Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@:22]([C@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH2:18]1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@@]2(C)COC(=O)N2)C3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@](C)(N)CO)C3)CC1

Procedure:
The mixture of (S)-4-((S)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (46.6 mg, 0.000121 mol) (isomer 2) and lithium hydroxide (31.8 mg, 0.00133 mol) in ethanol (0.77 mL, 0.013 mol) and water (0.26 mL, 0.014 mol) was heated to reflux for overnight. LCMS showed starting material was consumed and peak Rf=1.66 min left. The solvent was removed under vacuum and the residue was partitioned between water and dichloromethane. The aqueous was extensively extracted with dichloromethane. And the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into dichloromethane and subjected to chromatography purification with dichloromethane/MeOH (10:90 to 80:20) to give the product (29.0 mg, 66% yield). LCMS360.42 ([M+1], 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.89 (s, 9H), 1.06 (s, 3H), 1.04-1.40 (m, 6H), 1.77-1.88 (m, 3H), 1.97 (m, 1H), 2.15 (m, 2H), 2.56 (dd, J=15.8, 12.1 Hz, 1H), 2.71-2.84 (m, 3H), 3.47 (d, J=10.9 Hz, 1H), 3.51 (d, J=10.9 Hz, 1H), 4.07 (m, 1H), 6.58 (d, J=2.5 Hz, 1H), 6.63 (dd, J=8.2, 2.5 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H).
Reaction SMILES: [Br:1]C[CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br-:1].[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[C:4]([CH2:3][P+:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cccc(CCBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(bromoethyl)benzoic acid, ethyl ester (12.2 g, 0.050 mol) and triphenyl phosphine (13.1 g, 0.05 mol) in toluene (50 ml) was stirred at 70° C. for 16 hours to yield [[3-(ethoxycarbonyl)phenyl]methyl]triphenylphosphonium bromide as a colorless crystalline solid which was filtered off, washed with toluene and dried under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>COCCOC.O>[N:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])=[CH:17][CH:16]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1cccc(-c2ccncc2)c1
Yield: 93.5 %

Procedure:
3-Bromoaniline (0.24 ml, 2.2 mmol) and sodium carbonate (0.70 g, 6.6 mmol) were suspended in a mixture of 1,2-dimethoxyethane (16 ml) and water (4 ml). The reaction mixture was then treated with 4-pyridyl boronic acid (0.27 g, 2.2 mmol), and flushed with Argon. Tetrakis (triphenylphosphine)-palladium (0) (0.35 g) was then added, and the mixture was heated to reflux under Argon for 24 hours. The reaction mixture was allowed to cool after which it was partitioned between dichloromethane and water. The aqueous layer was again extracted with dichloromethane. The combined extracts were then dried (Na2SO4) and concentrated in vacuo to afford a pale yellow solid (0.35 g). This was chromatographed on silica gel eluting with ethyl acetate to afford the title compound as a white solid (0.15 g, 41%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](N1C=CN=C1)(N1C=CN=C1)=[O:8].[CH2:19]([O:21][C:22](=[O:31])[C:23]([NH2:30])([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH3:20]>O1CCCC1>[CH2:19]([O:21][C:22](=[O:31])[C:23]([CH2:27][CH2:28][CH3:29])([NH:30][C:7]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:8])[CH2:24][CH2:25][CH3:26])[CH3:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nccs1
Reactant: CCCC(N)(CCC)C(=O)OCC
Solvent: C1CCOC1
Product: CCCC(CCC)(NC(=O)Nc1nccs1)C(=O)OCC
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
A solution of 5.40 g of 2-aminothiazole in 150 ml of tetrahydrofuran was combined at 20° C. with 8.75 g of 1,1'-carbonyldiimidazole and the mixture stirred for 30 minutes. The mixture was then raised within 20 minutes to a bath temperature of between 55 and 60° C. and a solution of 9.80 g of the product from stage 3 in 30 ml of tetrahydrofuran was added dropwise. A clear, red-brown solution was obtained, which was stirred for 60 hours at a temperature of between 55° C. and 60° C. Once the solvent had been removed by distillation, the residue was purified by passage through a silica gel column with ethyl acetate. 10.20 g of 2-propyl-2-(3-thiazol-2-ylureido)pentanoic acid ethyl ester (62% of th.) were obtained in the form of a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].[CH:26](=O)[CH3:27].[Na]>O1CCCC1.C(O)(=O)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][N:19]([CH2:26][CH3:27])[CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]
Reactant: O=C(NC1CCNC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(pyrrolidin-3-yl)thiophene-2-carboxamide (0.1 g, 0.24 mmol) and acetaldehyde (31.9 mg, 0.72 mmol) in tetrahydrofuran (3.0 mL) under nitrogen, was added 2 drops of acetic acid. The resulting mixture was stirred at ambient temperature for 30 minutes. Then sodium triacetoxyboronhidride was added and the reaction mixture was stirred at ambient temperature for additional 12 hours. After this time, the reaction mixture was diluted with ethylacetate and washed with brine and water. The organic layer was separated, dried (Na2SO4) and concentrated. The crude residue was purified by silica gel chromatography using a 90:10 mixture of dichloromethane and methanol as eluent to afford the title product as a solid (40 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 7.57 (1H, m), 7.44 (1H, m), 7.06 (1H, m), 4.07 (2H, m), 3.81 (3H, s), 3.812 (3H, s), 3.807 (2H, s), 2.33 (2H, m), 2.13 (6H, s), 1.86 (2H, m). MS m/z: 268.26 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[Cl:30].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:30][C:24]1[CH:25]=[C:26]([NH2:27])[CH:28]=[CH:29][C:23]=1[C:10]1[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: Nc1ccc(Br)c(Cl)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: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2cc(C(F)(F)F)ccc2OCc2ccccc2)c(Cl)c1

Procedure:
The product from example 32 step (ii) (0.5 g) and 4-bromo-3-chloroaniline (0.38 g) were dissolved in toluene (4 ml). Ethanol (1 ml), 2M aqueous sodium carbonate (1 ml) and Pd(PPh3)4 (0.115 g) were added sequentially and the mixture heated at reflux for 4 h. The reaction was cooled, evaporated, dissolved in EtOAc, washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 10% EtOAc/isohexane. Yield 0.23 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH2:8][C:9]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[O:12])[O:5][CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCN(CC)CC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C:11](=[O:12])[C:10]3[C:9]([CH:8]=2)=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:27])[O:5][CH:6]=1
Reactant: O=C(Cc1cccc(Cl)c1C(=O)NCc1ccc(F)cc1F)c1cc(Br)co1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1c2c(Cl)cccc2cc(-c2cc(Br)co2)n1Cc1ccc(F)cc1F
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 2-[2-(4-bromofuran-2-yl)-2-oxoethyl]-6-chloro-N-(2,4-difluorobenzyl)benzamide (2.4 g, 5.1 mmol), prepared in a manner similar to that described above in Paragraph B, in dioxane (30 mL) was added 4-toluenesulfonic acid monohydrate (450 mg, 2.4 mmol). The resulting solution was heated to reflux. After 20 hours at reflux the reaction solution was allowed to cool to ambient temperature, and treated with Et3N (2.0 mL, 14 mmol). The crude product was purified by adsorbing the material onto silica gel from the reaction solution, loading the resulting solid onto the column and eluting with a gradient from 10% to 50% EtOAc in hexane containing 10% CH2Cl2 (to improve the solubility of the product). The broad peak that eluted was collected to afford 3-(4-bromofuran-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one (1.9 g, 82% yield) as a brown powder. 1H-NMR (400 MHz, CDCl3): δ 7.56-7.51 (2H, m), 7.47 (1H, d, J=0.8 Hz), 7.43 (1H, dd, J=6.3, 2.8 Hz), 7.06-6.99 (1H, m), 6.79-6.73 (2H, m), 6.68 (1H, s), 6.49 (1H, d, J=0.8 Hz), 5.32 (2H, s).
Reaction SMILES: [ClH:1].CNC.CCN(C(C)C)C(C)C.C(OC([NH:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([OH:25])=O)=O)(C)(C)C.CN(C(O[N:41]1[N:49]=[N:48][C:43]2C=CC=C[C:42]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[ClH:1].[NH2:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([N:49]([NH:41][CH3:42])[NH:48][CH3:43])=[O:25]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNN(NC)C(=O)[C@@H](N)Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of dimethylamine hydrochloride (0.153 g, 1.87 mmol) in DMF (8 mL) was added DIPEA (2 mL, 6.55 mmol), (S)-2-tert-butoxycarbonylamino-3-pyridin-2-ylpropionic acid (0.50 g, 1.87 mmol, Acros) and TBTU (0.60 g, 1.87 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was dissolved in methanol (15 mL). To this was added 4M hydrochloric acid in dioxane (20 mL) and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (100 mL) and ethyl acetate (2×100 mL). The aqueous layer was evaporated to dryness to give a solid, which was recrystallised from ethanol to give the title compound as a pale brown solid. m/z (ES+)=194.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21](Cl)=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:27]1([NH:26][C:21]([N:17]2[CH2:16][C:15]3[CH:14]=[N:13][C:12]4[NH:8][N:9]=[CH:10][C:11]=4[C:20]=3[CH2:19][CH2:18]2)=[O:22])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Cl)CC4)cc1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2ccccc2)CC4)cc1
Product: O=C(Nc1ccccc1)N1CCc2c(cnc3[nH]ncc23)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Step (i): To a 0.1M solution of 3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carbonyl chloride (0.5 mL, 0.050 mmol) in anhydrous DMF was added a 0.1M solution of aniline (0.75 mL, 0.075 mmol) in anhydrous DMF. The reaction mixture allowed shaken at 80° C. for 16 hours. The solvent was removed under reduced pressure and to give the desired product, 3-(4-methoxybenzyl)-N-phenyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide as a solid, which was used in the next step without any further purification. Step (ii): To the product obtained in Step 2(i) was added trifluoroacetic acid (1 mL). The reaction mixture was heated at 70° C. for 16 hours. On the completion of the reaction, toluene (3 mL) was added and the solvent removed under reduced pressure. The crude product was purified using reverse phase HPLC to give the desired product, N-phenyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide as a white solid. LCMS [M+H]: 294.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C@H:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:21][CH:20]=3)[C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:31]=1)(=[NH:5])[NH2:4].Cl.[C:33](=[NH:38])(OCC)[CH3:34].[OH-].[Na+].Cl>O.O.C(#N)C>[ClH:1].[ClH:1].[C:33]([N:28]1[CH2:29][CH2:30][C@H:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([CH:15]([CH2:14][C:12]3[O:13][C:9]4[CH:8]=[CH:7][C:6]([C:3](=[NH:4])[NH2:5])=[CH:31][C:10]=4[CH:11]=3)[C:16]([OH:18])=[O:17])=[CH:24][CH:23]=2)[CH2:27]1)(=[NH:38])[CH3:34]
Reactant: N=C(N)c1ccc2oc(CC(C(=O)O)c3ccc(O[C@H]4CCNC4)cc3)cc2c1
Reactant: CCOC(C)=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(=N)N1CC[C@H](Oc2ccc(C(Cc3cc4cc(C(=N)N)ccc4o3)C(=O)O)cc2)C1
Yield: 130.3 %

Procedure:
1.1 g of 3-(5-amidino-2-benzofuranyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride was dissolved in 20 ml of water. During ice cooling and stirring, 1.4 g of ethyl acetimidate hydrochloride was added gradually to the thus prepared solution while adjusting the pH of the solution to 8.5 with 1N sodium hydroxide aqueous solution. The resulting mixture was stirred for 15 minutes with ice cooling, and then adjusted to pH 2.0 with dilute hydrochloric acid. After concentrating the resulting reaction solution to dryness, the thus obtained residue was subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel and using a water/acetonitrile mixture as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, mixed with dilute hydrochloric acid, and then concentrated to dryness. In this way, 780 mg of the title compound was obtained in a solid form.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH3:3].[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N+:14]=[N-:15]>C(O)C>[N:13]([C:16](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][CH2:2][CH3:3])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N+:14]=[N-:15]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CCOc1ccccc1C=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccccc1OCC)N=[N+]=[N-]
Temperature: -18 °C
Reaction time: 3 h

Procedure:
Pieces of sodium (3.678 g, 160 mmol) were added to ethanol (200 ml) over a period of 30 minutes. The resulting solution was cooled to −18° C. and a mixture of 2-ethoxybenzaldehyde (6.007 g, 40 mmol) and ethyl azidoacetate (160 mmol) was then added, over one hour, at a rate which allowed the temperature to be maintained below −15° C. After three hours, the solution was stored at 5° C. for two days in order to give a crystalline product which was collected and washed with cold hexane in order to give an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].Cl.[OH-].[K+].[C:11](=O)(OC(Cl)(Cl)Cl)[O:12]C(Cl)(Cl)Cl>O.CCOC(C)=O.C1COCC1>[O:7]1[C@@H:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[NH:1][C:11]1=[O:12]
Reactant: N[C@H]1CCC[C@H]1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1N[C@H]2CCC[C@H]2O1
Temperature: 0 °C
Yield: 24.2 %

Procedure:
To a solution of (1R,2S)-2-aminocyclopentanol (1.0 g, 9.9 mmol) as the HCl salt in water (50 mL) was added potassium hydroxide (3.9 g, 69 mmol) and the slurry stirred until all the material was in solute ion. To the reaction was added THF (100 mL) and the reaction was cooled to 0° C., followed by bis(trichloromethyl) carbonate (2.9 g, 9.9 mmol) as a solid and the reaction stirred at 0° C. for 2 hours. The reaction was poured into EtOAc and the layers were separated. The organic layer was washed with 1N HCl, 1N NaOH and brine, dried over MgSO4 and concentrated in vacuo. The material was purified by silica gel chromatography using 20% EtOAc/DCM as the eluent to yield (3aS,6aR)-hexahydro-2H-cyclopenta[d]oxazol-2-one (0.30 g, 2.4 mmol, 24% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(-c2cccnc2)ncn1
Temperature: 125 °C

Procedure:
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-3-ylboronic acid (0.385 g, 3.13 mmol), Na2CO3 (0.795 g, 7.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05 mmol) were suspended in a mixture of dioxane/EtOH/water. The mixture was heated in the microwave synthesizer at 125° C. for 20 min (reaction was run twice) and concentrated. The residue was purified on by silica gel chromatography using a 10-60% ethyl acetate/hexanes gradient, followed by a 5-25% 9:1 methanol:ammonium hydroxide in ethyl acetate gradient. The desired fractions were concentrated to give an off-white solid. MS(LC/MS) R.T.=0.28; (M+H=173.13).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:25]=[C:24]([O:42][CH3:43])[N:23]=1>CN1C(=O)CCC1>[CH3:38][N:34]1[C:33]2[C:39]([CH3:41])=[CH:40][C:30]([C:28]([C:26]3[CH:25]=[C:24]([O:42][CH3:43])[N:23]=[C:22]([N:15]4[CH2:14][CH2:13][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=6[NH:7][C:8]5=[O:18])[CH2:17][CH2:16]4)[CH:27]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37]
Reactant: COc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(Cl)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(OC)n3)CC1)C(=O)N2
Temperature: 120 °C
Reaction time: 12 h

Procedure:
991 mg (3.60 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one and 420 mg (1.26 mmol) 6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were combined in 3 mL NMP and stirred for 12 h at 120° C. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the acetonitrile was eliminated i. vac. The residue was diluted with water, the precipitated solid was suction filtered, washed with water and dried.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].Cl.[CH2:22]([C:26]1[N:27]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:28](CCl)=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[CH2:22]([C:26]1[N:27]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:28]([C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:6]([O:5][CH2:4][CH3:3])=[O:7])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1ncc(CCl)n1Cc1ccccc1Cl
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(C(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To dry dimethylformamide (50 mL) under argon was added sodium hydride (0.53 g, 0.022 mol) followed by diethyl benzyl malonate (5.51 g, 0.022 mol) in dimethylformamide (10 mL) at 0° C. The mixture was stirred at ambient temperature for one hour. A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-chloromethyl-1H-imidazole hydrochloride (3.5 g, 0.0105 mol) in dimethylformamide (40 mL) was added over 5 minutes. The reaction mixture was stirred at 25° C. for 18 hours, then partitioned between water and methylene chloride. The organic layer was washed with water, dried, and concentrated. The crude product was flash chromatographed over silica gel to give 4.54 g (85%) of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][C:10]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[C:17]2[C:12](=[CH:13][C:14]([O:37][CH3:38])=[C:15]([O:35][CH3:36])[CH:16]=2)[N:11]=1>CN(C)C=O.O>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([C:18]2[C:17]3[C:12](=[CH:13][C:14]([O:37][CH3:38])=[C:15]([O:35][CH3:36])[CH:16]=3)[N:11]=[C:10]([CH2:9][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
To a solution of 1H-1,2,4-triazole (0.558 g) in N,N-dimethylformamide (30 ml) was added sodium hydride in oil and the mixture was stirred at room temperature for 15 minutes. Then, ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (3.0 g) was added. The mixture was stirred at 80° C. for 1 hour, after which it was poured in water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography. Form the first eluate with chloroform-methanol (40:1, v/v), ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (1.7 g, 53%) was obtained. Recrystallization from ethyl acetate-hexane provided colorless prisms, m.p. 176°-177° C.