Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(Cl)=O.[C:6]1([CH2:12][CH:13]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:14][O:15][CH2:16][C:17](O)=[O:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([N:33](CC)CC)C.N>ClCCl>[C:25]1([CH2:24][O:23][C:21](=[O:22])[NH:20][CH:13]([CH2:14][O:15][CH2:16][C:17]([NH2:33])=[O:18])[CH2:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)COCC(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: NC(=O)COCC(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Methylchloroformate, 0.89 g (0.0094 mol) is added dropwise with stirring to a solution of 2.75 g (0.008 mol) of (±)-[3-phenyl-2-[[(phenylmethoxy)carbonyl]amino]propoxy]acetic acid and 0.96 g (0.0095 mol) of triethylamine in 100 ml of dichloromethane at -5°-10° C. The mixture is stirred for 30 minutes at -5° C., allowed to reach 0° C. and saturated with ammonia for 5 minutes. The mixture is allowed to reach room temperature and stirred for one hour, the solvent is evaporated in vacuo, the residue dissolved in 200 ml of dichloromethane, washed with a saturated aqueous solution of sodium chloride, 2×200 ml, the dichloromethane layer separated, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (±)-phenylmethyl-[1-[(2-amino-2-oxoethoxy)methyl]-2-phenylethyl]carbamate, 2.5 g; mp 135°-137°.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]([C:26]1[CH:27]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:33](=[O:34])[CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:27]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cccc(Oc2ccccc2)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-phenoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.36-7.43 (m, 3H), 7.14-7.18 (m, 2H), 7.00-7.08 (m, 3H), 6.91 (dd, J=8.2, 2.5 Hz, 1H), 3.80-3.85 (m, 4H), 3.67 (s, 2H) 3.06-3.12 (m, 4H); MS (ESI+) M/Z 457 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@@H:3]([NH:20]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[NH:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:6][CH:5]=1.N1CCCCC1>C(O)C>[NH2:20][C@@H:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[O:19])=[CH:8][CH:9]=1)[CH:2]([CH3:38])[CH3:1]
Reactant: CC(C)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(C(=O)NOC2CCCCO2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)[C@@H](N)c1ccc(C(=O)NOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
To a 1-L round-bottom flask was added (9H-fluoren-9-yl)methyl (1R)-2-methyl-1-(4-(tetrahydro-2H-pyran-2-yloxycarbamoyl)phenyl)propylcarbamate (10.0 g, 0.0195 mol), ethanol (588 mL), and piperidine (51.7 mL). The solution was stirred at rt for 16 h, then concentrated to give a solid. Flash column chromatography gave 4-((R)-1-amino-2-methylpropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide (2.3 g, 41%). 1H NMR (CDCl3, 400 MHz) δ7.59 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 5.00 (m, 1H), 3.95 (m, 1H), 3.59 (m, 2H), 1.83 (m, 4H), 1.57 (m, 3H), 1.20 (m, 1H), J=6.8 Hz, 3H), 0.67 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.[CH2:23](O)C=C>C(N(CC)CC)C>[CH2:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])[CH:1]=[CH2:23]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C=CCO
Agent: FB(F)F
Solvent: CCN(CC)CC
Product: C=CCOCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
Using the procedure of Step A of Example 8, 27.2 g of 7-amino-cephalosporanic acid, 170 ml of the etherate of boron trifluoride, 136 ml of allyl alcohol and 115 ml of triethylamine were reacted and the 9 g of raw product was purified successively twice with hot hydrochloric acid and ammonium hydroxide to obtain 4.72 g of 3-allyloxymethyl-7-amino-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:34])[NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([CH3:17])[N:13]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=4)[N:21]=[C:20]([NH2:33])[N:19]=3)[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:35][NH2:36]>C(O)C>[C:1]1([CH2:7][O:8][C:9](=[O:34])[NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([CH3:17])[N:13]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]5[C:27]([C:30]([NH2:31])=[N:35][NH:36]5)=[CH:28][CH:29]=4)[N:21]=[C:20]([NH2:33])[N:19]=3)[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Product: C[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
To phenylmethyl{(3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinyl}carbamate (57 mg, 0.124 mmol) in ethanol (3 mL) was added hydrazine (0.182 mL, 3.71 mmol) into a 5 mL sealable vial. The solution was then capped and heated at 100° C. overnight. The reaction was then concentrated, re-dissolved in 2 mL of DMSO, and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (30 ml/min, 33% CH3CN/H2O, 0.1% TFA to 58% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined, and the volume was reduced to remove the CH3CN. To the resulting aqueous mixture was added 5 mL of saturated aqueous NaHCO3, and then extracted 3× with EtOAc. The organics were then combined, washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound (37 mg) as a light yellow solid. LC-MS (ES) m/z=473 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=6.8 Hz, 3H), 1.66 (m, 4H), 2.67 (dt, J=3.7, 1.8 Hz, 1H), 3.38 (bs, 1H), 4.50 (bs, 1H), 4.73 (bs, 1H), 5.06 (d, J=5.3 Hz, 2H), 5.39 (s, 2H), 6.04-6.20 (bs, 2H), 6.58 (bs, 1H), 7.30-7.46 (m, 6H), 7.55 (d, J=8.3 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 11.52 (bs, 1H).
Reaction SMILES: [CH2:1]([CH:19]1[CH2:33][NH:32][C:31](=O)[CH2:30][N:29](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][CH2:27][N:26](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24][N:23](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:22][C:21](=O)[NH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[CH2:1]([CH:19]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCC1CNC(=O)CN(S(=O)(=O)c2ccc(C)cc2)CCN(S(=O)(=O)c2ccc(C)cc2)CCN(S(=O)(=O)c2ccc(C)cc2)CC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCC1CNCCNCCNCCNCCN1
Reaction time: 1 h
Yield: 62 %

Procedure:
To a slurry of 5-octadecyl-1,10,13-tris(p-toluenesulfonyl)-1,4,7,10,13-pentaazacylopentadecane-3,8-dione prepared as in Example 28H (4.00 g, 4.18 mmol) in anhydrous THF (100 ml) under a dry argon atmosphere was added a solution of lithium aluminum hydride in anhydrous THF (105 ml--1.0M, 105 mmol). The resulting solution was refluxed for 40 h. The mixture was quenched by the dropwise addition at 0° C. of H2O (3.25 ml), then 15% NaOH (3.25 ml) and finally H2O (9.60 ml). The resulting slurry was stirred for 1 h, THF (200 ml) was added and the white solid was filtered. The solid was washed with THF (200 ml) and then hot THF (300 ml). The filtrate and washings were combined and the solvent was removed in vacuo. The crude product was purified by recrystallization from THF--ethyl ether and then hexanes to give 1.21 g (62% yield) of the product as a white crystalline solid: mp 99°-100° C.; 1H NMR (CDCl3) δ 0.88 (t, J=6.7 Hz, 3 H), 1.25 (m, 33 H), 1.52 (m, 1 H), 1.66 (br s, 5 H), 2.34 (m, 1 H), 2.72 (m, 18 H); Exact mass (M+H)+ : calcd., 468.5005; found, 468.5034 (C28H62N5).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][CH2:12][C:13](=[O:16])[CH2:14][CH3:15].[C:17]([O:24][CH2:25][CH3:26])(=[O:23])[C:18]([O:20]CC)=O>CCOCC>[CH2:25]([O:24][C:17](=[O:23])[C:18](=[O:20])[CH:12]([CH3:11])[C:13](=[O:16])[CH2:14][CH3:15])[CH3:26]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=O)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(C)C(=O)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
LHMDS solution (35.7 mL, 35.7 mmol, 1M in hexanes) was added to 200 mL of diethyl ether and the mixture was cooled to −78° C. 3-Pentanone (3.8 mL, 35.7 mmol) dissolved in 50 mL of ether was added dropwise, and the resulting mixture was stirred at −78° C. for 1 h. Diethyl oxalate (5.3 mL, 39.3 mmol) was added dropwise, and the cooling bath was removed and the mixture was allowed to come to room temperature. After the mixture was stirred for 16 h, the resulting precipitate was isolated by filtration. The solid was partitioned between CH2Cl2 (150 mL) and 1M hydrochloric acid (100 mL), and the aqueous layer was extracted with additional CH2Cl2. The combined organic layer was dried over MgSO4 and concentrated to give 6.37 g of the title compound. MS: (−) m/z 185.28 (M−1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)=[CH:3][CH:2]=1.[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH2:28])=[N:20][CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH:28][C:11]2[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:13][N:12]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CSc1ncc(Cc2ccncc2)c(=O)[nH]1
Reactant: NCCSCc1ncccc1Br
Product: O=c1[nH]c(NCCSCc2ncccc2Br)ncc1Cc1ccncc1

Procedure:
5-(4-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.1 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.15 g) according to the procedure of Example 2. The reaction mixture was triturated under hot water to give 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone. This product was acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue crystallised from ethanol to give the title compound m.p. 211°-215° (decomp).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][N:10]1[C:14]([C:15]2[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[S:18][CH:19]=2)=[CH:13][CH:12]=[N:11]1>O1CCCC1>[Br:8][C:13]1[CH:12]=[N:11][N:10]([CH3:9])[C:14]=1[C:15]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[S:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccnn2C)cs1
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(Br)cnn2C)cs1
Temperature: 70 °C
Yield: 82.7 %

Procedure:
NBS (747 mg, 4.20 mmol) was added in portions to a 50 mL sealed tube reactor containing methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (860 mg, 3.48 mmol) [prepared according to the procedure of Example 37] in Tetrahydrofuran (THF) (17 mL) at room temperature. The mixture was heated to 70° C. for 1.5 hours, cooled to room temperature and partitioned between CHCl3 and H2O. The organic layer was dried with Na2SO4, adsorbed onto silica and purified via column chromatography (20-40% EtOAc/hexanes) affording the title compound (867 mg, 83%): LC-MS (ES) m/z=303 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH2:17])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl.O>[C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([Br:19])=[CH:21][CH:22]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CN)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
2-{[4-(Aminomethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 13 and 4-bromobenzoic acid (2.51 g) was dissolved in dichloromethane (50 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (2.99 g) and hydroxybenzotriazole (HOBT) monohydrate (2.39 g) were successively added thereto, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (3.5 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH:16]=[N:17][O:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:42][Si:43]([C:46]#[CH:47])([CH3:45])[CH3:44]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:47]#[C:46][Si:43]([CH3:45])([CH3:44])[CH3:42])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(C)(O)CON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)c(F)c1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl-propoxyimino)-methyl]-benzamide (14.6 mg, 0.025 mmol) prepared in Example 12 was dissolved in anhydrous tetrahydrofuran (2.0 ml). Next, (PPh3)2PdCl2 (20,867-1, Sigma-Aldrich, Inc.) (1.0 mg, 0.00127 mmol), copper iodide (2.0 mg, 0.0094 mmol), N,N-diisopropylethylamine (10 μL, 0.057 mmol), and trimethylsilylacetylene (35 μL, 0.25 mmol) were added thereto at room temperature, and the mixture was stirred at 50° C. overnight.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:3]1[NH:2][N:1]=[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:10][CH:11]=2)[NH:4]1
Reactant: O=C([O-])O
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2ccc(-c3nnn[nH]3)cc2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2ccc(C3=NNN(C)N3)cc2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.2 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide (32 mg, 0.0524 mmol) in acetone (5 mL), sodium bicarbonate (45 mg, 0.6 mmol) and dimethyl sulfate (0.11 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (18 mg) and the other regioisomer (3 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>CC(N(C)C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 90 °C

Procedure:
Cesium carbonate (14.19 g, 43.56 mmoles, 2 equivalents) was added to a stirred solution of 4-amino-3-nitrophenol (3.35 g, 21.78 mmoles, 1 equivalent) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (6.69 g, 23.96 mmoles, 1.1 equivalent) in anhydrous DMA (30 ml). The stirred reaction mixture was then heated to 90° C. (thermostatically controlled heating mantle) for 22 hours. The reaction mixture was then allowed to cool to room temperature and was filtered through a plug of Celite. The reaction flask and the Celite were then washed with ethyl acetate (250 ml). The organic solution was then transferred to a separatory funnel and extracted with additional ethyl acetate (3×200 ml). The combined ethyl acetate solution was then washed with water (2×100 ml), saturated sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[CH:6]1([C:12](OC)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1C=CC=CC=1>[CH:6]1([C:12]([CH2:4][C:3]#[N:5])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC#N
Reactant: COC(=O)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CCC(=O)C1CCCCC1
Temperature: 25 °C

Procedure:
60% Sodium hydride (oil suspension) is added to benzene (90 ml) and the mixture is refluxed under heating. Acetonitrile (23 ml) dissolved in benzene (23 ml) is added and the mixture is refluxed for 1 hour. A solution of methyl cyclohexanecarboxylate (63 g) dissolved in benzene (70 ml) is dropwise added and the mixture is refluxed under heating for 5 hours. After the completion of the reaction, the mixture is cooled to room temperature and poured into ice water (200 ml). The organic layer is removed and the aqueous layer is washed with isopropyl ether. The aqueous layer is adjusted to pH 2 with conc. hydrochloric acid and extracted 3 times with isopropyl ether. The extract is dried over anhydrous magnesium sulfate and the solvent is distilled away under reduced pressure to give 34 g of cyanomethyl cyclohexyl ketone. The obtained cyanomethyl cyclohexyl ketone (34 g), morpholine (17.6 ml) and ethyl methyl ketone (18 ml) are dissolved in ethanol (150 ml) and sulfur (6.47 g) is suspended. The suspension is refluxed under heating for 10 hours. After the completion of the reaction, the solvent is distilled away under reduced pressure.
Reaction SMILES: C(N(CC)CC)C.Br.[NH2:9][C:10]1[N:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH:12]=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[Br:18][C:15]1[CH:14]=[C:11]([CH2:12][NH:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:10]([NH2:9])=[N:17][CH:16]=1
Reactant: Nc1ncc(Br)cc1C=O
Reactant: CN1CCN(CCN)CC1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCN(CCNCc2cc(Br)cnc2N)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (1.0 mL, 7.09 mmol) was added to a solution of 2-amino-5-bromonicotinaldehyde hydrobromide (1.0 g, 3.54 mmol) in methanol (24 mL) at room temperature. The reaction mixture was stirred for 10 minutes prior to the addition of 2-(4-methylpiperazin-1-yl)ethanamine (558 mg, 3.90 mmol). The reaction mixture was then stirred overnight and cooled to 0° C. Sodium borohydride (201 mg, 5.32 mmol) was added portionwise at 0° C. and the reaction mixture was allowed to reach room temperature and stirred for 4 hours. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (10:0:0.1 to 9:1:0.1) as eluent. The title product was obtained as a yellow solid (560 mg, 48%).
Reaction SMILES: [C:1]([Cl:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][NH2:22])=[N:13][N:12]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Cl:9][C:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]2=[N:13][N:12]=[C:11]([C:20]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:21]2[N:22]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Reaction time: 8 h
Yield: 74.1 %

Procedure:
128 μl (1.1 mmol) of benzoyl chloride was added to a xylene solution (10 ml) of 194 mg (1.0 mmol) of (4-chloro-phthalazin-1-yl)-hydrazine and 182 μl (1.3 mmol) of triethylamine, and stirred overnight under reflux. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with chloroform. The organic layer was washed with saturated saline solution, dried and concentrated under reduced pressure to obtain 208 mg (yield: 74%) of 6-chloro-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine as a yellow solid.
Reaction SMILES: CN(C(N[C@H](C(O)=O)C(C)C)=[O:13])CC1N=C(C(C)C)SC=1.[NH2:22][C@@H:23]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:24][C@H:25](O)[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[NH2:22][C@H:23]([C@@H:24]([OH:13])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 126.3 %

Procedure:
A solution of 70 mg (0.223 mmol) of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 79 mg (0.186 mmol) of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmol) of N-ethyl-N'-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 97:3 CH2Cl2 :CH3OH to provide 100 mg (74%) of the desired compound (Rf 0.4, 95:5 CH2Cl2 :CH3OH) as a solid. 1H NMR (d6 -DMSO) δ0.73 (d, J=7 Hz, 6H), 1.30 (d, J=7 Hz, 6H), 1.45 (m, 2H), 1.87 (m, 1H), 2.5-2.7 (m, 4H), 2.87 (s, 3H), 3.23 (heptet, J=7 Hz, 1H), 3.57 (m, 1H), 3.81 (m, 1H), 3.93 (m, 1H), 4.15 (m, 1H), 4.44 (AA', 2H), 4.62 (d, J=6 Hz, 1H), 5.13 (AA', 2H), 6.01 (d, J=9 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 7.1-7.2 (m, 11H), 7.68 (d, J=9 Hz, 1H), 7.85 (s, 1H), 9.05 (s, 1H). Mass spectrum: (M+H)+ =721.Anal. Calcd for C37H48N6O5S2.0.5H2O: C, 60.88; H, 6.77; N, 11.51.Found: C, 60.68; H, 6.53; N, 11.36.