Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[O:23][CH3:24])=O)(C)(C)C.[N+:25]([O-])([OH:27])=[O:26].C(Cl)(Cl)Cl>O>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:23][CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC)c(OCCCN)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
The ester 198 (4.0 g, 11.8 mmol) was added in small portions to a stirred solution of 70% HNO3 (2 mL acid/g of substrate) at room temperature and the reaction mixture was allowed to stir overnight. After 16 hours TLC (CHCl3) revealed the complete loss of starting material. The reaction mixture was cooled in an ice bath, and 15 g of iced water was added, precipitating the product. The precipitate was collected by vacuum filtration and washed with small amount of iced water. The filtrate was cooled and a second crop of precipitate was collected by vacuum filtration and washed with iced water. The combined precipitate was dried in vacuo to provide compound 199 as a yellow solid, which was not purified further, but used directly in the subsequent reaction (2.3 g, 70%). mp=101-103° C.; 1H-NMR (CDCl3/DMSO-d6, 270 MHz): δ 2.31 (m, 2H, H2′), 3.20 (br, 2H, H3′), 3.95 (s, 3H, OCH3 ether), 3.98 (s, 3H, OCH3ester), 4.24 (t, 2H, J=5.95 Hz, H1′), 7.11 (s, 1H, H6), 7.49 (s, 1H, H3), 8.21 (s, 3H, NH); 13C-NMR (CDCl3, 68.7 MHz): δ 26.5 (C2′), 37.0 (C3′), 53.0 (OCH3ester), 56.0 (OCH3ether), 66.7 (C1′), 108.3 (C3), 111.0 (C6), 121.6 (Carom), 140.9 (C2), 149.3 (Carom), 152.6 (Carom), 166.8 (C═O); Ms (E/I) m/z (relative intensity): 284 (M+., 90), 237 (70), 227 (93), 196 (47), 181 (38), 137 (100), 122 (81), 93 (52), 79 (44); HRMS (E/I) exact mass calcd for C12H17N2O6: m/e 284.1008, obsd m/e 284.1018; IR (Nujol®) n: (cm−1) 3472, 2937, 2911, 2855, 1733, 1532, 1516, 1462, 1377, 1292, 1224, 1143, 1052, 884, 812, 792, 773, 756, 724, 646.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([CH2:27][CH:28]=O)=[CH:23][CH:22]=1>>[CH3:30][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])=[CH:23][CH:22]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: Cc1ccc(CC=O)cc1
Product: Cc1ccc(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)cc1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and p-Tolyl-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 380; HRMS: calcd for C23H16F3NO+H+, 380.12567; found (ESI, [M+H]+), 380.1259.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:60][CH3:61])=[C:53]([C:58]#[N:59])[CH:54]=4)[O:49][C:48]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:60][CH3:61])=[C:53]([C:58]#[N:59])[CH:54]=4)[O:49][C:48]=3[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1C#N
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)c(=O)c2cc1C#N
Yield: 59.6 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(6-cyano-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (81 mg, 0.155 mmol) was reacted to give the title compound (39 mg, 60%). LCMS (Method E): RT=3.57 min, [M+H]+=423. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.53 (s, 1H), 7.41-7.26 (m, 7H), 7.09 (d, J=8.1 Hz, 2H), 4.01 (s, 3H), 2.85 (bs, 2H), 2.37-2.27 (m, 2H), 2.10-1.88 (m, 3H), 1.66-1.54 (m, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48](O)[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3].C(N(S(F)(F)[F:63])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([F:63])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
Treatment of 17-allyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile as in Example 62 yields 17-Allyl-1-hydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: [C:1]([C@@H:4]([C@H:8]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9]1)[CH2:5][CH:6]=[CH2:7])([OH:3])=O.Cl.[CH2:17]([O:24][C:25](=[O:32])[C@H:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[NH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@@H:26]([NH:27][C:1](=[O:3])[C@@H:4]([C@H:8]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9]1)[CH2:5][CH:6]=[CH2:7])[C:28]([CH3:30])([CH3:29])[CH3:31])=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CC[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Reactant: CC(C)(C)[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Product: C=CC[C@@H](C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)C)[C@@H]1OC(C)(C)OC1=O
Yield: 86.8 %

Procedure:
According to the method of Preparation 2, (4S)-4-[(1R)-1-carboxy-but-3-enyl]-2,2-dimethyl-1,3-dioxolan-5-one (Preparation 14b)(2.39 g, 11.20 mmol) was reacted with L-tert-leucine benzyl ester hydrochloride (3.03 g, 11.76 mmol) for 1 h at 4° C. and then 17 h at 20° C. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate (200 mL), washed with 0.5M aqueous sodium dihydrogenphosphate (2×200 mL), 5% saturated sodium bicarbonate (200 mL), water, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate 10:1 to 1:1) to give (2R)-N-[(1S)-1-[(benzyloxy)carbonyl]-2,2-dimethylpropyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]pent-4-enamide (4.06 g, 87%), as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][CH2:23]C#C>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH2:17][C:22]#[CH:23])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCl
Reactant: CC(=O)Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Product: C#CCCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1

Procedure:
In analogy to the procedure described in example 5A], (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid tert-butyl ester (example 4A]) and 4-chloro-but-1-yne gave the title compound as orange oil.
Reaction SMILES: BrC1C(NC(=O)C(=O)CC(C)(C2C=CC=CC=2)C)=CC=C2C=1COC2=O.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:33](=[O:34])[O:32][CH2:31]2.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([CH3:52])[CH2:46][C:47](=[O:51])[C:48](O)=[O:49])=[C:41]([O:53][CH3:54])[CH:40]=1>>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([CH3:52])[CH2:46][C:47](=[O:51])[C:48]([NH:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C:33](=[O:34])[O:32][CH2:31]3)=[O:49])=[C:41]([O:53][CH3:54])[CH:40]=1
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: COc1cc(Br)ccc1C(C)CC(=O)C(=O)O
Agent: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Product: COc1cc(Br)ccc1C(C)CC(=O)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(4-bromo-2-methoxyphenyl)-2-oxo-valeric acid, melting point 136-140° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1)(=O)=O.[Li+].[Cl-].[CH:30]1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:35]=1.C([Sn](CCCC)(CCCC)CCCC)=C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:23]1([NH:22][C:18]2[N:17]=[C:16]([C:15]3[CH:14]=[N:13][N:11]4[C:10]=3[CH:9]=[CH:8][C:7]([CH:30]=[CH2:35])=[N:12]4)[CH:21]=[CH:20][N:19]=2)[CH2:25][CH2:24]1
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1)C(F)(F)F
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1
Temperature: 60 °C
Yield: 93.4 %

Procedure:
To a solution of 3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl trifluoromethanesulfonate (100 mg, 0.25 mmol) in DMF (3 mL) was added Pd2(dba)3 (12 mg, 0.0125 mmol), LiCl (32 mg, 0.75 mmol), AsPh3 (31 mg, 0.10 mmol), and vinyl-tributylstannane (120 mg, 0.375 mmol). The reaction mixture was heated at an oil bath temperature of 60° C. for about 4 hours. The mixture was cooled to RT and water (20 mL) was added. The aqueous layer was washed with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and purified by silica-gel column chromatography (gradient, 10-80% EtOAc in hexanes) to give the title compound as an off-white solid (26 mg, 37%). 1H-NMR (300 MHz, CDCl3). δ 9.05 (d, 1H, J=9.3 Hz), 8.44 (s, 1H), 8.30 (d, 1H, J=5.3 Hz), 7.40 (d, 1H, J=9.4 Hz), 6.92 (m, 2H), 6.22 (d, 1H, J=17.7 Hz), 5.75 (d, 1H, J=11.2 Hz), 5.48 (bs, 1H), 2.86 (m, 1H), 0.90 (m, 2H), 0.66 (m, 2H); MS (ESI) (M+H)+ 279.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:23])[CH2:9][C@H:10]([OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][CH:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:26](O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([O:7][C:8](=[O:23])[CH2:9][C@H:10]([O:22][C:26](=[O:27])[CH:25]([Br:24])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCC(Br)C(=O)O
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)Oc1ccccc1)OC(=O)C(Br)CCCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
A mixture of 1.02 g phenyl-(R)-3-hydroxytetradecanoate (3.19 mmol), 22 mL dichloromethane, 0.74 g 2-bromooctanoic acid (3.19 mmol), 0.66 g N,N'-dicyclohexylcarbodiimide (3.20 mmol) and 0.39 g 4-dimethylaminopyridine (3.19 mmol) was stirred at room temperature for 1.5 hours. The solution was then concentrated to dryness on a rotary evaporator (ca. 26 mm Hg, 30° C.). 25 mL hexanes was added to the white powdery residue and the resultant mixture was stirred at room temperature for 5 minutes. The slurry was filtered through a coarse sintered glass funnel and the solids were washed with 2×20 mL hexanes. The combined filtrates were placed in a separatory funnel and washed with 2×50 mL 1M HCL, 2×50 mL 10% saturated sodium bicarbonate and 2×50 mL city water. The organic layer was dryed over magnesium sulfate, then gravity filtered through paper, and concentrated on a rotary evaporator (ca. 10 mm Hg, 30° C.). The residue was chromatographed on a 2' by 1" column slurry packed with silica gel (80 g) in hexanes. Product was eluted with 50/50 hexanes and dichloromethane. The chromatography was monitored by TLC (silica gel, 50/50 hexanes: dichloromethane, phosphomolybidic acid visualization). Fractions containing only product were pooled and concentrated on a rotary evaporator (ca. 100 mm Hg, 30° C.). A cloudy oil (0.98 g, 58% yield) was obtained.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH3:14])C)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)=O.C(NS(C1C=CC=C([CH:27]=[O:28])C=1)(=O)=O)C.C(C1C=C(S(NCCC)(=O)=O)C=CC=1)=O.C(C1C=C(S(NC(C)C)(=O)=O)C=CC=1)=O>>[CH:27]([C:8]1[CH:3]=[CH:4][C:5]([S:9]([NH:12][CH3:14])(=[O:10])=[O:11])=[CH:6][CH:7]=1)=[O:28]
Reactant: CN(C)S(=O)(=O)c1cccc(C=O)c1
Reactant: CCNS(=O)(=O)c1cccc(C=O)c1
Agent: CC(C)NS(=O)(=O)c1cccc(C=O)c1
Agent: CCCNS(=O)(=O)c1cccc(C=O)c1
Product: CNS(=O)(=O)c1ccc(C=O)cc1

Procedure:
3-Formyl-N,N-dimethyl-benzenesulfonamide, N-ethyl-3-formyl-benzenesulfonamide, 3-formyl-N-propyl-benzenesulfonamide and 3-formyl-N-isopropyl-benzenesulfonamide were oils and were used without further purification in the next step of reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([C:17](Cl)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)c1ccccc1
Reactant: Nc1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)nc1)C(=O)c1ccccc1

Procedure:
In analogy to the procedure described for the synthesis example 41 (step 1), the title compound N-(6-chloro-pyridin-3-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 241.2 [M+H]+) was prepared from 6-chloro-pyridin-3-ylamine and benzoylformic acid chloride.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7].C(N(C(C)C)CC)(C)C>>[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:4][O:3][CH3:2])=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7]
Reactant: CON
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
N-Methoxyamine hydrochloride (123 mg, 1.5 mmol) was added to a solution of 5-(S)-azidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (600 mg, 1.3 mmol) and diisopropylethylamine (0.26 ml, 1.5 mmol) in TBIF (8 ml), and the mixture stirred overnight at r.t. Solvent was removed under vacuum, and ethyl acetate with 3% aq. citric acid added. Organic layer was washed twice with 3% citric acid, brine, and dried (Na2SO4). Solvent was removed under vacuum, and the crude material crystallized from ethanol-ether to give a white crystalline product (335 mg, 83%). HPLC Rt=4.8. MS (m/z): [M+H]+=310.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:11][NH2:12].[BH4-].[Na+]>CO>[CH3:11][NH:12][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:3][CH:4]=1
Reactant: COc1cccc(C=O)c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 138.6 %

Procedure:
To a solution of 3-methoxybenzaldehyde (180 g, 1.32 mol) in methanol (1 L) was added a 40% aqueous solution of methylamine (113 ml, 1.31 mol) followed by 1 hour stirring at 0° C. Sodium borohydride (75 g, 1.98 mol) was added portionwise at 0° C. and the reaction mixture was stirred for 1 hour. The solution was concentrated to a smaller volume then, was diluted with water (200 mL) and the resulting solution was extracted with methylene chloride (3×500 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude N-methylbenzylamine (220 g, quantitative) as clear oil, which was used in the next step without further purification: 1H NMR (CDCl3, 500 MHz) δ.7.23 (t, J=8.0 Hz, 1H), 6.92-6.88 (m, 2H), 6.81-6.78 (m, 1H), 3.80 (s, 3H), 3.73 (s, 2H), 2.45 (s, 3H), 2.07 (broad s, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9](O)([CH3:13])[CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.[Cl-].[In+3].[Cl-].[Cl-].[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[C:29]2[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:4][CH:5]=1)([CH3:13])[CH2:10][CH2:11][OH:12]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(CCO)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSCc1cccc2c(C(C)(CCO)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1.59 g (91% purity, approx. 6.77 mmol) of the compound from Example 89A and 1.50 g (6.77 mmol) of indium(III) chloride were added to 1.20 g (6.77 mmol) of the compound from Example 8A in 29 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate, and the solid was filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 0.14 g (5% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:9]4=[C:10]([C@H:12]5[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]5[N:8]4[CH2:7][CH2:6][CH2:5]3)[CH:11]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)c(Cl)c3)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 109 from tert-butyl (±)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (101.7 mg, 0.26 mmol) and 3,4-dichlorophenylboronic acid (97 mg, 0.52 mmol), after chromatographic purification (91.6 mg, 77%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.57 (d, 1H, J=1.8 Hz), 7.42 (d, 1H, J=8.4 Hz), 7.31 (dd, 1H, J=2.2, 8.4 Hz), 7.12 (bs, 1H), 7.07 (bs, 1H), 3.62-3.75 (m, 1H), 3.48-60 (m, 1H), 3.15-3.35 (m, 4H), 2.65-2.80 (m, 4H), 2.10-2.20 (m, 2H), 1.85-2.00 (m, 2H), 1.46 (s, 9H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N(C(C)C)CC)(C)C.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[B-](F)(F)(F)F.CCCC[P+](C1SC(C(OC)=O)=C(C(OC)=O)S1)(CCCC)CCCC.[C:73]([O:77][CH2:78][C@@H:79]([NH2:94])[CH2:80][CH2:81][N:82]1[CH2:85][CH:84]([O:86][C:87]2[CH:92]=[CH:91][C:90]([F:93])=[CH:89][CH:88]=2)[CH2:83]1)([CH3:76])([CH3:75])[CH3:74]>CN(C)C=O>[C:73]([O:77][CH2:78][C@@H:79]([NH:94][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:80][CH2:81][N:82]1[CH2:83][CH:84]([O:86][C:87]2[CH:88]=[CH:89][C:90]([F:93])=[CH:91][CH:92]=2)[CH2:85]1)([CH3:76])([CH3:74])[CH3:75]
Reactant: CC(C)(C)OC[C@@H](N)CCN1CC(Oc2ccc(F)cc2)C1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CCCC[P+](CCCC)(CCCC)C1SC(C(=O)OC)=C(C(=O)OC)S1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@@H](CCN2CC(Oc3ccc(F)cc3)C2)COC(C)(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 3,4,5-trimethoxy-benzoic acid (0.246 g, 1.16 mmol) and diisopropylethylamine (0.62 ml, 3.47 mmol) in dry dimethylformamide (10 ml) is treated with [(benzotriazol-1-yloxy)-dimethylamino methylene]-dimethyl-ammonium; tetrafluoro borate (0.32 g, 1.0 mmol). The reaction mixture is stirred at ambient temperature for 5 minutes, then (S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.968 mmol) is added and the reaction mixture stirred for 20 hours. The dimethylformamide is evaporated and the residue partitioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution 50% ethylacetate/hexane to 100% ethylacetate) to afford N-{(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3,4,5-trimethoxy-benzamide [MH]+ 505.3.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[OH:14])([CH3:3])[CH3:2]>[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([OH:14])[CH:7]=1
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1O
Agent: [Pd]
Product: CC(C)Oc1ccc(N)cc1O
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A flask charged with 2-isopropoxy-5-nitro-phenol (100 mg, 0.47 mmol) and palladium on carbon (50 mg, 0.47 mmol) was flushed with N2 followed by evacuating under vacuum. EtOAc (2 mL) and methanol (2 mL) were added under an inert atmosphere followed by evacuating under vacuum. The reaction mixture was then stirred overnight under an atmosphere of hydrogen. The palladium catalyst was removed by filtration and solvent was removed under reduced pressure to give 5-amino-2-isopropoxyphenol (65 mg, 76%). 1H NMR (400.0 MHz, CDCl3) δ 6.73 (d, J=8.3 Hz, 1H), 6.31 (d, J=2.5 Hz, 1H), 6.22 (dd, J=2.5, 8.3 Hz, 1H), 5.22 (s, 1H), 4.50 (qn, J=6.1 Hz, 1H), 3.37 (s, 2H) and 1.37-1.26 (m, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:5][C:4]=2[N:3]=1.[OH-].[NH4+]>O>[CH2:31]([O:30][CH2:29][C:13]1[N:14]([CH2:15][CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:32]
Reactant: CCOCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CC1CCNCC1
Yield: 54.3 %

Procedure:
tert-Butyl 4-[(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (0.64 g) was deprotected according to the method described in Example 177. The crude solid was dissolved in water (10 mL), and ammonium hydroxide was added until the solution was basic. The mixture was then extracted with chloroform (2×10 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile and dried for 16 hours in a vacuum oven at 60° C. to provide 0.28 g of 2-ethoxymethyl-7-phenyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 142–143° C.