Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH2:26][C:25]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[O:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CN1C(=O)CCC1>C(#N)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH2:26][C:25]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH2:35][C:36](=[O:37])[O:38][C:39]([CH3:42])([CH3:40])[CH3:41])[O:24][N:23]=3)[CH:17]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cccc(OC(=O)c3ccc(NC(=N)N)cc3)c2)=NO1
Reaction time: 8 h
Yield: 25.1 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (317 mg) was added to a mixture of di-tert-butyl 2,2′-(3-(3-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (265 mg), pyridine (0.3 mL), and NMP (0.3 mL) at 50 C, and the obtained mixture was stirred overnight at 50 C. To the reaction mixture, acetonitrile was added. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, subsequently acetonitrile/acetic acid) and then further fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (94 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([C@@H:26]([NH2:28])[CH3:27])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])[C:5]([NH:28][C@H:26]([C:24]1[NH:23][C:22]2[CH:29]=[CH:30][C:19]([Cl:18])=[CH:20][C:21]=2[N:25]=1)[CH3:27])=[O:7]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(N2CCCNC2=O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CCCNC2=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 0 °C

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then pouring into ice water, adding conc. ammonia solution, filtering, washing with water and purifying by chromatography on silica gel (eluting gradient ethyl acetate/(methanol/conc. ammonia solution 19:1)=98:2->90:10) with subsequent filtration through activated charcoal, trituration with ether and drying in the drying pistol at 70° C.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:8]([CH3:13])[C:9]=1[C:10](N)=[O:11])(=O)C.[O:23]1CCOCC1>Cl>[NH2:4][C:5]1[S:6][C:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:8]([CH3:13])[C:9]=1[C:10]([OH:11])=[O:23]
Reactant: C1COCCO1
Reactant: CC(=O)Nc1sc(S(=O)(=O)c2ccccc2)c(C)c1C(N)=O
Agent: Cl
Product: Cc1c(S(=O)(=O)c2ccccc2)sc(N)c1C(=O)O
Temperature: 80 °C

Procedure:
2-Acetylamino-5-benzenesulfonyl-4-methyl-thiophene-3-carboxylic acid amide (980 mg 2.9 mmol) is dissolved in a mixture of 6 M aqueous HCl and 1,4-dioxane (1:1, 10 mL). This mixture is then heated at 80° C. for 6 h, and concentrated by evaporation to yield a residue that is as such.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[C:12]([O-:15])(O)=[O:13].[Na+].[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]C2C(=O)N(C([O-])=O)C=CC=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C1COCC1>[OH:11][C@@H:6]([C:7]([CH3:8])([CH3:10])[CH3:9])[C@@H:2]([NH:1][C:12]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])n1cccc(CCCCCc2ccccc2)c1=O
Reactant: CC(C)(C)[C@@H](O)[C@H](N)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 44 %

Procedure:
To a stirred mixture of (2S*,3R*)-2-amino-3-hydroxy-4,4-dimethyl-pentanoic acid (0.36 g, 2.24 mmol) and NaHCO3 (0.188 g, 2.24 mmol) in H2O (15 mL), at rt, the isomeric mixture containing 5-phenyl-pentyl-2-pyridyl-carbonate and 5-phenyl-pentyl-2-oxopyridine-1-carboxylate (1.95 g, 6.84 mmol) [prepared as for example 32, step 1] in THF (15 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×40 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×40 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.346 g, 44%), as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z: 352 [M−H]+; (ESI) m/z: 350 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (s, 9H), 1.33 (tt, J=5.95, 9.00 Hz, 2H), 1.57 (ddt, J=3.93, 6.59, 10.94 Hz, 4H), 2.57 (t, J=7.70 Hz, 2H), 3.59 (s, 1H), 3.87-4.03 (m, 2H), 4.12-4.21 (m, 1H), 6.25 (d, J=9.37 Hz, 1H), 7.10-7.32 (m, 5H), 11.55 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][N:32]=[CH:31]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]ncc4c3)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Yield: 43 %

Procedure:
A mixture of 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (235 mg, 0.62 mmol), (prepared as described for the starting material in Example 7), 5-hydroxyindazole (100 mg, 0.75 mmol) and cesium carbonate (303 mg, 0.93 mmol) in acetone (15 ml) was heated at reflux for 1.25 hours. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The residue was further purified by preparative HPLC to give 7-[3-(4-acetylpiperazin-1-yl]propoxy]-4-(1H-indazol-5-yloxy)-6-methoxyquinazoline (127 mg, 43%) as a white foam.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[CH2:26][CH2:25][O:24][C:23]2=[O:27])[CH:7]=1)C.[OH-].[Li+]>CO.O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:28])=[O:3])[CH:11]=[C:10]([Cl:12])[CH:9]=2)=[C:15]([CH2:21][N:22]2[CH2:26][CH2:25][O:24][C:23]2=[O:27])[CH:16]=1
Reactant: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
{3-[4-Bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-5-chloro-phenyl}-acetic acid ethyl ester (0.06 g, 0.13 mmol) in MeOH and H2O was treated with lithium hydroxide, and the reaction was stirred at 60° C. for 30 minutes to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13]C)[CH:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)#[N:2].[NH:22]1[C:30]2[C:25](=[C:26]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:13][CH:12]([N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:6]([CH:15]2[CH2:20][CH2:19][CH:18]([N:34]3[CH2:35][CH2:36][N:31]([C:26]4[C:25]5[CH:24]=[CH:23][NH:22][C:30]=5[CH:29]=[CH:28][CH:27]=4)[CH2:32][CH2:33]3)[CH2:17][CH2:16]2)=[CH:7]1)[CH3:37]
Reactant: CCCn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)n1cc(C2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
A solution of 4-(5-cyano-1-n-propyl-indol-3-yl)-cyclohexanone (1.68 g, 6 mmol), 1-(indol-4-yl)piperazine (1.27 g, 6.3 mmol), sodium triacetoxyborohydride (1.84 g, 8.9 mmol) and acetic acid (0.94 ml, 16 mmol) in 1,2-dichloroethane (80 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (20 ml), extracted with methylene chloride (3×100 ml), and washed with brine (3×100 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.49 g (18%) of product as a white powder.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[NH:10])[CH:3]([CH3:5])[CH3:4].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C(O)(=O)C>C(O)C>[O:18]=[C:19]1[NH:11][C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH2:2][CH:3]([CH3:5])[CH3:4])=[N:10][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)COc1ccccc1C(=N)N
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O

Procedure:
To a stirred solution of sodium (3.15 g., 0.137 g-atom) in ethanol (250 ml.) was added 2-isobutoxybenzamidine (26.3 g., 0.137 mole) followed by diethyl ethoxymethylenemalonate (29.6 g., 0.137 mole). The mixture was heated under reflux for 3 hours. The cooled mixture was added to icewater (300 ml.) which was then acidified to pH 5 with glacial acetic acid. The crystalline product (36.4 g., 85%) m.p. 89°-91°, which formed on cooling was collected and a portion recrystallized from 50% aqueous ethanol to give the title compound, m.p. 92°-93°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:16]1[CH:20]=[CH:19][S:18][C:17]=1[CH:21]=[O:22])=[CH:6][NH:7]2.[BH4-].[Na+].ClCCl>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:16]1[CH:20]=[CH:19][S:18][C:17]=1[CH2:21][OH:22])=[CH:6][NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccsc3C=O)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccsc3CO)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
3-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)thiophene-2-carbaldehyde (120 mg, 0.39 mmol) was suspended in ethanol (5 ml), and sodium borohydride (19.24 mg) was added to the suspension. The resulting mixture was stirred at room temperature for 1 hour. Dichloromethane was added to the reaction mixture, which was washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 110 mg of powdery white 5-fluoro-3-(2-hydroxymethylthiophen-3-yl)-8-propoxy-1H-quinolin-4-one (yield: 82%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:8]=1)=O.[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([NH:31]N)=[CH:30][C:25]=2[O:24][CH2:23]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([N:31]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: NNc1ccc2c(c1)OCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(F)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(F)c2)nc1-c1ccnn1-c1ccc2c(c1)OCO2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-fluoro-phenyl)-1H-pyridazin-4-one (A-13) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]([CH2:12][CH:13]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH2:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].C(O)(=O)C.[CH:34](=O)[C:35]([CH3:38])([CH3:37])[CH3:36].C([BH3-])#N.[Na+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]([CH2:12][CH:13]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: COC(=O)CN(CC(c1cc(Cl)ccc1N)c1ccccc1Cl)C(=O)C(F)(F)F
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CN(CC(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of N-[2-(2-amino-5-chlorophenyl)-2-(2-chlorophenyl)ethyl]-N-(trifluoroacetyl)glycine methyl ester (0.39 g) in methanol (5 ml) were added acetic acid (0.05 ml) and pivalaldehyde (78 mg). The mixture was stirred for 30 minutes at room temperature, to which was added sodium cyanoborohydride (57 mg). The mixture was stirred for one hour at room temperature, followed by addition of dichloromethane (50 ml) thereto. This solution was washed with a 1N aqueous solution of sodium hydroxide, then with water, followed by distilling off the solvent. The residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=5:1 v/v as an eluent) to give 0.27 g of an oily compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:22]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)=[N+:23]=[N-:24]
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of [2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) and sodium azide (10.6 g) in dimethyl sulfoxide (350 ml) was stirred at 90° C. overnight and the solution was diluted with ethyl acetate (600 ml). The solution was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4R)-4-azido-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (20.0 g) as a pale brown oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:9]([O:11]C)Cl>>[SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]=[O:11])=[CH:4][CH:3]=1
Reactant: Sc1ccccc1
Reactant: COC(Cl)Cl
Product: O=Cc1ccc(S)cc1

Procedure:
The above reaction of Example 21A is repeated except that the starting materials are mercaptobenzene and dichloromethyl methylether. Using the same reaction conditions and techniques, there is obtained 4-mercaptobenzaldehyde.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:12]=3[F:14])[C:7](=[O:27])[CH:6]=[C:5]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1.O>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:47][CH2:46][C:45]4[CH:48]=[CH:49][C:42]([O:41][CH3:40])=[CH:43][CH:44]=4)[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:12]=3[F:14])[C:7](=[O:27])[CH:6]=[C:5]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(=O)c2c(F)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cc(=O)c2c(NCc3ccc(OC)cc3)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Yield: 67 %

Procedure:
A solution of ethyl 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7-[(2-pyridylamino)ethylamino]quinoline-2-carboxylate (705 mg, 1.58 mmol) and triethylamine (0.66 mL, 4.74 mmol) and 4-methoxybenzylamine (0.600 mL, 4.62 mmol) in DMSO (15 mL) was stirred at 100° C. for 18 h. The reaction mixture was poured into water, and then extracted with EtOAc. The organic layer washed with water and brine, and dried over anhyd. Na2SO4 followed by the removal of EtOAc. The crude product was purified by column chromatography (Hexane:EtOAc 1:1) to yield ethyl 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-(4-methoxybenzylamino)-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (597 mg, 67%) as a orange amorphous solid.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:11]1)=[O:7])(C)(C)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35](C(O)=O)=[C:34]([O:42][CH3:43])[CH:33]=1>>[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])[CH2:11]2)=[O:7])=[C:34]([O:42][CH3:43])[CH:33]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C=Nc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCCCNC(=O)Nc2ccccc2)C1

Procedure:
6-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-hexylamine (1.50 g) as starting compound was reacted and treated in the same manner as in Example 34 using phenyl isocyanate (0.57 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (1.01 g) to give 4-amino-5-chloro-2-methoxy-N-((3R)-1-(6-(3-phenylureido)hexyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:15]([CH2:17][C:18](=[C:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:35]([O:36][CH3:37])=[C:34]3[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]3[CH:38]3[CH2:40][CH2:39]3)=[CH:28][C:27]=2[F:45])[CH2:22][CH2:21]1)Cl)C)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:38]1([N:33]2[C:34]3[C:29](=[CH:28][C:27]([F:45])=[C:26]([N:23]4[CH2:24][CH2:25][C:20](=[CH:18][CH2:17][NH:15][CH3:8])[CH2:21][CH2:22]4)[C:35]=3[O:36][CH3:37])[C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32]2)[CH2:39][CH2:40]1
Reactant: COc1c(N2CCC(=C(Cl)CN(C)Cc3ccccc3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNCC=C1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)CC1
Reaction time: 3 h
Yield: 14.3 %

Procedure:
A solution of 161 (70 mg, 0.11 mmol) in methanol/formic acid (v/v=20/1) (14 mL) was treated with 10% Pd/C (35 mg, 7.3 mmol) under nitrogen at rt and stirred for 3 h. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by HPLC (reverse phase C-18 column, 35–90% acetonitrile/water containing 0.1% trifluoroacetic acid) to afford the trifluoroacetic acid salt of 221 (8.3 mg, 15%) as a yellow solid. MS 416 (M+H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH2:5].[CH:6]1([C:9]2[C:13]([O:14][C:15]3[CH:16]=[C:17]([C:23]#[N:24])[CH:18]=[C:19]([CH:22]=3)[C:20]#[N:21])=[C:12]([CH:25]3[CH2:27][CH2:26]3)[NH:11][N:10]=2)[CH2:8][CH2:7]1>>[NH3:5].[NH2:5][CH2:4][CH2:3][N:10]1[C:9]([CH:6]2[CH2:8][CH2:7]2)=[C:13]([O:14][C:15]2[CH:22]=[C:19]([C:20]#[N:21])[CH:18]=[C:17]([CH:16]=2)[C:23]#[N:24])[C:12]([CH:25]2[CH2:27][CH2:26]2)=[N:11]1
Reactant: N#Cc1cc(C#N)cc(Oc2c(C3CC3)n[nH]c2C2CC2)c1
Reactant: NCCCl
Agent: Cl
Product: N
Product: N#Cc1cc(C#N)cc(Oc2c(C3CC3)nn(CCN)c2C2CC2)c1
Yield: 3.3 %

Procedure:
2-Chloroethylamine hydrochloride (192 mg, 1.65 mmol) and the pyrazole from Example 189 (440 mg, 1.50 mmol) were heated as a melt at 160° C. for 18 hours and the residue was partitioned between dichloromethane (25 ml) and 10% aqueous potassium carbonate solution (25 ml). The organic phase was dried over magnesium sulphate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0 changing to 95:5:0.5, by volume) to provide the title compound (9.2 mg) as a white solid, m.p. 175-177° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:15]1([C:18](=[S:20])[NH2:19])[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:18]([CH:15]2[CH2:17][CH2:16]2)[S:20][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-Chloro-2-oxo-3-phenyl-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=0.99 min; [M+H]+=260.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:24]([C:23]3[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]([OH:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=3)[NH:33][C:34](=[O:35])[NH:36][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccc(F)c(F)c1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccc(F)c(F)c2)cc([N+](=O)[O-])c1O
Yield: 43.4 %

Procedure:
To a solution of 2-(3,4-difluorophenyl)-1-phenylethanone (Intermediate 12) (150 mg, 0.65 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (128.1 mg, 0.65 mmol), and urea (117 mg, 1.95 mmol) in 20 mL of ethanol was added 0.2 ml con. HCl. The mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 30 (132 mg, yield 43.3%). 1H NMR (DMSO-d6 400 MHz): δ 10.30 (s, 1H), 8.82 (s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 7.30-7.20 (m, 6H), 7.07 (m, 1H), 6.86 (m, 1H), 6.59 (s, 1H), 5.27 (s, 1H), 4.08 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 468.0 [M+1]+
Reaction SMILES: CC(C1C=CC(=C)CC1)C.[CH3:11][C:12]1[CH:17]=[CH:16][C@@H:15]([C@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19])[CH2:14][CH:13]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH3:34])=[CH:29][CH:28]=1>>[CH3:11][C:12]1[CH:13]=[CH:14][C@@H:15]([C@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[CH3:19])[CH2:16][CH:17]=1.[CH3:26][C:27]1[CH:28]=[CH:29][C@@H:30]([C@@H:33]([CH2:35][CH2:36][CH:37]=[C:38]([CH3:39])[CH3:40])[CH3:34])[CH2:31][CH:32]=1
Reactant: CC(C)=CCCC(C)c1ccc(C)cc1
Agent: C=C1C=CC(C(C)C)CC1
Agent: CC(C)=CCC[C@H](C)[C@@H]1C=CC(C)=CC1
Product: CC(C)=CCC[C@@H](C)[C@@H]1C=CC(C)=CC1

Procedure:
beta-phellandrene, zingiberene and curcumene were not commercially available and had to be synthesised. Zingiberene and S-curcumene were isolated from ginger oil and 7-epi zingiberene and R-curcumene from S. habrochaites (PI27826) leaf material after Millar (1998, J. Nat. Prod 61, 1025).