Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N:7][C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][N:4]=1)[NH2:2].[C:19](OCC)(=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:9]([C:8]1[C:3]2[N:4]([C:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:2][N:1]=2)[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Cc1nc(-c2cccnc2)cnc1NN
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)Cc1nnc2c(CC(C)C)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing 2-hydrazino-3-isobutyl-5-(3-pyridyl)pyrazine with diethyl malonate there is obtained ethyl 8-isobutyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 339 (M)+, which is converted by saponification into the above acid: MS 267 (M-CO2)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH3:23])[C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].C([Li])CCC.[CH:29](N1CCOCC1)=[O:30].Cl>C1COCC1.C(OCC)(=O)C>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([CH:19]=[C:6]([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[C:5]=1[O:20][CH3:21])[CH:29]=[O:30]
Reactant: O=CN1CCOCC1
Reactant: COc1cc(Br)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Reaction time: 0.25 h

Procedure:
To a solution of the 3.616 g of (5-bromo-2,3-dimethoxybenzyloxy)triisopropylsilane in 60 ml of THF there was added dropwise 3.6 ml of n-butyllithium (2.66 M, hexane solution) at −78° C. under a nitrogen atmosphere. After stirring for 15 minutes, 2 ml of N-formylmorpholine was added and the mixture was stirred at room temperature for 20 minutes. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.605 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][C:30]1[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1>>[NH2:36][C:34]1[N:35]=[C:30]([CH3:29])[C:31]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:32][CH:33]=1
Reactant: Cc1nc(N)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: Cc1nc(N)ccc1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
2-(1-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (70 mg) was reacted with 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to produce 32.1 mg of 116 following reverse phase HPLC purification. MS (Q1) 478.3 (M)+
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][C@H:36]([CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[C:49]([NH:57][C:58](=[O:89])[C@@H:59]2[CH2:63][C@@H:62]([NH:64][C:65](=[O:76])[C@H:66]([OH:75])[CH2:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[CH2:61][N:60]2C(=O)[C@H]2C[C@H](NC(=O)CN)CN2)[CH:48]=1>ClCCl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[N:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[C:49]([NH:57][C:58](=[O:89])[C@@H:59]2[CH2:63][C@@H:62]([NH:64][C:65](=[O:76])[C@H:66]([OH:75])[CH2:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[CH2:61][N:60]2[C:32](=[O:34])[C@@H:31]2[CH2:35][C@@H:36]([CH2:38][NH:39][C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH:48]=1
Reactant: NCC(=O)N[C@@H]1CN[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)C1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Triethylamine (36 μL), 1-hydroxybenzotriazole (9 mg) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (49 mg) were added to a stirred solution of N-tert-butoxycarbonyl-trans-4-(N-tert-butoxycarbonylamino)methyl-L-Proline (D, 80 mg) and trans-4-((R)-2-hydroxy-4-phenylbutrylamino)-L-proline 3-quinolylamide (CompoundDlol (H), 97 mg) in dichloromethane (4 mL) at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1, v/v) to give the title compound (97 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 1.45 (s, 9H), 1.97-2.31 (m, 6H), 2.71 (m, 1H), 2.74 (m, 2H), 3.21 (m, 2H), 3.64 (m, 2H), 3.79 (m, 1H), 3.91 (m, 1H), 4.49-4.55 (m, 2H), 4.79 (m, 1H), 4.93 (m, 2H), 7.17-7.52 (m, 9H), 8.49 (s, 1H), 8.57 (s, 1H), and 10.2 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([O:13][CH3:14])[CH:9]=[C:8]1[CH2:15][CH2:16][CH2:17][CH2:18][C:7]=21)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH2:19]([N:5]1[C:6]2[C:11](=[C:10]([O:13][CH3:14])[CH:9]=[C:8]3[CH2:15][CH2:16][CH2:17][CH2:18][C:7]3=2)[CH:12]=[C:4]1[CH:1]([OH:3])[CH3:2])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2c(c3c1cc(C(C)=O)n3Cc1ccccc1)CCCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(c3c1cc(C(C)O)n3Cc1ccccc1)CCCC2
Reaction time: 2 h

Procedure:
To a solution of 2-acetyl-1-benzyl-4-methoxy-6,7,8,9-tetrahydro-1H-benz[g]indole (4.68 g, 14.0 mmol) in ethanol (50 mL) was added sodium borohydride (537 mg, 14.0 mmol). After stirring for 2 h, 10% aqueous citric acid (10 mL) was added and the mixture concentrated in vacuo. The residue was dissolved in ethyl acetate, washed once with water, and once with saturated sodium bicarbonate solution. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo to provide the title compound in quantitative yield. 1H NMR (CDCl3) δ 7.20 (m, 3H), 6.79 (d, J=7.0 Hz, 2H), 6.65 (s, 1H), 6.24 (s, 1H), 5.76 (s, 2H), 4.75 (quintet, J=6.6 Hz, 1H), 3.91 (s, 3H), 2.97 (m, 1H), 2.84 (m, 3H), 1.70 (m, 4H), 1.60 (d, J=6.6 Hz, 3H); MS ES+ m/e 336 (p+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H-].[Na+]>O>[NH2:2][C:1]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7]=1[C:8]#[N:9]
Reactant: N#CCCCCCC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#CC1=C(N)CCCC1

Procedure:
1,5-Dicyanopentane (Aldrich Chemicals) (25.0 g, 205 mmol), sodium hydride (60% oil dispersion; 8.2 g, 205 mmol) and T.H.F. (150 ml) were heated under reflux for 17 hours. After cooling, water (150 ml) was added and the upper organic layer removed, dried (Na2SO4) filtered and the solvent evaporated. Recrystallisation from hot toluene (80° C.) gave the product as beige crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.N1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27](=O)[CH2:28][CH2:29][CH2:30][OH:31])=[CH:21][CH:20]=1>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:27]([CH2:28][CH2:29][CH2:30][OH:31])[CH:26]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
4-Methoxyphenylhydrazine hydrochloride [35.0 grams (g), 0.20 moles] was added to CH3OH [50 milliters (ml)] containing pyridine (20 ml). An additional amount of CH3OH (25 ml) was added to the thick resulting slurry. 1-(4-Chlorophenyl)-6-hydroxyhexan-1,3-dione (48.2 g, 0.20 moles), was added neat, followed by more CH3OH (25 ml). The slurry was stirred at room-temperature for 1.5 hours, after which time the mixture was concentrated and taken up in CHCl3 (300 ml). The CHCl3 solution was washed with 1N HCl (300 ml), dried (Na2SO4), fitered, and concentrated. The oil was decolorized (Norit) in hot diethyl ether (Et2O) (300 ml). The Et2O solution was cooled, and crystallization from Et2O (300 ml) afforded 2 (49.4 g). From the filtrate was obtained additional 2 (9.28 g), total yield 91%, mp 87.5°-88°. NMR (CDCl3) 1.7-2.3 (m, 2H, CH2CH2CH2), 2.55 (brs, 1H, OH), 2.80 (t, 2H, J=7 Hz, CH2), 3.75 (t, 2H, J=6 Hz, CH2O), 3.77 (s, 3H, OCH3), 6.28 (s, 1H, C4 --H), 6.93 (ABq, 4H, J=12, 9, 4--OMe--C6H4), 6.9-7.3 (m, 4H, 4--Cl--C6H4); IR (KBr) 3320, 2920, 1495; MS, m/e 342 (M+), 312, 298 (100%);
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]=C)[N:4]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:3]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:31].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1[C:10]2[C:9]([CH:11]=[O:31])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:3]=1
Reactant: C=Cc1cccc2c1c(C)cn2S(=O)(=O)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2cccc(C=O)c12
Reaction time: 0.83 h
Yield: 134.5 %

Procedure:
OsO4 (29 mg, 0.12 mmol) was added to a stirred mixture of 3-methyl-1-(phenylsulfonyl)-4-vinyl-1H-indole (342 mg, 1.15 mmol; Intermediate 30) and 2,6-lutidine (268 μL, 2.3 mmol) in dioxane (15 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.984 g, 4.6 mmol) in water (5 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 50 min, combined with an earlier batch of this intermediate (followed this experimental and starting with 3-methyl-1-(phenylsulfonyl)-4-vinyl-1H-indole, 70 mg; Intermediate 30), extracted with water (30 mL) and DCM (2×30 mL). The organic layers were combined, dried, filtered and concentrated to give the title compound (463 mg, 89%) as a black solid. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[O:5][CH2:4]1.[C:12]([O-:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].CS(C)=O>O>[C:12]([O:20][CH2:2][CH:3]1[CH2:4][O:5][C:6]2=[CH:11][S:10][CH:9]=[C:7]2[O:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C([O-])c1ccccc1
Reactant: BrCC1COc2cscc2O1
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCC1COc2cscc2O1)c1ccccc1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
In a 100 mL round bottom flask 9.00 g (0.0382 mol) 2-(bromomethyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine, 6.39 g (0.0459 mol) ammonium benzoate, and 55 g DMSO were combined. A reflux condenser was equipped and the reaction was heated to 100 C overnight. After cooling to room temperature, the reaction mixture was poured into water and the product was extracted with methylene chloride. The organic fractions were combined and the solvent removed under reduced pressure. Purification by column chromatography provided 7.5 g (71% yield) of a white solid whose structure was confirmed by 1H/13C NMR and LC-MS.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([F:13])[C:6]=1[Cl:14].[BH4-].[Li+]>C1COCC1>[Cl:14][C:6]1[C:7]([F:13])=[C:8]([CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][OH:2])[C:11]#[N:12]
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CCO)c(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl(2-chloro-4-cyano-3-fluorophenyl)acetate (400 mg, 1.8 mmol) in THF (5 mL) was treated with lithium borohydride solution in THF (2M, 1.1 mL, 2.2 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with 2N HCl and the mixture was partitioned with ethyl acetate and water. The aqueous was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a CombiFlash Rf (24 gm, gradient 10-40% ethyl acetate in hexanes) to afford the title alcohol. 1H-NMR (500 MHz, CDCl3) δ ppm 1.66 (br s, 1H), 3.088 (t, J=6.4 Hz, 2H), 3.922 (t, J=6.4 Hz, 2H), 7.242 (d, J=8.1 Hz, 1H), 7.469 (dd, J=6.5 and 8.1 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:13]([O-:15])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[Cl-:18].[C:1]1([CH:7]([C:13]([O-:15])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Agent: CCOC(=O)C(C(=O)[O-])c1ccccc1
Product: [Cl-]

Procedure:
One hundred five grams (0.5 mol) of monoethyl phenylmalonate [JACS 74, 5897 (1952)] were refluxed with 119 gm of thionyl chloride in a water bath for 90 minutes, under stirring. The excess thionyl chloride was eliminated in vacuo, and the residue was distilled under reduced pressure (130° to 135° C./15 mm). An amount of 85.0 gm (75% of theory) of monoethyl phenylmalonate chloride was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:36]1([NH:46]N)[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:37]4[C:36](=[C:45]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]5=[CH:39][CH:38]=4)[NH:46][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(C(F)(F)F)cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 598.2 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][C:14]([C:17](Cl)=[O:18])=[CH:15][CH:16]=[C:9]3[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][OH:22]>>[C:1]1([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][C:14]([C:17]([O:22][CH3:21])=[O:18])=[CH:15][CH:16]=[C:9]3[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)N(c1ccccc1)C2=O
Reactant: CO
Product: COC(=O)c1ccc2c(c1)C(=O)N(c1ccccc1)C2=O
Yield: 94.7 %

Procedure:
A mixture of 137 g of N-phenyl-4-chlorocarbonylphthalimide and methanol (1.37 L) was refluxed for 1 hr. The solid which formed on cooling was collected and dried to afford 128 g (94.7%) of N-phenyl-4-carbomethoxyphthalimide, Compound 1, mp 200-207° C. Recrystallization of 91.3 g from 2 L of acetonitrile yielded 77.8 g (80.7%) of Compound 1, mp 205-207° C.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.[CH2:51]([O:53][CH2:54][CH2:55][NH2:56])[CH3:52]>CS(C)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:56][CH2:55][CH2:54][O:53][CH2:51][CH3:52])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: CCOCCN
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOCCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 130 °C
Yield: 32 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (100 mg, 0.28 mmol) was dissolved in a mixture solution of dimethylsulfoxide (2 mL) and N,N-diisopropylethylamine (1 mL), 2-ethoxyethylamine (0.051 mL, 0.49 mmol) was added thereto, followed by heating in a sealed tube for 32 hours 40 minutes (oil bath temperature: 130° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (37 mg, 0.09 mmol, 32%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:30]=2[F:29])[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Reactant: O=C(Cl)c1cccc(F)c1F
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4F)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure VII as describeed above, the acylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 2,3-difluorobenzoyl chloride gave the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cnn(C)c(=O)c2)cc1
Agent: BrB(Br)Br
Product: Cn1ncc(-c2ccc(O)cc2)cc1=O

Procedure:
5-(4-Hydroxyphenyl)-2-methyl-2H-pyridazin-3-one was prepared from 5-(4-methoxy-phenyl)-2-methyl-2H-pyridazin-3-one with BBr3 using the procedure described in Example 86 Step 2; Mp 296-8° C.; MS m/z 203 (M+H).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:9]=[CH:8][C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[C:12]1([C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N+]=[N-])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[C:1]([O:11][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:10])[C:2]1[CH:9]=[CH:8][C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(O)c(O)c1
Reaction time: 2 h
Yield: 55.9 %

Procedure:
Ethyl acetate (2.5 ml) was mixed with 50.0 mg of protocatechuic acid and 63.0 mg of diphenyldiazomethane to form a solution. The solution was left over at room temperature for 2 hours. Diphenyldiazomethane (25.8 mg) was added further and the resultant mixture was left over at room temperature for 2 hours. The pale reddish purple-colored reaction solution was concentrated under reduced pressure, and the colorless residue obtained was purified by chromatography on a silica gel column {developer: chloroform - chloroform-methanol (30:1)} to obtain 58.1 mg of the titled compound as a colorless syrup. EIMS: m/z 320 (M+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:11]C)[C:8]=1[O:9]C.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)[CH:6]=[C:7]([OH:11])[C:8]=1[OH:9]
Reactant: COc1cc(CCc2ccc(Nc3ccccc3C(=O)O)cc2)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccccc1Nc1ccc(CCc2cc(O)c(O)c(O)c2)cc1
Yield: 55.3 %

Procedure:
The title compound was prepared from 2-{4-[2-(3,4,5-trimethoxy-phenyl)-ethyl]phenylamino}benzoic acid (0.50 g, 1.23 mmol) in CH2Cl2 (40 mL) and BBr3 (10 mL, 1M in CH2Cl2, 10.0 mmol) using the procedure described in Example 4, Step D. This procedure yielded a green solid, 0.25 g (0.68 mmol, 65%) of the desired product. mp: 160.0-162.0° C.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][NH:65][C:64](=[O:67])[CH2:63]2)[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][NH:65][C:64](=[O:67])[CH2:63]4)[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CN1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CNC(=O)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 77.1 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (6.67 g, 11.2 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer A (3.9 g, 10.7 mmol, compound of Reference Example 18-4) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer A (6.01 g, yield: 77.1%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O-:5])=[O:4].[Ca+2].O[CH:12](CCSC)C([O-])=O.CO.OS(O)(=O)=O>C(Cl)Cl>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH3:12])=[O:4]
Reactant: CSCCC(O)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(O)CCSC
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Commercial calcium 2-hydroxy-4-(methylthio)butyrate (20 g, 0.12 mol) was suspended in 250 ml CH2Cl2. CH3OH (15 ml, 0.36 mol) was added and the mixture cooled to 10° C., at which point H2SO4 (3.7 ml, 0.07 mol) was added. An obvious physical change in the slurry was noted. The mixture was heated at reflux for 60 minutes, by which time tlc indicated reaction was nearly complete. As a matter of convenience, the reaction mixture was stirred 64 hours at room temperature, at which time insoluble byproducts were removed by filtration. The filtrate was washed with 150 ml each of saturated NaHCO3 and brine, dried (MgSO4) and stripped to yield title product as an oil; tlc Rf 0.8 (ethyl acetate)0.25 (3:1 hexane:ethyl acetate).