Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:11](O)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](O)=[O:15].C(OCC)C>O>[C:11]1(=[O:21])[N:1]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: Nc1n[nH]c2ccccc12
Reactant: O=C(O)c1ccccc1C(=O)O
Solvent: O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
5.0 g of the same 3-aminoindazole as Example 1 and 6.68 g of phthalic acid were added to 50 ml of dixoane, and the mixture was stirred for 5 hours at 120° C. The mixture was condensed under reduced pressure, 30 ml of diethyl ether was added and the mixture was stirred under cooling with ice and water for 30 minutes to separate crystals. The crystals were obtained by filtration and dried under reduced pressure to give 8.6 g of 3-phthalimidoindazole in a yield of 87%.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:8]([NH:1][C@H:2]([C:3]([NH2:5])=[O:4])[C:6]#[N:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CC(N)C(N)=O
Solvent: c1ccncc1
Product: N#C[C@H](NC(=O)c1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-amino-2-cyanacetamide (8 g, 0.08 mol) in pyridine (10 mL) is added a solution of benzoyl chloride (0.08 mol) in pyridine (15 mL) and the mixture is stirred at rt for 40 min. It is then concentrated under reduced pressure to provide crude product which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([OH:22])[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:27]C([O-])(C)C.[K+].CI>C1COCC1>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]([CH3:27])[C:20](=[O:22])[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc2nc(O)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(sc(=O)n2C)c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a solution of (S)-2-(7-bromo-2-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67B) (40 mg, 0.090 mmol) in THF (1 ml) was added KOtBu (0.14 ml, 0.135 mmol, 1M in THF) slowly at −78° C. After 15 min, MeI (8.5 ul, 0.135 mmol) was added at −78° C. and stirred at −78° C. for 15 min. Then the reaction was reacted at rt for 3 hs. The reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 67C (30 mg, 73%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(tetrahydropyran-4-yl)-ethanol (1.5 g, 11.5 mmol) in 10 mL of CH2Cl2 and 7 mL of pyridine was added p-toluenesulfonyl chloride (2.4 g, 12.7 mmol) portion wise over 15 minutes. The mixture stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 302 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6][CH2:5]1.[CH3:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[N:13]1[C:19]1[N:23]2[CH:24]=[C:25](F)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1>CN(C=O)C>[CH3:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[N:13]1[C:19]1[N:23]2[CH:24]=[C:25]([O:10][CH:7]3[CH2:8][CH2:9][CH:4]([NH2:3])[CH2:5][CH2:6]3)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(N)CC3)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.24 g, 6.00 mmol) was added to a stirred solution of trans-4-amino cyclohexanol (0.24 g, 2.08 mmol) in anhydrous DMF (8 mL) at RT under an argon atmosphere. The reaction mixture was stirred at RT for 30 min, then Intermediate 3c (0.50 g, 2.01 mmol) in anhydrous DMF (7 mL) was added and stirred at 60° C. for 4 h. After cooling, the reaction mixture was quenched by careful addition of a saturated aqueous solution of NH4Cl and water (1:1) and extracted with DCM (3×50 mL). The combined organic layers were washed with water followed by brine, dried and concentrated in vacuo. The resultant residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to afford the title compound (0.61 g, 88%) as a brown oil. LCMS (Method 3): Rt 2.19 min, m/z 344 [MH+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:30][CH:31](Br)[CH2:32][CH2:33][CH3:34])(=[O:29])[CH3:28].[I-].[Na+]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:31]([O:30][C:27](=[O:29])[CH3:28])[CH2:32][CH2:33][CH3:34])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCCC(Br)OC(C)=O
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Product: CCCC(OC(C)=O)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12

Procedure:
In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer) was reacted with 1-bromobutyl acetate in the presence of sodium iodide to give 1-acetoxybutyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 100°-105° C. (decompn.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.C1(C)C=CC=CC=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.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.C(O)C>[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]4[CH2:26][CH2:25][CH2:24][O:23]4)=[CH:16][CH:15]=2)[CH2:6][CH2:5]3)[CH:36]=1
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Reactant: OB(O)c1cccnc1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCc2cc(-c3cccnc3)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.00 g), toluene (10 ml) and Pd(PPh3)4 (2.69 g) was admixed with 3-pyridylboronic acid (0.28 g), ethanol (3 ml) and cesium carbonate solution (1.2 ml; 2 M in water). The mixture was boiled at reflux for 7 hours. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product was thus obtained with the molecular weight of 428.54 (C27H28N2O3); MS (ESI): 429 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12])=[O:3].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.N1CCCC1>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:2](=[O:3])[CH2:1][C:17]3([O:12][C:5]=2[CH:6]=1)[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: CN1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)OC1(CCN(C)CC1)CC2=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 98.7 %

Procedure:
To a stirred solution of 2-hydroxy-4-methoxyacetophenone (4.08 g, 24.58 mmol) in anhydrous methyl alcohol (60 cm3) under an atmosphere of dry nitrogen was added 1-methyl-4-piperidinone (3 cm3, 24.58 mmol) followed by pyrrolidine (4 cm3, 47.92 mmol) and the solution was heated to reflux. After 7 h, a further portion of 1-methyl-4-piperidinone (0.6 cm3, 4.76 mmol) was added and the mixture was heated to reflux for a further 4.5 h. It was then allowed to cool to room temperature before the volatile fractions were removed under reduced pressure. The resulting oil was treated with dichloromethane (100 cm3), washed with water (5×100 cm3), dried over anhydrous sodium sulfate to afford a dark viscous oil (6.33 g, 24.25 mmol) which partially crystallised on standing over a long period of time.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:18](Cl)(=[O:20])=[O:19])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12].N1C=CC=CC=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36].CCCC(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:18](=[O:20])(=[O:19])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35](=[O:37])(=[O:36])[NH2:38])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2S(N)(=O)=O)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl]amino]benzenesulfonyl chloride (110 mg, 0.3 mmol) in DCM (5 ml) and pyridine (30 μl, 0.33 mmol) was added DMAP (˜2 mg) followed by 2-aminobenzenesulfonamide (52 mg, 0.3 mmol). The resulting mixture was stirred at RT for 18 h. The solution was concentrated and partitioned between ethyl acetate (6 ml) and 1M HCl (5 ml). The organic layer was separated, washed with saturated NaHCO3, dried (MgSO4) and evaporated to give a gum which was dissolved in a small amount of ethyl acetate and then iso-hexane was added to precipitate the title compound as a solid. LCMS 502.2 (M+H), Rf 7.64 min. [Column: HYPERSIL ODS; Flow Rate: 1.5 ml/min; Detector Wavelength: 254 nm; Solvent A: 0.1% Formic Acid in Water; Solvent B: 0.1% Formic Acid in Acetonitrile; Gradient: 5-95% B]
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[C:19]1([C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:30]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccccc2)n1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with 6-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 389.14 g/mol.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][C@@H:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C[C@@H]1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (91 mg, 82%), MS (ISP) m/z=443.6 [(M+H)+], mp 183.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (S)-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:30])[CH:18]([CH3:29])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:23]3[C:22]([F:28])=[CH:21][C:20]([CH2:19][CH:18]([CH3:29])[C:17]([OH:30])=[O:16])=[CH:25][C:24]=3[F:26])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCC1
Product: CC(Cc1cc(F)c(OCc2cccnc2SC2CCC2)c(F)c1)C(=O)O
Yield: 31.5 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.045 g, 0.21 mmol) obtained in Step C of Preparation Example 23 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (49 mg, 0.21 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.026 g, 31%).
Reaction SMILES: C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]([C:60](=[O:71])[C:61]([O:63]CC1C=CC=CC=1)=[O:62])[C:24]1[CH:59]=[CH:58][C:27]([CH2:28][C@@H:29]([C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[C:44]([C:54]([O:56][CH3:57])=[O:55])=[C:45]([OH:53])[C:46]3[C:51]([CH:52]=2)=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:36])[NH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.[Pd]>[C:61]([C:60]([N:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([OH:16])=[O:14])[C:24]1[CH:59]=[CH:58][C:27]([CH2:28][C@@H:29]([C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[C:44]([C:54]([O:56][CH3:57])=[O:55])=[C:45]([OH:53])[C:46]3[C:51]([CH:52]=2)=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:36])[NH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1)=[O:71])([OH:63])=[O:62]
Reactant: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OCc2ccccc2)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)NCCCCOc1cc2ccccc2c(O)c1C(=O)OC
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)O)c2ccccc2C(=O)O)cc1)C(=O)NCCCCOc1cc2ccccc2c(O)c1C(=O)OC
Reaction time: 4 h
Yield: 56.1 %

Procedure:
To methyl 3-(4-{[4-{{2-[(benzhydryloxy)carbonyl]phenyl}[(benzyloxy)(oxo)acetyl]amino}-N-(methoxycarbonyl)-L-phenylalanyl]amino}butoxy)-1-hydroxy-2-naphthoate (32 mg, 0.033 mmol) in dioxane (1 mL) under N2 was added 10% Pd—C (5 mg) followed by 60% HClO4 (1 drop). The reaction was stirred under 1 atmosphere of H2 for 4 hours and filtered. The solution was applied to a reverse phase HPLC column and purified by eluting with 0% to 70% gradient of acetonitrile/0.1% aqueous trifluoroacetic acid to provide the titled compound (13 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:30])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133, 319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol) in 5 mL CH2Cl2 was cooled to 0° C. and N-bromosuccinimide (309.0 mg, 1.74 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 350.0 mg (84%), was isolated by column chromatography (2-3% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].[CH3:13]OC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CB(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1nc(C)cnc1N

Procedure:
3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (1.0 g), palladium acetate (0.101 g), and S-Phos (2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl) were placed in a flask, with toluene (15 mL) and water (3 drops). Methyl boronic acid (0.394 g) and potassium phosphate (1.71 g) were added and the reaction mixture was refluxed for 24 hours. After allowing the reaction mixture to cool, the mixture was diluted with aqueous hydrochloric acid (1M) and extracted with ethyl acetate. The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent: diethyl ether) to give 3-amino-6-methylpyrazine-2-carboxylic acid methyl ester as a yellow solid (0.114 g).
Reaction SMILES: C(OC([O:8][CH2:9][C@@:10]1([C:24]#[CH:25])[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH:12]=[CH:11]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:24]([C@:10]1([CH2:9][OH:8])[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH:12]=[CH:11]1)#[CH:25]
Reactant: C#C[C@@]1(COC(=O)OC(C)(C)C)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#C[C@@]1(CO)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 37 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
(2R,5R)-5-t-Butoxycarbonyloxymethyl-5-ethynyl-2-(thymin-1-yl)-2,5-dihydrofuran (5 g) was added to a glass reactor under nitrogen, and methanol (150 g) and potassium carbonate (9.9 g) were added. The mixture was stirred at 37° C. for 4 hours. The reaction mixture was concentrated and dissolved in water. Aqueous sodium hydroxide and toluene were added to the solution under stirring for phase separation, and hydrochloric acid and methyl ethyl ketone were added to the aqueous layer, followed by stirring for further phase separation. The thus-separated organic layer was concentrated, and the residue was purified through recrystallization from ethanol and heptane, to thereby yield 3.2 g of 4′-ethynyl-2′,3′-didehydro-3′-deoxythymidine (yield: 91%, β/α=>99/1). The 1H-NMR data of the compound are the same as those of the compound produced in Example 3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20](=[S:22])[NH2:21])=[N:14]2)[CH:7]=1)[CH3:2].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)=O>CCO>[CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[S:22][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[N:21]=3)=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(C(N)=S)ccc2=O)c1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Solvent: CCO
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3nc(-c4ccncc4)cs3)ccc2=O)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
100 mg (0.30 mmol) of ethyl[3-(6-oxo-3-thiocarbamoyl-6H-pyridazin-1-yl-methyl)phenyl]carbamate are suspended in 2 ml of EtOH, and 101 mg (0.36 mmol) of 2-bromo-1-(4-pyridinyl)ethanone hydrobromide are added. The reaction mixture is stirred at 80° C. for 15 h. The precipitate formed is filtered off with suction and washed with ethanol and dried in vacuo. The crude product is purified by means of preparative HPLC.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:40]=[C:39]([C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)[O:38][N:37]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[N:40]=[C:39]([C:41]3[CH:45]=[CH:44][S:43][CH:42]=3)[O:38][N:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1noc(-c2ccsc2)n1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2noc(-c3ccsc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.23 g), potassium carbonate (0.94 g), 3-(chloromethyl)-5-(3-thienyl)-1,2,4-oxadiazole (0.75 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.79 g, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:22][CH3:23])[C:14]([NH:16][C:17]([CH3:21])([CH3:20])[CH:18]=O)=[O:15])=[CH:7][CH:6]=2.N1C=CC=CC=1.Cl.[CH2:31]([O:35][NH2:36])[CH2:32][CH2:33][CH3:34].C([O-])(O)=O.[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:22][CH3:23])[C:14]([NH:16][C:17]([CH3:21])([CH3:20])[CH:18]=[N:36][O:35][CH2:31][CH2:32][CH2:33][CH3:34])=[O:15])=[CH:7][CH:6]=2
Reactant: CCCCON
Reactant: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CCCCON=CC(C)(C)NC(=O)C(Oc1ccc2ncc(Br)cc2c1)SC
Yield: 97.5 %

Procedure:
2-(3-Bromo-quinolin-6-yloxy)-N-(1,1-dimethyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide (0.1 g) from Stage 2, Step 2 above, pyridine (0.022 ml) and O-n-butyl-hydroxylamine hydrochloride (0.035 g) in methanol (5 ml) were stirred at rt for 3 hours. The reaction mixture was diluted with ethyl acetate and poured onto sat. NaHCO3 (30 ml). The two phases were separated and the aqueous layer was extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over magnesium sulphate, filtered and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate 3:1) to give 2-(3-bromo-quinolin-6-yloxy)-N-(2-butoxyimino-1,1-dimethyl-ethyl)-2-methylsulfanyl-acetamide as white solid (0.115 g). 1H NMR (CDCl3) δ ppm: 8.81 (1H, d); 8.24 (1H, d); 8.04 (1H, d); 7.71 (1H, s); 7.45 (1H, dd); 7.39 (1H, s); 7.17 (1H, d); 5.64 (1H, s); 4.08 (2H, t); 2.19 (3H, s); 1.68-1.58 (8H, m); 1.45-1.36 (2H, m), 0.94 (3H, t).