Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=1)=[N+]=[N-].C(N(CC)CC)C.[H][H]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
To a stirred solution of 2-Azido-5,6-diphenylpyrazine (45 mg, 0.17 mmol) in 50 mL EtOAc at room temperature was added triethylamine (100 μL) followed by Pearlman's Catalyst (50 mg). The suspension was put through a vacuum/purge cycle three times with hydrogen gas and then held under I atmosphere of hydrogen for 2 hours. The suspension was then filtered through GF/F filter paper with EtOAc and concentrated. The crude product was eluted through a Biotage 12S column with 1/1 EtOAc/hexane to give pure product, as a clear oil (25 mg, 59%)., 1H-NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.42-7.20 (m, 10H), 4.62 (br s, 2H).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+:10].C([Li])CCC.[Na+].[C:17]([CH2:25][CH2:26][C:27]([O-:29])=[O:28])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:17]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24][C:1](=[O:6])[CH:2]=1.[Na+:10].[C:17]([CH2:25][CH2:26][C:27]([O-:29])=[O:28])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])CCC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)CCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium in hexane in 50 mL of tetrahydrofuran and 25 mmol of 3-benzoylpropionic acid sodium salt in 60 mL of tetrahydrofuran. 3-Benzoylpropionic acid sodium salt was prepared by reacting the acid (25 mmol) with hexane washed NaH (26.25 mmol) in tetrahydrofuran at 0° C. for 30 minutes. The crude product was flash chromatographed using CH2Cl2 /MeOH/CH3CO2H (90/10/0.2) to give a viscous gum. 1H NMR (CDCl3) δ 2.1-2.6 (m, 4 H), 2.9 (d, 1 H), 3.0 (d, 1 H), 3.3 (d, 1 H), 3.4 (d, 1 H), 7.2-7.5 (m, 5 H).
Reaction SMILES: [F:1][C:2]1([F:27])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:4]=2[O:3]1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:27][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]([CH:18]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[OH:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:4]=2[O:3]1
Reactant: CCOC(=O)C(Cc1ccc2c(c1)OC(F)(F)O2)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc2c(c1)OC(F)(F)O2)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (3.50 g, 25.7 mmol) in diethyl ether (50 ml), sodium borohydride (1.94 g, 51.4 mmol) was added at room temperature and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 2-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-3-(4-fluorophenyl)-3-oxopropionate (4.888 g, 12.85 mmol) in diethyl ether (30 ml) at room, temperature and the mixture was stirred as it was for 2 hrs. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated-under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[O:25]=[C:26]1[N:30]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[C:33]([F:43])[CH:32]=2)[CH2:29][C@H:28]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:27]1>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:40]1[CH2:41][CH2:42][CH:37]([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[CH2:29][C@H:28]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:27][C:26]3=[O:25])=[CH:32][C:33]=2[F:43])[CH2:38][CH2:39]1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)c4cc5ccccc5[nH]4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of indole-2-carboxylic acid (79 mg) and 1,1'-carbonyldiimidazole (80 mg) in dry tetrahydrofuran (2.0 mL) is stirred at ambient temperature for one hour, and a solution of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg) in dry tetrahydrofuran (6.0 mL) is added. The mixture is then stirred at ambient temperature for 19 hours, concentrated under reduced pressure, diluted with methylene chloride (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced. pressure to give the crude product which is chromagraphed on silica gel (70-230 mesh, 10 g), eluting with methanol/methylene chloride (7.5/92.5). Pooling and concentration of those fractions with an Rf =0.67 by TLC (methanol/chloroform, 10/90) and recrystallization from chloroform/diethyl ether gives the title compound, mp 223-225° C.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([C@@H:8]1[CH2:17][C@H:16]([NH2:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[NH:9]1)[CH3:7].Cl.[CH3:24][O:25]N.C([O-])(=O)C.[Na+]>O.C1(C)C=CC=CC=1.O1CCCC1>[CH3:24][O:25][N:18]=[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[NH:9][C@H:8]([CH2:6][CH3:7])[CH2:17]1
Reactant: CC[C@@H]1C[C@H](N)c2cc(C(F)(F)F)ccc2N1
Reactant: CON
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@@H]1CC(=NOC)c2cc(C(F)(F)F)ccc2N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound obtained in Example 2 (2) above (2.43 g), methoxyamine hydrochloride (1.25 g), sodium acetate (1.64 g) and water (2.4 ml) were added to tetrahydrofuran (22 ml) and the mixture was stirred at room temperature for about 48 hours. Toluene (24 ml) and water (12 ml) were added to the reaction mixture, the organic layer was separated, and washed with water (12 ml) and a saturated brine (12 ml). The organic layer was concentrated at reduced pressure and the resulting residue was purified by column chromatography and concentrated to give the titled compound as an oily material (1.92 g, yield 71%). MS (APCI) m/z: 273 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH2:35][F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH2:35][F:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCCF)c1
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)c(OCCF)c1

Procedure:
[(4S,5R)-2-[4-tert-Butyl-2-(2-fluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-[4-tert-butyl-2-(2-fluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12m) and 1-(2-methanesulfonylethyl)-piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 703.5 [(M+H)+]
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[BrH:13]>C1CCCCC1>[Br:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: OCCCCCCCCCCO
Reactant: Br
Solvent: C1CCCCC1
Product: OCCCCCCCCCCBr
Yield: 89 %

Procedure:
1,10-Decanediol (4 g) was dissolved in 100 ml of cyclohexane, and 57% aqueous hydrobromic acid solution (58 ml) was added to this solution. The reaction mixture was refluxed for six hours while stirring. After the reaction, the mixture was extracted three times with diethyl ether. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane:ethyl acetate=7:3) gave 10-bromodecan-1-ol as white crystals at an 89% yield.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([CH:10]2[O:14][CH:13]([CH2:15][O:16]C(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)[CH:12]([OH:40])[CH2:11]2)[CH:3]=1.[Si:41](Cl)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N1C=CN=C1>CN(C=O)C>[Si:41]([C@@:12]1([OH:40])[C@@H:13]([CH2:15][OH:16])[O:14][C@@H:10]([N:4]2[CH:3]=[C:2]([CH3:1])[C:8](=[O:9])[NH:7][C:5]2=[O:6])[CH2:11]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@@](O)([Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5′-O-Dimethoxytritylthymidine is silylated with 1 equivalent of t-butyldiphenylsilyl chloride (TBDPSCl) and 2 equivalents of imidazole in DMF solvent at room temperature. The 5′-protecting group is removed by treating with 3% dichloracetic acid in CH2Cl2.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[O:20][C:19]=2[CH3:29])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[O:20][C:19]=2[CH3:29])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:15])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2cccnc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2cccnc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of 4-{cyclohexyl[2-methyl-5-(pyridin-3-yl)furan-3-yl]methoxy}benzoic acid (137 mg), ethyl 3-(methylamino)propanoate (55 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), hydroxybenzotriazole monohydrate (64 mg) and triethylamine (59 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (104 mg, 90%).
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:33][CH2:34][CH3:35])[C:5]=1[OH:36])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:33][CH2:34][CH3:35])[C:5]=1[OH:36])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCCCC(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCCCC(=O)O)cc2)ccc(C(C)=O)c1O

Procedure:
The compound of Step C above, (800 mg, 1.54 mmoles, 1N NaOH (3.2 ml), water (3.2 ml) and THF (10 ml) were stirred at room temperature for three hours. The THF layer was removed and the aqueous portion diluted with water and extracted with ether. The aqueous portion was acidified with concentrated HCl. A solid precipitate formed which was extracted into ether, dried and concentrated. Trituration of the residue with ether-methanol afforded the title compound; mp 138°-140°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH:12]([C:18](OCC)=[O:19])[C:13](OCC)=[O:14].[BH4-].[Na+].CO.[Cl-].[Li+]>O1CCCC1>[OH:19][CH2:18][CH:12]([CH2:11]/[CH:10]=[CH:9]\[CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:13][OH:14]
Reactant: CCOC(=O)C(C/C=C\COC1CCCCO1)C(=O)OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCC(CO)C/C=C\COC1CCCCO1
Yield: 47.5 %

Procedure:
Diethyl [4-(tetrahydro-2H-pyran-2-yloxy)-(Z)-2-butenyl]malonate (65.5 g) was dissolved in 650 ml of dry tetrahydrofuran, and 15.1 g of sodium borohydride was added thereto. A solution of 110 g of methanol/275 ml of tetrahydrofuran was added dropwise gradually with stirring under heating to reflux. Then, 13.18 g of lithium chloride and 11 g of sodium borohydride were added and refluxed for 1.5 hours. The reaction solution was cooled and poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform) to provide 22.8 g of the objective compound as oil.
Reaction SMILES: Br[CH:2]1[CH2:14][CH2:13][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[S:8][C:4]=2[C:3]1=O.[CH:16]1([CH2:19][C:20]([NH2:22])=[S:21])[CH2:18][CH2:17]1>CO.[OH-].[O-2].[P-3].[Mo]>[CH:16]1([CH2:19][C:20]2[S:21][C:2]3[CH2:14][CH2:13][C:5]4[N:6]=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[S:8][C:4]=4[C:3]=3[N:22]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)Nc1nc2c(s1)C(=O)C(Br)CC2
Reactant: NC(=S)CC1CC1
Agent: [Mo]
Agent: [O-2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1nc2c(s1)-c1nc(CC3CC3)sc1CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-(6-Bromo-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (Stage T.3, 347 mg, 1.200 mmol) was dissolved in MeOH (10 mL) and 2-cyclopropyl-thioacetamide (Can. J. Chem 1995 Vol. 73 1468-1477, 166 mg, 1.440 mmol) and ammonium phosphomolybdate (225 mg, 0.120 mmol) were added. The RM was stirred at rt for 20 h then heated at 50° C. for 3 h, 60° C. for 2 h and then refluxed for 24 h. The RM was partitioned between EtOAc/H2O. The organic layer was dried over Na2SO4 and evaporated. The raw material was chromatographied with MPLC C18 H2O 0.1% TFA/CH3CN 0.1% TFA, gradient 0-50%. Product containing fractions were neutralized with NaHCO3, extracted with EtOAc and lyophilized from dioxane to give the title compound as a white solid (M+H=306.2; M−H=304.2; tR 5.12 min (Method F)).
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([OH:9])[CH2:2]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:9][CH:3]1[CH:4]2[CH:5]([O:6][CH2:7][CH2:8]2)[O:1][CH2:2]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: OC1COC2OCCC12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1COC2OCCC12
Temperature: 5 °C
Yield: 87.7 %

Procedure:
Hexahydrofuro[2,3-b]furan-3-ol (25 g) was dissolved in dichloromethane (250 ml) and added triethylamine (23.3 g). N,N-dimethylaminopyridine (0.46 g) was added to the reaction mass. Reaction mass was cooled to 0-10° C. Acetic anhydride (21.5 g) was diluted with dichloromethane (50 ml) & added slowly drop-wise to the reaction mass. Reaction mass was stirred at 0-5° C. till completion. Reaction mass was washed with water (2×100 ml) & 10% Sodium chloride solution (100 ml). Reaction mass was concentrated under vacuum at <40° C. to get residue of Hexahydrofuro[2,3-b]furan-3-yl acetate (yield 29 g). Further, the product was purified by distillation (20 g) under vacuum using fractional distillation at 88-102° C. to get main fraction 17 g having purity 92.6%
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>C(Cl)Cl>[CH:3]12[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:4]1[CH2:5][N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2]2
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Solvent: ClCCl
Product: CCOC(=O)C1C2CN(C(=O)OC(C)(C)C)CC21
Yield: 44.4 %

Procedure:
To a solution of tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (10.0 g, 59.1 mmol) and Rh(OAc)2 (500 mg) in CH2Cl2 (200 mL) was added a solution of ethyl diazoacetate (8.14 g, 71.5 mmol) in CH2Cl2 (80 mL) over 12 h with a syringe pump. The reaction was filtered through celite, concentrated under vacuum and purified by column chromatography (silica gel) using 0 to 45% EtOAc in hexanes to afford ester 1 (6.70 g, 44%) as a clear straw colored oil; 1H-nmr (400 MHz, CDCl3) δ 4.18-4.03 (m, 2H), 3.71-3.53 (m, 2H), 3.39 (s, 2H), 2.04 (s, 2H), 1.42 (s, 9H), 1.28-1.19 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH2:14][NH:29][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][CH2:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Product: O=[N+]([O-])c1ccc(Sc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 73A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: COC(=O)CCCBr
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCOC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (150 mg, 0.34 mmol) in 10 ml of anhydrous DMF were added methyl 4-bromobutanoate (123 mg, 0.68 mmol) and potassium carbonate (94 mg, 0.68 mmol). The mixture was heated at 60 C. for 2 hours, cooled to room temperature, and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2˜3% of methanol in chloroform to give 4-methoxy-4-oxobutyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as off-white solid. Yield: 130 mg, 71%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[C:16]2[C:7]([C:8]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[N:9][C@@H:10]3[C@H:15]2[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:6][C:5]=1[O:26][CH3:27])[CH3:2].[Cl-].[NH4+].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:17]=[C:16]2[C:7]([C:8]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[N:30]=[N:31][NH:32][N:25]=4)=[CH:22][CH:23]=3)=[N:9][C@@H:10]3[C@H:15]2[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:6][C:5]=1[O:26][CH3:27])[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C#N)cc1)=N[C@H]1CCCC[C@@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(-c3nn[nH]n3)cc1)=N[C@H]1CCCC[C@@H]21

Procedure:
4.2 g of (+/−)-cis-9-ethoxy-8-methoxy-6-(4-cyano-phenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine (compound A1), 0.65 g of ammonium chloride and 0.83 g of sodium azide are suspended in 150 ml of abs. dimethylformamide and heated at 120° C. for 24 h. The reaction mixture is partitioned between water and diethyl ether, and the organic phase is dried with sodium sulfate and concentrated. The residue is chromatographed on silica gel using methylene chloride/methanol in the ratio 4/1. After concentration of the corresponding eluate fractions, the title compound is obtained as a solidified oil.