Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.B(F)(F)F.CCOCC>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:24]/[NH:23][C:20](=[NH:21])[NH2:22])/[CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(CCC(F)(F)C(F)(F)F)c1cc(Cl)ccc1Br
Reactant: N=C(N)NN
Agent: Cl
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Product: N=C(N)N/N=C(\CCC(F)(F)C(F)(F)F)c1cc(Cl)ccc1Br
Temperature: 100 °C

Procedure:
To a screw cap pressure vessel was added the intermediate from Step B (0.450 g, 1.2 mmol), aminoguanidine hydrochloride (0.456 g, 6.2 mmol), methanol (20 mL) and boron trifluoride diethyl etherate (0.94 mL, 7.4 mmol). The reaction solution was heated at 100° C. for 3 hours. The solution was concentrated and the residue partitioned between EtOAc and aqueous 1N NaOH. The organic phase was washed twice with aqueous 1N NaOH and brine (1×). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the indicated compound as a mixture of E,Z hyrazone isomers. 1H NMR (500 MHz, CH3OH-d4): δ 7.60 (d, J=8.6 Hz, 1H); 7.26-7.23 (m, 1H); 7.18 (d, J=2.5 Hz, 1H); 2.74 (s, 2H); 2.56 (s, 2H). m/z=421.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12])=[N:6][CH:7]=1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: O
Solvent: CS(C)=O
Product: COCCCNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (5.12 g, 21.6 mmol) in DMSO (20.5 mL) was added 3-methoxypropylamine (4.40 mL, 43.1 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated in vacuo to give a light yellow brown solid as 5-bromo-N-(3-methoxypropyl)-3-nitropyridin-2-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H, br. s.), 8.54 (1H, d, J=2.3 Hz), 8.43 (1H, d, J=2.3 Hz), 3.69-3.78 (2H, m), 3.56 (2H, t, J=5.7 Hz), 3.40 (3H, s), 1.96 (2H, dt, J=12.2, 6.2 Hz).
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][C:13]([CH3:16])=[CH:14]2)[C:9](=O)[NH:8][C:7]1=[O:18])([CH3:5])[CH3:4].[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.Cl>O1CCCC1>[CH:3]([N:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][C:13]([CH3:16])=[CH:14]2)[C:9]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[N:8][C:7]1=[O:18])([CH3:5])[CH3:4]
Reactant: CC1=CC2C(CC1)C(=O)NC(=O)N2C(C)C
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CC2C(CC1)C(c1ccc(F)cc1)=NC(=O)N2C(C)C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 2.37 g sodium hydride in 45 ml tetrahydrofurane are added portionwise at room temperature 13.32 g 1-isopropyl-7-methyl-4a,5,6,8a-tetrahydro-2,4-(1H)-quinazolindione and the mixture stirred for 45 minutes. 39 ml of a 2N solution of 4-fluorophenyl magnesium bromide in tetrahydrufurane are then added dropwise within 2 hours at an internal temperature of 40° and the resulting suspension stirred at 40° for 15 hours. 23 ml 15% hydrochloric acid are then added under ice cooling and the solvent removed in vacuo. The residue is taken up with water and methylene chloride. The methylene chloride phase is evaporated to dryness to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:33][N:32]=3)[C:27](=[O:44])[N:26]([CH3:45])[CH:25]=2)[C:5]([CH2:22][OH:23])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1.[C:46]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]4)=[CH:33][N:32]=3)[C:27](=[O:44])[N:26]([CH3:45])[CH:25]=2)[C:5]([CH2:22][O:23][CH3:46])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1
Reactant: CN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 2-(5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 197 (200 mg, 0.33 mmol) and K2CO3(135 mg, 0.99 mmol) in DMF(30 mL) was added the solution of iodomethane (70 mg, 0.50 mmol) in DMF(5 mL) at room temperature. The reaction mixture was stirred for 1 h. It was then filtered and the residue was purified by prep-HPLC to afford 333 as a yellow solid (165 mg, 80%). MS: [M+H]+ 626. 1H NMR (500 MHz, DMSO) δ 8.59 (d, J=2.0, 1H), 8.49 (s, 1H), 7.97 (d, J=2.0, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.32 (m, 2H), 7.17 (m, 1H), 6.52 (s, 1H), 4.31 (s, 2H), 4.14 (m, 3H), 3.88 (s, 1H), 3.56 (s, 3H), 3.54 (s, 4H), 3.44 (s, 4H), 3.12 (s, 6H), 2.58 (m, 2H), 2.46 (s, 2H), 1.79 (s, 2H), 1.68 (s, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[C:7]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)(=O)[CH3:8]>CO>[C:7](=[N:2][OH:3])([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH3:8]
Reactant: CC(=O)c1ccncc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.5 %

Procedure:
To a solution of 7.64 g. (110 mmole) of hydroxylamine hydrochloride in 150 ml. of methyl alcohol were added 5.94 g. (110 mmole) of sodium methylate and the mixture was stirred at room temperature for 10 minutes. A solution of 12.11 g. (110 mmoles) of 4-acetylpyridine in 50 ml. of methyl alcohol was added dropwise over 3 minutes and the reaction mixture was stirred at room temperature for 3 hours and at the reflux temperature for 2.5 hours. After the mixture had cooled, the precipitate of sodium chloride was separated by filtration and the filtrate was concentrated by evaporation to one-half of the original volume. The concentrate was diluted with 50 ml. of water and the solution concentrated to a volume of about 100 ml. This concentrate was chilled in an ice bath for 30 minutes and the precipitate of the oxime was separated by filtration in the cold. There were obtained 8.38 g. (61.5% yield) of 4-acetylpyridine oxime.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[NH:8][C:9]2[C:13]([C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[N:8]([CH2:30][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[C:13]([C:14]=1[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2n(CC(=O)c2ccccc2)c1=O
Yield: 66 %

Procedure:
The compound was prepared from 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (40) and 2-bromoacetophenone by applying general procedure A. Yield 66%; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, J=7.2 Hz, 3H), 3.34 (m, 4H), 3.86 (m, 4H), 4.24 (q, J=7.2 Hz, 2H), 5.58 (s, 2H), 7.15 (dd, J=3.6, 4.6 Hz, 1H), 7.24 (d, J=3.2 Hz, 1H), 7.48 (dd, J=1.2, 3.6 Hz, 1H), 7.60 (m, 2H), 7.71 (m, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 8.09 (m, 2H), 8.16 (d, J=3.2 Hz, 1H) ppm; MS m/z=535 amu (M++1). Anal. (C27H25N3O5S2) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH4+].[Cl-].CCO>[Fe].O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2ccc(Cl)nc12
Temperature: 60 °C

Procedure:
A solution of 2-chloro-8-nitroquinoline (1.02 grams), iron powder (2.05 grams) and NH4Cl (2.6 grams) in 5:1 EtOH:Water (50 mL) was refluxed for 9 hours. After the reaction was complete, the solution was cooled to 60° C. and filtered through celite. The cake was washed with isopropyl alcohol followed by ethyl acetate. The filtrate was concentrated to dryness, dissolved in ethyl acetate and washed with water, dilute aqueous NaHCO3, brine and dried (Na2SO4) and concentrated to an oil. The desired product crystallized with the addition of pentane, brown solid (0.818 grams).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[F:13][CH2:14][C:15](O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:12]=[C:15]([CH2:14][F:13])[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: O=C(O)CF
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)c2nc(CF)[nH]c2c1
Yield: 75.4 %

Procedure:
To a 250 mL round bottomed flask was added 3-bromo-5-nitrobenzene-1,2-diamine (6.75 g, 29.1 mmol) and 2-fluoroacetic acid (4.54 g, 58.2 mmol) in Toluene (100 mL). The solution was heated to reflux 48 h. The reaction was found to be incomplete so an additional equivalent of acid (2.25 g) was added and solution was heated 6 hours. The mixture was allowed to cool and was evaporated. The residue was dissolved in 20 ml of DCM and was filtered through a sintered glass funnel where a brown precipitate (5.5 g, 69%) was isolated to obtain 4-bromo-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (6.01 g, 21.93 mmol, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.69 (s, 1H) 5.81 (s, 1H) 8.33 (d, J=2.02 Hz, 1H) 8.49 (br. s., 1H); LC/MS: MS (ES+) m/e 275 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][C:5]([O:7][CH2:8][O:9][C:10](=[O:17])[CH2:11][CH:12](OC)[O:13][CH3:14])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][O:13][CH:12]=[CH:11][C:10]([O:9][CH2:8][O:7][C:5](=[O:6])[CH:4]=[CH:3][O:2][CH3:1])=[O:17]
Reactant: COC(CC(=O)OCOC(=O)CC(OC)OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC=CC(=O)OCOC(=O)C=COC
Yield: 79 %

Procedure:
Methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 (14.01 g, 50 mmol) and a catalytic amount of p-toluene sulfonic acid is added to toluene (250 ml). The methanol is removed by warming the reaction under an N2 atmosphere. When the reaction is complete the toluene is distilled off under reduced pressure. Diethyl ether (250 ml) is added and the mixture is washed with saturated aqueous sodium hydrogen carbonate (5×50 ml) and water (3×50 ml). The organic layer is dried (MgSO4) before evaporation to give 8.52 g (79%) product.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]2[C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[O:14])=[CH:11][N:10]=2)[CH2:3]1.Br[C:39]1[S:43][CH:42]=[N:41][CH:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[OH:1][C@H:2]1[C@H:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]2[C:28]([C:39]3[S:43][CH:42]=[N:41][CH:40]=3)=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:18][CH:17]=3)=[O:14])=[CH:11][N:10]=2)[CH2:3]1
Reactant: CC1(C)OB(c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2C[C@H](CO)[C@@H](O)C2)OC1(C)C
Reactant: Brc1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](CO)[C@H](O)C2)c(-c2cncs2)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
6-((3R,4R)-3-Hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 17.1, 50 mg, 0.096 mmol), 5-bromothiazole (78 mg, 0.478 mmol), Pd(Ph3P)4 (11.04 mg, 9.55 μmol), K3PO4 (81 mg, 0.382 mmol) toluene (478 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and the RM was stirred for 16 h at 110° C. The RM was diluted with DME (2 mL)/EtOAc (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 39.8 mg, 0.057 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column Diol, isocratic at 30% in 8 min) to afford the title compound as an amber wax. UPLC-MS (Condition 3) tR=0.90 min, m/z=481.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.05-2.15 (m, 1H) 2.99 (dd, J=10.79, 3.14 Hz, 1H) 3.18-3.23 (m, 1H) 3.22-3.28 (m, 1H) 3.39 (m, J=5.40 Hz, 2H) 3.52 (dd, J=11.30 Hz, 1H) 3.94-4.03 (m, 1H) 4.66 (t, J=5.27 Hz, 1H) 5.00 (d, J=4.27 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.83-7.89 (m, 2H) 7.94 (d, J=0.50 Hz, 1H) 8.09 (d, J=2.38 Hz, 1H) 8.78 (d, J=2.38 Hz, 1H) 9.20 (d, J=0.50 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][OH:24])[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2COS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
[3-(2-Hydroxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.355 g, 1.0 mmol) and triethylamine (0.21 mL, 1.5 mmol) were combined in CH2Cl2 (7.2 mL) and cooled to 0° C. Methanesulfonyl chloride (0.09 mL, 1.1 mmol) was added, and the reaction was stirred for 3 hours. Some starting material was still seen by analytical LCMS, so additional methanesulfonyl chloride (0.04 mL) and triethylamine (0.07 mL) was added at 0° C., and the reaction was stirred for another 2 hours. The mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14](=[O:31])[CH:15]([NH2:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14](=[O:31])[CH:15]([NH:30][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)C(N)Cc1ccc(-c2cccc(O)c2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(-c2cccc(O)c2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 36 %

Procedure:
A solution of 2-amino-5-chloro-benzoic acid (1.95 g, 11.38 mmol) in DMF (10.0 mL) was reacted with 2-amino-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester (3.50 g, 11.38 mmol), HBTU (3.98 g, 10.50 mmol), and DIEA (6.08 mL, 34.15 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silical gel using DCM (+15% hexane) and increasing the gradient to DCM and finally DCM (+0.25% methanol) to give 1.75 g, (36%) of 2-(2-amino-5-chloro-benzoylamino)-3-(3′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester as a white solid. LCMS: 425 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:20][CH2:19][CH2:18][C:8]3([CH2:12][CH2:11][CH:10](C(OC)=O)[C:9]3=[O:17])[C:6]=2[CH:7]=1>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:20][CH2:19][CH2:18][C:8]3([CH2:12][CH2:11][CH2:10][C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: COC(=O)C1CCC2(CCOc3ccc(F)cc32)C1=O
Agent: Cl
Product: O=C1CCCC12CCOc1ccc(F)cc12
Temperature: 25 °C

Procedure:
A mixture of 10.6 g (0.038 mol) of Methyl 6-fluoro-2,3-dihydro-2'-oxo-Spiro[4H-benzopyran-4,1'-cyclopentane]-3'-carboxylate in 280 ml of 1N HCl containing 8 ml of concentrated HCl was heated at reflux for 3 hours. The reaction was cooled to room temperature and extracted twice with EtOAc. The combined extracts were dried over NaSO4 and filtered. The filtrate was evaporated in vacuo to a solid residue (5.7 g, 68%) which was recrystallized from petroleum ether: m.p. 49°-51° C. NMR (CDCl3) (delta) 1.7-2.7 (m, 8H, CH2), 4.0-4.5 (m, 2H, CH2), 6.4-6.9 (m, 3H, arom).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15]CC)=O)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.C1COCC1.Cl.[Na+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:15])[N:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Cl)c2cccc(F)c2n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1nc(Cl)c2cccc(F)c2n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of ethyl 4-chloro-8-fluoroquinazoline-2-carboxylate (360 mg, 1.42 mmol) in THF (20 mL) at −40° C. was added 1M 4-fluorophenylmagnesium bromide/THF (1.7 mL, 1.7 mmol) and the mixture was stirred at −40° C. for 3 h. After this time, and additional portion of 1M 4-fluorophenylmagnesium bromide/THF (0.3 mL, 0.3 mmol) was added and the mixture was stirred at −40° C. for 2 h. To the mixture was added 0.5N HCl to give pH 2, and then saturated aq NaCl (50 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (4-chloro-8-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (0.4 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 7.04-7.25 (m, 1H), 7.31-7.58 (m, 2H), 7.70-8.36 (m, 4H); LC-MS (ESI) m/z 305 (M+H)+, 327 (M+Na)+.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH:2]1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[Br:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[CH:17][C:16]=1[N:24]=[C:25]=[O:26]>>[Br:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[CH:17][C:16]=1[NH:24][C:25]([N:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH:2]1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:26]
Reactant: O=C1C=CNC(c2cccnc2)C1
Reactant: COc1cc(N=C=O)c(Br)cc1C
Product: COc1cc(NC(=O)N2C=CC(=O)CC2c2cccnc2)c(Br)cc1C

Procedure:
2,3-Dihydro-1H-[2,3′]bipyridinyl-4-one was reacted with 1-bromo-2-isocyanato-4-methoxy-5-methyl-benzene using the procedure of step 3 of Example 1 to afford 4-oxo-3,4-dihydro-2H-[2,3′]bipyridinyl-1-carboxylic acid (2-bromo-5-methoxy-4-methyl-phenyl)-amide, MS (M+H) 417.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.[CH3:23][C:24](=O)[CH2:25][CH2:26][C:27](=O)[CH3:28].C(O)(=O)C>C(O)C>[CH3:28][C:27]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=3)[CH:7]=2)[C:24]([CH3:23])=[CH:25][CH:26]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCOc1ccc(-n2c(C)ccc2C)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Yield: 43.9 %

Procedure:
The compound (200 mg, 0.66 mmol) of example 42 and 2,5-hexanedione (76 mg, 0.66 mmol) were dissolved in ethanol (10 ml) and added with glacial acetic acid (0.1 ml), followed by refluxing for 12 h. The reaction mixture was concentrated to dryness, dissolved in CH2Cl2 (10 ml), and washed with saturated NaHCO3 (10 ml) and saturated saline (10 ml), dried and concentrated. The residue was passed through a silica gel column to give the title compound (110 mg, yield: 44%). 1H NMR (CDCl3) δ: 11.20 (1H, br), 8.42 (1H, d), 7.30 (1H, dd), 7.10 (1H, d), 5.93 (2H, s), 4.23 (2H, t), 2.63 (2H, q), 2.59 (2H, q), 2.06 (6H, s), 2.04 (2H, m), 1.24 (3H, t), 1.18 (3H, t), 1.15 (3H, t).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.[NH2:9][C@H:10]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:11][C@:12]([CH2:17][O:18][CH2:19][CH3:20])([CH3:16])[C:13]([OH:15])=[O:14]>>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([CH2:21][C@@H:10]([NH:9][C:6]([C:4]2[N:3]=[N:2][NH:1][CH:5]=2)=[O:8])[CH2:11][C@:12]([CH2:17][O:18][CH2:19][CH3:20])([CH3:16])[C:13]([OH:15])=[O:14])=[CH:27][CH:26]=1
Reactant: O=C(O)c1c[nH]nn1
Reactant: CCOC[C@](C)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)O
Product: CCOC[C@](C)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O

Procedure:
1H-[1,2,3]Triazole-4-carboxylic acid and (2S,4R)-4-amino-5-biphenyl-4-yl-2-ethoxymethyl-2-methylpentanoic acid were reacted as described herein to yield the title compound (0.8 mg). MS m/z [M+H]+ calc'd for C24H28N4O4, 437.21. found 437.2.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Cl[CH2:12][C:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:15]=2[O:16][C:17]=1[CH3:18].Cl>C(O)C.O>[CH2:9]([O:8][C:2]([CH:3]([C:4](=[O:5])[CH3:6])[CH2:12][C:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:15]=2[O:16][C:17]=1[CH3:18])=[O:7])[CH3:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1c(C)oc2c([N+](=O)[O-])cccc12)C(C)=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
To a solution of sodium (52 mg) in ethanol (5 ml) was added ethyl acetoacetate (293 mg) and 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (339 mg). The mixture was stirred at 60° C. for 3 hours, cooled and poured into cold water. The pH of the aqueous solution was adjusted to 3 with 1N-hydrochloric acid and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from n-hexane to give 3-(2-ethoxycarbonyl-3-oxobutyl)-2-methyl-7-nitrobenzo[b]furan (205 mg).