Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:12])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:13]([N:20]=[C:21]=[S:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([NH:20][C:21]([NH:12][C:1]1[C:10]2[C:5](=[C:6]([NH:11][C:21](=[S:22])[NH:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[S:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1cccc2c(N)cccc12
Solvent: CCOC(C)=O
Product: S=C(NCc1ccccc1)Nc1cccc2c(NC(=S)NCc3ccccc3)cccc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
1,5-Naphthalenediamine (0.791 g, 5 mM) was dissolved in 20 ml of ethyl acetate, and 2 equivalents of benzylisothiocyanate (1.492 g, 10 mM) were added. The mixture was stirred at 80° C. for 30 minutes. After cooling, the reaction mixture was filtered, and washed with ethylacetate/n-hexane to obtain 0.70 g (30.7% yield) of a colorless crystal of compound A-29.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][S:8]([C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13])(=[O:10])=[O:9])=[O:5])C.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:15][C:11]([S:8]([CH2:7][C@@H:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]([OH:3])=[O:5])(=[O:9])=[O:10])([C:12]([N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)Cl
Reactant: C1CSCCN1
Product: CC(C)(C(=O)N1CCSCC1)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In an analogous manner to that described in Example 1, paragraphs (d) and (e), starting from 2-mercaptoisobutyric acid and ethyl 2-benzylacrylate there was obtained (RS)-2-[[2-[(ethoxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride, reaction of which with thiomorpholine analogously to Example 2, paragraph (a), and subsequent enzymatic hydrolysis analogously to Example 6, paragraph (c), yielded (S)-α-[[[1-methyl-1-[(tetrahydro-4H-1,4-thiazin-4-yl)carbonyl]ethyl]sulfonyl]methyl]hydrocinnamic acid, MS: 399 (M)+, as a colourless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[N:23]([CH2:2][CH2:3][O:4][C:5]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(-c2ccccc2)oc2c(OCCCl)cccc2c1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)oc2c(OCCN=[N+]=[N-])cccc2c1=O
Reaction time: 12 h
Yield: 90.2 %

Procedure:
A mixture of 15.2 g of Intermediate XI and 6.24 g of sodium azide in 150 ml of anhydrous dimethylformamide was stirred at 70°-75° C. for 12 hours. After cooling to 20°-25° C., the reaction mixture was poured into 1.5 liters of water and extracted with dichloromethane. The organic solution was washed with aqueous sodium chloride solution and dried on anhydrous sodium sulfate. The solvents were evaporated off in vacuo. The residue was taken up in water, collected by suction filtration and dried to give 14 g of the title compound, m.p. 119°-120° C.
Reaction SMILES: [C:1]([O:7][CH2:8]Br)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[I-].[Na+].[I-].[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:41]/[O:42][CH3:43])/[C:20]([NH:22][C@@H:23]2[C:39](=[O:40])[N:25]3[C:26]([C:36]([O-:38])=[O:37])=[C:27]([CH:30]4[O:34][C:33](=[O:35])[CH2:32][CH2:31]4)[CH2:28][S:29][C@H:24]23)=[O:21])[N:18]=1.[Na+]>CC(C)=O.C1(C)C=CC=CC=1.CN1CCCC1=O.C(OCC)(=O)C>[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:41]/[O:42][CH3:43])/[C:20]([NH:22][C@@H:23]2[C:39](=[O:40])[N:25]3[C:26]([C:36]([O:38][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:37])=[C:27]([CH:30]4[O:34][C:33](=[O:35])[CH2:32][CH2:31]4)[CH2:28][S:29][C@H:24]23)=[O:21])[N:18]=1
Reactant: CC(C)(C)C(=O)OCBr
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C3CCC(=O)O3)CS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(C3CCC(=O)O3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Pivaloyloxymethyl bromide (0.10 g, ca. 0.5 mmol) and sodium iodide (0.1 g) in acetone (1 ml) were stirred for 0.25 h, filtered and evaporated in vacuo. The iodide in toluene (0.5 ml) was added to sodium (6R,7R)-7-[2(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(5RS)-2-oxotetrahydrofuran-5-yl]ceph-3-em-4-carboxylate (0.124 g, 0.25 mmol) in N-methylpyrrolidone (2 ml) and stirred for 0.5 h. The reaction mixture was diluted with ethyl acetate, washed twice with water, and with brine, dried, concentrated and flash chromatographed on silica gel eluting with 80,90,100% ethyl acetate in hexane to give the title compound (86 mg, 59%), νmax (CH2Cl2) 1780, 1753, 1735, 1682, 1532, 1374, 1121, 1046 cm-1 ; δH (250 MHz, CDCl3) (9H, s), 1.9-2.2 (1H, m), 2.4-2.8 (3H, m), 3.34 and 3.64, 3.48 and 3.59 (together 2H, 2ABq, J 18.9, 18.4 Hz), 4.08 (3H, s), 5.10, 5.11 (together 1H, 2d, J 4.9 Hz), 5.35 (2H, bs), 5.5-5.95 (3H, m), 6.00, 6.10 (together 1H, 2dd, J 9, 4.9 Hz), 6.85, 6.87 (together 1H, 2s), 7.52, 7.54 (together 1H, 2d, J 9 Hz); [mass spectrum: +ve ion (3-nitrobenzyl alcohol-sodium acetate) MH+(582) MNa+(604)].
Reaction SMILES: [CH3:1][Si:2]([CH:5]([Si:7]([CH3:10])([CH3:9])[CH3:8])Cl)([CH3:4])[CH3:3].[C:11]([O-:15])(=[O:14])[CH:12]=[CH2:13].[Na+].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(#N)CCC>[CH3:1][Si:2]([CH:5]([O:15][C:11](=[O:14])[CH:12]=[CH2:13])[Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:4])[CH3:3]
Reactant: C=CC(=O)[O-]
Reactant: C[Si](C)(C)C(Cl)[Si](C)(C)C
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCC#N
Product: C=CC(=O)OC([Si](C)(C)C)[Si](C)(C)C
Reaction time: 6 h

Procedure:
Bis(trimethylsilyl)chloromethane (Aldrich) 39 g, 0.2 mole), sodium acrylate (28 g, 0.3 mole), Adogen 464 (Aldrich) (6.96 g), and phenothiazine (0.10 grams) were placed in a round bottom flask equipped with a condenser, mechanical stirrer and a nitrogen inlet. The flask was charged with 100 ml of butyronitrile and heated to reflux while stirring. After 6 hours, the mixture was diluted with 150 ml hexanes and filtered to remove the solids. The solvents were removed under reduced pressure. Fractional distillation of the residue under reduced pressure gave 35.5 grams 975%) of the desired product at 45-58° C. at 0.5 mm pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH3:10][C:11]1[C:12]([N:16]=[C:17]=[S:18])=[CH:13][S:14][CH:15]=1>C1COCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:17]([NH:16][C:12]1[C:11]([CH3:10])=[CH:15][S:14][CH:13]=1)=[S:18]
Reactant: Nc1ccc(F)cc1N
Reactant: Cc1cscc1N=C=S
Solvent: C1CCOC1
Product: Cc1cscc1NC(=S)Nc1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.02 mol of 4-fluoro-1,2-diaminobenzene is added to a solution of 0.02 mol of 4-methyl-3-thienyl isothiocyanate in 60 ml of anhydrous THF. The reaction mixture is stirred at room temperature for 2 hours and then allowed to stand overnight, and the solvent is then distilled off under reduced pressure using a rotary evaporator and the oily residue is purified on a silica gel column using a mixture of identical proportions of toluene and ethyl acetate.
Reaction SMILES: C[O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ccnc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cn2ccnc2)cc1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a stirred solution of the compound of Step A (16.3 g, 86.1 mmole) in methylene chloride (860 ml) cooled to 5° C., was added boron tribromide (32.6 ml, 344.4 mmole) dropwise over 15 minutes. After 2 hours at 5° C., the reaction was quenched with methanol dropwise, evaporated to dryness, and redissolved in methanol, water, and methylene chloride The pH was adjusted to 8.4 with sodium hydroxide. The organic layer was dried over sodium sulfate and evaporated to dryness to give N-p-hydroxybenzylimidazole (13.6 g, 91%) which was used without further purification:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>C(OCC)(=O)C>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[C:2]2[NH:1][C:26](=[O:29])[CH2:27][CH3:28]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2cc(Cl)ccc21
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 2 (Method A) from 3-amino-5-chloro-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)indole (step 1) and propionyl chloride. m.p.: 206.5-207.5° C. (ethyl acetate) 1H-NMR (CDCl3) δ: 9.78 (1H, br s), 8.31 (1H, s), 8.28 (1H, br s), 7.78 (1H, s), 7.70-7.59 (2H, m), 7.51 (1H, t, J=8 Hz), 7.34 (1H, dd, J=8, 1.5 Hz), 7.25 (1H, d, J=8 Hz), 2.51 (2H, q, J=7 Hz), 1.30 (3H, t, J=7 Hz)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)=[O:15].[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[O:24]=[C:23]([O:25][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC(=O)OC2CCCCO2)cc1
Yield: 170.8 %

Procedure:
To a saturated solution of anhydrous p-toluenesulphonic acid in dry dichloromethane (35 ml) successively 2-[4-(methoxycarbonyl)phenyl]acetic acid (E11) (0.671 g, 3.45 mmol) and 3,4-dihydro-2H-pyran (3 ml, 32.9 mmol) were added, and the resultant solution was stirred for 45 minutes at room temperature. To the reaction mixture triethylamine (1 ml, 7.2 mmol) was added and the volatiles were evaporated. The obtained crude title product (1.64 g) was immediately utilized in the next step of the synthesis.
Reaction SMILES: C([NH:4][C@H:5]([CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)[C:6]([O:8]CC)=[O:7])(=O)C>Cl>[NH2:4][C@H:5]([CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(C)=O
Agent: Cl
Product: N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)O
Temperature: 0 °C

Procedure:
A mixture of 10.0 g (34.6 mmol) ethyl (R)-2-acetylamino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate and 120 mL 6 M HCl was refluxed for 3 h. The reaction mixture was cooled in the ice bath, the precipitate was suction filtered, washed with water and diisopropylether and dried.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[N:20]([CH3:33])[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[C:23]=3[CH2:24][CH3:25])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[C:23]([CH2:24][CH3:25])=[C:19]([CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[CH:9][N:8]4[CH2:7][C:6]([OH:34])=[O:5])=[CH:12][CH:13]=3)[N:20]([CH3:33])[N:21]=2)=[CH:27][CH:28]=1
Reactant: CCc1c(-c2ccc(Cl)cc2)nn(C)c1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: CCc1c(-c2ccc(Cl)cc2)nn(C)c1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], {6-[5-(4-chloro-phenyl)-4-ethyl-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {6-[5-(4-chloro-phenyl)-4-ethyl-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as brown crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+](C1C=CC(NN[CH:23]=[O:24])=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH:11][CH:23]=[O:24])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CNNc1ccc([N+](=O)[O-])cc1
Reactant: NNc1cccc([N+](=O)[O-])c1
Product: O=CNNc1cccc([N+](=O)[O-])c1

Procedure:
By reacting 3-nitrophenylhydrazine as in the same manner as (1), 430 g of 2-(3-nitrophenyl)-1-formylhydrazine was obtained. Melting point: 168° to 169° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:10][CH2:9]2)[N:7]=1.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([NH2:26])[CH3:25])=[CH:19][CH:18]=1)([O:15][CH3:16])=[O:14]>C(O)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([NH:26][CH2:9][CH:8]([OH:10])[C:6]2[N:7]=[C:3]([C:2]([F:12])([F:11])[F:1])[S:4][CH:5]=2)[CH3:25])=[CH:19][CH:18]=1)([O:15][CH3:16])=[O:14]
Reactant: FC(F)(F)c1nc(C2CO2)cs1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Solvent: CCO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
0.54 g (0.030 mol) of 2-(2-trifluoromethyl-thiazol-4-yl)ethylene oxide is dissolved in 5 ml of ethanol, and the solution is added dropwise within 10 minutes to a boiling solution of 0.58 g (0.0030 mol) of 2-(4-carbomethoxyphenyl)-1-methylethylamine in 13 ml ethanol. The mixture is then boiled under reflux for 5 hours, the solvent is removed by distillation, and the base is purified on a silica gel column using methylene chloride/methanol=20:1 as eluant.
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][C:5]3[N:6]([CH3:15])[C:7](=[O:14])[C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[N:10][CH:9]=4)=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C[C@@H](COc1cc2c(cc1-c1ccc(F)cc1)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 30.3 %

Procedure:
(S)-tert-Butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.297 mmol) (prepared as described in Example 3, Part A) 4-fluorophenylboronic acid (49.9 mg, 0.357 mmol), Cs2CO3 (291 mg, 0.892 mmol) and PdCl2(dppf)-CH2Cl2 adduct (12.14 mg, 0.015 mmol) in 1,4-dioxane (8 mL) and water (0.4 mL) was degassed with nitrogen gas for 5 min then heated at 80° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in dichloromethane (10 mL) and water (8 mL). The organic layer was separated, dried with sodium sulfate, filtered and concentrated under reduced pressure to afford (S)-tert-butyl (1-((9-(4-fluorophenyl)-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.13 g, 0.09 mmol, 31% yield) as a brown gum. The material was carried forward without further purification. LC/MS, (ESI) m/z 520.4 [(M+H)+, calcd for C30H35FN3O4 520.25]; LC/MS retention time (method D): tR=1.08 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.O1CCCC1>O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Product: Nc1ccc([N+](=O)[O-])c(CO)c1

Procedure:
To a solution of 5-amino-2-nitrobenzoic acid (3.0 g, 16.4 mmol) in 40 ml of tetrahydrofuran was added 50 ml of borane-tetrahydrofuran complex (1.0 M solution in THF). The mixture was heated under reflux for one hour. The usual workup afforded the product. 1H NMR (400 MHz, DMSO-d6): 4.79 (2H, d, J=5.4 Hz), 5.37 (1H, t, J=5.4 Hz), 6.48 (1H, dd, J=9.0 Hz, J=2.5 Hz), 6.68 (2H, s), 6.99 (1H, d, J=2.5 Hz), 7.94 (1H, d, J=9.0 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][C:13]2[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=2)[CH:2]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:46]=1[C:47]([NH:49][NH2:50])=[O:48]>CN(C)C=O>[Cl:44][C:45]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:46]=1[C:47]([NH:49][NH:50][C:19]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:12]#[C:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:18]=1)=[O:21])=[O:48]
Reactant: O=C(O)c1cccc(C#Cc2cnc3ccccc3c2)n1
Reactant: Cc1cccc(Cl)c1C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1C(=O)NNC(=O)c1cccc(C#Cc2cnc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-[(quinolin-3-yl)ethynyl]pyridine-2-carboxylic acid (0.05 g, 0.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.04 g, 0.2 mmol) and 1-hydroxybenzotriazole (0.03 g, 0.2 mmol) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 1 hr. 2-chloro-6-methylbenzohydrazide (0.03 g, 0.2 mmol) was added and the mixture stirred for 12 hrs at ambient temperature. Concentration and trituration of the residue with water produced a solid which was filtered, washed with water and dried in vacuo. Leaching the product with methanol and drying in vacuo gave N′-(2-Chloro-6-methylbenzoyl)-6-[2-(3-quinolyl)ethynyl]pyridine-2-carboxylic acid hydrazide as a white solid.
Reaction SMILES: N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([CH:29]=[N:30][O:31][CH2:32][CH2:33][OH:34])[CH:20]=1.O[C:36]1[CH:68]=[CH:67][C:39]([CH2:40][CH:41]2[S:45][C:44](=[O:46])[N:43]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]2=[O:66])=[CH:38][CH:37]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.O1CCCC1>[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([CH:29]=[N:30][O:31][CH2:32][CH2:33][O:34][C:36]2[CH:68]=[CH:67][C:39]([CH2:40][CH:41]3[S:45][C:44](=[O:46])[N:43]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]3=[O:66])=[CH:38][CH:37]=2)[CH:20]=1
Reactant: OCCON=Cc1cnc2ccccc2c1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3cnc4ccccc4c3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A solution of 0.73 g of 1,1'-(azodicarbonyl)dipiperazine in 10 ml of toluene was added dropwise at room temperature to a suspension of 0.60 g of 2-(3-quinolylmethyleneaminooxy)ethanol (prepared as described in Preparation 3), 1.10 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione and 0.72 ml of tributylphosphine in 30 ml of tetrahydrofuran, and the resulting mixture was stirred for 16 hours. At the end of this time, the reaction product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.45 g of the title compound as a crystalline powder, melting at 127°-130° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH2:14]([CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(Cc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(CC2CNCCO2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The above compound could be made in the following manner: 1 eq. 2-Benzyl-morpholine-4-carboxylic acid tert-butyl ester could be dissolved in 4N solution of hydrogen chloride in dioxane and the mixture could be stirred at 60° C. for 3 h. The solvent could be removed in vacuo and 1N aqueous hydrogen chloride solution could be added to the resulting residue, and the mixture could be washed with diethyl ether. The aqueous layer could be adjusted to pH 14 by addition of 2N NaOH solution and extracted with methylene chloride. The organic layer could be washed with brine and dried over sodium sulfate. After filtering, the material could be purified by column chromatography.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH:27]=[CH2:28])[CH2:15][C:16]([O:18]C)=O)=[O:13])=[CH:7][CH:6]=1)[CH3:4].O(C)[Na]>CO>[CH2:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:14]1[CH2:15][C:16](=[O:18])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3](=[N:2][OH:1])[CH3:4])=[CH:10][CH:9]=2)[C:12]1=[O:13])[CH:27]=[CH2:28]
Reactant: C=CCc1ccccc1N(CC(=O)OC)C(=O)Nc1ccc(C(C)=NO)cc1
Agent: CO[Na]
Solvent: CO
Product: C=CCc1ccccc1N1CC(=O)N(c2ccc(C(C)=NO)cc2)C1=O

Procedure:
0.01 mol of this urea is dissolved in 150 mL of CH3OH. the pH is adjusted to approximately 10.0 using 25% NaOCH3 solution in CH3OH. The solution is heated to reflux for 2.5 hours, after which time the solvent is removed in vacuo. The residue is washed with cold water and dried in vacuo to yield crude 1-(2-allylphenyl)-3-[4-(1-hydroxyiminoethyl)phenyl]hydantoin. The hydantoin is purified by recrystallization from CH3OH: H2O.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH3:2]>ClCCl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOc1cc(CO)ccc1-c1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C=O)ccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above prepared (2-ethoxy-4′-trifluoromethyl-biphenyl-4-yl)-methanol (0.359 g, 1.21 mmol) was dissolved in 12 ml of dichloromethane and treated with MnO2 (2.11 g, 20 eq.). After vigorous stirring for 8 h at ambient temperature, the reaction mixture was filtered over a pad of Celite, rinsed generously with dichloromethane, and evaporated to dryness to leave, after flash chromatography (silica gel, hexane/AcOEt=9/1) 0.372 g of the title aldehyde as yellow solid.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C([Li])CCC.[CH3:15][C:16]([CH3:18])=[O:17]>C1(C)C=CC=CC=1>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:16]([OH:17])([CH3:18])[CH3:15])=[N:3][CH:4]=1
Reactant: CC(C)=O
Reactant: Fc1cc(Br)cnc1Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ncc(Br)cc1F
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To 2,5-dibromo-3-fluoropyridine in toluene at −78° C. was added n-butyllithium drop wise. The resulting solution was stirred at −78° C. for 1.5 hours. Then at −78° C., added acetone drop wise to the reaction mixture and continue to stir reaction at −78° C. for 2 hours at which point LC-MS and TLC indicated the reaction was complete. The reaction was warmed to 0° C. and quenched with saturated ammonium chloride solution (aq.) and then diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford crude product. Gradient column chromatography on silica eluting with 0 to 30% EtOAc/hexanes gave the desired product (1.04 g).