Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@H:3]1[F:15].[O-]S([O-])(=O)=O.[Na+].[Na+].[N:23]1[C:31]2[C:26](=[N:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[S:25][N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCO>[F:15][C@@H:3]1[C@H:2]([NH:1][CH2:32][C:29]2[CH:30]=[C:31]3[N:23]=[N:24][S:25][C:26]3=[N:27][CH:28]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: O=Cc1cnc2snnc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: F[C@H]1CNCC[C@H]1NCc1cnc2snnc2c1
Temperature: 25 °C

Procedure:
A solution of cis-4-amino-1-tert-butoxycarbonyl-3-fluoropiperidine (1a) (1.00 mmole) in CH2Cl2 (5 mL) and EtOH (0.5 mL) is treated with anhydrous Na2SO4 (280 mg) and [1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxaldehyde (1b) (1.10 mmole). The resulting solution is stirred at room temperature, then sodium triacetoxy borohydride (320 mg, 1.50 mmole) is added. The mixture is quenched by the addition of water (2 mL) and the volatiles removed in vacuo. Purification gives the desired compound.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH3:19][O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:2]=1[C:27]1[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:21]([O:20][CH3:19])=[O:22])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: COc1ccc(Br)c(CNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccc(OC)cc2CNC(=O)OC(C)(C)C)c1
Temperature: 100 °C
Yield: 31.8 %

Procedure:
1.26 g of t-Butyl N-(2-bromo-5-methoxybenzyl)carbamate, 790 mg of 3-methoxycarbonylphenylboronic acid, 231 mg of tetrakistriphenyl phosphine palladium and 2.20 g of potassium carbonate were dissolved in 25 ml of toluene, and the mixture was heated at 100° C. for 7 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column, to give 470 mg of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O-:15].[Na+]>C1(C)C=CC=CC=1>[CH3:14][O:15][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2c(Cl)cc(Cl)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c2ccc(Cl)cc2n1
Temperature: 130 °C
Yield: 89 %

Procedure:
To a solution of 2,4,7-trichloroquinoline (150 mg, 0.685 mmol) in toluene (3 mL) was added a suspension of NaOMe (136 mg, 3.4 eq.) in toluene (3 mL). The mixture was refluxed at 130° C. for 24 h. After cooling to r.t. the solid was filtered and the filtrate was evaporated. The residue was dissolved in MeOH and evaporated to afford 2-methoxy-4,7-dichloroquinoline (139 mg) as an off-white solid. To it was added 1-N-Boc piperazine (455 mg, 4.0 eq.). The mixture was heated in a sealed tube at 150° C. for 3 h, additional piperazine (6 eq.) was added and treated with n-BuOH (2 mL). The reaction mixture was heated at the same temperature overnight. Evaporation of solvent under vacuum and flash chromatography on silica gel with AcOEt in hexane affords the corresponding t-butoxy-carbonylpiperazinylquinoline (20 mg), which was treated with TFA:DCM(1:1, 0.4 mL) at rt. for 1 h. Evaporation of the solvents and dilution with DCM and evaporation affords the corresponding unsubstituted piperazine as the TFA salt, which was dissolved in DCM (15 mL), in an ice bath. NEt3 (7 eq.) and 4-fluorophenylisocyanate (9 μl, 1.5 eq.) was added. After stirring at rt. for 3 h, the mixture was diluted with DCM and washed with water, followed by the usual work up. Flash chromatography on silica gel with MeOH in DCM afforded the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[N:9]=1)[C:5]#[N:6].[NH:11]([CH3:13])[CH3:12]>C1COCC1.CC(=O)OCC>[Cl:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([N:11]([CH3:13])[CH3:12])[N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1cc(C#N)cc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 2,6-dichloroisonicotinonitrile (2.50 g, 14.5 mmol) in 2 N Me2NH in THF (20 mL) is stirred in a sealed vessel at 105° C. for 24 h. The dark suspension is cooled to rt, diluted with EA (200 mL), washed with water (2×50 mL) followed by sat. aq. NaHCO3-solution (50 mL), dried over Na2SO4, filtered and concentrated to give crude 2-chloro-6-dimethylamino-isonicotinonitrile; LC-MS: tR=0.96 min, [M+1]+=182.00. This material is dissolved in dioxane (100 mL) and Pd(dppf) (120 mg, 0.147 mmol) is added. To this solution, MeZnCl (5.02 g, 43.4 mmol, 2 M solution in THF) is slowly added. The mixture is stirred at rt for 30 min, then at 75° C. for 16 h. The orange suspension is cooled to rt, diluted with EA (150 mL) and washed with water (2×50 mL). The aq. washings are basified by adding NaOH and the precipitate that forms is filtered off. The filtrate is extracted with DCM (3×70 mL). The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with EA containing methanol to give 2-dimethylamino-6-methyl-isonicotinonitrile (699 mg) as a brownish oil which slowly solidifies; LC-MS: tR=0.50 min, [M+1]+=162.05.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[OH:17])[C:9]([O:11]CC)=[O:10])[C:3]([CH3:5])=[CH2:4].[OH-].[K+]>CO.O>[CH3:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[OH:17])[C:9]([OH:11])=[O:10])[C:3]([CH3:5])=[CH2:4]
Reactant: C=C(C)C(C)c1cc(C(=O)OCC)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)C(C)c1cc(C(=O)O)ccc1O
Yield: 51.1 %

Procedure:
Ethyl 3-(1,2-dimethyl-allyl)-4-hydroxy-benzoate (600 mg, 2.56 mmol) was dissolved in methanol (20 ml), a solution of potassium hydroxide (560 mg, 10.0 mmol) in water (10 ml) was added and the mixture was stirred and held at reflux for 16 hours. Upon cooling the methanol was removed in vacuo and the solution acidified to pH 2 or below by the addition of 2M hydrochloric acid. The solution was extracted with dichloromethane, the organic layer was separated and the solvent was removed in vacuo to afford 3-(1,2-dimethyl-allyl)-4-hydroxy-benzoic acid (270 mg, 51%) as a colourless gum. 1H NMR (DMSO-d6) 12.38 (1H, brs), 10.22 (1H, brs), 7.63 (2H, m), 6.88 (1H, d), 4.90 (1H, s), 4.87 (1H, s), 3.75 (1H, q), 1.60 (3H, s), 1.28 (3H, d). MS: [M−H]+ 205.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: BrCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCc3cccnc3)cc2)c2ccccc21
Temperature: 90 °C

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was dissolved in DMF (5 mL) at room temperature. K2CO3 was added followed by 3-(3-bromo-propyl)-pyridine and the reaction was allowed to stir at 90° C. over night. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by HPLC to afford the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1oc(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c1OCc1ccccc1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Product: O=C(O)c1oc(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c1OCc1ccccc1
Yield: 84.93 %

Procedure:
3-Benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-07) (3.0 g, 84.93%) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-4-chloro-benzenesulfonamide (11-07) (3.4 g, 7.85 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:11][C:21]([NH:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[S:22])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccn1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccn1NC(=S)NC(=O)c1ccccc1
Reaction time: 8 h
Yield: 50.8 %

Procedure:
1-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (53.0 g, 0.344 mol) was dissolved in Tetrahydrofuran (2000 mL). Benzoyl isothiocyanate (56.1 g, 0.344 mol) was added and the reaction was allowed to stir overnight. The reaction mixture was reduced and 55.47 grams of 1-(3-Benzoyl-thioureido)-1H-pyrrole-2-carboxylic acid ethyl ester was isolated as a white solid via trituration with ether. (M+Na)=339.98. 1H NMR (400 MHz, DMSO, d6) δ 12.91 (s, 1H), 11.94 (s, 1H), 7.98 (d, 1H, J=7.32 Hz), 7.68 (t, 1H, J=7.52 Hz), 7.56 (t, 2H, J=7.64 Hz), 7.16 (m, 1H), 6.89 (m, 1H), 6.19 (m, 1H), 4.14 (q, 2H, J=7.12 Hz), 1.18 (d, 3H, J=14.17 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[F:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36].[Cl-].[NH4+]>ClCCl>[F:32][CH2:33][CH2:34][S:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:37])=[O:36]
Reactant: Cn1cc(-c2cc(N)ccc2OC2CCOC2)c2cc[nH]c2c1=O
Reactant: O=S(=O)(Cl)CCF
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc(NS(=O)(=O)CCF)ccc2OC2CCOC2)c2cc[nH]c2c1=O
Reaction time: 1 h
Yield: 6.5 %

Procedure:
To a mixture of Example 91b (80.0 mg, 0.246 mmol) and triethylamine (74.6 mg, 0.738 mmol) in dichloromethane (4 mL) was added dropwise 2-fluoroethanesulfonyl chloride (144 mg, 0.984 mmol), and the reaction mixture was stirred at about ambient temperature for about 1 hour. The reaction mixture was neutralized with saturated aqueous ammonium chloride solution (50 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water) to provide the title compound (7.0 mg, 6.5% yield). 1H NMR (300 MHz, CDCl3) ppm 11.54 (bs, 1H), 7.45 (t, J=2.8 Hz, 1H), 7.19 (s, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H) 6.67 (dd, J=3.1, 8.8 Hz, 1H), 6.40 (dd, J=2.0, 2.7 Hz, 1H), 4.76 (m, 1H), 3.82 (s, 3H), 3.85-3.62 (m, 8H), 2.97 (bs, 1H), 2.24-1.85 (m, 2H). MS (ESI+) m/z 436.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1)=[O:9])=[O:4].C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.O>ClCCl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=2[NH:5][C:3]([CH2:2][N:37]2[CH2:38][CH2:39][N:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)[CH2:35][CH2:36]2)=[O:4])=[N:12][CH:13]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(CBr)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CN1CCN(c2ccncc2)CC1)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 2-(bromoacetyl)amino-N-(5-chloropyridin-2-yl)benzamide (0.369 g, 1 mmol) in dichloromethane (10 ml) was added potassium carbonate (0.169 g, 1.22 mmol) and 1-(4-pyridyl)piperazine (0.171 mg, 1.05 mmol). The reaction was stirred overnight at room temperature. Water (2 mL) was added and the mixture was passed through a column of flux-calcined, high purity, inert diatomaceous earth packed into a polypropylene tube (article number CE 1103 from Varian) to remove water. The solvent was removed and the residue was purified by RPHPLC (CH2Cl2/5% 2 N ammonia in methanol) to give 0.08 g of pure title product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][O:26][CH2:27][CH2:28][OH:29]>CN1CCCC1=O>[CH3:25][O:26][CH2:27][CH2:28][O:29][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[CH:3]=1
Reactant: COCCO
Reactant: O=[N+]([O-])c1c(NCCO)cc(Cl)cc1NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COCCOc1cc(NCCO)c([N+](=O)[O-])c(NCCO)c1
Temperature: 0 °C

Procedure:
0.09 mole (25 g) of 4-chloro-2-(β-hydroxyethyl)amino-6-(β-hydroxyethyl)aminonitrobenzene, synthesized in stage 1 of example 2, was added to a solution of 11.9 g of pelletized potash in 60 ml of 2-methoxyethanol and 25 ml of N-methylpyrrolidone and heated for 4 hours over a boiling water bath. The reaction medium was diluted with 350 ml of ice water and the desired product obtained by high pressure liquid chromatography (HPLC). About 150 ml of the aqueous solution obtained by dilution of the reaction medium were injected onto a C18RD chromatographic column (Instrument: Waters Prep 500). The desired product was eluted by a 40% methanol--60% water solution. After evaporation of the fractions containing the desired product, a dry extract was obtained which was recrystallized from isopropanol. After recrystallization, it melted at 116° C.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=2[O:31][CH3:32])[N:20]=[C:19]1[NH2:33]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=2[O:31][CH3:32])[N:20]=[C:19]1[NH2:33])=[NH:5]
Reactant: COc1ccc(OC)c(-c2cn(N)c(N)n2)c1
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(OC)c(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)c1
Temperature: 80 °C

Procedure:
0.6 ml of concentrated hydrochloric acid is added, with stirring, to a mixture of 0.41 g (0.002 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.47 g (0.002 mol) of 1,2-diamino-4-(2,5-dimethoxyphenyl)-imidazole and 10 ml of isopropanol, and the reaction mixture is stirred at 80° C. for 3.hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and dried. In that manner there is obtained the title compound, m.p. >220° C., 1H-NMR (DMSO/D2 0): δ=8.23 (d, 1H); 7.75 (m, 2H); 7.61 (t, 1H); 7.17 (d, 1H); 7.07 (d, 1H); 6.93 (q, 1H); 3.82 (s, 3H), 3.71 (s, 3H); 3.25 (bs, 4H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[CH:19])[CH:16]=2)[C:11](=[O:20])[C:10]([CH3:22])([CH3:21])[CH:9]=1>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[C:10]([CH3:21])([CH3:22])[CH:9]=1
Reactant: C#Cc1ccc2c(c1)C(n1ccccc1=O)=CC(C)(C)C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc2c(c1)C(n1ccccc1=O)=CC(C)(C)C2=O
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 0.15 g (0.51 mol) of the product obtained in example 50 in 9 mL ethyl acetate, were added 0.03 g of 5% Pd/C and the mixture was hydrogenated at atmospheric pressure for 2 h. After filtration, the solvent was removed, affording 0.110 g of the title compound of this example as a white solid (yield: 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[OH:8].[Br:29][CH:30]=[CH:31][CH2:32][CH2:33]Br.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[O:8][CH2:33][CH:32]=[CH:31][CH2:30][Br:29]
Reactant: BrC=CCCBr
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c(OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CCBr)c(OCC)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(3-bromo-5-ethoxy-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (3.04 g), 1,4-dibromobutene (11.68 g) and potassium carbonate (1.887 g) in dioxane (100 ml) was stirred at 80° C. for 5 h. The mixture was poured into water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in acetonitrile, washed with petroleum ether and heptane to remove most of the excess of dibromobutene. The acetonitrile layer was concentrated in vacuo and the residue recrystallized from dichloromethane and heptane. Yield: 3.02 g. MS-ESI: [M+H]+=579.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1I.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[Cl:21]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1cnccc1I
Reactant: OB(O)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from [tert-butoxycarbonyl-(4-iodo-pyridin-3-yl)-amino]-acetic acid methyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 60:40) for the chromatographic purification. Colorless oil (49%). MS (ESI): m/z=377.126 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19].[CH3:22][C:23]1[CH:27]=[C:26]([CH2:28][C:29](O)=[O:30])[O:25][N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=2)=[CH:4][C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:26]2[O:25][N:24]=[C:23]([CH3:22])[CH:27]=2)[CH:7]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1NC(=O)Cc1cc(C)no1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.8 %

Procedure:
To a solution of methyl 4-amino-6-chloro-4′-(dimethylamino)-[1,1′-biphenyl]-3-carboxylate (Intermediate 47) (10.8 g, 35.4 mmol) in dichloromethane (525 mL) was added 2-(3-methylisoxazol-5-yl)acetic acid (Aldrich, 5 g, 35.4 mmol), HATU (17.52 g, 46.1 mmol) and triethylamine (11.85 mL, 85 mmol) and the reaction mixture was stirred at room temperature for 72 h. The mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with hot methanol, filtered and dried to give the title compound methyl 6-chloro-4′-(dimethylamino)-4-(2-(3-methylisoxazol-5-yl)acetamido)-[1,1′-biphenyl]-3-carboxylate (13.91 g, 32.5 mmol, 92% yield) as a beige solid. LCMS: (M+H)+=428; Rt=3.86 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[N:7]=1.[C:12]([O:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>C(O)C.CN(C)C=O>[C:12]([O:15][CH2:16][C:17]1[NH:11][C:9](=[O:10])[C:3]2[C:2](=[N:7][C:6]([OH:8])=[CH:5][N:4]=2)[N:1]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ncc(O)nc1N
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)OCc1nc2nc(O)cnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 5.0 g (0.0324 mole) of 3-amino-5-hydroxy-2-pyrazinecarboxamide, 29.5 g (0.134 mole) of triethyl orthoacetoxyacetate and 9.5 ml of acetic anhydride. Refluxing time: 1 hour 45 minutes. Yld: 3.8 g (50%), m.p.>300° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]=[C:11]=S.[NH:13]([C:15](=[O:37])[C:16]([NH:18][C:19]1[CH:36]=[CH:35][C:22]([O:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:21][CH:20]=1)=[O:17])[NH2:14].CCN=C=NCCCN(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:37][C:15]([C:16]([NH:18][C:19]2[CH:36]=[CH:35][C:22]([O:23][C@H:24]3[CH2:25][CH2:26][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:21][CH:20]=2)=[O:17])=[N:13][N:14]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: Fc1cc(F)c(N=C=S)cc1F
Agent: CCN=C=NCCCN(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,4,5-trifluorophenyl isothiocyanate (70 mg, 0.37 mmol) in DMA (1 mL) was added in one portion to a stirred solution of ethyl trans-4-(4-{[hydrazino(oxo)acetyl]amino}-phenoxy)cyclohexanecarboxylate (Intermediate 80, 129 mg, 0.37 mmol) in DMA (3 mL) and the reaction mixture was stirred at room temperature for 1 h. EDCI (71 mg, 0.37 mmol) was added in one portion and the reaction mixture was heated to 85° C. for 20 minutes in a microwave. The mixture was cooled to room temperature and a further portion of EDCI (7.1 mg, 0.04 mmol) was added and the reaction mixture stirred at 85° C. for 10 minutes in a microwave. The reaction mixture was concentrated in vacuo to leave a solid, which was recrystallised (CH3CN) to give the title compound (125 mg, 69%) as a solid; 1H NMR δ1.33 (3H, t), 1.48-1.58 (2H, m), 1.68-1.72 (2H, m), 2.06-2.10 (2H, m), 2.18-2.22 (2H, m), 2.45-2.53 (1H, m), 4.21 (2H, q), 4.39-4.46 (1H, m), 7.07-7.11 (2H, d), 7.81-7.84 (2H, d), 7.80-7.91 (1H, m), 8.29-8.36 (1H, m), 11.12-11.25 (1H, m); MS m/e MH+ 505.