Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([Br:7])[CH:4]=[N:3]1.[N:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[Br:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:15])[CH:6]=1
Reactant: On1cc(Br)cn1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(On1cc(Br)cn1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-4-bromopyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (85%, crystals).
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)[CH:12]=O)[CH3:7].C(OP([CH2:31][C:32](=[O:43])[NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)(=O)OCC)C.O.[OH-].[Li+]>C(OCC)(=O)C.O>[CH2:6]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:31]/[C:32]([NH:33][CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36][CH2:35]2)=[O:43])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)[CH3:7]
Reactant: CCOP(=O)(CC(=O)NC1CCc2ccccc21)OCC
Reactant: CCOc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 22.8 %

Procedure:
To a THF (8 mL) solution of 3-ethoxy-4-(4-methyl-1H-imidazole-1-yl)benzaldehyde (60 mg), (indan-1-ylcarbamoylmethyl)phosphonic acid diethyl ester (81 mg) and lithium hydroxide monohydrate (22 mg) were added, and the reaction mixture was agitated at room temperature for 14 hours. Water and ethyl acetate were added to the reaction solution after the reaction ended, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 1:4), and 23 mg (23%) of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: O1C=CC([NH:6][CH2:7][C:8]#[N:9])=C1.C(N(CC)CC)C.[CH3:17][C:18]1[S:19][C:20]([C:24](Cl)=[O:25])=[C:21]([CH3:23])[N:22]=1.[O:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:17][C:18]1[S:19][C:20]([C:24]([NH:9][CH:8]([C:29]2[CH:30]=[CH:31][O:27][CH:28]=2)[C:7]#[N:6])=[O:25])=[C:21]([CH3:23])[N:22]=1
Reactant: N#CCNc1ccoc1
Reactant: C1CCOC1
Reactant: Cc1nc(C)c(C(=O)Cl)s1
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(C(=O)NC(C#N)c2ccoc2)s1
Reaction time: 3 h

Procedure:
To a solution of 2-(3-furyl)aminoacetonitrile (1.46 g; 12 mmol) and triethylamine (1.20 g; 12 mmol) in tetrahydrofuran (30 ml) was added slowly a solution of 2,4-dimethylthiazole-5-carbonyl chloride (1.75 g; 10 mmol) in tetrahydrofuran (10 ml) with ice-cooling. After the addition, the mixture was turned to room temperature and stirring was continued for 3 hours. The solvent was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude oil. The oil was purified by silica-gel column chromatography (eluent:n-hexane:ethyl acetate=2:1 by volume) to give 1.93 g of 2-(2,4-dimethylthiazole-5-carboxamido)-2-(3-furyl)acetonitrile as colorless crystals. m.p., 94°-96° C. Yield, 74%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24]CC)=[O:23])=[CH:10]1.[C:27](#[N:29])[CH3:28]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([NH:29][CH:27]3[CH2:2][CH2:3][NH:9][CH2:10][CH2:28]3)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(F)c(F)cc2c1=O
Reactant: CC#N
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(NC3CCNCC3)c(F)cc2c1=O
Reaction time: 2 h
Yield: 74 %

Procedure:
Ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-naphthyridine-3-carboxylate (0.5 g, 1.3 mmole) and (3-N-ethoxycarbonyl)aminopyrrolidine (0.3 g, 1.74 mmole) in acetonitril (5 ml) was stirred at 80° C. for 3 hr and cooled. Solvent was concentrated to dryness and 5% aqueous NaOH (10 ml) was added to reaction mixture and stirred for 2 hr, acidified with conc. HCl solid separated was filtered, dried to furnish the required product. Yield 74%, m.p >320° C., C20H17F3N4O3, m/z 419. (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10]C(=O)C.O.C(O)CC.[Cl-]>Cl.CC(O)=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10]
Reactant: CC(=O)Nc1c(Cl)ccc(C)c1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCCO
Solvent: O
Product: Cc1ccc(Cl)c(N)c1Cl
Yield: 90.1 %

Procedure:
N-(2,6-Dichloro-3-methylphenyl)acetamide (22 g) was suspended in HCl (5.0 N, 100 mL), H2O (300 mL) and propanol (or AcOH, 20-50 mL). The mixture was refluxed for several hr after which the solution was cooled, chloride (3×200 mL). The organic extractions were combined, washed with water, dried over MgSP4, and concentrated to give 16 g of product as a low melting solid (m.p. 36°-38° C.). 1H NMR (CCl4) δ6.97 (d, 9.0), 6.46 (d, 9.0 Hz, 1H), 2.28 (s, 3H, CH3)
Reaction SMILES: C(OC([NH:11][C@H:12]([C:28]([NH:30][CH2:31][C:32]([N:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1[C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:35])=[O:33])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.B(Cl)(Cl)[Cl:52]>ClCCl>[ClH:42].[ClH:52].[NH2:11][C@H:12]([C:28]([NH:30][CH2:31][C:32]([N:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1[C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:35])=[O:33])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: CN(C(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: ClB(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)CNC(=O)[C@@H](N)CCCCN)c1ccc(Cl)cc1C(=O)c1ccccc1
Product: Cl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1.4 g of (Nα,Nε -bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide were dissolved in 30 ml of dry dichloromethane, cooled to approximately -70° C and treated, while stirring, with 2 ml of pre-cooled boron trichloride. The mixture was stirred under anhydrous conditions at approximately -70° C for 30 minutes and then allowed to warm slowly to room temperature over a period of 2 hours. The mixture was evaporated to dryness in vacuo, the residue re-dissolved in 30 ml of fresh dry dichloromethane and the solution again evaporated to dryness in vacuo. This operation was repeated twice using dichloromethane and then four times using methanol in order to remove the residual boron compounds as volatile trimethyl borate. A concentrated methanolic solution of the residue was added slowly to 750 ml of anhydrous diethyl ether with vigorous stirring, the solid hygroscopic product collected by filtration and dried in vacuo. This product was dissolved in 30 ml of water, shaken with three 20 ml portions of ethyl acetate to remove traces of 5-chloro-2-methylaminobenzophenone and the aqueous solution lyophilised to give 0.7 g of L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide dihydrochloride which was identical to that described in part (i) of this Example.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:7][S:6][C:5]1=[N:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1.C([N:31]([CH2:34]C)CC)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:38].O.N>C1COCC1>[F:28][C:24]1[CH:23]=[C:22]([N:21]=[C:5]2[N:4]([CH2:3][CH2:2][NH:1][C:34]([NH2:31])=[O:38])[C:8]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)=[CH:7][S:6]2)[CH:27]=[CH:26][CH:25]=1
Reactant: NCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1cccc(F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)NCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1cccc(F)c1
Reaction time: 2 h

Procedure:
N-[3-(2-aminoethyl)-4-(4-morpholinophenyl)thiazol-2(3H)-ylidene]-3-fluoroaniline obtained in Example 1 was dissolved in THF, and thereto was added triethylamine, and then thereto was added 4-nitrophenyl chloroformate under ice-cooling. The mixture was stirred for 2 hours. Thereto was added ammonia water, and the mixture was stirred for 2 hours at room temperature. The resulting compound was recrystallized from methanol to give the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C@@H:9]([CH2:25][OH:26])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C@@H:9]([CH2:25][O:26][S:34]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC(C)(C)C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-5-tert-butoxy-2-(hydroxymethyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (244 mg, 0.63 mmol) in anhydrous DCM (6 mL) was added pyridine (2 mL) and catalytic amount of DMAP, the solution was chilled to 0° C. TsCl (360 mg, 1.88 mmol) was added and stirred at rt overnight. The reaction mixture was diluted with EtOAc (40 mL) and washed with 1 N HCl (two times, 50 ml+20 ml), followed by H2O, aq. NaHCO3, brine, dried over Na2SO4, and filtered. After evaporation, the residue was purified on silica gel column, eluted with 0-20% EtOAc in hexane to afford (S)-tert-butyl 4-((R)-5-tert-butoxy-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (317 mg, yield 93%). MS ESI +ve m/z 564 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[N:25]1.N1C=CC=CC=1.O>ClCCl>[C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[S:29]([C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)(=[O:31])=[O:30])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: CC(C)(C)OC(=O)c1cccc(NCc2ccc(Cl)cc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)OC(C)(C)C)c2)n1
Yield: 9.6 %

Procedure:
A solution of 3-(4-chloro-benzylamino)-benzoic acid tert-butyl ester (1 g, 0.03 mol), 1-Methyl-1H-Pyrazole-3-sulfonyl chloride (1.13 g, 0.06 mol) and pyridine (0.5 ml, 0.06 mol) in dichloromethane (40 ml) were refluxed for 48 hrs. On cooling, water (50 ml) was added with stirring, the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/dichloromethane 0% to 10% v/v) to afford the title compound as a clear oil (1.33 g). Mass spectrum (ES+) m/z 49 (M+H).
Reaction SMILES: [I:1][C:2]#[C:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[CH2:14][N:15]=[N+:16]=[N-:17]>>[I:1][C:2]1[N:15]([CH2:14][C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([C:10]([F:9])([F:22])[F:21])[CH:12]=2)[N:16]=[N:17][C:3]=1[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1
Reactant: IC#Cc1ccsc1
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(Cn2nnc(-c3ccsc3)c2I)c1

Procedure:
Synthesized from 3-(iodoethynyl)thiophene and 3-trifluoromethyl-benzylazide using general procedure; 0.994 g, 2.284 mmol, 99%; mp=153-158° C. (dec.); IR (υ[cm−1]) 3121, 1326, 1194, 1163, 1096, 1075, 853, 792, 702; 1H NMR (600 MHz, CDCl3) δ=7.97-7.93 (m, 1H), 7.75 (d, J=5.0, 1H), 7.59 (d, J=7.7, 2H), 7.58 (s, 1H), 7.47 (t, J=7.7, 1H), 7.45-7.38 (m, 2H), 5.69 (s, 2H); 13C NMR (151 MHz, CDCl3) δ=147.5, 135.4, 131.6 (q, J=32.7), 131.3, 131.0, 129.8, 126.7, 126.2, 125.7 (q, J=3.7), 124.9 (q, J=3.8), 123.9 (q, J=272.4), 123.5, 76.0, 53.9; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C14H10F3IN3S, 435.9587; found 435.9586.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1.I[C:20]1[C:28]2[C:23](=[N:24][CH:25]=[N:26][C:27]=2[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=[C:20]([C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([F:15])[CH:12]=3)[C:28]=12
Reactant: OB(O)c1cc(F)cc(OCc2ccccc2)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 77.6 %

Procedure:
A solution of (3-Benzyloxy-5-fluorophenyl)boronic acid (29 mg, 5.80 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA22 (15.6 mg, 60% yield). ESI-MS (M+H)+ m/z calcd 378.1, found 378.0.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][O:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cncc(OCCOC2CCCCO2)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
Sodium hydride (1.02 g of a 50% suspension in mineral oil, 42 mmol) was added to a solution of 3-hydroxypyridine (2.01 g, 21 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (4.0 g, 19 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), was added and the mixture heated at 100° C. for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 3-(2-(tetrahydropyran-2-yloxy)ethoxy)pyridine (2.28 g, 48%).
Reaction SMILES: CO[C:3]([C:5]1[C:13]2C(=C(C3C=CC=CC=3)N(CC3C=CC=CC=3)N=2)C=CC=1)=O.[CH2:27]([N:34]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:41]2[C:36]([C:37](C(O)=O)=[CH:38][CH:39]=[CH:40]2)=[N:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C[Mg+].[Br-].C1C[O:58]CC1>>[CH2:27]([N:34]1[C:42]([C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:43]2[C:48]([C:47]([C:5]([OH:58])([CH3:3])[CH3:13])=[CH:46][CH:45]=[CH:44]2)=[N:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Reactant: O=C(O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Agent: C[Mg+]
Agent: [Br-]
Product: CC(C)(O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ninety milligrams (90 mg; 0.24 mmol) of 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid methyl ester, prepared from 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid (see preparation of Example 518), were dissolved in THF and 0.5 ml of 3M MeMgBr in THF (1.4 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with aq NH4Cl solution and product was extracted with EtOAc, and then flash column chromatography (SiO2, dichloromethane as an eluant) afforded 2-(2-benzyl-3-phenyl-2H-indazol-7-yl)propan-2-ol in 86% yleld.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:19][NH2:20].CO>C(O)C>[NH:19]([C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:20]
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CO
Product: NNc1cc(-c2ccccc2)c2ccccc2n1

Procedure:
In carrying out the process of the present invention, a 2-chloro-4-phenylquinoline I is heated with hydrazine hydrate. In the preferred embodiment of this invention, the reaction is carried out at the reflux temperature of the mixture; however, temperatures between 25° and 118° C. with a reaction time of 1 to 18 hours are operative. A solvent, such as lower alkanol, e.g., methanol, ethanol, 1- and 2-propanol can be used but is not necessary. In the preferred embodiment of the invention, one hour reflux under nitrogen is sufficient. At the termination of the reaction, the mixture is concentrated, poured into water and the insoluble product collected on a filter. Purification is carried out by conventional means such as extraction, chromatography or more commonly recrystallization to obtain the corresponding 2-hydrazino-4-phenylquinoline II.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[S:42][C:41]=12)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[C:43]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])[S:42][C:41]=12)=[N+:28]=[N-:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCCCCCN=[N+]=[N-])c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCCCCCN=[N+]=[N-])c4s3)[C@H](C)[C@H]12
Yield: 46.7 %

Procedure:
The procedure of Example 1a) was repeated, except that 611 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.01 g of 7-(6-azidohexyl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 493 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(6-azidohexyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [N+:1](=[C:3]1[N:7]=[CH:6][N:5]=[C:4]1[C:8]([NH2:10])=[O:9])=[N-:2].CC[O:13][CH2:14][CH3:15]>CS(C)=O>[CH3:4][C:3]1[N:7]=[C:14]([CH2:15][N:10]2[C:8](=[O:9])[N:7]3[CH:6]=[N:5][C:4]([C:8]([NH2:10])=[O:9])=[C:3]3[N:1]=[N:2]2)[O:13][N:1]=1
Reactant: CCOCC
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: Cc1noc(Cn2nnc3c(C(N)=O)ncn3c2=O)n1
Temperature: 0 °C
Yield: 56 %

Procedure:
An aqueous solution of NaNO2 (84 mg, 1.2 mmol) was added to a cooled (0° C.) solution of (3-methyl-[1,2,4]oxadiazol-5-yl)-acetic acid hydrazide (1.02 mmol) in a 1:1 mixture of CH2Cl2:1M HCl (1.5 mL). The reaction mixture was stirred at this temperature for 5 minutes before being poured onto crushed ice. The crude azide was extracted with CH2Cl2 and then dried (MgSO4), filtered and concentrated in vacuo. Toluene (1.5 mL) was added to the crude residue and the resultant mixture heated to 80° C. for 1 hour whereupon it was cooled and concentrated in vacuo to give a crude orange residue corresponding to 5-isocyanatomethyl-3-methyl-[1,2,4]oxadiazole (quantitative yield assumed) (1H NMR (400 MHz, CDCl3) δ ppm: 4.56 (2H, s), 2.36 (3H, s). IR (μmax, cm−1): 2260.7 (s, N═C═O), 1593.3 (m), 1494.9 (m), 1435.1 (w), 1325.1 (m)) which was then diluted in DMSO (1.5 mL) and added to a solution of 5-diazoimidazole-4-carboxamide (355 mg, 2.58 mmol) in 3.5 mL DMSO. The reaction mixture was stirred at room temperature for 10 minutes before the addition of sufficient ice water to cause precipitation of the crude product which was collected by vacuum filtration and washed with EtOH (1 reaction volume and then Et2O (1 reaction volume) to give the title compound as a yellow solid (56% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.92 (1H, s), 7.88 (1H, s), 7.74 (1H, s), 5.89 (2H, s), 2.34 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:36](=[O:37])[CH2:35][N:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: O=C(O)CN1CCOCC1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)CN1CCOCC1)c1ccc(F)cc1
Yield: 9.3 %

Procedure:
A solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.16 g, 0.42 mmol), 2-morpholinoacetic acid (0.06 g, 0.42 mmol), HBTU (0.16 g, 0.42 mmol) and DIEA (0.16 g, 1.2 mmol) in DCM (3 ml) was stirred at room temperature for 1 hour. The reaction was then quenched with a saturated aqueous solution of NaHCO3, and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.02 g, 10%). 1H NMR (400 MHz, CD3OD) δ 7.35 (br s, 2H), 7.17 (br s, 1H), 7.01-6.97 (m, 2H), 6.06 (br s, 1H), 5.16-4.99 (m, 1H), 4.30 (br s, 2H), 3.68 (br s, 4H), 3.06 (br s, 2H), 2.48 (br s, 4H), 1.87-1.82 (m, 1H), 1.51 (d, J=6.4 Hz, 3H), 0.91 (br s, 2H), 0.64 (br s, 2H). MS: Calcd.: 511. Found: [M+H]+ 512.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[CH:7]=[C:8]([CH2:10][C:11]([OH:13])=O)[S:9][C:5]=2[CH:4]=1.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:11](=[O:13])[CH2:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:15]=[CH:14][C:6]=2[CH:7]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: COc1ccc2cc(CC(=O)O)sc2c1
Product: COc1ccc2cc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)sc2c1

Procedure:
Following General Procedure I′ above, and using (6-methoxybenzothiophen-2-yl)acetic acid and alanine iso-butyl ester (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.