Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][C:24]=3[N:25]=[C:16]2[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:3])[CH3:2]>CO.O1CCOCC1.[Pd]>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][C:24]=3[N:25]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCC=Cc1nc3ccc(OC)cc3nc1O2
Agent: [Pd]
Agent: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCC/C=C/c1nc3ccc(OC)cc3nc1O2
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1nc3ccc(OC)cc3nc1O2
Reaction time: 4 h
Yield: 98 %

Procedure:
A solution (0.05 M) of methyl (1aR,5S,8S,10R,18E,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,20,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate in MeOH/dioxane (1:1 ratio) was treated with Pd/C (8% in weight). The resulting mixture was stirred under atmosphere of hydrogen for 4 h. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (98%) as a solid. MS (ES+) m/z 569 (M+H)+
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=C[C@@H]([C@H]([C@H](CO)O)O)O.OP([O-])([O-])=O.[K+:26].[K+].OP([O-])(O)=O.[K+]>>[O:1]=[C:2]([O-:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[K+:26]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)CO
Temperature: 30 °C
Reaction time: 12 h

Procedure:
For microbial oxidation of D-xylose or L-arabinose, fermentation medium (1 L) contains K2HPO4 (2 g), KH2PO4 (1 g), (NH4)2SO4 (5 g) and yeast extract (5 g). Solutions of D-xylose (100 g) or L-arabinose (100 g) and MgSO4 (0.24 g) are autoclaved separately and added immediately prior to initiation of the fermentation. Inoculants are started by introduction of a Pseudomonas fragi single colony picked from a nutrient agar plate into 5 mL of fermentation medium. Cultures are grown at 30° C. with agitation at 250 rpm until they are turbid (˜24 h) and subsequently transferred to 100 mL of fermentation medium. Cultures are grown at 30° C. and 250 rpm for an additional 12 h. The inoculant (OD600=1.0-3.0) is then transferred into the fermentation vessel and the batch fermentation is initiated (t=0 h). The fermentation control settings are: 30° C., stirring speed at 650 rpm, and airflow at 0.5 L/L/min. The culture medium is maintained at pH 6.4 by addition of 2 N H2SO4 and a base solution, which is 30% CaCO3 for oxidation of D-xylose or concentrated NH4OH for oxidation of L-arabinose. A standard curve is determined for each metabolite using solutions of authentic, chemically synthesized samples. (Moore, S.; Link, K. P. J. Biol. Chem. 1940, 133, 293.) Compounds are quantified by 1H NMR using the following resonances: D-xylonic acid (δ4.08, d, 1H); L-arabinonic acid (δ4.24, d, 1H); and L-arabino-1,4-lactone (δ4.64, d, 1H). A modified procedure by Buchert is employed for the purification of D-xylonate. Following treatment with activated carbon and concentration (1-1.1 L to 250 mL) of D-xylonate containing fermentation broth, EtOH (3:1, v/v) is added. After 12 h at 4° C., the precipitated calcium xylonate is filtered and dried under vacuum (95% recovery based on D-xylonate in the crude fermentation broth). Potassium D-xylonate is obtained by passing an aqueous solution of calcium xylonate through a Dowex 50 (K+ form) column (Applied Membranes, Vista, Calif., USA).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([NH2:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F.C(N(CC)CC)C>C(OCC)(=O)C.O>[CH:1]([N:14]1[CH2:17][CH:16]([NH:18][C:25]2[CH:24]=[CH:23][C:22]([N+:27]([O-:29])=[O:28])=[CH:21][C:20]=2[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NC2CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1

Procedure:
A solution of 7.96 g of 1-benzhydrylazetidin-3-ylamine (33.41 mmol), 3.69 ml 3.4-difluoronitrobenzene (33.41 mmol) and 4.65 ml triethylamine (33.41 mmol)) in 50 ml ethyl acetate was stirred for 2 weeks at 60° C. The reaction was diluted with water and the product extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:27][CH3:28])=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([CH:23]=1)[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][OH:22])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl>CO>[NH2:24][C:12]1[CH:11]=[C:10]([O:27][CH3:28])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][C:13]=1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][OH:22])=[O:15]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)N2CCCC2CO)cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COc1cc(N)c(C(=O)N2CCCC2CO)cc1OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of the nitro compound 2 (15.49 g, 40.12 mmol, 1.0 equiv) and tin (II) chloride (45.27 g, 200.64 mol, 5.0 equiv) in methanol (300 mL) was heated at reflux for 4 h. Excess solvent was removed by rotary evaporation under reduced pressure. The residue was treated carefully with a saturated aqueous sodium bicarbonate solution to basify the mixture to pH 9. The resulting suspension was allowed to stir overnight with ethyl acetate (100 mL), and filtrated through Celite to remove precipitated tin salts. The aqueous phase was extracted with EtOAc (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4), and evaporated in vavuo to provide 3 as a pink oil, which was used in the subsequent reaction without further purification: [α]20D=−97° (c=0.18, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.50-1.81 (m, 3H, 1-H, 2-H), 2.05-2.15 (m, 1H, 1-H), 3.03-3.16 (m, 1H, 3-H), 3.23-3.36 (m, 1H, 3-H), 3.56-3.78 (m, 2H, 11-H), 3.88 (s, 3H, 7-OMe), 4.21-4.38 (m, 1H, 11a-H), 4.47-4.75 (m, 1H, 3-H), 5.03 (d, 1H, J=12.4 Hz, OBn), 5.10 (d, 1H, J=12.4 Hz, OBn), 6.26 (s, 1H, 9-H), 6.66 (s, 1H, 6-H), 7.28-7.41 (m, 5H, Ph); 13C NMR (CDCl3, 400 MHz): δ 24.8, 28.5, 51.1, 55.7, 61.1, 67.5, 72.5, 100.8, 116.9, 127.5, 127.7, 128.4, 137.4, 138.8, 142.6, 153.0, 171.1, 171.7; IR (neat): 3436, 33.52, 29.67, 28.73, 1621, 1589, 1513, 1448, 1402, 1264, 1216, 1172, 1110, 1025 cm−1; MS (FAB) m/z (relative intensity) 379 ([M+Na]+., 5), 357 (M+., 100), 255 (58).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Li]CCCC.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>C1COCC1.CCOCC>[CH3:24][O:23][C:17]1[CH:22]=[CH:21][C:20]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[C:6]([CH:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:19][CH:18]=1
Reactant: COc1ccccc1
Reactant: CNC(=O)c1ccccc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a solution of N-methyl-o-toluamide (4.47 g) in THF (100 ml) was added dropwise 1.6 M n-BuLi (40 ml, 2.2 equivalents) in nitrogen atmosphere at 0° C. After stirring for 2 hr, the resulting solution was cooled in a dry ice/acetone bath to −70° C., followed by the addition of anisole (4.0 g) at once. The reaction mixture was drawn out of dry ice/acetone bath, and then returned to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride and ether were added thereto, which was stirred for further 1 hr. The resulting white precipitates were collected by filtration, and then washed with water, ether and n-hexane, in this order. The resulting precipitates were dried, to give the title compound (1.72 g, yield; 24%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:11]2[N:15]=[C:14]([NH:16][C:17]3[N:22]=[CH:21][C:20]([S:23][CH2:24]CC(OC)=O)=[CH:19][C:18]=3[O:30][C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)[S:13][N:12]=2)([CH3:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[C:44]([O:47][CH2:48]CBr)(=[O:46])[CH3:45].O>C1COCC1>[C:44]([O:47][CH2:48][CH2:24][S:23][C:20]1[CH:21]=[N:22][C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C:7]3([CH3:10])[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)[N:15]=2)=[C:18]([O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:19]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OCCBr
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3(C)CCN(C(C)=O)CC3)ns2)c(Oc2cccnc2C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCSc1cnc(Nc2nc(C3(C)CCN(C(C)=O)CC3)ns2)c(Oc2cccnc2C)c1
Reaction time: 0.01 h
Yield: 71.3 %

Procedure:
Methyl 3-(6-(3-(1-acetyl-4-methylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (125 mg, 0.230 mmol) was dissolved in THF (10 mL) and potassium tert-butoxide (64.6 mg, 0.576 mmol) was added. The reaction was stirred for 30 seconds and 2-bromoethyl acetate (38.5 mg, 0.230 mmol) was added. The reaction was stirred for 3 hours. Water was added and the reaction was extracted with dichloromethane. The organic layer was concentrated, and the crude material was purified by silica gel chromatography (5-7% methanol in dichloromethane) to give 2-(6-(3-(1-acetyl-4-methylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)ethyl acetate (89 mg, 0.164 mmol, 71.2% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccs2)c1
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To a solution of {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (87.3 mg, 0.213 mmol), prepared in Step A of Example 13i, triethylamine (47.3 mg, 0.234 mmol) and dichloroethane (10 mL) was added thiophene-2-sulfonyl chloride (42.7 mg, 0.234 mmol). The reaction was stirred for 24 h and additional triethylamine (0.234 mmol) and thiophene-2-sulfonyl chloride (42.7 mg, 0.234 mmol) were added. The reaction was stirred for an additional 24 h. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (63 mg). MS 556 (M+1)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]1)=[O:16].C(OCC)(=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1.[Cu]I.C1(C2C=CC=CC=2O)C=CC=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][C:9]=1[C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]1)=[O:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COC1CCN(C(=O)c2cc(I)ccc2F)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 215 %

Procedure:
Cesium carbonate (2.308 g, 7.08 mmol) was added in one portion to (2-fluoro-5-iodophenyl)(4-methoxypiperidin-1-yl)methanone (41) (1.06 g, 2.92 mmol), diethyl malonate (1.329 mL, 8.76 mmol), 2-phenylphenol (0.099 g, 0.58 mmol) and copper(I) iodide (0.056 g, 0.29 mmol) in THF (10 mL) at 25° C. under nitrogen. The resulting mixture was stirred at 160° C. in the microwave reactor for 90 minutes. The reaction mixture was evaporated to dryness and redissolved in Et2O (200 mL), and washed sequentially with water (100 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a colourless gum (2.03 g, 72% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.25 (3H, t), 1.53-1.61 (1H, m), 1.67-1.74 (1H, m), 1.77-1.84 (1H, m), 1.89-1.97 (1H, m), 3.12-3.20 (1H, m), 3.36 (3H, s), 3.44-3.62 (3H, m), 3.59 (2H, s), 3.96-4.05 (1H, m), 4.15 (2H, q), 7.02-7.06 (1H, m), 7.26-7.33 (2H, m); m/z (LC-MS, ESI+), RT=1.08 (M+H 324.3).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[C:12][OH:13])[N:5]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][OH:13])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(CC#CO)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(CCCO)n1
Yield: 82.7 %

Procedure:
A suspension of 1.3 g of 2-acetyl-6-(3-hydroxy-2-propynyl)pyridine and 0.5 g of 10% Pd/C in 50 ml of ethyl acetate was hydrogenated at 50 psi (H2) overnight. The mixture was filtered and the filtrate was concentrated in vacuo to yield 1.1 g (84.6%) of 2-acetyl-6-(3-hydroxypropyl)-pyridine, as a yellow oil (crude).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>N1CCCCC1.C(O)C>[O:16]=[C:10]1[C:9](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1[nH]cc2c1CCOC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.6 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (117 mg, 0.54 mmol), 4-oxo-2,4,6,7-tetrahydropyrano[3,4-c]pyrrole-1-carbaldehyde (89.3 mg, 0.54 mmol) and piperidine (1 drop) in ethanol (3 mL) was stirred at room temperature for 2 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 54.1 mg (28%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([O:41]C)=[O:40])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[F:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:29]([NH:28][CH:12]2[C:11](=[O:43])[N:10]([CH2:9][C:7]([C:2]3[C:1]([CH3:44])=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:13]2)=[O:30])=[CH:33][C:34]=1[C:39]([OH:41])=[O:40]
Reactant: COC(=O)c1cc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1ccc(F)c(C(=O)O)c1)CN2C(=O)C(C)(C)C
Yield: 64.2 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-fluorophenyl)urea (510 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxide monohydrate (178 mg) solution (12 ml) and tetrahydrofuran (12 ml) was added, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 320 mg of the titled compound.
Reaction SMILES: [CH3:1]P(C)CCCP(C)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:39]=[C:40]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[CH2:39]=[C:40]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].[CH:40]([P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:1]
Reactant: CP(C)CCCP(C)C
Agent: C=C(CCCCCC)P(=O)(OCC)OCC
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CCCCCCC=CP(=O)(OCC)OCC
Reaction time: 36 h

Procedure:
Example 8 was repeated in the same manner as described except that 1,3-bis(dimethylphosphino)propane was substituted for 1,3-bis(diphenylphosphino)propane and that the reaction was carried out for 36 hours. The proton NMR analysis of the resulting reaction mixture revealed that an isomeric mixture of (a) dimethyl 1-octen-2-yl-phosphonate and (b) dimethyl 1-octen-1-yl-phosphonate was obtained with a yield of 85% and that the weight ratio of the former phosphonate (a) to the latter phosphonate (b) was 94:6.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7].[BH4-].[Na+]>C(OC(=O)C)C>[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1C(=O)c1cc(Cl)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccccc1C(O)c1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a methanol (5 ml) solution of 2-amino-2′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.5 g) was added sodium borohydride (79 mg). The mixture was stirred for 3 hours at room temperature. To the reaction mixture was added acetic acid ethyl ester (100 ml), which was washed with water and, then, dried over anhydrous MgSO4. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give the object 2-amino-5-chloro-α-(2-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) as a colorless oily product.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:10]([C:11](Cl)=[O:12])[CH:9]=[C:8]2[Cl:18])CCC.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>>[Cl:18][C:8]1[C:7]2[C:15](=[CH:16][CH:17]=[CH:5][CH:6]=2)[N:14]=[C:10]([C:11]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:12])[CH:9]=1
Reactant: Nc1nnn[nH]1
Reactant: CCCCc1ccc2nc(C(=O)Cl)cc(Cl)c2c1
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1

Procedure:
In a similar manner 6-butyl-4-chloro-N-(1H-tetrazol-5-yl)quinaldamine, m.p. 275° was prepared from 6-butyl-4-chloroquinaldoyl chloride and 5-aminotetrazole.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:1][N:2]=[C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCOC(=O)C(=NO)c1ccccc1
Product: CCCCCCOC(=O)C(=NOS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Yield: 79.6 %

Procedure:
18.0 g (0.0722 mol) of hexyl α-(hydroxyimino)-2-phenylacetate are reacted with 15.1 g of p-toluenesulfonic acid chloride as described in example 1.3 to give 23.2 g (80%) of hexyl α-(4-methylphenylsulfonyloxyimino)-2-phenylacetate as a colorless liquid after purification by chromatography. According to 1H-NMR-analysis, the product is a mixture of 69% of the trans isomer and 31% of the cis isomer.
Reaction SMILES: C([O:5][C:6](=[O:32])[C@H:7]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18](C(OC(C)(C)C)=O)[CH:19]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:13]=12)[CH2:8][CH3:9])(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:24][O:23][C:21]([C:20]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][C@H:7]([CH2:8][CH3:9])[C:6]([OH:32])=[O:5])[NH:18][CH:19]=1)=[O:22]
Reactant: CC[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](NCc1ccnc2[nH]cc(C(=O)OC)c12)C(=O)O
Yield: 99 %

Procedure:
To a 100 mL round bottom flask equipped for stirring was added (R)-1-tert-butyl 3-methyl 4-((1-tert-butoxy-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (1.45 g, 3.24 mmol) and DCM (10 mL). TFA (10 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and dried in vacuo to afford the title compound as a yellow oil (1.3 g, 99%) (TFA salt). [M+H] calc'd for C14H17N3O4, 292; found, 292.6.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC([O-])(C)C.[K+].Cl[C:24]1[CH:29]=[C:28]([C:30]([NH2:32])=[O:31])[N:27]=[C:26]([C:33]([NH2:35])=[O:34])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:30]([C:28]1[CH:29]=[C:24]([O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:10][C:11]=2[F:16])[CH:25]=[C:26]([C:33](=[O:34])[NH2:35])[N:27]=1)(=[O:31])[NH2:32]
Reactant: NC(=O)c1cc(Cl)cc(C(N)=O)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2cc(C(N)=O)nc(C(N)=O)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A solution of N-Boc-4-amino-2-fluorophenol (228 mg, 1.0 mmol) in DMF (2 mL) was treated with t-BuOK (124 mg, 1.1 mmol) and the mixture stirred at room temperature for 2 h. The mixture was treated with 4-chloropyridine-2,6-dicarboxamide (200 mg, 1.0 mmol) and K2CO3 (35 mg, 0.5 mmol) and heated at 80° C. for 1.5 h. The mixture was concentrated in vacuo, treated with EtOAc (10 mL) and H2O (10 mL) and filtered to remove the insoluble material. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the residue by flash column chromatography on SiO2 eluting with 30-100% EtOAc/hexanes gave the title compound (170 mg, 44%) as a white solid containing 10% of the starting chloropyridine. 1H NMR (DMSO-d6) δ 9.77 (s, 1H), 8.86 (s, 2H), 7.87 (s, 1H), 7.63 (d, 1H, J=12.1 Hz), 7.55 (s, 2H), 7.38-7.31 (m, 2H), 1.48 (s, 9H).