Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].NN.O.O[N:27]1C2C=CC=CC=2N=[N:28]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([NH:27][NH2:28])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 94.6 mg (0.3 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1) in 1.5 mL of anhydrous dichloromethane, stirred in an ice bath under protection from moisture, was added 0.0106 mL (10.8 mmol) of anhydrous 98% hydrazine. Then 91.8 mg of 1-hydroxybenzotriazole hydrate was added, followed by 63.4 mg (0.33 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and finally 0.0574 mL (42.6 mg, 0.33 mmol) of N,N-diisopropylethylamine. After 15 minutes, an additional 0.0574 mL (42.6 mg, 0.33 mmol) of N,N-diisopropylethylamine was added. After 2 h, the mixture was removed from the ice bath and allowed to warm to room temperature, and precipitation gradually increased. After 22 h, the precipitated solid was collected on a filter, washed with small volumes of dichloromethane, and dried to give the title compound as a white solid, mp 168-169° C. LC-MS 230 (M+1-Boc).
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH:34]12[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[C:35]1=O)[CH2:41]2>C1COCC1.CCCCCC.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[O:8]([C:16]1[CH:17]=[C:18]([C:19](=[C:35]2[CH:36]3[CH2:42][CH:40]4[CH2:39][CH:38]([CH2:43][CH:34]2[CH2:41]4)[CH2:37]3)[O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCOc2ccccc2)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCOc2ccccc2)=C2C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 500 mL three-neck flask equipped with magnetic stirrer, pressure-equalizing addition funnel and nitrogen line was charged with 200 mL anhydrous THF. Fifteen parts of titanium tetrachloride was added dropwise over a period of 30 minutes. After stirring the suspension for 20 minutes, 22 parts of zinc was added in small portions. The reaction mixture was heated under reflux for 2 hours and 37 mL of triethylamine was added dropwise. After refluxing one hour a solution 5.9 parts of alkene (54) and 3.0 parts of adamantan-2-one in 40 mL of dry THF was added over a period of 90 minutes. The reaction mixture was heated for one hour. TLC on silica gel plate of the mixture showed the presence of starting ester. One and a half part of Adamantan-2-one in 20 mL of dry THF was added dropwise over 30 minutes and refluxed for two hours. The mixture was cooled to room temperature, diluted with 500 mL of hexane and decanated. The residue was washed three times with 200 mL of hexane. The combined hexane layer was filtered and evaporated under reduced pressure to give an oily material which was purified by chromatography on silica gel column using 2.5% ethyl acetate/hexane as an eluant. The fractions were checked by TLC on silica gel plate and the desired fractions were combined. The solvent was evaporated under reduced pressure to give an oil, yield 6.30 parts. The structure was confirmed by 1H NMR. The reaction proceeded as follows:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(NC1CCNCC1)c1ccccc1
Reaction time: 30 h
Yield: 93 %

Procedure:
To a suspension of 10% palladium on carbon (0.2 g) in 30 mL of ethyl alcohol was added a solution of 1-benzyl-4-benzamido-piperidine (0.5 g, 1.79 mmol) in ethyl alcohol (10 mL). The resulting suspension was hydrogenated at 100 psi at 50° C. for 30 h after which it was filtered through a pad of celite and the solvent was removed in vacuo to obtain 0.34 g (100%) of 4-benzamidopiperidine as a white solid. It was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.CN(C=O)C.[CH3:26][C@:27]12[C:33]([CH3:35])([CH3:34])[C@H:30]([CH2:31][CH2:32]1)[CH:29]=[C:28]2B(O)O.C(=O)([O-])[O-].[K+].[K+]>[Cl-].[Na+].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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[C:28]1[C@@:27]2([CH3:26])[C:33]([CH3:35])([CH3:34])[C@@H:30]([CH:29]=1)[CH2:31][CH2:32]2
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Reactant: CC1(C)[C@H]2C=C(B(O)O)[C@]1(C)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=C[C@H]3CC[C@]2(C)C3(C)C)c1
Temperature: 90 °C
Yield: 81 %

Procedure:
To a stirred solution of 66.15D (0.200 g, 0.52 mmol) in DMF (4.00 mL, 52 mmol) at 23° C. was added (1S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-ylboronic acid (0.19 g, 1.0 mmol, commercially available from Combi-Blocks, Cat. No. BB-2567), potassium carbonate (0.21 g, 1.6 mmol), and then tetrakis(triphenylphosphine)palladium (0.060 g, 0.052 mmol). The mixture was heated at 90° C. for 19 hours and then cooled to room temperature. The reaction was diluted with brine and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-10% EtOAc in hexanes) to yield 66.15E as a colorless oil (0.165 g, 81% yield).
Reaction SMILES: [CH:1]1([CH2:11][C:12](=O)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[NH2:15][CH:16]([CH3:26])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[OH:18].Cl>CO>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([CH:17]([OH:18])[CH:16]([NH:15][CH:12]([CH3:13])[CH2:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][O:2]2)[CH3:26])=[CH:24][CH:23]=1
Reactant: CC(=O)CC1OCCc2ccccc21
Reactant: CC(N)C(O)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: CC(CC1OCCc2ccccc21)NC(C)C(O)c1ccc(O)cc1
Yield: 72 %

Procedure:
An oily product was obtained in the same manner as in Example 1, using (isochroman-1-yl)acetone and 2-amino-1-(4-hydroxyphenyl)-1-propanol [J. Med. Chem., 14, 148 (1971)]. The product was dissolved in anhydrous methanol, and concentrated hydrochloric acid was added thereto. The solvent was evaporated off to give a hydrochloride. The hydrochloride was then washed with ether to give Compound 24 as crystals in a yield of 72%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:21])=[O:20])[C:3]=1[Cl:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=2)=[O:20])[C:3]=1[Cl:22]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c1F
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccc(OC(F)(F)F)cc3)c(Cl)c(N)c2F)c1F
Temperature: 50 °C
Yield: 51.4 %

Procedure:
A suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid (200 mg, 0.573 mmol), 1-(bromomethyl)-4-(trifluoromethoxy)benzene (161 mg, 0.630 mmol) and K2CO3 (119 mg, 0.859 mmol) in DMF (2 mL) was heated at 50° C. overnight. The reaction mixture was then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-80% EtOAc/hexane gradient) to yield a white solid (154 mg, 51.4%): mp 155-156° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J=8.7 Hz, 2H), 7.47 (dd, J=8.5, 1.5 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.29 (dd, J=8.5, 7.1 Hz, 1H), 7.14 (s, 2H), 5.41 (s, 2H), 3.95-3.90 (m, 3H); ESIMS m/z 523 ([M+H]+), 521 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[C:3]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:41][CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].O>CN(C)C=O>[F:1][C:2]1[C:3]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[C:6]([O:8][CH2:41][CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1cc(F)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-fluoro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenol (0.46 g) and cesium carbonate (0.48 g) in N,N-dimethylformamide (5 mL) was added 1-bromo-2-(tert-butyl-dimethylsilyloxy)ethane (0.25 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane n-hexane/ethyl acetate=1/1) to give 5-fluoro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-[2-(tert-butyldimethylsilyloxy)ethoxy]-benzene (66 mg). This material was dissolved in tetrahydrofuran (3 mL). To the solution was added hydrazine monohydrate (0.026 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (52 mg).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[C:8]([N+:15]([O-])=O)[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH:6]=[CH:5]1)([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[CH:1]([N:4]1[C:12]2[C:7](=[C:8]([NH2:15])[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc([N+](=O)[O-])c2ccn(C(C)C)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(N)c2ccn(C(C)C)c12

Procedure:
A solution of 1-isopropyl-7-methoxy-4-nitro-1H-indole (T) (1 eq) and palladium 10% on activated carbon (0.1 wt eq) in methanol/ethyl acetate (1:1) was shaken on a Parr hydrogenation apparatus under hydrogen for 1 hr. The reaction was then filtered through Celite and evaporated to dryness to produce the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C[O:17][C:18]([C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19].C1COCC1.[Li+].[OH-]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:26][C:25]2[C:20]([C:18]([OH:19])=[O:17])=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COC(=O)c1ncccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Prepared from 0.60 g (2.17 mmol) of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride and 0.30 g (1.97 mmol) of 3-amino-pyridine-2-carboxylic acid methyl ester in 3 mL pyridine using procedure x. The solvent was switched to THF, followed by the addition of 1 M aqueous LiOH and the mixture stirred for 1 h. The pH of the mixture was adjusted to neutral and the product was extracted with ethyl acetate. LC-MSD, m/z for C13H8ClF3N2O4S [M+H]+=380.9, 383.0; HPLC retention time: 1.8 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1([F:26])[CH2:22][CH:21]1[C:23](O)=[O:24]>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]([CH:21]3[CH2:22][C:20]3([F:26])[F:19])=[O:24])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Reactant: O=C(O)C1CC1(F)F
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)C2CC2(F)F)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 2,2-difluoro-cyclopropanecarboxylic acid (CAS 107873-03-0) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=360.3 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][CH2:13][C@@H:14]1[C@H:32]([OH:33])[C@H:31]([CH3:34])[CH:30]=[C:29]([CH3:35])[CH:28]=[C:27]([O:36][CH3:37])[C:25](=[O:26])[O:24][C@H:23]([C@H:38]([C@@H:40]([OH:66])[C@@H:41]([C@@H:43]2[O:48][C@H:47](/[CH:49]=[CH:50]/[CH3:51])[C@@H:46]([CH3:52])[C@H:45]([O:53][C@@H]3O[C@H](C)[C@@H](OC(N)=O)[C@H](O)C3)[CH2:44]2)[CH3:42])[CH3:39])[C@@H:22]([O:67][CH3:68])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:69])[CH2:17][C@@H:16]([CH3:70])[C@@H:15]1[OH:71].P([O-])([O-])([O-])=O>Cl.CO>[CH3:12][CH2:13][C@@H:14]1[C@H:32]([OH:33])[C@H:31]([CH3:34])[CH:30]=[C:29]([CH3:35])[CH:28]=[C:27]([O:36][CH3:37])[C:25](=[O:26])[O:24][C@H:23]([C@H:38]([C@@H:40]([OH:66])[C@@H:41]([C@@H:43]2[O:48][C@H:47](/[CH:49]=[CH:50]/[CH3:51])[C@@H:46]([CH3:52])[C@H:45]([OH:53])[CH2:44]2)[CH3:42])[CH3:39])[C@@H:22]([O:67][CH3:68])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:69])[CH2:17][C@@H:16]([CH3:70])[C@@H:15]1[OH:71]
Reactant: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O)[C@@H]1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
500 mg (2.6 mmol, 22.5 equiv.) of toluene-4-sulfonic acid in 3 ml of 1N HCl are added to a solution of 100 mg of 21-deoxyconcanamycin A (0.117 mmol) in 15 ml of MeOH and the reaction mixture is stirred for 48 hours at room temperature. After the addition of 20 ml of phosphate buffer (pH=7) the solvent is removed in vacuo. Standard working-up, followed by column chromatography on silica gel (system E then system D), yields the title compound. M.p. 104° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:14])[CH:3]=1.S(=O)(=O)(O)[OH:16]>>[NH2:1][C:2]1[C:11]([C:12](=[O:16])[NH2:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:14])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc(C#N)c(N)cc1O
Product: COC(=O)c1cc(C(N)=O)c(N)cc1O
Temperature: 80 °C

Procedure:
Methyl 4-amino-5-cyano-2-hydroxybenzoate (J. Chem. Soc. Perkin I. 1979, 677; 4 g) was added to stirred concentrated sulphuric acid (6 ml) and the mixture was heated to 80° C. for 30 minutes. The mixture was cooled to ambient temperature and poured onto crushed ice. The resultant solid was filtered off, washed well with water and dried to give methyl 4-amino-5-carbamoyl-2-hydroxybenzoate (2.8 g); NMR Spectrum: (DMSOd6) 3.83 (s, 3H), 6.1 (s, 1H), 6.75 (br m, 2H), 8.08 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].CC(C)C[AlH]CC(C)C>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CO)c(Cl)c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
In a 250 mL round bottom flask, methyl 2-chloro-4-nitrobenzoate (5 g, 23 mmol) was dissolved in anhydrous dichloromethane (100 mL). The solution was cooled to −78° C. under nitrogen. Bis(2-methylpropyl)alumane (35 mL, 35 mmol, 1 M in hexane) was added dropwise. The mixture was stirred at −78° C. for 4 hours and quenched by addition of water (5 mL). The resulting mixture was warmed up to room temperature in 20 minutes. Na2SO4 (15 g) was added. After 10 minutes, the mixture was filtered. The filtrate was evaporated to provide (2-chloro-4-nitrophenyl)methanol (95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N+:8]([O-:14])=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.[CH2:22](C(CC)(CC)C([O-])([O-])[O-])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([CH3:23])=[N:13][N:12]=[C:10]3[CH2:9][N+:8]([O-:14])=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=[N+]([O-])C2

Procedure:
A mixture of 13.5 g. of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 4-oxide, 200 ml. of ethanol, 9 ml. of triethylorthoacetate and 0.5 g. of p-toluenesulfonic acid was refluxed for 20 minutes. The ethanol was removed under reduced pressure. The residue was partitioned between methylene chloride and aqueous sodium carbonate solution. The methylene chloride layer was dried and evaporated. The remaining crystals were recrystallized from ethyl acetate to yield 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 5-oxide with a melting point of 280°-282°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:20])=[O:5])[CH3:2].C(O)C.[H][H]>[C].[Pd].O1CCCC1>[NH2:17][C:15]1[CH:14]=[CH:13][C:12]2[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8](=[O:20])[CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CCOC(=O)CN1C(=O)COc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CN1C(=O)COc2cc(N)ccc21
Yield: 74.7 %

Procedure:
A mixture of 4-ethoxycarbonylmethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (30 g), 10% palladium-carbon (3 g) and ethanol (150 ml) was charged in an autoclave, and catalytically reduced under conditions of 20 kg/cm2 of hydrogen pressure and at a temperature of 60° C. to 70° C. Tetrahydrofuran was added thereto, and the liquor was filtered, then the filtrate was distilled under reduced pressure. Recrystallization of the resulting solid from ethanol gave the desired 7-amino-4-ethoxycarbonylmethyl-2H-1,4-benzoxazin-3(4H)-one (20 g). mp. 136°-137° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][C@@H:31]3[CH2:35][CH2:34][CH2:33][NH:32]3)[CH:28]=2)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:43]COCC>C1COCC1.O>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][C@@H:31]3[CH2:35][CH2:34][CH2:33][N:32]3[CH3:43])[CH:28]=2)[CH2:21][CH2:22]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOCC
Reactant: c1ccc(COCCC2CCN(c3cncc(OC[C@@H]4CCCN4)c3)CC2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a suspension of lithium aluminum hydride (60 mg, 1.59 mmol, 5.0 equiv.) in THF (5 mL) was added a solution of 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[(2(S)-pyrrolidinyl)methoxy]pyridine (156 mg, 0.32 mmol) in THF (1 mL). The mixture was refluxed for 1.5 h and then cooled to room temperature. To a flask containing 4-5 g of Na2SO4 was added with stirring 40-50 mL of ether followed by the cooled reaction mixture. Water was subsequently added dropwise to quench residual hydride. When no more gas was generated, the mixture was filtered, and the solid phase was washed with CH2Cl2/MeOH 4:1 (100-150 mL). Solvent removal furnished crude 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[(1-methyl-2(S)-pyrrolidinyl)methoxy]pyridine (106 mg, 81%), which could be used in the following step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=2[O:19][CH3:20])=[CH:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 4-Benzyloxy-phenol following the Standard Procedure J. MS (ES) for C27H30O7 [M+Na]+: 489.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]>C(O)COCCO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: NCCCCO
Solvent: OCCOCCO
Product: Cc1ccccc1N1CCc2c(NCCCCO)nc3c(OCC(F)(F)F)cccc3c21
Yield: 85.5 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in diethylene glycol(10 ml), then hereto was added 4-amino-1-butanol(175 μl, 1.9 mmol), and reacted at the same condition of Step 6 in the Example 30 to obtain 495 mg of desired compound as solid in 87% of yield.