, 72.22; H, 4.62; N, 10.53; Found: C, 72.32; H, 4.68; N, 10.65.
Reaction SMILES: [Cl:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].Cl>C(O)(=O)C>[Cl:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C(Cl)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 52.5 g. (0.167 moles) of ethyl α,2'-dichloro-4-biphenylylacetate and 160 ml. of glacial acetic acid containing 40 ml. of 37% hydrochloric acid is refluxed for 20 hours. The mixture is concentrated under reduced pressure to give a gummy residue. The latter material is dissolved in 300 ml. of n-hexane, washed with ice-cold water (100 ml. total), dried over sodium sulfate and filtered. The hexane is removed to give α,2'-dichloro-4-biphenylylacetic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[OH:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.[H-].[Na+]>CN(C=O)C>[N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][C:5]3[N:4]=[N:3][C:2]([O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]=[CH:25][CH:26]=[N:27]5)=[CH:22][CH:21]=4)=[C:7]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:6]=3)[CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)nnc2Oc2ccc3cccnc3c2)cc1

Procedure:
To a solution of 3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 45(d)), (441 mg, 1.5 mmol) and 7-hydroxyquinoline (441 mg, 3.0 mmol, Acros) in DMF (10 mL) was added 60% NaH (150 mg, 3.8 mmol) and the mixture was heated at 80C for 14 h. The solvent was removed in vacuum, the residue was partitioned between EtOAc/H2O and the aqueous layer was extracted with EtOAc. The combined organic layers were evaporated onto SiO2 and purified by flash silica gel chromatography with EtOAc/hexanes (0:1→1:0) as eluant to give the title compound as an off-white amorphous solid. Mp: 158-162° C. MS (ESI, pos ion.) m/z: 511 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=O)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]23[NH:22][CH2:19][CH2:20][N:21]2[C:10](=[O:12])[C:9]2[C:8]3=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reactant: NCCN
Product: O=C1c2ccccc2C2(c3ccc(F)cc3)NCCN12

Procedure:
Condense o-(p-fluorobenzoyl)benzoic acid with ethylenediamine by the procedure of Example 1 to obtain 9b-(p-fluorophenyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, reduce with lithium aluminum hydride and treat with hydrogen chloride as described in Example 1 to obtain 1-(p-fluorophenyl)-1,2,3,4,5,6-hexahydro-2,5-benzodiazocine, dihydrochloride, m.p. 303° C. (dec.).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Br:5][C:6]1[N:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH:14]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([Cl:33])[CH:24]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[N:10][CH:11]=1>CO.N1C=CC=CC=1>[Br:5][C:6]1[N:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH:14]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:25]([Cl:33])[CH:24]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][C:19](=[N:4][O:2][CH3:3])[CH2:18][CH2:17]2)=[N:10][CH:11]=1
Reactant: CON
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCC(CC(C(=O)Nc2cnc(Br)cn2)c2ccc(S(C)(=O)=O)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A solution of methoxylamine hydrochloride (16 mg, 0.18 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 59, 62 mg, 0.12 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water 1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 7/3 hexanes/ethyl acetate eluted to 4/6 hexanes/ethyl acetate) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-methoxyimino-cyclohexyl)-propionamide (51 mg, 80%) as a white foam: EI-HRMS m/e calcd for C21H24BrClN4O4S (M+H)+ 543.0463. found 543.0464.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30].C(N(CC)CC)C>C(O)C>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=3[N+:29]([O-:31])=[O:30])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccc(C(F)(F)F)cc3[N+](=O)[O-])cc12
Yield: 38 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 4-chloro-3-nitrobenzotrifluoride were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 4.5 hours. Column chromatography afforded the title compound (38%) as a red foam: Rf =0.30 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 13C NMR (CDCl3) δ147.0, 139.7, 135.1, 131.6, 131.0, 129.2, 128.5, 124.7, 124.2, 120.7, 118.6, 116.8, 116.6, 113.6, 112.6, 67.1, 57.4, 40.8, 31.3, 29.2, 21.9. FAB LRMS 419 [MH+]. Anal. calcd for C21H21N4O2.0.6 CH2Cl2 : C, 55.27; H, 4.77; N, 11.94. Found: C, 55.44; H 4.58; N 11.52.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:14][CH2:13][CH:12](O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:9][CH:10]1[CH2:14][CH2:13][CH:12]([N:30]=[N+:31]=[N-:32])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(OC1CCC(O)C1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1CCC(OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 3-hydroxycyclopentyl benzoate (630 mg) in anhydrous tetrahydrofuran (15 mL) were added diphenylphosphoryl azide (925 mg), diethyl azodicarboxylate (585 mg) and triphenylphosphine (881 mg). After stirring for 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1) to give 3-azidocyclopentyl benzoate as pale yellow oil (531 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C@@:7]3([OH:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26](CO)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][CH2:19][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)=[O:17])[CH2:15][C@@:7]3([OH:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: COc1ccc(CO)cc1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(COC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)cc1
Yield: 85.6 %

Procedure:
A stirred solution of methyl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1, 2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 118 25 g), para-methoxybenzyl alcohol (115 g) and titanium tetraethoxide (1.5 g) in toluene (300 ml) was heated at reflux for 1 hour. The reaction mixture was cooled, evaporated to a small volume and purified by flash column chromatography on silica gel eluting with a gradient of ethyl acetate:hexane (1:4 to 2:3) to give the product (29 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](OCC2C=CC=CC=2)=O)[CH:5]=[CH:4][C:3]=1[N:19]1[CH2:23][CH2:22][S:21][CH2:20]1.C([Li])CCC.[CH2:29]([O:33][C:34](=[O:38])CCC)[C@@H:30]1[O:32]C1>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][C@H:29]([CH2:30][OH:32])[O:33][C:34]2=[O:38])[CH:5]=[CH:4][C:3]=1[N:19]1[CH2:23][CH2:22][S:21][CH2:20]1
Reactant: O=C(Nc1ccc(N2CCSC2)c(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Li]CCCC
Product: O=C1O[C@@H](CO)CN1c1ccc(N2CCSC2)c(F)c1
Yield: 74.8 %

Procedure:
Using the same general procedure as step 3 of example 1, 3-[2-fluoro-4-(benzyloxycarbonyl) aminophenyl]thiazolidine (692 mg, 2.24 mmol) was treated sequentially with n-butyllitium (1.5 mL, 2.40 mmol) and (R)-(-)-glycidylbutyrate (0.33 mL, 2.33 mmol) to provide 500 mg (78%) of the title compound. Recystallization from methylene chloride/hexane provided an analytical sample with a melting point of 96°97° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].[CH2:25]([NH2:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([NH:33][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:21]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and phenethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.90 (1H, br), 10.65 (1H br), 8.30 (1H, br), 7.37-7.22 (1H, m), 4.04 (2H, br s), 3.53 (2H, m, J˜5 Hz), 2.83 (2H, t, J=7 Hz); Anal. Calcd for C24H21N3O3.0.25 CH2Cl2: C, 69.45; H, 5.12; N, 9.92. Found: C, 69.40; H, 4.92; N, 10.11.
Reaction SMILES: C(O[C:5](=[O:16])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH3:15])C=C.[C:17]1([C:27]([NH:29][CH:30]2[CH2:36][CH:35]=[CH:34][CH2:33][N:32]([CH2:37]C(O)=O)[C:31]2=[O:41])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O.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>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH2:37][N:32]2[CH2:33][CH:34]=[CH:35][CH2:36][CH:30]([NH:29][C:27]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][N:18]=3)=[O:28])[C:31]2=[O:41])=[O:16])[CH2:11][C:10](=[O:12])[O:9]1)[CH3:15]
Reactant: O=C(O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC1OC(=O)CC1NC(=O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reaction time: 0.25 h

Procedure:
A catalytic amount of Pd(Ph3P)4 is added to a solution of (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)-carbamic acid allyl ester (338 mg, 1.48 mmol) and N,N-dimethylbarbituric acid (483 mg, 3.1 mmol) in CH2Cl2 (5 mL) at room temperature. The solution is stirred for 15 min then {3-[(isoquinolin-1-carbonyl)amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl} acetic acid, 5, (178 mg) as prepared above is added as a solution in CH2Cl2 (1 mL) followed by 1-hydroxybenzotriazole (416 mg, 3.1 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (584 mg, 3.1 mmol). The solution is stirred for an additional 3 hours, then diluted with EtOAc, washed with saturated NaHCO3, brine, dried (MgSO4), and concentrated in vacuo to afford the desired product in sufficient purity to be used directly.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]12[CH2:78][CH2:77][CH:74]([CH2:75][CH2:76]1)[CH:73]([NH2:79])[CH2:72]2>CN1C(=O)CCC1>[O:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:79][CH:73]5[CH:74]6[CH2:77][CH2:78][N:71]([CH2:76][CH2:75]6)[CH2:72]5)=[O:34])=[CH:30][CH:29]=4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:18][CH2:17]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: NC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(C(=O)NC2CN3CCC2CC3)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 40 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to according to example 68 with quinuclidin-3-amine (79 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (24.3 mg, 40% yield); MS (ESI) m/z=614.7
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([CH:37]([CH3:39])[CH3:38])=[N:35][N:36]=4)[N:33]=3)=[C:17]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[F:27])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Na+]>C1COCC1.O>[OH:4][CH2:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([CH:37]([CH3:39])[CH3:38])=[N:35][N:36]=4)[N:33]=3)=[C:17]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[F:27])[N:18]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: CC(=O)OCC(=O)N1CCC(c2nc(-c3cc(F)c(F)cc3F)c(-c3ccc4nnc(C(C)C)n4n3)s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(-c3sc(C4CCN(C(=O)CO)CC4)nc3-c3cc(F)c(F)cc3F)nn12
Temperature: 40 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A round-bottomed flask equipped with rubber septum and nitrogen inlet needle was charged with 2-(4-(5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-(2,4,5-trifluorophenyl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl acetate (0.22 g, 0.39 mmol, prepared using General Procedure Q.1 from Preparation #O.1.1.1 with TFA, General Procedure T.1 with acetoxyacetyl chloride) in THF (5.0 mL). A 1.0 M aqueous NaOH solution (2 mL, 2 mmol) was added. The reaction mixture was stirred at about 40° C. for about 1 h. The reaction was diluted with water and then extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by RP-HPLC (Table 1, Method f) to give the title compound (0.145 g, 71%): LC/MS (Table 1, Method a) Rt=2.89 min; MS m/z: 518.1 (M+H)+.
Reaction SMILES: I[CH2:2][C@H:3]([NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6].[N-:19]=[N+:20]=[N-:21].[Na+]>CC#N.O>[CH2:14]([O:7][C:5](=[O:6])[CH2:4][C@@H:3]([NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:2][N:19]=[N+:20]=[N-:21])[CH:15]([CH3:17])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CI)CC(=O)O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N[C@@H](CN=[N+]=[N-])CC(=O)OCC(C)C)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 196.4 %

Procedure:
To a solution of 1 g of 5b (2.27 mmol) in 10 ml of CH3CN and 2 ml of water, NaN3 (0.592 g, 9.11 mmol) was added. The resulting suspension was stirred at 80° C. for 6 hours, then the solvent was removed under vacuum and the crude residue was diluted with water and extracted twice with ether. The organic layer was dried over anhydrous Na2SO4, and finally evaporated to obtain 0.790 g of crude product as a light yellow wax which was used without further purification with a yield of 98%;