Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:15](=[O:28])[CH2:16][CH2:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1.CC1N=C(NC2C=CC=CC=2)C([C:43](=[O:55])[CH2:44]CC2C=NC(S(C)=O)=CC=2)=CC=1.C1C[O:59][CH2:58]C1>C1(C)C=CC=CC=1>[CH3:58][O:59][C:43]([C:44]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[C:5]([C:15](=[O:28])[C:16]=1[CH2:17][C:18]1[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[O:55]
Reactant: Cc1ccc(C(=O)CCc2ccc(S(C)(=O)=O)nc2)c(Nc2ccccc2)n1
Reactant: Cc1ccc(C(=O)CCc2ccc(S(C)=O)nc2)c(Nc2ccccc2)n1
Reactant: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Cc2ccc(S(C)(=O)=O)nc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 80 °C

Procedure:
A 2:1 mixture of 1-(6-methyl-2-phenylamino-pyridin-3-yl)-3-(6-methylsulfonyl-pyridin-3-yl)-propan-1-one and 1-(6-methyl-2-phenylamino-pyridin-3-yl)-3-(6-methylsulfinyl-pyridin-3-yl)-propan-1-one (0.22 g) was dissolved in THF (3 mL) and toluene (1.5 mL), and monomethyl oxalyl chloride (0.27 g) added. The mixture was heated to 80° C. for 2.5 h, concentrated to a semi-solid, taken up in MeOH, and K2CO3 (0.22 g) added. This mixture was heated to 80° C. for 15 min, then cooled to RT. The product was worked up in EtOAc/H2O, the organic layer washed with LiCl (2×, 0.3 wt % aq), dried over MgSO4, and purified by prep TLC (1:1 EtOAc/hexane) to provide 3-(6-methanesulfonyl-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (compound 92) (8 mg) as a yellow solid. M+H=464, mp=217-218° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:26])=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)C>[F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:26])=[CH:22]/[C:23]([N:52]=[N+:53]=[N-:54])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C/C(=C\C(=O)O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C/C(=C\C(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To (E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoic acid (C28) (1.14 g, 2.93 mmol) in isopropanol (9.8 mL) was added triethylamine (0.53 mL, 3.81 mmol) and diphenyl phosphorazidate (0.68 mL, 3.23 mmol). The reaction was stirred at room temperature overnight. The white precipitate was vacuum-filtered and dried in a vacuum oven to afford the title compound as a white solid (0.978 g, 80%): 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.25-8.19 (m, 2H), 7.85-7.78 (m, 2H), 7.65-7.58 (m, 2H), 7.44-7.37 (m, 2H), 6.16 (d, J=1.3 Hz, 1H), 2.68 (d, J=1.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 387 ([M+H]+) (isocyanate).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1CCCCC1>CO.C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:37])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2ccc(C3CCNCC3)nc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Cc1cnc(Nc2ccc(C3CCN(C)CC3)nc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A solution of 1-(2-(2-(5-methyl-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A46 (0.121 g, 0.265 mmol) in MeOH (10 mL) was treated with formaldehyde solution (37% in water, 59 μL, 0.80 mmol) and sodium triacetoxyborohydride (0.225 g, 1.06 mmol) and stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, aq. NaOH (2 M, ˜30 mL) was added and the aqueous phase was extracted with EtOAc (3×30 mL). The organics were combined, washed with brine, dried (MgSO4) and the solvent evaporated under reduced pressure to give a colourless oil. The oil was taken up in DCM and cyclohexane was added until a white precipitate formed. The suspension was sonicated for 10 minutes and the solid was isolated by vacuum filtration and dried under high vacuum for 4 hours to give the title compound 49 as a white solid (0.051 g, 41%). LCMS-D: rt 3.13 min; m/z 471 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]=[CH:10]N(C)C)=[C:4]([N+:14]([O-])=O)[CH:3]=1>[Pd].CO>[F:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[NH:14][CH:10]=[CH:9]2
Reactant: CN(C)C=Cc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Fc1cc2cc[nH]c2cc1F
Reaction time: 2 h
Yield: 27.2 %

Procedure:
A suspension of [2-(4,5-difluoro-2-nitro-phenyl)-vinyl]-dimethyl-amine (7.0 g, 30.7 mmol) and 10% palladium on charcoal (1.4 g) in methyl alcohol was hydrogenated in a Parr apparatus at 50 psi for 2 h and then filtered through Celite. The filtrate was concentrated in vacuo and the crude product purified by silica gel column chromatography (hexanes/ethyl acetate, 8:2) to afford 5,6-difluoroindole (1.28 g, 28%) as a yellow solid. 1H-NMR δ(400 MHz, CDCl3) 8.10 (1H, br s), 7.36 (1H, dd, J=10.7, 7.8 Hz), 7.22 (1H, t, J=2.8 Hz), 7.17 (1H, dd, J=7.4, 3.1 Hz), 6.50 (1H, m).
Reaction SMILES: [CH2:1]([N:5]([CH2:37][CH2:38][CH2:39][CH3:40])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=2[C:23]([N:25]2[C@H:34]([CH2:35][OH:36])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].C(S)C.ClCCl>O>[CH2:37]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[C:23]([N:25]2[C@H:34]([CH2:35][OH:36])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCS
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Yield: 22.9 %

Procedure:
A mixture of 4-chloro-1-[2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-4-methoxy-phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (40 mg, 0.071 mmol) and aluminium chloride (75 mg, 0.56 mmol) was stirred in ethanethiol (0.052 mL, 0.71 mmol) and dichloromethane (0.5 mL) for 12 hours at ambient temperature under a nitrogen atmosphere. The mixture was added with water and extracted with 1:4 methanol:methylene chloride. The organic layer was removed in vacuo. After eluting through a short pad of silica gel column and C18 column, the crude material was purified by HPLC to afford the title compound (9 mg, 33% yield). MS (ESI) [m/e, (M+H)+]=553.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.66-7.50 (m, 7H), 2.03-5.08 (m, 14H), 0.53-1.62 (m, 14H).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:2][NH2:3])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=C(O)c1ccc(OCc2ccc(Cl)cc2)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
2.75 mol of hydrazine hydrate was added to a solution of 0.275 mol of ethyl ester of 4-(4-chloro benzyloxy) benzoic acid (X) in 300 ml ethanol. The reaction medium was reflux-heated for 48 hours. After cooling, the expected product was separated by filtration and recrystallised from ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:11])([CH2:9][CH3:10])[NH:3]1.[OH-].[K+]>C(O)COCCO.O>[CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH2:5][C:4]([CH3:11])([CH2:9][CH3:10])[NH:3]1
Reactant: CCC1(C)CC(=O)CC(C)(C)N1
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCC1(C)CCCC(C)(C)N1
Yield: 19.3 %

Procedure:
33.8 g (0.2 mol) 2,2,6-trimethyl-6-ethyl-4-oxopiperidine, 14 g (0.28 mol) hydrazinhydrate and 13 g KOH in 80 ml diethylenglykol are stirred for 4 h at 160° C. Subsequently an additional amount of 30 g KOH dissolved in 30 ml water are added. 30 ml are distilled off. To the residue two times 40 ml of water are added and removed by distillation. The combined distillates are saturated with solid K2CO3 and extracted with methyl-tert.-butylether. From the extracts 6 g (19%) 2,2,6-trimethyl-6-ethyl-piperidin are isolated by fractionated distillation. A colorless liquid is obtained with a b.p. of 78-88° C./15 mbar.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([O:27]CC)=[O:26])=[O:8])C.Cl>O1CCCC1.O>[NH2:31][C@@:9]1([C:7]([OH:8])=[O:6])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
5.53 g of lithium hydroxide hydrate was added to 22.9 g of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 480 mL of tetrahydrofuran and 240 mL of water, and the mixture was stirred for three days at room temperature. 443 mg of lithium hydroxide hydrate was further added thereto, and the mixture was stirred for 1 day at room temperature. 169 mL of 1N hydrochloric acid was added dropwise thereto at ice-cooling, and the mixture was stirred for 14 hours at room temperature. The precipitated solids were filtered, and then washed with 200 mL of tetrahydrofuran and 100 mL of water, thereby yielding 12.3 g of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35](Br)[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1.[C:40]([O:44][C:45]([N:47]1[C@@H:51]([CH3:52])[CH2:50][CH2:49][C@H:48]1[C:53]([OH:55])=[O:54])=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35]([O:55][C:53]([C@@H:48]6[CH2:49][CH2:50][C@H:51]([CH3:52])[N:47]6[C:45]([O:44][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:46])=[O:54])[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(OC(=O)[C@@H]2CC[C@H](C)N2C(=O)OC(C)(C)C)C4=O)N1C(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 53.1 %

Procedure:
(2S,5 S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (700 mg, 1.17 mmol) was treated with a solution of (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (375 mg, 1.64 mmol) in acetone (6 mL) and Cs2CO3 (267 mg, 0.82 mmol). The stirred reaction mixture was heated to 40° C. for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (464 mg, 53%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][C:18]([Cl:23])=[C:19]([Br:22])[C:20]=1[I:21])(C)(C)C>C(Cl)Cl>[Br:22][C:19]1[C:20]([I:21])=[C:15]([NH2:14])[CH:16]=[N:17][C:18]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)c(Br)c1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(Cl)c(Br)c1I
Yield: 78.4 %

Procedure:
Trifluoroacetic acid (30 mL) was added to a solution of (5-bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (19.0 g, 44 mmol) in DCM (120 mL) and the resultant solution was stirred at ambient temperature for 2 h then concentrated in vacuo. The resultant residue was loaded onto an SCX-2 cartridge (70 g) eluting with acetonitrile (100 mL) then 2N ammonia in methanol (100 mL). The basic fraction was concentrated in vacuo to afford the title compound (11.5 g, 78%). 1H NMR (DMSO-D6, 400 MHz): 7.23 (s, 1H), 5.92 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:7]2.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>C1COCC1.N1C=CC=CC=1>[CH2:27]([NH:29][C:30](=[O:31])[O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:6]1[CH2:7][C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH2:5]1)[CH3:28]
Reactant: CCN=C=O
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCNC(=O)OCCCCCCCCC1Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octanol (1.20 g) and ethyl isocyanate (0.517 ml) in THF (12 ml) was added one drop of pyridine. After being stirred for 12 hr at 40° C., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the entitled compound (1.42 g) as crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][N:7]=[C:8]([C:24](=[O:26])[CH3:25])[C:9]([NH:11][CH:12]1[C:22](=[O:23])[N:14]2[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10].[BrH:27].[NH+]1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1.O>[CH3:5][O:6][N:7]=[C:8]([C:24](=[O:26])[CH2:25][Br:27])[C:9]([NH:11][CH:12]1[C:22](=[O:23])[N:14]2[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10]
Reactant: CON=C(C(C)=O)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: Br
Agent: [Al+3]
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Aluminum chloride (120 mg.) was added to a solution of 7-(2-methoxyimino-3-oxobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 50 mg.) in dry tetrahydrofuran (10 ml.). Pridinium hydrobromide perbromide (50 mg.) was added to the solution, and stirred at room temperature for 20 minutes. Ethyl acetate (50 ml.) and water (10 ml.) were added to the resultant solution and the mixture was treated in a similar manner to that of the above Example 10-(8) to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 52.5 mg.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[N:6]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: O=C(O)c1ccc(Br)c(OCC2CCCO2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(Br)c(OCC2CCCO2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 a) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=416.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:12]2[C:11](=[O:13])[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=CC=1OC.[Cl:16][C:17]1[C:18]([O:29][CH3:30])=[CH:19][C:20]2[C:26](=[O:27])[NH:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:28]=1.C(OC1C(CCl)=C(C)C=C(C)N=1)C1C=CC=CC=1.CC([O-])=O.[Na+].CC(O)=O>CN(C=O)C>[Cl:16][C:17]1[C:18]([O:29][CH3:30])=[CH:19][C:20]2[C:26](=[O:27])[N:25]([CH2:2][C:12]3[C:11](=[O:13])[NH:10][C:9]([CH3:8])=[CH:7][C:6]=3[CH3:5])[CH2:24][CH2:23][CH2:22][C:21]=2[CH:28]=1
Reactant: COc1cc2c(cc1Cl)CCCNC2=O
Reactant: COc1ccc2c(c1Cl)C(=O)NCCC2
Agent: CC(=O)[O-]
Agent: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2c(cc1Cl)CCCN(Cc1c(C)cc(C)[nH]c1=O)C2=O
Temperature: 80 °C
Yield: 36 %

Procedure:
To a mixture of 9-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (132a) and 7-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (132b) (35.0 mg, 0.150 mmol) in DMF (5 mL) was added 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 47.1 mg, 0.180 mmol). The reaction mixture was heated at 80° C. for 24 hours. The reaction mixture was poured into a NaOAc-HOAc buffer (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The resulting brown oil was dissolved in MeOH (1 mL) and HCl (3 M in n-butanol, 0.05 mL) was added. The reaction mixture was heated at 70° C. for 24 hours. The solvent was removed in vacuum and the residue was purified by preparative HPLC to give the title compounds (Example 132-A, first eluting product, 20 mg, 36%); 1H NMR (400 MHz, methanol-d4) δ 7.09-7.14 (m, 1H), 7.05-7.10 (m, 1H), 6.13 (s, 1H), 4.89 (s, 1H), 4.71-4.79 (m, 1H), 3.88 (s, 3H), 3.38 (dd, J=5.93, 14.86 Hz, 1H), 2.92-3.01 (m, 1H), 2.57-2.73 (m, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.06-2.14 (m, 1H), 1.53-1.64 (m, 1H); MS 361.1 [M+1]; and (Example 132-B, second eluting product, 4 mg, 7%); 1H NMR (400 MHz, methanol-d4) δ 7.26 (s, 1H), 7.22 (s, 1H), 6.13 (s, 1H), 4.78 (s, 2H), 3.91 (s, 3H), 3.26-3.29 (m, 2H), 2.63 (t, J=7.09 Hz, 2H), 2.34 (s, 3H), 2.26 (s, 3H), 1.78 (t, J=6.66 Hz, 2H); MS 361.1 [M+1]; as a white solids.
Reaction SMILES: [CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1.Cl[C:48]1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][C:23]([CH3:48])([CH3:24])[CH3:25])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@H:28]2[O:30][C@@H:29]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C\C[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Cryptophycin 289 (13.2 g, 20.2 mmol) in chloroform (43 mL) is stirred and treated with m-chloroperbenzoic acid (m-CPBA) (95% pure, 5.19 g, 30.1 mmol). After stirring overnight at room temperature, the solution is diluted with chloroform until clear, washed with sodium bicarbonate (saturated aqueous, 100 mL), sodium sulfite (saturated aqueous, 100 mL), sodium chloride (saturated aqueous, 100 mL), dried (magnesium sulfate), filtered, and the filtrate evaporated (40° C., 20 mm Hg) to provide 14 g of the Cryptophycin-292 as a mixture of epoxide isomers, as a white foam. The foam is dissolved in chloroform, cooled to −63° C., and treated with chlorotrimethylsilane (23.5 mL, 185 mmol) via syringe. The mixture is stirred at −63° C. for 5 hours, then allowed to stand in the freezer at −20° C. overnight. The mixture is again cooled to −63° C. and treated with sodium bicarbonate (saturated aqueous, 60 mL) with vigorous stirring. The cold bath is removed and the mixture allowed to warm to room temperature over a 1 hour period. The layers are separated and the aqueous layer extracted with chloroform. The organic layers are washed with sodium bicarbonate (saturated aqueous, 60 mL), sodium chloride (saturated aqueous, 100 mL), dried (magnesium sulfate), filtered, and the filtrate evaporated to 14 g of a white residue. The residue is chromatographed on silica gel (70×160 mm of silica gel, packed and eluted in 2:1:1 tBuOMe/CH2Cl2/hexanes) to provide 4.51 g of Cryptophycin 296 as a colorless foam (32%)
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:27])[CH:8]([O:24][CH2:25][CH3:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)C>O.O1CCOCC1>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH:8]([O:24][CH2:25][CH3:26])[C:7]([OH:27])=[O:6])=[CH:15][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Yield: 99.2 %

Procedure:
Lithium hydroxide hydrate (7.4 g; 177 mmole) dissolved in water (150 ml) was added to a solution of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid ethyl ester (23.25 g; 70.8 mmole) in dioxan (150 ml). After stirring at room temperature over night dioxan was evaporated in vacuo, water was added and the mixture was washed with diethyl ether. The water phase was acidified with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and the solvent was evaporated in vacuo to give 21.1 g (yield 99.2%) of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].I[C:11]1[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=1.[F-].[Cs+].[CH:21]1(N)CCCCC1N.C(OCC)(OCC)OCC>[Cu]I>[NH:18]1[C:13]2[CH:12]=[CH:11][C:16]([N:5]3[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]3=[O:9])=[CH:15][C:14]=2[N:17]=[CH:21]1
Reactant: NC1CCCCC1N
Reactant: Nc1ccc(I)cc1N
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(OCC)OCC
Product: CC(C)[C@H]1COC(=O)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from (S)-4-isopropyloxazolidin-2-one (0.065 g, 0.5 mmol), 4-iodobenzene-1,2-diamine (0.117 g, 0.5 mmol), copper(I) iodide (0.010 g, 0.05 mmol), cesium fluoride (0.276 g, 1 mmol), cyclohexane-1,2-diamine (0.006 mL, 0.05 mmol), triethyl orthoformate (3 mL) as described in method 5 step D.