Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]([CH3:41])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[C:29]([CH3:41])[CH:30]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ncc(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)ccc1C
Temperature: 80 °C
Yield: 76.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (98 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol) and the reaction mixture was heated to 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The aqueous layer was back extracted with ethyl acetate (5 mL). The organics were dried over sodium sulfate and evaporated. The resulting crude material was purified by silica gel chromatography (eluting with 0-30% ethyl acetate in hexanes) to yield the product (95 mg, 76%). ESI-MS m/z calc. 415.48. found 416.1 (M+1)+. Retention time 1.92 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol), prepared as described in Step A, was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([NH:17][C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=[C:7]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:6]=2.[CH2:32]([O:39][C:40]1C=CC2C3N(CC(N(C(C)C)C(N)=O)(C)C)C(COCC)=NC=3C=NC=2[CH:49]=1)[C:33]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([NH:17][C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:16])[CH3:15])[C:33]([CH2:32][O:39][CH2:40][CH3:49])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)NC(=O)NC(C)(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)N(C(N)=O)C(C)C
Solvent: Cc1ccccc1
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C

Procedure:
The material from Part B was combined with N-(2-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea from another experiment, suspended in toluene, and concentrated under reduced pressure. The N-(2-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea (4.57 g, 10.8 mmol) was converted into N-{2-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N-isopropylurea using the method described in Part D of Example 45. The crude product was purified using flash chromatography (silica gel, elution with 6% methanol in dichloromethane) to afford 3.81 g of N-{2-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea as an off white solid.
Reaction SMILES: [I-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].O1CCCC1.C([Li])CCC.[CH2:35]([O:42][CH2:43][CH:44]([CH3:53])[CH2:45]/[CH:46]=[CH:47]/[CH:48]([CH3:52])[CH2:49][CH:50]=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCCCCC.O>[CH3:53][CH:44]([CH2:45][CH:46]=[CH:47][CH:48]([CH3:52])[CH2:49][CH:50]=[CH:2][CH:3]([CH3:5])[CH3:4])[CH2:43][O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(/C=C/CC(C)COCc1ccccc1)CC=O
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C=CCC(C)C=CCC(C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1.52 g. (3.42 mmoles) of isobutyltriphenylphosphonium iodide in 30 ml. of anhydrous tetrahydrofuran was stirred and cooled to 0° C. while 1.55 ml. (3.42 mmoles) of n-butyllithium solution in hexane was added. The resulting red solution was stirred for 10 minutes at room temperature then treated with a solution of rac. E-8-benzyloxy-3,7-dimethyl-4-octenal (0.594 g.; 2.28 mmoles) in 10 ml. of anhydrous tetrahydrofuran. After stirring at room temperature for 30 minutes, the reaction mixture was treated with water and worked up by extraction with hexane as in Example 1. The semi-solid residue was treated with hexane and filtered to remove insoluble material. The filtrate was concentrated in vacuo to give 0.72 g. of yellow oil. This material was chromatographed on 30 g. of silica gel. Elution with 9:1 parts by voluem hexane-ether afforded 0.427 g. (62.5%) of an oil. Evaporative distillation yielded rac. benzyl 2,6,10-trimethyl-undeca-4,8-dien-1-yl ether as a colorless liquid, b.p. 110°-115° C. (bath temperature) (0.03 mm Hg.).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:21][C:22]1[CH:45]=[C:44]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH:43]=[CH:42][C:23]=1[C:24]([C:26]1[CH:27]=[CH:28][C:29]([O:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[C:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:31]=1)=O)[CH:18]([CH3:20])[CH3:19].C(OCC)(=O)C>CN(C)C=O.O>[CH2:17]([O:21][C:22]1[CH:45]=[C:44]([O:46][CH2:47][CH:48]([CH3:49])[CH3:50])[CH:43]=[CH:42][C:23]=1[C:24]([C:26]1[CH:27]=[CH:28][C:29]([O:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[C:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:31]=1)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:20])[CH3:19]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C=C(c1ccc(OCC(C)C)c(CCC(=O)O)c1)c1ccc(OCC(C)C)cc1OCC(C)C
Temperature: 25 °C

Procedure:
In 5 ml of N,N-dimethylformamide is suspended 0.85 g of 60% sodium hydride, to which is dropwise added 4.2 ml of ethyl diethylphosphonoacetate at ambient temperature over a period of 10 minutes. After stirring the mixture thus obtained for 30 minutes, 1.00 g of 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoic acid is added and stirred at 110° C. for 5 hours. The reaction mixture is cooled to ambient temperature and added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 0.36 g of 3-{5-[1-(2,4-diisobutoxyphenyl)-3-ethoxy-3-oxo-1-propenyl]-2-isobutoxyphenyl}propanoic acid as a light yellow oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].[CH3:28][CH2:29][O-].[Na+].C(Br)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:28][CH3:29])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[N:8]=[C:7]1[NH2:27])=[O:5])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CCO
Solvent: CCBr
Product: CCOC(=O)C1=C(C)N=C(N)C(CC)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A solution of 37.4 g of 2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol is brought to the boil and treated with 10.9 g of ethyl bromide. After boiling for a further 60 minutes under reflux, the mixture is concentrated by distillation and the residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water. Concentration of the organic phase and recrystallization from ethanol gave 2-amino-3-ethyl-6-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 122°-3°C (16.5 g, 41% of theory).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29]C)=[O:28])[CH:18]=4)[N:13]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].O>O1CCCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:21]([N:22]([CH:24]([CH3:25])[CH3:26])[CH3:23])=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:27]([OH:29])=[O:28])[CH:18]=4)[N:13]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2cc(-c3nc4ccc(C(=O)OC)cc4nc3N(C)C(C)C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1ncc2cc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a solution of methyl 2-(1-ethyl-1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (80 mg, 0.20 mmol) in tetrahydrofuran (25 mL) was added sodium hydroxide (34 mg, 0.85 mmol) and water (2 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 2-(1-ethyl-1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as yellow solid (18.6 mg, 24%).
Reaction SMILES: C(OC(=O)[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18](=[O:19])[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]#[N:34])=[CH:23][C:22]=3[F:35])=[C:16]([CH2:36][CH2:37][CH3:38])[N:15]3[N:39]=[CH:40][CH:41]=[C:14]23)[CH2:9][CH2:8]1)C.[CH3:43][Mg]Br.C([O:49][CH2:50][CH3:51])(=O)C>O1CCCC1>[F:35][C:22]1[CH:23]=[C:24]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:26][C:21]=1[CH2:20][C:17]1[C:18](=[O:19])[N:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([O:6][CH2:5][C:50]([OH:49])([CH3:51])[CH3:43])[CH2:12][CH2:11]2)[C:14]2[N:15]([N:39]=[CH:40][CH:41]=2)[C:16]=1[CH2:36][CH2:37][CH3:38]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reactant: CCOC(C)=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reaction time: 0.5 h

Procedure:
To a solution of ethyl[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (0.40 g) in tetrahydrofuran (4 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.71 mL) at 0° C., and the mixture was stirred for 30 min. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.26 g, 88%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([C:14]1[C:22]2[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH2:12][CH3:13])(=O)=O.O.ClCCl>CS(C)=O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:11]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([CH2:12][CH3:13])[CH2:10][CH2:9][C:1]#[N:2])=[CH:31][CH:30]=1
Reactant: [C-]#N
Reactant: CCC(CCOS(C)(=O)=O)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCC(CCC#N)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 80 °C
Reaction time: 12 h

Procedure:
223 mg (3.43 mmol) of potassium cyanide were added to 775 mg (1.71 mmol) of the compound from Example 115A in 12 ml of DMSO. The mixture was stirred at 80° C. for 12 h, water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phase was extracted with dichloromethane, and the combined organic phases were freed of solvent. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 551 mg (84% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-].Cl>C1COCC1.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C#N)nc(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)cc(C#N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under N2, methyl 2-cyano-6-methoxyisonicotinate (0.433 g, 2.25 mmol, Eq: 1.00) was dissolved in THF (25.0 ml) and Methanol (3.03 ml). At 0° C., 1M LiOH in H2O (2.82 ml, 2.82 mmol, Eq: 1.25) was added and the RM was stirred at 0° C. for 30 minutes. Control with TLC: the reaction was finished. The reaction mixture was acidified with 1M HCl. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over MgSO4; filtered; concentrated in vacuo. Light yellow solid. MS (EIC): 176.8 ([M−H]−)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([N:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:14]([CH3:15])[CH2:13][C:12]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])=[O:16])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: C/C=C/C(=O)N1CCOC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(CC(=O)N1CCOC1=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a solution of 4-trifluoromethylaniline (193 mg, 1.2 mmol) and 3-crotonoyl-1,3-oxazolidin-2-one (155 mg, 1.0 mmol) in toluene (3 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (26.6 mg, 0.025 mmol) and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was then evaporated off and the crude product obtained was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective compound 3-(4-trifluoromethylanilino)butyryl-1,3-oxazolidin-2-one (238 mg, 75% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: AD-H) to be 83% e.e.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:22])[C:16]=1[CH3:32].C(N(CC)CC)C.ClC(OCC)=O.[NH2:46][OH:47]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:46][OH:47])=[O:31])=[O:22])[C:16]=1[CH3:32]
Reactant: NO
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (441 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (201 mg, 44%) as a red solid. LC-MS (m/z) 457 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18].[Na+].Cl>O1CCCC1>[F:14][C:4]1[CH:3]=[C:2]([C:17]([OH:18])([CH3:19])[C:16]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)C(=O)[O-]
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Yield: 71 %

Procedure:
A solution of 4-bromo-2-fluorobiphenyl (5 g., 0.02 mole) in dry tetrahydrofuran (20 ml.) was added dropwise, with stirring, to magnesium turnings (0.49 g.) in dry tetrahydrofuran (13 ml.). When the addition was complete, the mixture was stirred and boiled under reflux for one hour. A suspension of sodium pyruvate (2.2 g., 0.02 mole) in dry tetrahydrofuran (20 ml.) was added rapidly to the refluxing solution. Frothing occurred and when this had subsided the mixture was boiled under reflux with stirring for a further hour. The mixture was then cooled in an ice-bath and dilute hydrochloric acid (5 N; 50 ml.) was added. The mixture was stirred and extracted with ether. The extract was then extracted with aqueous potassium carbonate (1 N) and this extract acidified with dilute hydrochloric acid. The precipitate which separated, was collected and dried to give 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid, m.p. 166°-9° C. in 71% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:16][CH2:17][CH2:18][C:13]=2[N:12]=[C:11]1[CH:25]([CH3:27])[CH3:26].CO.[OH-].[Na+]>CC1OCCC1>[NH3:10].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]([CH2:19][C:20]([OH:22])=[O:21])[CH2:16][CH2:17][CH2:18][C:13]=2[N:12]=[C:11]1[CH:25]([CH3:26])[CH3:27]
Reactant: CCOC(=O)CC1CCCc2nc(C(C)C)n(Cc3ccc(Cl)cc3Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC1CCCO1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1Cl)C(CC(=O)O)CCC2
Product: N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 46 (35 mg) was dissolved in 2 ml of MeTHF. Potassium trimethylsilanoate (12.19 mg) was added and the mixture stirred at room temperature overnight. 2 ml further MeTHF was added to the reaction, followed by Methanol. 4 M equivalent of sodium hydroxide was added and the reaction stirred at 50° C. for 2 hours. The reaction mixture passed through an SCX ion exchange column (10 g) and eluted with 2M Ammonia and methanol. (28 mg). LC/MS MH+ 381, Rt 2.06 min (5 min run, TFA modifier).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-:3])=[O:2].[CH3:14][CH2:15][O:16][C:17](OCC)(OCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7](=[C:17]([O:16][CH2:15][CH3:14])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]1=[O:13])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1

Procedure:
5.07 g (23 mmol) of 5-nitro-2-indolinone are stirred for 2.5 hours at 100° C. together with 15.5 g (69 mmol) of triethyl orthobenzoate in 50 ml of acetic anhydride. After cooling, 100 ml of ether/petroleum ether (1:1) are added. The precipitate formed is suction filtered, washed with ether/petroleum ether (1:1) and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26](O)=[O:27])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:33][NH2:34]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([NH:34][CH3:33])=[O:27])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)O)CC4)nc23)c1
Reactant: CN
Solvent: O=S(Cl)Cl
Product: CNC(=O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4cccc(C)c4)c3n2)CC1

Procedure:
Prepared from compound 134 of Example 1 by reaction with thionyl chloride and methylamine.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:23]O)[N:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1>ClCCCl>[ClH:3].[Cl:3][CH2:23][C:17]1[N:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=1
Reactant: CC(C)Cn1c(CO)nc2c(N)nc3c(c21)CCCC3
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C)Cn1c(CCl)nc2c(N)nc3c(c21)CCCC3
Product: Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Thionyl chloride (2.65 mL, 36.2 mmol) was added dropwise to a stirred suspension of [4-amino-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methanol (4.97 g, 18.1 mmol) in 1,2-dichloroethane (200 mL). The suspension dissolved, then a precipitate formed after 5 minutes. The reaction mixture was stirred at room temperature for 6 hours, then was concentrated under reduced pressure to yield crude 2-(chloromethyl)-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride, all of which was used in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])(C)(C)C.C(C(O)=O)(F)(F)F.O>C(Cl)Cl>[CH3:1][O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19]
Reactant: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1ccc(O)cc1CNC(=O)OC(C)C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
A solution of 3-[4-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (3.0 mmol, 1.0 g) in CH2Cl2 (10 mL) was treated with 90% CF3CO2H/H2O (20 mL) at ambient temperature. The mixture was stirred for 3 h and concentrated. The residue was dissolved in MeOH (20 mL), treated with conc. H2SO4 (1 mL), and heated at reflux for 14 h. The mixture was cooled and concentrated. The residue was dissolved in water/ethyl acetate and neutralized with K2CO3. The organic layer was dried (Na2SO4), and concentrated to give the title compound (0.76 g, 86%). HRMS Calculated for C15H22NO5: m/z 296.1498. Found: 296.1504.