Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O>[N+:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH:1][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:6][C:5]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2s1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc2cc([N+](=O)[O-])ccc2s1)c1ccccc1
Temperature: 60 °C
Yield: 78.5 %

Procedure:
A mixture of 2-amino-5-nitrobenzothiazole (1.52 g, 7.8 mmol), benzoyl chloride (1.36 mL, 11.7 mmol) and pyridine (15 mL) was heated to 60° C. for 24 h. The mixture was poured into water (250 mL), and the resulting precipitate was separated by filtration to yield N-(5-nitrobenzothiazol-2-yl)benzamide (1:83 g, 6.12 mmol, 78%) as a yellow solid.
Reaction SMILES: FC1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[C:31]1[C:32]([C:40]([O:42]C)=[O:41])=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[C:31]1[C:32]([C:40]([OH:42])=[O:41])=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(C)ccc1OC
Agent: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc(C)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 100.2 %

Procedure:
This compound was prepared in a manner similar to that of 5′-Fluoro-2′-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2′-methoxy-5′-methyl-4-nitro-2-biphenylcarboxylate (2.02 g) to afford 1.93 g (99%) of 2′-methoxy-5′-methyl-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 2′-methoxy-5′-methyl-4-nitro-2-biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.63 (d, J=2.5, 1H), 8.42 (dd, J=8.5, 2.5, 1H), 7.63 (d, J=8.5, 1H), 7.19 (m, 1H), 7.14 (d, J=2.2, 1H), 6.93 (d, J=8.4, 1H), 3.70 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.Cl.[C:13]([Cl:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.Cl>>[ClH:21].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:10]=2)[CH:7]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc2ccc(Br)cn2n1
Agent: Cl
Product: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A5), 5.0 g; 23.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (5.01 g; 28.2 mmol; 1.2 eq.) as a light yellow solid (6.30 g; 84%). HPLC, Rt: 1.32 min. (purity 99.6%). LC/MS, M+(ESI): 317.9. CHN analysis: [C12H8N5OBr.1.0 HCl.1.0 H20] Corrected: C, 38.68%; H, 2.98%; N 18.80%. Found: C, 38.76%; H, 3.11%; N, 18.66%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:30][O:31][C:32]1[N:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][CH:36]=[C:35]2[CH:42]=[O:43]>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([C@H:5]1[CH2:6][CH2:7][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:9][CH2:10]1)[CH:42]([OH:43])[C:35]1[C:34]2[C:39](=[CH:40][CH:41]=[C:32]([O:31][CH3:30])[N:33]=2)[N:38]=[CH:37][CH:36]=1
Reactant: COC(=O)C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2nccc(C=O)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(O)c1ccnc2ccc(OC)nc12)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of trans-(4-tert-butoxycarbonylaminocyclohexyl)-acetic acid methyl ester (1.80 g, 6.63 mmol; prepared according to WO 2000/024717) in THF (20 mL) cooled to −78° C. was added LiHMDS (1M in THF, 17.1 mL) dropwise over 10 minutes. The resulting solution was stirred for 1.5 h in a dry-ice bath letting the temperature settle at −40° C. The reaction was cooled again to −78° C. and 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (3.35 g, 17.82 mmol; prepared according to WO 2006/032466) was added quickly as a solid (2 mL THF were also added for rinse) and stirring was continued for 1.75 h at −78° C. Aq. NH4Cl (50 mL) and EA (50 mL) were added. The two layers were separated and the aq. layer was extracted once with EA (50 mL). The combined org. layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (Hept-EA 1-1 to 1-4) to give the title compound as a pale yellow solid (2.68 g, 88% yield). The compound was obtained as a 1-1 mixture of (syn,anti)-isomers, contaminated by 10% of the starting aldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[Cl:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Reactant: Nc1ccccc1Cl
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Nc1ccccc1Cl
Yield: 57.8 %

Procedure:
A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and 2-chloroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 107-109° C., was obtained in 57.8% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[CH:15]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:26][C:27]#[N:28])C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])/[CH:15]=[CH:26]/[C:27]#[N:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)N1CCN(c2ccc(F)cc2)CC1
Solvent: ClCCl
Product: CC(C)(/C=C/C#N)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
To the stirred solution of 2-(4-(4-fluorophenyl)piperazin-1-yl)-2-methylpropanal (1.0 g, 4 mmol) in 10 ml of dichloromethane was added 2-(triphenylphosphoranylidene)acetonitrile (1.445 g, 4.8 mmol) at 25° C. The reaction was stirred for 2 days at room temperature. After completion of reaction, the solvent was evaporated to give a crude product. The crude product was purified by column chromatography using 10% ethyl acetate in hexane as an eluent to obtain the title compound (0.7 g, 64.1%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][C:7]=1[CH3:8].[H][H]>C(O)(=O)C.[Pd]>[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[N:4]=[N:3][CH:2]=[C:7]([CH3:8])[CH:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(-c2cccc(Cl)c2)nnc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cnnc(-c2cccc(Cl)c2)c1

Procedure:
3-Chloro-6-(m-chlorophenyl)-4-methylpyridazine (7.2 g) is partially dissolved in 150 mL of acetic acid containing 1.5 g of 10% palladium on carbon. The mixture is shaken on the Parr hydrogenator until the theoretical amount of hydrogen is consumed.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:14])[C:11]([OH:13])=O)[C:4](=[O:15])[CH:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:14])[C:11]([NH:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:19][CH:18]=2)=[O:13])[C:4](=[O:15])[CH:3]=1
Reactant: CC(C(=O)O)n1cc(C#N)c(Br)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(Br)cc1=O

Procedure:
750 mg (purity 70%, 1.94 mmol) of 2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 704 mg (purity 70%, 57% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:31])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 62.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.25 mmol), 4-chloro-3-(trifluoromethyl)benzoic acid (57 mg, 0.25 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 318, the title compound (83 mg, 63%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:12]=1)[C:10]#[N:11])[CH2:3][CH3:4].[Cl:13][C:14]1[C:21]([C:22]#[C:23][Si](C)(C)C)=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:13][C:14]1[C:15]([C:16]#[N:17])=[CH:18][CH:19]=[C:20]2[C:21]=1[CH:22]=[CH:23][N:1]2[C@@H:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:10]#[N:11])[CH:12]=1)[CH2:3][CH3:4]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Reactant: CC[C@@H](N)c1cncc(C#N)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC[C@H](c1cncc(C#N)c1)n1ccc2c(Cl)c(C#N)ccc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
An oven-dried vial was charged with commercially available (R)-5-(1-aminopropyl)nicotinonitrile (0.165 g, 1.023 mmol), 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.234 g, 0.93 mmol), and K2CO3 (0.141 g, 1.023 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 18 h, the septum was replaced with a PTFE-faced crimp top and the mixture was subjected to microwave heating (140° C.) for 15 min. Upon cooling the mixture was poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), the combined washes were filtered (Whatman #2) and re-extracted with EtOAc (×1). Combined organics were dried over Na2SO4, filtered through a short pad of silica and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-4-chloro-1-(1-(5-cyanopyridin-3-yl)propyl)-1H-indole-5-carbonitrile (0.1024 g, 34% yield) as a gum which formed a tan solid upon trituration with Et2O/hexanes: 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=1.1 Hz, 1H), 8.68 (d, J=1.8 Hz, 1H), 7.66-7.58 (m, 1H), 7.44 (d, J=3.4 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.88 (d, J=3.1 Hz, 1H), 5.43 (dd, J=8.5, 6.9 Hz, 1H), 2.50-2.30 (m, 2H), 1.03 (t, J=7.3 Hz, 3H); MS (LCMS ES+) m/z 321 ([M+H]+, 55%), 362 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:32])=[N:19][C:20]([CH2:23][O:24]CC2C=CC=CC=2)=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:32])=[N:19][C:20]([CH2:23][OH:24])=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(COCc2ccccc2)nc1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(CO)nc1O
Yield: 21 %

Procedure:
A mixture of step E product, 2-f, (3.0 g, 7 mmol), ammonium formate (0.9 g, 14 mmol) and Pd/C (0.6 g) in MeOH (70 mL) was refluxed overnight. The reaction solution was filtered. The filtrate was evaporated under vacuum to obtain a residue, which was purified by silica gel chromatography by eluting with PE:EA=1:2 and DCM:MeOH=10:1 to afford the product, 2-g, (0.51 g, 21%). 1H NMR (300 MHz, CDCl3): δ4.47 (s, 2H), 6.30-6.32 (d, Hz, 1H), 7.23-7.25 (m, 11H), 8.72 (s, 1H), 9.98-10.00 (s, 1H).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C(N(CC)CC)C.[CH2:32]([C:34]1[C:42]2[C:41]([NH2:43])=[CH:40][CH:39]=[CH:38][C:37]=2[N:36]([CH2:44][C:45]2[CH:49]=[CH:48][N:47]([CH3:50])[N:46]=2)[N:35]=1)[CH3:33]>CN1C(=O)CCC1.[OH-].[Na+].CCOC(C)=O>[CH2:32]([C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[NH:43][C:10]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][CH:2]=2)=[O:12])[N:36]([CH2:44][C:45]2[CH:49]=[CH:48][N:47]([CH3:50])[N:46]=2)[N:35]=1)[CH3:33]
Reactant: CCc1nn(Cc2ccn(C)n2)c2cccc(N)c12
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCc1nn(Cc2ccn(C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 87 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (47.6 mg, 0.294 mmol) in NMP (4 mL) was added 2,4,6-trichlorobenzoyl chloride (45.9 μL, 0.294 mmol) and triethylamine (40.9 μL, 0.294 mmol). The reaction mixture was stirred for 30 minutes. 3-Ethyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (50 mg, 0.196 mmol) was added and the mixture was heated at 87° C. for three hours. The mixture was cooled to ambient temperature and diluted with 10% NaOH aqueous solution (5 mL) and EtOAc (20 mL). The organic phase was washed with water and brine and concentrated under reduced pressure. The residue was triturated with Et2O to give the final product (52 mg). MS (ES+APCI) m/z=400 (M+H).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:10]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])[C:11](=[O:12])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([CH3:20])=[C:13]([N:10]2[C:11](=[O:12])[C:4]3[CH:3]=[C:2]([C:33]4[C:34]([O:36][CH3:37])=[N:35][C:30]([O:29][CH3:28])=[N:31][CH:32]=4)[N:6]([CH2:7][CH3:8])[C:5]=3[CH:9]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:18]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CCn1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: CCn1c(-c2cnc(OC)nc2OC)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-ethyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate K) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The product was purified by flash chromatography to afford the title compound as a white solid. tR: 5.69 min (HPLC 4); ESI-MS: tR=1.30 min, [M+H]+ 523/525 (LC-MS 1); 1H-NMR (d6-DMSO, 600 MHz, 100° C.): (rotamers) 8.31 (s, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 7.26 (m, 2H), 7.15-7.23 (m, 2H), 6.37 (s, 1H), 6.29 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.38/3.59 (m, 2H), 2.07 (s, 3H), 0.86 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[F:23][C:24]([F:37])([F:36])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:33]([C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:24]([F:37])([F:36])[F:23])=[CH:32][N:31]=3)=[O:34])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=525.2.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.Br[C:41]1[S:42][CH:43]=[CH:44][N:45]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:37][CH:36]([F:38])[O:35][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:2])=[O:39])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)=[CH:24][CH:25]=1
Reactant: Brc1nccs1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-c2nccs2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.052 g), 2-bromothiazole (0.076 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.060 g), 1,4-dioxane (2.0 mL) and 2.0M aqueous cesium carbonate solution (0.19 mL) was heated at 90° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure, and the residue dissolved in tetrahydrofuran (5.0 mL) and 1.0M aqueous lithium hydroxide solution (0.19 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrate to low bulk under reduced pressure, and the residue acidified by the addition 0.1M aqueous hydrochloric acid solution and then extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on C-18 column gave title compound (0.020 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][CH2:41][CH2:42]Cl>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH2:42][CH2:41][O:40][CH3:39])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COCCCl
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.1 eq) and 2-chloroethyl methyl ether (21 mg, 0.220 mmol, 1.5 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had progressed to 80% completion. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-65% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (24 mg, 33%). MS(ES)+ m/e 487.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:12]([OH:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26]Cl.[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[C:12]([O:13][CH2:26][CH2:25][O:24][CH3:23])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1Br
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(OCCOC)c1Br
Temperature: 70 °C
Yield: 93.5 %

Procedure:
Using a procedure similar to that of Example 2, 0.2 moles of ethyl 2-bromo-3-hydroxy-4-nitrobenzoate and an excess of potassium carbonate (0.35 moles) and 2-chloroethyl methyl ether (0.35 moles) along with a catalytic amount of potassium iodide (7.2 g, 0.045 m) were combined with 350 mL of dimethylformamide. After heating at 70° C. for 4 hours, normal workup gave 0.187 moles of ethyl 2-bromo-3-(2-methoxyethoxy)-4-nitrobenzoate as a viscous oil. This ester can be readily hydrolyzed to its acid using the procedure of Example 8.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21].[CH2:23](O)[CH3:24]>>[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]([O:18][CH2:23][CH3:24])=[O:17])=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21]
Reactant: Cc1cc2oc(C(=O)O)cc(=O)c2c(C)c1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)c2c(C)c(Cl)c(C)cc2o1

Procedure:
10 Parts of concentrated sulphuric acid were added to a suspension of 66.1 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxylic acid in 600 parts of ethanol, and the mixture was heated at reflux for 24 hr. Most of the ethanol was removed by evaporation under reduced pressure, and 1500 parts of water were added to the reaction mixture. The precipitated solid was filtered, dissolved in chloroform and the solution, dried and evaporated, leaving 58.5 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester as a colourless solid. On recrystallisation from ethanol, the product had melting point 114.5°-115.5° C.