Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH3:20][O:21][CH2:22][CH2:23][NH:24][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Product: COCCNc1cccc2nc(NC(=O)c3ccccc3)nn12

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and 2-methoxyethylamine (1.0 mL) as an off-white solid (52 mg, 91%). HPLC, Rt: 2.08 min. (purity 90.1%). LC/MS, M+(ESI): 312.1, M−(ESI): 310.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NC(=O)C(c2ccc(Cl)cc2)=C1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CO
Product: O=C1NC(=O)C(c2ccc(Cl)cc2)=C1Nc1cccc(Br)c1

Procedure:
A solution of 3-bromoaniline (227 mL, 0.020 mol) and 3-chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione (2.02 g, 0.0083 mol; prepared by analogy with the methods described in WO97/34890 and Wiley, R P H, and Slaymaker, S. C. J. Am. Chem. Soc (80) 1385 (1958)) in methanol (50 mL) was heated at reflux for 40 hours, cooled and concentrated. The residue was acidified with aqueous hydrochloric acid (1M, 200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic solutions were washed with water and brine, dried with magnesium sulphate, evaporated and the residue chromatographed on silica gel using dichloromethane-diethyl ether (gradient from 100:0 to 95:5 v/v) as eluent to afford the title compound as a solid.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6](=O)[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.C(N(CC)CC)C>CO>[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:4]([C:1](=[O:3])[CH3:2])=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=3)[C:6]2=[O:5])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.9 %

Procedure:
[Step 2] To a solution of 3-acetyl-6-bromo-4-phenyl-isochromen-1-one (1.03 g) in methanol (100 ml) were added 4-aminomethyl-benzoic acid methyl ester hydrochloride (3.02 g) and triethylamine (4.2 ml) and the mixture was stirred at room temperature for 18 hrs. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→3/1) to give the title compound (220 mg, 15%).
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].O.P([O-])(O)(O)=O.[Na+].[Cl:13][C:14]1[N:15]=[C:16]2[N:20]([C:21]=1[CH:22]=[O:23])[CH:19]=[CH:18][S:17]2>O.C(O)(C)(C)C>[Cl:13][C:14]1[N:15]=[C:16]2[N:20]([C:21]=1[C:22]([OH:5])=[O:23])[CH:19]=[CH:18][S:17]2
Reactant: O=Cc1c(Cl)nc2sccn12
Reactant: O
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Product: O=C(O)c1c(Cl)nc2sccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium chlorite (230 mmol) and sodium dihydrogen phosphate dihydrate (176 mmol) in water (195 mL) is added dropwise to a solution of 6-chloro-imidazo[2,1-b]thiazole-5-carbaldehyde (26.8 mmol) in tert.-butanol (195 mL) and the mixture is stirred for 8 h at RT. The solvents are partially removed in vacuo and the obtained precipitate is filtered off. The filtrate is made acidic and the obtained precipitate is filtered off to give the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:31]=1)[CH2:27]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O[C:56]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:57]=1[CH:58]=[O:59].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:31]=1)[CH2:27][C:56]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:57]=1[CH:58]=[O:59])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(Cc2cc(OC)ccc2C=O)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
3,5-Di(docosyloxy)benzylchloride (450 mg, 0.58 mmol), 2-hydroxy-4-methoxybenzaldehyde (185 mg, 1.22 mmol) and potassium carbonate (200 mg, 1.45 mmol) were suspended in DMF (4.5 ml), and the mixture was stirred at 80° C. for 6 hr. The reaction mixture was extracted with chloroform (20 ml), and washed 3 times with 1N hydrochloric acid (7 ml). The solvent was evaporated and the obtained residue was precipitated with methanol (5 ml) to give 2-[3′,5′-di(docosyloxy)benzyl]-4-methoxybenzaldehyde (502 g, 0.56 mmol, 97%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.[CH3:29][NH:30][NH2:31]>C(O)C>[CH3:29][N:30]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4](=[O:18])[C:3]=2[C:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[N:31]1
Reactant: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: CNN
Solvent: CCO
Product: Cn1nc(CCc2ccncc2)c2c(=O)n(-c3ccccc3)c3ncccc3c21
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (100 mg, 0.27 mmol, prepared in Synthetic Example 1) in ethanol (2 ml) was added methylhydrazine (40 μl, 0.75 mmol, 2.8 eq.) and the mixture was stirred at room temperature to form a solution which was then stirred for 30 minutes. After it was perceived that precipitation started, the mixture was heated under reflux for 3 hours and cooled to room temperature. Next, to the liquid mixture was added additional methylhydrazine (40 μl, 0.75 mmol, 2.8 eq.) and the resultant mixture was heated overnight with stirring at 70° C. The liquid reaction mixture was cooled to room temperature, and then filtered to give precipitates which were dried to obtain 1-methyl-5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (94 mg, 92%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([CH3:15])[C:5]=1[CH:6]=O.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]>O1CCCC1.[Cl-].[Na+].O>[CH3:14][O:13][C:10]1[CH:9]=[C:8]([CH3:15])[C:5]([CH:6]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([CH3:3])[C:11]=1[CH3:12]
Reactant: COc1cc(C)c(C=O)c(C)c1C
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=Cc1c(C)cc(OC)c(C)c1C
Temperature: 0 °C

Procedure:
A suspension of NaH (9.3 g, 50% dispersion in oil, 0.19 mol) in 150 mL of tetrahydrofuran (THF) was stirred in an ice bath under an atmosphere of nitrogen and triethyl phosphonoacetate (43.5 g, 0.19 mol) was added dropwise within 15 min. The mixture was stirred for 1 hr in the ice bath and a solution of 2,3,6-trimethyl-p-anisaldehyde (24.3 g, 0.14 mol) in 100 mL of THF was added. The resulting mixture was stirred at room temperature for 18 hrs and brine (250 mL) and ethyl acetate (250 mL) was added. The layers were separated; the organic layer was washed with brine and dried (Na2SO4). Removal of solvent in vacuo afforded 32.3 g of yellow oil. A small portion of this product was recrystallized from ethyl ether to give white powders: mp 42°-44° C.; MS(CI): 249(m+ +1), 203. The rest of the product was used in the reaction described in Example 3 without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[CH3:35][C:36](OC(C)=O)=[O:37]>N1C=CC=CC=1>[CH3:11][C:7]1[N:6]=[C:5]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:17][CH:18]=3)[C:2]([NH:1][C:36](=[O:37])[CH3:35])=[N:3][C:4]2=[C:9]([CH3:10])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(N)nc4c(C)cc(C)nc43)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 5 %

Procedure:
2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (73 mg) was treated with pyridine (1 ml) and Ac2O (0.2 ml) at room temperature for 3 hours. After evaporation in vacuo, the residue was purified by preparative TLC (hexane/acetone=1/1) to afford 4 mg (5%) of the title compounds.
Reaction SMILES: [N:1](=[C:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]3[CH:18]3[CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:25])[CH2:4]1)O.[H][H].[ClH:28]>[Ni].CN(C)C=O>[ClH:28].[NH2:1][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]3[CH:18]3[CH2:19][CH2:20]3)=[CH:10][C:9]=2[F:25])[CH2:4]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(C3CCC(=NO)C3)c(F)cc2c1=O
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Solvent: CN(C)C=O
Product: NC1CCC(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 71.4 %

Procedure:
A suspension of 17.2 g (50 mmol) of 7-[(3-oximino)cyclopentyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3.0 g of Raney-nickel and 300 ml of N,N-dimethylformamide was shaken in a hydrogen atmosphere at 45-50 psi for 24 hours. After removing the catalyst by filtration through Celite and addition of 100 ml of 6.0 M hydrochloric acid (60 mmol), the mixture was evaporated in high vacuo at 50° . The residue was triturated with a mixture of 200 ml of ethanol/ether (1:1) and the solid was removed by filtration, washed with ethanol/ether (1:1) and dried in vacuo to give 13.1 g of the title compound.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([N:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][CH:14]([C:24]([O:26]C)=[O:25])[CH2:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.CO>[C:1]1([C@H:7]([NH:9][C:10]([N:12]2[CH2:17][CH:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][CH:14]([C:24]([OH:26])=[O:25])[CH2:13]2)=[O:11])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CC(c2ccccc2)CN(C(=O)N[C@H](C)c2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)N1CC(C(=O)O)CC(c2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 150 mL RBF was added the mixture from step 1 (150 mg), THF:MeOH (3:1, 15 mL), and LiOH, 1M (1.00 ml, 1.0 mmol) and the mixture was stirred at RT. After 2 hours, the reaction was neutralized and extracted with EtOAc (3×20 mL). The combined organic layers were concentrated in vacuo to give a white solid. The material was carried forward without further purification.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[C:8]=2[CH:26]=1.[ClH:28]>CO.C(O)C>[ClH:28].[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:8]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccc(OC(F)F)cc32)CC1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=c1[nH]c2ccc(OC(F)F)cc2n1C1CCNCC1
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl 4-{6-[(difluoromethyl)oxy]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D53, 0.54 g) in methanol (5 ml) was treated with a saturated solution of hydrogen chloride in ethanol (5 ml). The mixture was stirred for 1 hour when the solvent was removed to give the title compound as a white solid (0.45 g). Mass Spectrum 284 M+H+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(NC3CCCCC3)nncc2c1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
A mixture of 6-bromo-I-chlorophthalazine (Example 1, 0.245 g, 1 mmol), cyclohexanamine (0.22 g, 2 mmol) and potassium carbonate (0.14 g, 1 mmol) in 5 mL acetonitrile were added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. After 20 min., all starting material was converted to product (M+1=306, 308). The mixture was concentrated under vacuum, and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give (0.21 g) 6-bromo-N-cyclohexylphthalazin-1-amine as a yellow solid. Found MS (ES+): 306, 308(M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=1)[C:11]([CH3:26])=[CH:10]2.CN(C)[CH:29]=[O:30]>>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:11]([CH3:26])=[C:10]2[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(-n2c(C)cc3cc(Cl)ccc32)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2cc(Cl)ccc2n1-c1ccc(O)cc1
Yield: 85 %

Procedure:
Phosphorous oxychloride (5 mL) was added to anhydrous dimethylformamide (10 mL) and stirred at room temperature for 15 min whereupon a solution of 5-chloro-1-(4-methoxymethyloxyphenyl)-2-methyl-1H-indole (1.22 g, 3.5 mmol) in dimethylformamide (10 mL) was added. The solution was reacted according to the procedure used in Example 2a to afford a tan solid (85%): mp>240° C.; 1H NMR (DMSO-d6): δ 2.52 (3H, s), 6.97-7.02 (3H, m), 7.22 (1H, dd, J=2.3 Hz, J=8.7 Hz), 7.30 (2H, d, J=8.6 Hz), 8.40 (1H, d, J=2.1 Hz), 10.02 (1H, s), 10.16 (1H, s); MS m/Z (M+H)+ 286/288 (1 Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.C(OC(=O)C)C>[O:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH2:10]1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirring solution of a mixture of (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (2.85 g, 12.43 mmol) and potassium carbonate (4.33 g, 24.87 mmol) in anhydrous N,N-dimethylformamide (60 mL) was added benzyl bromide (4.25 g, 24.87 mmol). The mixture was stirred at room temperature overnight. The resulting crude mixture was diluted with ethylacetate and the organic layer was washed with 10% sodium carbonate and brine. The organic layer was dried over sodium sulfate and volatiles were removed in-vacuo. The residue was purified on normal phase column to yield 2.82 g (71%) of desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH2:27])[CH3:9])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 65 °C
Yield: 41.9 %

Procedure:
1-[8-Chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridine-6-yl]ethanone (0.12 g, 0.42 mmol) and ammonium acetate (0.32 g, 4.2 mmol) were stirred in methanol (4.6 mL) and heated to 65° C. for 1 hour. Sodium cyanoborohydride (78 mg, 1.3 mmol) was added and the mixture was heated at 65° C. for 16 hours. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (51 mg, 42%). LCMS calculated for C15H14ClFN3 (M+H)+: m/z=290.1. found: 290.0. 1H NMR (300 MHz, DMSO-d6): δ 7.63 (m, 2H), 7.41 (m, 3H), 7.35 (m, 2H), 3.60 (m, 1H), 1.18 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:16]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])#[N:17]>Cl.O1CCOCC1>[O:6]=[C:4]1[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=[C:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[NH:17]1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: N#CC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(C(=O)OCc3ccccc3)nc2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of dimethyl 2-aminoterephthalate (1.70 g, 8.1 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (20 mL) was added benzyl cyanoformate (2.0 mL, 14 mmol). The reaction mixture was heated to 50° C. and stirred for 3 h. The mixture was then cooled to rt, concentrated and the residue was twice co-evaporated with toluene. Diethyl ether was added and the solid was filtered to afford 2-benzyl 7-methyl 4-oxo-3,4-dihydroquinazoline-2,7-dicarboxylate (2.7 g, 98%). LC-MS: (FA) ES+ 339.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[NH:6][C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[C:13]([O:12][C:11]([N:10]([CH2:9][C:7]1[N:6]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]2[CH:19]=[C:20]([Cl:21])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)[CH3:18])=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl [(5,6-dichloro-1H-benzimidazol-2-yl)methyl]methylcarbamate (400 mg) and DMF (4 mL) were added ethyl bromoacetate (201 μL) and K2CO3 (335 mg), followed by heating and stirring at 70° C. for 2 hours. The reaction mixture was diluted with EtOAc, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=50/50-0/100) to obtain ethyl (2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-5,6-dichloro-1H-benzimidazol-1-yl)acetate (393 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.ClC1C=CC=C(C(OO)=[O:19])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[C:9]([N+:10]=1[O-:19])=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: Cc1nc2cccnc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1sc2ncccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step 2 (8.00 g) in 400 mL of CH2Cl2 was added m-chloroperbenzoic acid (26.0 g) and the mixture was stirred at room temperature overnight. NaOH 0.5M was added and the product was extracted in CH2Cl2 (6×), dried over Na2SO4, and purified by flash chromatography on silica with acetone: toluene 70:30 and acetone: toluene: methanol 40:40:20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10]O.S(Cl)([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][Cl:20]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(Oc2cccc(CO)c2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(Oc2cccc(CCl)c2)c1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
The alcohol (5.31 g, 23 mmol) was dissolved in dichloromethane (40 ml) and treated with thionyl chloride (2.6 ml, 35 mmol) and dimethylformamide (catalytic 5 drops). The mixture was stirred overnight. The reaction mixture was evaporated in vacuo and azeotroped with toluene (2×10 ml) to give 3-(3-methoxyphenoxy)benzyl chloride as a light brown oil (5.57 g, 97%). The chloride (5.30 g, 21.3 mmol) was dissolved in dimethyl sulphoxide (20 ml), potassium cyanide (1.45 g, 22.4 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was diluted with water (100 ml) and extracted with ether. The combined extracts were dried (MgSO4) and evaporated to give 3-(3-methoxyphenoxy)phenyl acetonitrile as a brown oil (4.04 g, 79%).