Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[C:12]([CH2:19][CH3:20])[CH:11]=1)(C(C)(C)C)(C)C.[F:21][C:22]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=O)=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[F:21][C:22]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:23]=1[O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]2[O:18][N:17]=[C:15]([C:13]3[S:14][C:10]([CH2:9][OH:8])=[CH:11][C:12]=3[CH2:19][CH3:20])[N:16]=2)=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2F)cc1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d), 4-(2,3-difluorophenoxy)benzoic acid (0.14 g, 0.55 mmol) that was obtained in Example 18 (18a), N,N′-dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), and 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.75 mL, 0.75 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:8 to 3:7) as the eluent to afford the title compound (0.18 g) in a yield of 88% as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=2)[CH2:25][CH2:24]1>>[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]3[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:9]=3)=[O:21])[O:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: NCc1cc(C2CC2)no1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Product: O=C(NCc1cc(C2CC2)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 3-cyclopropyl-5-isoxazolemethanamine (CAN 851434-73-6) as starting materials, LC-MS (UV peak area/ESI) 92.9%, 453.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[ClH:13].[CH3:14][N:15]([CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH3:16]>C(O)C.O.C(O)(C)C>[ClH:13].[ClH:13].[CH3:14][N:15]([CH2:17][C:18]([NH:20][N:21]=[C:1]([C:4]1[N:5]=[C:6]([C:10](=[N:21][NH:20][C:18](=[O:19])[CH2:17][N:15]([CH3:16])[CH3:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2])=[O:19])[CH3:16]
Reactant: CN(C)CC(=O)NN
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: O
Product: CC(=NNC(=O)CN(C)C)c1cccc(C(C)=NNC(=O)CN(C)C)n1
Yield: 95 %

Procedure:
A solution of 2,6-diacetylpyridine (Aldrich Chemical, Milwaukee, Wis., 0.815 g, 5 mmole) in hot ethanol (10 ml) was mixed with a solution of dimethylaminoacethydrazide hydrochloride (Avocado/Alfa Aesar, Ward Hill, Mass.) in warm water (10 ml). The mixture was heated to reflux briefly and allowed to cool. After 3 hrs the mixture was diluted with 20 ml isopropanol, causing a copious precipitate to form. The precipitate was filtered out and washed with isopropanol. Drying gave 2.065 g (95%) white crystalline solid, melting pt. 280-282° C. (dec.).
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][C:11]1[CH:20]=[C:14]2[C:15](=[O:19])[NH:16][CH2:17][CH2:18][N:13]2[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:22].[NH4+].[Cl-]>CN(C=O)C>[CH3:22][N:16]1[CH2:17][CH2:18][N:13]2[N:12]=[C:11]([CH2:10][O:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:20]=[C:14]2[C:15]1=[O:19]
Reactant: O=C1NCCn2nc(COc3ccccc3)cc21
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1CCn2nc(COc3ccccc3)cc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (9 mg, 0.22 mmol) was added to a stirred solution of 2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.05 g, 0.20 mmol) in DMF (3 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes. Then iodomethane (15 μL, 0.24 mmol) was added at 0° C., the mixture stirred at 0° C. for 1 hour and allowed to warm to room temperature. Then additional iodomethane (15 μL, 0.24 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was treated with a saturated solution of NH4Cl and the solvents evaporated in vacuo. The crude product was diluted with H2O and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 40/60). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (49 mg, 97% yield) as an oil which solidified upon standing. 1H NMR (500 MHz, CDCl3) δ ppm 3.14 (s, 3H), 3.69-3.83 (m, 2H), 4.32-4.49 (m, 2H), 5.09 (s, 2H), 6.93 (s, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.99 (d, J=8.1 Hz, 2H), 7.27-7.32 (m, 2H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[I:13][C:14]1[CH:15]=[N:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:18]([CH:22]=1)[C:19]([OH:21])=O.[NH2:28][C:29]1[C:30]([CH2:41][CH3:42])=[N:31][N:32]([CH2:37][CH2:38][O:39][CH3:40])[C:33]=1[C:34]([NH2:36])=[O:35].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:36][C:34]([C:33]1[N:32]([CH2:37][CH2:38][O:39][CH3:40])[N:31]=[C:30]([CH2:41][CH3:42])[C:29]=1[NH:28][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([I:13])[CH:15]=[N:16][C:17]=1[O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:35]
Reactant: CCc1nn(CCOC)c(C(N)=O)c1N
Reactant: CCCCOc1ncc(I)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCOc1ncc(I)cc1C(=O)Nc1c(CC)nn(CCOC)c1C(N)=O
Yield: 133.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (434 mg, 2.26 mmol) was added to a stirred solution of 5-iodo-2-butoxynicotinic acid (615 mg, 1.92 mmol), 4-amino-3-ethyl-1-(2-methoxyethyl)-pyrazole-5-carboxamide (370 mg, 1.74 mmol), 1-hydroxybenzotriazole hydrate (346 mg, 2.26 mmol) and diisopropylethylamine (0.9 mL, 5.22 mmol) in tetrahydrofuran (12 mL) at room temperature under a nitrogen atmosphere. After 20 h the solvent was evaporated and the product was extracted from 10% sodium bicarbonate solution with dichloromethane (3×100 mL). The organics were dried (MgSO4) and concentrated to give a fawn solid. The solid was triturated with di-isopropylether to give an off-white solid (1.2 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]([CH3:22])[NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:14]([CH3:22])[N:13]([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: OB(O)c1ccncc1
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Product: CC1N(c2ccncc2)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1

Procedure:
The title compound, MS: m/e=563.2 (M+H+), was prepared in accordance with the general method of example 63 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and pyridine-4-boronic acid.
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=3)[C:17](=[O:27])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=3)[C:17](=[O:27])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)=[N+:29]=[N-:30]
Reactant: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 65 °C
Reaction time: 5.5 h
Yield: 111.9 %

Procedure:
2-(4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-ylamino)ethyl methanesulfonate (50.0 g, 0.108 mol) was dissolved in N, N-dimethylformamide (83 mL). Sodium azide (10.5 g, 0.162 mol) was added. The reaction was stirred at 65° C. for 5-6 hours. LCMS indicated reaction completed (M+Na=435). The reaction was quenched with water (250 mL) and extracted with ethyl acetate (2×250 mL). The combined ethyl acetate solution was washed with water (250 mL, layer separation was slow, 100 mL of brine was added to improve the separation), dried over sodium sulfate, and concentrated to give 49.7 g crude brown solid. Crude yield is 112%. LCMS for C12H8BrFN8O3Na (M+Na)+: m/z=433.0, 435.0. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.75 (t, J=5.7 Hz, 1H), 3.54 (t, J=5.3 Hz, 2H), 3.45 (dd, J=11.1, 5.2 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([C@H:20]3[CH2:24][N:23](C(OC(C)(C)C)=O)[C@H:22]([C:32](=[O:35])[NH:33][CH3:34])[CH2:21]3)[CH:19]=2)=[CH:11][C:10]=1[C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([C@H:20]3[CH2:24][NH:23][C@H:22]([C:32]([NH:33][CH3:34])=[O:35])[CH2:21]3)[CH:19]=2)=[CH:11][C:10]=1[C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1
Reactant: CNC(=O)[C@@H]1C[C@@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H]1C[C@@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
Trifluoroacetic acid (5 ml) was added to (2S,4R)-tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-2-(methylcarbamoyl)pyrrolidine-1-carboxylate (70 mg) under argon. The resulting solution was stirred at 25° C. for 1 hour. The solution was evaporated under reduced pressure. The residue was basified with a solution of ammonia in methanol and the resultant mixture was adsorbed onto silica gel and purified by flash chromatography on silica gel eluting with 1 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N-methyl-pyrrolidine-2-carboxamide (55 mg) as a solid. NMR Spectrum: (CDCl3) 1.75 (bs, 1H), 2.48-2.58 (m, 1H), 2.68-2.76 (m, 1H), 2.85 (d, 1.5H), 2.87 (d, 1.5H), 3.08 (d, 0.5H), 3.10 (d, 0.5H), 3.43-3.46 (m, 0.5H), 3.46-3.49 (m, 0.5H), 4.11-4.17 (m, 1H), 4.79-4.85 (m, 1H), 6.95 (m, 2H), 7.34-7.42 (m, 2H), 7.58-7.62 (m, 1H), 7.63-7.68 (m, 1H), 7.69 (s, 1H), 7.73-7.78 (m, 2H), 8.36 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 404.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[CH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.II.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:33])C=CC=1)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:33])[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2c(C)cc(=O)n(C3CCCC3)c2n1
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ncc2c(C)c(I)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.45 h
Yield: 58 %

Procedure:
The sulfide, 8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (7.03 g, 25.51 mmol) and iodine (7.12 g, 28.06 mmol) were combined in dry dichloromethane (120 mL). The mixture was shielded from light and stirred at room temperature for 27 minutes. Bis(trifluoroacetoxy)iodobenzene (13.16 g, 30.61 mmol) was added in one portion and the reaction mixture was heated to 37° C. for 2 h, then cooled to room temperature for 2 h. 50% Aqueous (w/v) sodium thiosulfate (114 mL) was added and the two phases were stirred for 30 minutes then separated. The aqueous phase was extracted with dichloromethane (50 mL) and the combined organic phases were washed with 50% aqueous (w/v) sodium thiosulfate (50 mL) and water (4×130 mL). The organic phase was dried, filtered and concentrated in vacuo to give crude product which was purified by chromatography (15% heptane/dichloromethane) to give 8-cyclopentyl-6-iodo-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (5.94 g, 58%) as a white solid. MS (ESI); M++1: Calc'd, 401. Found 401. 1H NMR δ (300 MHz, CDCl3) 8.91 (s, 1H), 6.12-6.00 (m, 1H), 2.70 (s, 3H), 2.62 (s, 3H), 2.30-2.24 (m, 2H), 2.15-2.08 (m, 2H), 1.93-1.81 (m, 2H), 1.75-1.57 (m, 2H)
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9](OC)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCc1c(C(=O)OC)cccc1-c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(CO)cccc1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
After methyl 2-ethyl-4′-methoxy-1,1′-biphenyl-3-carboxylate (4.83 g, 17.9 mmol) obtained in Example (90-2) was added to a suspension of lithium aluminum hydride (1.02 g, 26.8 mmol) in tetrahydrofuran (90 ml) under ice-cooling, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled with ice and water (1 ml) was added dropwise thereto. After the mixture was stirred for 5 minutes, a 3N aqueous sodium hydroxide solution (1 ml) was added thereto at room temperature and the mixture was stirred for 5 minutes. Further, water (3 ml) was added thereto and the mixture was stirred for 20 minutes. After the insolubles were removed by filtration using Celite, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=4/1-3/1) to give (2-ethyl-4′-methoxy-1,1′-biphenyl-3-yl)methanol (4.39 g, yield: 100%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]3[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14]([C:20]4[C:21]([CH2:40][OH:41])=[C:22]([N:26]5[CH2:34][C:33]6[C:28](=[CH:29][CH:30]=[C:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:32]=6)[C:27]5=[O:39])[CH:23]=[CH:24][CH:25]=4)[CH:13]=3)=[N:9][CH:10]=2)[CH2:2]1.C=O.O.[C:45]([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:39])[N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]3[CH:13]=[C:12]([NH:11][C:8]4[CH:7]=[CH:6][C:5]([CH:3]5[CH2:2][N:1]([CH3:45])[CH2:4]5)=[CH:10][N:9]=4)[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=3)[C:21]=1[CH2:40][OH:41])[CH2:34]2)([CH3:37])([CH3:38])[CH3:36]
Reactant: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C3CNC3)cn2)c1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC(c2ccc(Nc3cc(-c4cccc(N5Cc6cc(C(C)(C)C)ccc6C5=O)c4CO)cn(C)c3=O)nc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.4 %

Procedure:
A 150-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 117(72 mg, 0.130 mmol), 37% solution of formaldehyde in water (5 mg, 0.170 mmol) and anhydrous methanol (5 mL). A suspension of sodium cyanoborohydride (25 mg, 0.400 mmol) and anhydrous zinc chloride (27 mg, 0.200 mmol) in anhydrous methanol (2.5 mL) was added, and the reaction was stirred at room temperature for 5 h. After this time, the reaction mixture was concentrated, and 10% aqueous potassium carbonate (5 mL) was added. The resulting suspension was filtered, and the filter cake was washed with water (2 mL). The filter cake was purified by column chromatography to afford a 64% yield (56 mg) of 118 as a white solid: mp 201-202° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.54 (s, 1H), 8.11 (s, 1H), 7.72 (d, 2H, J=8.5 Hz), 7.64 (m, 2H), 7.49 (t, 1H, J=8.0 Hz), 7.44 (d, 1H, J=6.5 Hz), 7.37 (m, 2H), 7.27 (d, 1H, J=8.5 Hz), 4.94 (s, 2H), 4.88 (t, 1H, J=4.5 Hz), 4.34 (d, 2H, J=4.5 Hz), 3.59 (s, 3H), 3.54 (t, 2H, J=7.0 Hz), 3.45 (m, 1H), 3.01 (t, 2H, J=6.5 Hz), 2.24 (s, 3H), 1.36 (s, 9H); MS (ESI+) m/z 564.3 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC)=O.[NH2:28][CH2:29][C:30]([NH2:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[NH2:33][C:30]([CH3:32])([CH3:31])[CH2:29][NH:28][C:12](=[O:14])[CH2:11][NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNC(=O)Cc1ccccc1
Reactant: CC(C)(N)CN
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CC(C)(N)CNC(=O)CNC(=O)Cc1ccccc1
Temperature: -23 °C
Reaction time: 0.08 h

Procedure:
A mixture of phenylacetylglycine (10.0 g.), N-methyl morpholine (5.78 ml.) and chloroform (60 ml.) was stirred for 5 minutes. After cooling to -23° C., ethyl chloroformate (4.7 ml.) was added rapidly to the mixture during 1 minute, whereupon the temperture of the mixture rose to -15° C. After stirring for 1 minute, 1,2-diamino-2-methyl-propane (5.4 ml.) was added rapidly to the reaction mixture and the temperature was allowed to rise to room-temperature. After 1 hour at room temperature, the reaction mixture was poured into water (50 ml.) and the organic layer discarded. The aqueous layer was basified with excess potassium carbonate, and extracted with chloroform (4×100 ml.). The combined extracts were dried (MgSO4) and evaporated. Trituration and filtration of the solid residue with ether gave N1 -(2-amino-2-methylpropyl)-N2 -phenylacetylglycinamide as a solid (8.8 g.), m.p. 150°-155° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][C@H:12]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:13](=[O:24])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][OH:36].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][C@H:12]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:13](=[O:24])[NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[NH:23])[NH:35][OH:36])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 152.7 %

Procedure:
A solution of compound Q (9.65 g, 20.0 mmol), hydroxylamine hydrochloride (2.10 g, 30.0 mmol) and DIEA (5.22 ml, 30.0 mmol) in ethanol (abs., 150 ml) was refluxed for 6 h. The reaction mixture was allowed to cool to room temperature and stirred for additional 16 h, then the solvents were evaporated in vacuo. The resultant residue was dried in vacuo to provide compound R (14.8 g, yield exceeded quantitative) as yellowish oil. LC-MS [M+H] 485.5 (C25H32N4O6+H, calc: 485.8). Compound R was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][CH2:5][Cl:6].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[NH:18][C:19]1[N:20]=[CH:21][C:22]2[CH2:28][NH:27][CH2:26][CH2:25][C:23]=2[N:24]=1.C(N(CC)CC)C>O1CCCC1.ClCCl.C(=O)(O)[O-].[Na+]>[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[NH:18][C:19]1[N:20]=[CH:21][C:22]2[CH2:28][N:27]([C:1]([O:2][CH2:3][CH2:4][CH2:5][Cl:6])=[O:7])[CH2:26][CH2:25][C:23]=2[N:24]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: O=C(Cl)OCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCCCCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 2 h

Procedure:
Add a solution of 3-chloropropyl carbonochloridate (0.55 mL; 1.2 equiv; 4.51 mmoles) in tetrahydrofuran (25 mL) over 1 hour to a mixture of N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (1.00 g; 1.0 equiv; 3.75 mmoles) and triethylamine (1.10 mL; 2.1 equiv; 7.88 mmoles) in tetrahydrofuran (25 mL). Stir for 2 hours, then dilute with dichloromethane and saturated sodium bicarbonate and separate the layers. Further extract the aqueous layer with dichloromethane (2×). Dry the combined organic extracts over sodium sulfate, filter, and concentrated to dryness to give a yellow oil. Purify the crude product by column chromatography (10% methanol in dichloromethane) to 3-chloropropyl 2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (1.146 g; 79%): MS (m/z): 387(M+1).
Reaction SMILES: [ClH:1].[CH2:2]([NH:20][C:21](=[O:40])[CH2:22][C:23]1[CH:39]=[CH:38][CH:37]=[CH:36][C:24]=1[CH2:25][CH:26]1[CH2:31][N:30]([CH3:32])[CH2:29][CH2:28][N:27]1[C:33]([O-:35])=[O:34])[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][CH3:19]>C(OCC)(=O)C>[ClH:1].[CH2:2]([NH:20][C:21](=[O:40])[CH2:22][C:23]1[CH:39]=[CH:38][CH:37]=[CH:36][C:24]=1[CH2:25][CH:26]1[CH2:31][N:30]([CH3:32])[CH2:29][CH2:28][N:27]1[C:33]([OH:35])=[O:34])[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][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)Cc1ccccc1CC1CN(C)CCN1C(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)Cc1ccccc1CC1CN(C)CCN1C(=O)O
Reaction time: 0.5 h

Procedure:
4N Hydrochloric acid--ethyl acetate solution (1.44 ml) was added to a solution of 2-[2-(octadecylamino)-2-oxoethyl]benzyl-4methyl-1-piperazinecarboxylate (2.60 g) in ethyl acetate (39 ml) at room temperature. After being stirred for 30 minutes, the reaction mixture was concentrated. The residue was recrystallized from ethyl acetate-ethanol mixed solvent, thereby yielding 2.42 g of the aimed compound as white solid.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11]([CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[CH:20]=1.C([O-])([O-])=O.[K+].[K+].[C:27]([CH:29](Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=1)#[N:28]>CCOCC.CS(C)=O.C1COCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11]([CH:13]([CH:17]([CH3:18])[CH3:19])[C:14]([O:16][CH:29]([C:27]#[N:28])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:31]=3)=[O:15])=[CH:10][C:9]=2[CH:20]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Reactant: N#CC(Cl)c1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1cc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 10 ml methylene chloride, 10 ml THF, 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (0.5 g), K2CO3 (0.25 g) and α-cyano-3-phenoxybenzyl chloride (0.42 g) is stirred at RT for 15 hours. Then 5 ml of DMSO is added and reaction mixture stirred for about 48 hours. The mixture is taken up in ether, washed with water and brine, dried over Na2SO4 and solvent removed. The crude product is plated developing with 10% ethyl acetate/hexane to give α-cyano-3-phenoxybenzyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.