Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:14]3[N:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].N1CCCCC1>CCO>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=[C:29]4[NH:23][C:24](=[O:25])[NH:26][C:27]4=[O:28])=[C:14]3[N:13]=2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)Oc1ccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)cc1
Temperature: 70 °C

Procedure:
To 5-(4-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (70 mg, 0.236 mmol) in EtOH was added hydantoin (23.6 mg, 0.236 mmol) and piperidine (23.9 μL, 0.236 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and air dried to yield 5-((5-(4-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=379)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][OH:18])=[N:9]2)=[CH:5][CH:4]=1.Br[CH2:22][C:23]([OH:25])=[O:24].[H-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][O:18][CH2:22][C:23]([OH:25])=[O:24])=[N:9]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Cn2nc(CO)c3ccccc32)cc1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(COCC(=O)O)c3ccccc32)cc1
Temperature: 0 °C
Yield: 62.7 %

Procedure:
A suspension containing [1-(4-methoxybenzyl)-1H-indazol-3-yl]methanol (6 g; 0.022 mol), bromoacetic acid (4 g; 0.03 mol) and 50% NaH (3 g; 0.066 mol) in THF (170 ml) was stirred at reflux for 72 hours. The reaction was then stopped by diluting with a suspension with water and ice (300 ml) and washing the aqueous phase with diethyl ether (3×150 ml). The aqueous phase was acidified with concentrated HCl. The solid thus formed was filtered off and purified by crystallization from isopropanol. 4.5 g of {[1-(4-methoxybenzyl)-1H-indazol-3-yl]methoxy}acetic acid were thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[F:16]C1C=C(C=CC=1F)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:16])[CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(F)c(F)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3,4-difluorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=O)[CH2:4][CH2:5][CH3:6].[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12].C(O)=O>CO>[CH3:1][C:2]([C:3]([CH2:4][CH2:5][CH3:6])=[N:12][C:11]1[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:10]=1[CH3:9])=[N:12][C:11]1[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:10]=1[CH3:9]
Reactant: Cc1cccc(C)c1N
Reactant: CCCC(=O)C(C)=O
Solvent: O=CO
Solvent: CO
Product: CCCC(=Nc1c(C)cccc1C)C(C)=Nc1c(C)cccc1C
Reaction time: 6 h

Procedure:
2,3-Hexanedione (4.0 mL, 33 mmol) was slowly added to the mixture of 2,6-dimethylaniline (10 g, 80 mmol) and 0.2 mL formic acid in 25 mL of methanol. The mixture was stirred for 6 hours. After this time period, the solvent and excess of aniline were removed under vacuum. The residual viscous oil was dissolved in n-pentane and cooled to give a yellow solid which was recrystallized from n-pentane. The product, 2-methyl-3-propyl-1,4-bis(2,6-dimethylphenyl)-1,4-diaza-1,3-butadiene was isolated as yellow crystals (1.9 g, 18%). 1H NMR (200 MHz, CDCl3, δ, ppm): 0.84 t (3H, J=7.28 Hz, (CH2)2CH3); 1.52 m (2H, CH2CH2CH3); 2.03 s (3H, N═CCH3); 2.05 s and 2.06 s (6H and 6H, 2,6- and 2′,6′-CH3); 2.50 m (2H, CH2CH2CH3); 6.89-7.15 m (6H, 2×C6H3). 13C NMR (50.3 MHz, CDCl3, δ, ppm): 14.59 (CH2CH2CH3); 16.38 (N═CCH3); 17.96 and 18.03 (0.2,6- and 2′, 6′-CCH3); 20.28 (CH2CH2CH3); 31.24 (CH2CH2CH3); 123.13 and 123.18 (4- and 4′-CH); 124.67 and 124.75 (2,6 and 2′,6′-C); 127.94 and 127.98 (3,5- and 3′,5′-CH); 147.99 (140 -C); 148.51 (1-C); 167.61 (N═CMe); 171.52 (N═CPr).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18]C)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(O)C=2)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:28])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: O=C1CCc2c(-c3ccccc3Cl)cc(O)cc2N1c1c(Cl)cccc1Cl

Procedure:
5-(2-Chlorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-7-hydroxy-2(1H)-quinolinone was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 6) by a procedure analogous to that described in INTERMEDIATE 3 Mass spectrum (ESI) 418.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.43-7.52 (m, 2H); 7.22-7.40 (m, 4H); 6.38 (d, J=2.5 Hz, 1H); 5.82 (d, J=2.5 Hz, 1H); 2.58-2.85 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].[I-].[K+].C(#N)C>O>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH2:2][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:4][CH:5]=1)(=[O:8])[NH2:9]
Reactant: NC(=O)c1ccc(CCl)cc1
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(N)=O)cc1)OCC
Yield: 93.3 %

Procedure:
The compound (44.83 g, 0.264 mol) obtained in Example 1, triethyl phosphite (53.21 g, 0.320 mol), potassium iodide (39.4 g, 0.237 mol) and acetonitrile (224 mL) were charged and stirred under reflux for 4 hrs. The reaction mixture was allowed to return to room temperature, and water (336 mL) was added. The mixture was concentrated under reduced pressure, and the residue (315 g) was stirred at room temperature for 1 hr. and under ice-cooling for 1 hr. The crystals were collected by filtration, washed with cold water (20 mL) and dried in vacuo at 40° C. for 7 hrs. to give the title compound (66.79 g, yield 93.2%) as slightly yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([CH3:17])[N:16]=1)[C:8](N(OC)C)=[O:9])[CH:2]([CH3:4])[CH3:3].[CH2:18]1COCC1>C[Mg]Br.CCOCC>[CH2:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH3:18])[CH:14]=[C:15]([CH3:17])[N:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CON(C)C(=O)c1cc(C)nc(CC(C)C)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)c1cc(C)nc(CC(C)C)c1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-isobutyl-N-methoxy-6,N-dimethyl-isonicotinamide (410 mg, 1.74 mmol) in THF (10 mL), methyl magnesium bromide (1.17 mL of a 3 M solution in ether, 3.47 mmol) is added at 5° C. The mixture is stirred at 5° C. for 1.5 h. The reaction is quenched by adding NH4Cl. The mixture is diluted with EA (50 mL), washed with sat. aq. NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(2-isobutyl-6-methyl-pyridin-4-yl)-ethanone (280 mg) as a colourless oil. LC-MS: tR=0.84 min; 1H NMR (CDCl3): δ 0.96 (d, J=6.5 Hz, 6H), 2.08-2.20 (m, 1H), 2.62 (s, 3H), 2.65 (s, 3H), 2.74 (d, J=7.3 Hz, 2H), 7.37 (s, 1H), 7.42 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:24])[N:8]([CH2:10][CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:9][C:5]2=[CH:4][N:3]=1.[ClH:25]>C(O)C>[ClH:25].[ClH:25].[CH3:1][C:2]1[N:6]2[C:7](=[O:24])[N:8]([CH2:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:9][C:5]2=[CH:4][N:3]=1
Reactant: Cc1ncc2n1C(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)C2
Agent: Cl
Solvent: CCO
Product: Cc1ncc2n1C(=O)N(CC1CCNCC1)C2
Yield: 78 %

Procedure:
To tert-butyl 4-((5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)methyl)-1-piperidinecarboxylate (3.5 g) obtained in Example 85a) was added concentrated hydrochloric acid (10 ml), and mixed for 10 minutes. To the reaction mixture was added ethanol, and the solvent was distilled off under reduced pressure. To the residue was further added ethanol, and the solvent was distilled off under reduced pressure. To the residue was added isopropyl alcohol, and the precipitate was collected by filtration. The precipitate was washed sequentially with isopropyl alcohol and diethyl ether and dried under reduced pressure to obtain 5-methyl-2-(4-piperidinyl)methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride as a colorless solid (2.5 g, 78%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:8]([O:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: Nc1cccc(OCc2ccco2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(OCc2ccco2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(furan-2-ylmethoxy)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-2-ylmethoxy)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 66%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[CH2:33][NH2:34])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](C1C=CC([O:44][C:45](=O)[NH:46][C:47]2[O:51][N:50]=[C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=2)=CC=1)([O-])=O>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[CH2:33][NH:34][C:45]([NH:46][C:47]4[O:51][N:50]=[C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=4)=[O:44])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4CN)ccc32)CC1
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4CNC(=O)Nc4cc(C(C)(C)C)no4)ccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
A solution of 4-{2-[5-(2-aminomethyl-4-fluorophenoxy)-indazol-1-yl]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (0.050 g, 0.107 mmol) dissolved in dichloromethane (2 mL) was treated with (3-tert-butyl-isoxazol-5-yl)-carbamic acid 4-nitrophenyl ester (0.081 g, 0.266 mmol) and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (60 mL), washed with 1N NaOH (5 mL), water (2×10 mL), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed eluting with acetone/hexanes (2:3, then 1:1) to afford 0.056 g of product (83% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[F:30])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[O:12])[CH3:9])=[CH:4][N:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]2[N:13]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[C:20]#[N:21])[C:11](=[O:12])[N:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[F:30])[CH:8]([CH3:9])[C:5]2=[CH:6][N:7]=1
Reactant: COc1ccc(N(C(=O)Nc2cccc(C#N)c2)C(C)c2cnc(Cl)nc2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Cl)ncc3C2C)c(F)c1
Reaction time: 0.25 h

Procedure:
This urea was suspended in freshly distilled tetrahydrofuran (10 mL) and cooled in an ice-brine bath. Potassium tert-butoxide (1.0 M in tetrahydrofuran; 2.70 mL; 2.70 mmol) (Aldrich) was added dropwise to the suspension over 8 minutes. The reaction mixture was stirred for an additional 15 minutes in the cold and then filtered through a bed of silica gel (7–8 g), eluting with 1:1 ethyl acetate-hexanes and then ethyl acetate. Purification by flash chromatography (Biotage 40M; 40:60 to 50:50 ethyl acetate-hexanes) gave (±)-3-[7-chloro-3-(2-fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile as a white solid. (Yield 1.11 g; 66.8% overall for two steps).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)C.C(=O)=O.C([N-]C(C)C)(C)C.[Li+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:30]#[N:31]>O1CCCC1.O>[CH3:38][O:37][C:33]1[CH:32]=[C:29]([C:30]2[N:31]=[C:4]([OH:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[CH:1]=2)[CH:28]=[C:27]([O:26][CH3:25])[C:34]=1[O:35][CH3:36]
Reactant: COc1cc(C#N)cc(OC)c1OC
Reactant: Cc1ncccc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(-c2cc3ncccc3c(O)n2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7 g 2-Methyl-nicotinic acid was suspended in 150 mL of tetrahydrofuran, and cooled to −70° C. with a bath of ethanol/dry ice. 80 mL lithium diisopropylamide (2.0 M in tetrahydrofuran/n-heptane/ethylbenzene) was added dropwise over 10 min and the mixture was stirred for 2 h at 0° C. Then it was cooled to −73° C. and a solution of 10 g 3,4,5-trimethoxy-benzonitrile (4.24) in 50 mL tetrahydrofuran was added. Then the reaction mixture was warmed overnight to ambient temperature. 30 mL Water was added and the solvent was distilled off before 200 mL ethyl acetate was added and the precipitate that formed was collected.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([C:29](=[O:36])[NH:30][O:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[Cl:28])=[C:18]([Cl:19])[C:13]2=[N:12][CH:11]=1)C)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[CH:33]1([CH2:32][O:31][NH:30][C:29]([C:16]2[C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[Cl:28])=[C:18]([Cl:19])[C:13]3[N:14]([C:10]([CH2:9][NH:7][CH3:6])=[CH:11][N:12]=3)[CH:15]=2)=[O:36])[CH2:35][CH2:34]1
Reactant: CN(Cc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCC3CC3)cn12)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCC3CC3)cn12
Yield: 83 %

Procedure:
A solution of [7-(4-bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxy-carbamoyl-imidazo[1,2-a]pyridin-3-ylmethyl]-methyl-carbamic acid tert-butyl ester (62) in 1:1 dichloromethane/trifluoroacetic acid was stirred for two hours. Solvent was removed under reduced pressure and the residue redissolved into ethyl acetate. The organic solution was washed with saturated aqueous potassium carbonate and brine. The aqueous washes were back-extracted with ethyl acetate. The combined organic extracts are dried over NaSO4, filtered, and concentrated in vacuo to provide the desired product as a yellow solid (8 mg, 83%). MS (APCI+) m/z 512, 514, 516 (M+; Cl, Br pattern) detected. 1H NMR (400 MHz, methanol-d4) δ 8.72 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.25 (d, 1H), 6.55 (d, 1H), 4.23 (s, 2H), 3.67 (d, 2H), 2.51 (s, 3H), 1.13 (m, 1H), 0.50 (d, 2H), 0.24 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[Br:24][CH2:25][C:26](Cl)=[O:27]>>[Br:24][CH2:25][C:26]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[C:11]1[N:20]([CH3:23])[C:21](=[O:22])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][C:10]2=1)=[O:27]
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3ccccc3n(C)c21
Reactant: O=C(Cl)CBr
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21

Procedure:
The process is carried out as indicated in preparation 1.1E above, with compound A 3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and bromo-acetyl chloride.
Reaction SMILES: C(O[C@H]1CC2C(=CC=CC=2)[C@H]1NC1C(CC)=NC(C2C=CC(Cl)=CC=2Cl)=C(CC)N=1)(=[O:3])C.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:41]1[C:42]([C:62]([O:64][CH3:65])=[O:63])=[N:43][C:44]([NH:49][C@@H:50]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH2:52][C@@H:51]2[O:59][CH2:60][CH3:61])=[C:45]([O:47][CH3:48])[N:46]=1>>[C:60]([O:59][C@H:51]1[CH2:52][C:53]2[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@H:50]1[NH:49][C:44]1[N:43]=[C:42]([C:62]([O:64][CH3:65])=[O:63])[C:41]([C:35]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=2[Cl:33])=[N:46][C:45]=1[O:47][CH3:48])(=[O:3])[CH3:61]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)=O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C(=O)OC)c(-c2ccc(Cl)cc2Cl)nc1OC
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2OC(C)=O)c(OC)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl acetate but substituting methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 2.03, 3.10-3.143.31-3.36, 3.75, 4.05, 5.68-5.77, 6.07-6.11, 7.31-7.48; MS (ESI+) for C24H21Cl2N3O5 m/z 502 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16]([Cl:19])(=[O:18])=[O:17])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].[N+:22]([O-])([O-:24])=[O:23].[K+]>ClCCl>[C:6]([C:10]1[CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([O:20][CH3:21])=[C:14]([S:16]([Cl:19])(=[O:18])=[O:17])[CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
Concentrated sulphuric acid (13 ml) was added dropwise to a cooled mixture of 5-t-butyl 2-methoxyphenylsulfonyl chloride (9.0 g) and potassium nitrate (6.90 g) in dichloromethane (100 ml). The reaction mixture was then stirred for 16 hours at ambient temperature. The mixture was then poured onto ice-cold water (200 ml) and the organic layer was separated and dried over sodium sulphate. Removal of solvent gave the title compound as a pale yellow solid (9.1 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][NH:15]C(OC(C)(C)C)=O)=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][NH2:15])=[O:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(-c2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NNC(=O)c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of tert-butyl 2-(5-phenylfuran-2-carbonyl)hydrazinecarboxylate (300 mg, 1 mmol) in DCM (10 mL), TFA (4.85 g, 50 mmol) was added dropwise. The mixture was stirred at RT overnight, then concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc:Petroleum ether:TEA=50:50:1) to afford 5-phenylfuran-2-carbohydrazide as a light yellow solid (150 mg, 74%). MS (ES+) C11H10N2O2 requires: 202. found: 203 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=O)=[C:8]([CH3:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO.O>[CH:18]([C:16]1[N:17]=[C:13]([C:11]2[N:2]=[C:1]([OH:3])[C:4]3[C:9](=[C:8]([CH3:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=3)[N:10]=2)[S:14][CH:15]=1)([CH3:20])[CH3:19]
Reactant: COc1ccc(C(N)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(O)nc(-c3nc(C(C)C)cs3)nc2c1C
Yield: 68.7 %

Procedure:
The above amide (79) (3.0 g, 9 mmol) was refluxed for three hours in a mixture of sodium carbonate (2.4 g, 22.5 mmol) in EtOH (70 ml) and water (70 ml). The mixture was acidified with 5% citric acid and extracted three times with a mixture of ethyl acetate-THF (4:1). The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was purified by column chromatography on silica gel eluted with DCM containing 3% MeOH which gave the title compound (1.95 g).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([C:19]2[NH:26][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccccn1
Reactant: NCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1-c1ccccn1
Yield: 23.4 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(2-pyridyl)propionate (6.0 g) and benzylamine (5.7 g) were dissolved in acetonitrile (100 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-phenyl-5-(2-pyridyl)imidazole-4-carboxylate (1.8 g), melting point 211-213° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=2)[C:33]([O:35][CH3:36])=[O:34])O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.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>[CH3:21][S:18]([C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[N:3]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:20])=[O:19]
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(Cl)nc3scnc23)c1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(S(C)(=O)=O)c3)c3ncsc3n2)c1
Yield: 57.7 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3-(methylsulfonyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.59 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (183 mg, 0.7 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol) and Na2CO3 (127 mg, 1.2 mmol) in 5 mL of water was added into the mixture solvent of 5 mL of water and 50 mL of 1,4-dioxane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give methyl 3-(7-(3-(methylsulfonyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (150 mg, 58%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 10.76 (s, 1H), 9.45 (s, 1H), 8.99-8.98 (m, 1H), 8.93 (s, 1H), 8.73 (d, 1H, J=7.8 Hz), 8.21-8.18 (m, 1H), 8.09 (d, 1H, J=7.8 Hz), 7.69-7.65 (m, 3H), 3.91 (s, 3H), 3.26 (s, 3H). LC-MS: 441 [M+H]+, 903 [2M+Na]+, 439 [M−H]−, tR=1.61 min. HPLC: 98.78% at 214 nm, 97.72% at 254 nm, tR=8.14 min.