Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=1)=[O:36]>C1COCC1>[C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:35]([O:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:46][CH:47]=3)=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@@H](NCC1CNCCC1c1ccccc1)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2CCC(c3ccccc3)C(CN[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 175 mg of the crude product of (1R)-1-(1-naphthyl)-N-[(4-phenylpiperidin-3-yl)methyl]ethaneamine and 142 μL of triethylamine in 3.5 mL of THF was added 120 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka) under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 237 mg of 4-(methoxycarbonyl)phenyl 3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:15]=[C:14](Br)[CH:13]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH3:12])[CH:5]=1)=[O:17]
Reactant: CCCNC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: OB(O)c1ccccc1
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: CCCNC(=O)c1cc(C(=O)OC)cc(-c2ccccc2)c1

Procedure:
Using Preparation Method 2, 68C (247 mg, 0.82 mmol) was reacted with phenyl boronic acid (109 mg, 0.9 mmol) in the presence of 5 mol % Pd(PPh3)4, 0.82 mL of 2N Na2CO3, 0.43 mL of Ethanol and 1.8 mL of toluene. The resulting reaction mixture was purified using SiO2 with CH2Cl2/AcOEt 98:2 to 90:10 to give a greenish oil (284 g, quant.). NMR 1H (ppm, CDCl3): 8.37 (t, J4=1.64 Hz, 1H), 8.27 (d. t., J3=6.03 Hz, J4=1.75 Hz, 1H), 7.63 (d, J3=6.97 Hz, 1H), 7.49-7.36 (m, 5H), 6.27 (br. s., 1H), 3.49-3.42 (m, 2H), 1.64 (sext., J3=7.25 Hz, 2H), 1.00 (t., J3=7.37 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:38]=[CH:37][C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[C:41]([C:39]1[CH:38]=[CH:37][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:26][C:27](=[O:36])[C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[O:18])=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:40]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2OC2CCNCC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 104.2 %

Procedure:
To an ice-water bath-chilled solution of N4-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-tert-butylbenzoyl]-N3-(4-methoxybenzoyl)-3,4-pyridinediamine (460 mg, 764 micromoles) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL) and the mixture stirred on ice for 90 min. The mixture was then concentrated in vacuo, the oily residue redissolved in 1:1 dichloromethane:toluene (10 mL) and re-concentrated in vacuo to provide a pale tan-yellow oil. The oil was dissolved in methanol (10 mL) and applied to a 10 gram×60 cubic centimeter strong cation exchange solid phase extraction column (SCX, Varian Sample Preparation Products, Harbor City, Calif.) that had been conditioned with methanol. After sample application, the cartridge was washed with methanol (4×50 mL) and the product was eluted with 3:1 chloroform:(2 M NH3 in methanol) (3×40 mL). The eluates were concentrated in vacuo to afford N4-[4-tert-butyl-2-(piperidin-4-yloxy)benzoyl]-N3-(4-methoxybenzoyl)-3,4-pyridinediamine as a yellow oil (400 mg, 104%). This material was used without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[S:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.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>[S:19]1[C:23]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:22][N:21]=[CH:20]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cncs3)ncnc21
Temperature: 200 °C
Yield: 63.8 %

Procedure:
4-Chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 0.0106 mol), and 1,3-thiazole (7.50 mL, 0.106 mol) were dissolved in N,N-dimethylacetamide (40.0 mL). The solution was distributed in equal portions into four 20 mL microwavable vessels. Into each reaction vessel was then added potassium acetate (0.777 g, 7.93 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.60 g, 2.1 mmol). Each reaction vessel was heated at 200° C. in the microwave reactor for 30 minutes. The reactions were combined and most of the solvent was removed in vacuo. The residue was diluted with DCM, filtered and concentrated. Purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (2.25 g, 64%).
Reaction SMILES: [ClH:1].Cl.[CH:3]1[CH:12]=[CH:11][C:10]2[CH2:13][CH2:14][CH2:15][N:8]3[C:9]=2[C:4]=1[C@@H:5]1[CH2:18][NH:17][CH2:16][C@H:6]1[CH2:7]3.C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>ClCCCl.CCOCC>[ClH:1].[ClH:1].[CH3:21][N:17]1[CH2:18][C@@H:5]2[C@H:6]([CH2:7][N:8]3[CH2:15][CH2:14][CH2:13][C:10]4[CH:11]=[CH:12][CH:3]=[C:4]2[C:9]3=4)[CH2:16]1
Reactant: c1cc2c3c(c1)[C@@H]1CNC[C@H]1CN3CCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCCl
Product: CN1C[C@H]2CN3CCCc4cccc(c43)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a solution of (±)-trans-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline from EXAMPLE 4 (95 mg, 0.44 mmol) in 5 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.043 mL, 0.53 mmol), sodium triacetoxyborohydride (168 mg, 0.79 mmol) and glacial acetic acid (0.027 mL, 0.48 mmol). The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (0.44 mL, 0.88 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 35 mg (27%) of the title compound of EXAMPLE 6 as an off white powder. 1H NMR (d6-dmso): δ 11.22 (broad s, 1H), 6.76 (d, 1H, J=7.7 Hz), 6.57 (dd, 1H, J=7.3, 12.5 Hz), 6.38 (t, 1H, J=7.3 Hz), 4.17-4.08 (m, 1H), 3.81-3.72 (m, 1H), 3.68-3.60 (m, 1H), 3.42-3.18 (m, 5H), 2.98-2.80 (m, 4H), 2.66-2.60 (m, 2H), 2.10-1.98 (m, 1H), 1.95-1.83 (m, 1H), 1.82-1.72 (m, 1H). LRMS (ES)+: 229.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[CH3:12])[C:2]([O:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:3][CH:4]=[CH:5]2
Reactant: Oc1ccccc1
Reactant: COc1cc2ccnc(Cl)c2cc1C
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COc1cc2ccnc(Oc3ccccc3)c2cc1C
Yield: 19.6 %

Procedure:
A mixture of 1-chloro-6-methoxy-7-methyl-isoquinoline (9 g, 43.48 mol), phenol (16.3 g), potassium hydroxide (9.45 g) and xylene (100 ml) was refluxed for 4 days. The reaction mixture was poured out into aqueous sodium hydroxide (4 M) and the xylene layer separated. The aqueous layer was extracted twice with toluene. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give a residue. The residue was purified by flash chromatography using dichloromethane gave 6-methoxy-7-methyl-1-phenoxyisoquinoline (9 g, 33.96 mmol).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:17][CH:16]=4)[C:13]([NH:35][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Reactant: NC1CCCCC1
Product: O=C1C=C(NC2CCCCC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.124 g, 0.3 mmol) and cyclohexylamine (0.48 ml, 4.2 mmol) according to method 7 described above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][N:28]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNC2)C[C@H]1c1ccc(Cl)cc1
Product: CCC(=O)N1CCC(C(=O)N2C[C@@H](N(C)C(=O)Oc3ccc(F)cc3)[C@H](c3ccc(Cl)cc3)C2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 73, the title [(3S,4R)-4-(4-chloro-phenyl)-1-(1-propionyl-pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-1-(pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using propionyl chloride and was obtained as a light yellow oil. MS m/e: 502.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([CH:8]([OH:11])[CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(Cl)(Cl)Cl.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(N(CC)CC)C>O>[C:17]([O:11][CH:8]([CH2:9][CH3:10])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([F:12])[F:1])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)C(F)(F)C(O)CC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCC
Temperature: 55 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A 25 ml reactor was charged with 1.50 g (8.2 mmol) of ethyl 2,2-difluoro-3-hydroxypentanoate, 6.5 g of chloroform, 10 mg of an antioxidant NONFLEX MBP made by Seiko Chemical Co., Ltd., 1.03 g (9.9 mmol, 1.2 eq) of methacrylic chloride, and 1.25 g (12.4 mmol, 1.5 eq) of triethylamine, followed by stirring at 55° C. for 4 hours. Then, 10 g of water was added, followed by extraction with chloroform one time. The obtained organic layer was washed with diluted hydrochloric acid and water, followed by removing water with magnesium sulfate. After conducting filtration, chloroform was distilled off, thereby obtaining 2.06 g of the target 1-ethoxycarbonyl-1,1-difluoro-2-butyl methacrylate. Purity was 66%, and yield was 66%.
Reaction SMILES: O[CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:5](=[O:18])[CH:4]2[CH2:19][C:20](=[CH2:22])[CH2:21][CH:3]12.[BH3-]C#N.[Na+].O>FC(F)(F)C(O)=O>[CH2:22]=[C:20]1[CH2:19][CH:4]2[C:5](=[O:18])[N:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]([F:16])([F:15])[F:17])=[CH:11][CH:12]=3)[CH2:2][CH:3]2[CH2:21]1
Reactant: C=C1CC2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(O)C2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=C1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 3-Hydroxy-5-methylene-2-(4-trifluoromethoxy-phenyl)-hexahydro-cyclopenta[c]pyrrol-1-one (0.1 g, 0.32 mmol) in trifluoroacetic acid (20 mL) was added NaCNBH3 (0.04 g, 0.64 mmol) at −20° C., and the mixture was stirred for 1 h. Water (30 mL) was added. The mixture was extracted with dichloromethane (3×20 mL), washed with brine (50 mL), and dried over anhydrous Na2SO4. The solvent was removed by reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (10:1 to 5:1) to yield the title compound (40 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 7.69-7.64 (m, 2H), 7.25-7.19 (m, 2H), 4.91 (s, 2H), 4.07-4.01 (m, 1H), 3.54-3.49 (m, 1H), 3.19-3.12 (m, 1H), 2.96-2.71 (m, 4H), 2.25-2.18 (m, 1H); LC-MS: [M+1]+ 298.1.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:12]([OH:14])=O)=[N:6][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH:52]([N:55]1[CH2:60][CH2:59][CH:58]([NH2:61])[CH2:57][CH2:56]1)([CH3:54])[CH3:53]>CN(C=O)C>[CH:52]([N:55]1[CH2:60][CH2:59][CH:58]([NH:61][C:12]([C:7]2[NH:8][C:9]3[C:10](=[O:11])[N:2]([CH3:1])[C:3](=[O:16])[N:4]([CH3:15])[C:5]=3[N:6]=2)=[O:14])[CH2:57][CH2:56]1)([CH3:54])[CH3:53]
Reactant: Cn1c(=O)c2[nH]c(C(=O)O)nc2n(C)c1=O
Reactant: CC(C)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.45 mmol) 1,3-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid were dissolved in 5 mL DMF. Subsequently 227 μl (1.35 mmol) DIPEA and 186.5 mg (0.495 mmol) HATU were added. After 1 h 105.6 mg (0.495 mmol) 1-isopropyl-piperidine-4-ylamine-dihydrochloride and 227 μl (1.35 mmol) DIPEA were added and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as its formiate.
Reaction SMILES: [F:1][C:2]1[C:15]([N+:16]([O-])=O)=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:16][C:15]1[C:2]([F:1])=[CH:3][C:4]2[O:9][CH2:8][C:7](=[O:10])[N:6]([CH2:11][C:12]#[CH:13])[C:5]=2[CH:14]=1
Reactant: C#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(N)cc21
Temperature: 80 °C
Yield: 74.9 %

Procedure:
Iron powder (1.05 g) was suspended in 5% aqueous acetic acid (2.0 ml) and heated to 80° C. To the suspension, a solution of 7-fluoro-6-nitro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.47 g) in acetic acid (1.9 ml) and ethyl acetate (1.9 ml) was dropwise added, and the resultant mixture was heated under reflux at 60° to 80° C. for 3 hours. After being allowed to cool, water and ethyl acetate were added to the mixture. The residue was removed by filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with water and aqueous sodium bicarbonate solution, dried and concentrated to give 6-amino-7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.31 g). m.p., 183°-185° C.
Reaction SMILES: [F:1][C:2]([F:17])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([OH:5])=O.CCN(CC)CC.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]2[O:37][N:36]=[C:35]([C@@H:38]3[CH2:42][CH2:41][CH2:40][NH:39]3)[CH:34]=2)[CH:26]=1.C(=O)(O)[O-].[Na+]>C1COCC1.ClC(OCC)=O>[F:17][C:2]([F:1])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([N:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[C:35]1[CH:34]=[C:33]([CH2:32][O:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[O:37][N:36]=1)=[O:5]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)O)C1
Reactant: c1cncc(OCc2cc([C@@H]3CCCN3)no2)c1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COc3cccnc3)on2)C1
Yield: 58.5 %

Procedure:
To a solution of 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetic acid (3.192 g) and Et3N (4.44 mL) in THF (100 mL), ethyl chloroformate (1.12 mL) was added at room temperature and the mixture was stirred for an hour. To the reaction mixture, a THF (50 mL) solution of the compound (2.607 g) obtained in Example 2-(3) was added dropwise at room temperature and the mixture was stirred at room temperature for 64 hours. To the reaction mixture, saturated aqueous sodium bicarbonate (200 mL) was added and the organic layer extracted with AcOEt (200 mL) was washed with brine (200 mL), dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by NH-form silica gel chromatography (AcOEt/hexane); the resulting compound was recrystallized (Et2O/pentane) to give the titled compound (2.969 g, colorless powder.)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)[OH:4].O=[C:18]([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:31][O:30][C:28]([CH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH:18]([NH:1][CH2:2][CH:3]([C:5]2[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=2)[OH:4])[CH3:32])=[CH:26][CH:25]=1)=[O:29]
Reactant: COc1cc(C(O)CN)cc(OC)c1OC
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cc(OC)c(OC)c(OC)c2)cc1
Yield: 82.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3,4,5-trimethoxyphenyl)ethanol (prepared as described in Preparation 14), 2.35 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 70 ml of benzene, 60 ml of absolute methanol and 4.8 g of sodium cyanoborohydride, 3.14 g of the title compound were obtained having an Rf=0.21 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33](O)[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:38]([O:45][C:46](=[O:50])[C@@H:47]([OH:49])[CH3:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:49][C@@H:47]([C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:50])[CH3:48])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)O)NC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 350 mg of (S)-2-Hydroxy-propionic acid benzyl ester in 20 ml of THF, 764 mg of Triphenyl-phosphane and 507 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:23]=2[CH:24]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([NH:29][C:12]([C:10]3[O:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)=[O:14])=[CH:25][C:23]=2[CH:24]=1)=[O:19])[CH3:16]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: CCOC(=O)c1cc2cc(N)ccc2s1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(-c4ccccc4)o3)ccc2s1

Procedure:
Carboxylic acid (56) (105 mg, 0.56 mmol) was coupled to 5-amino-benzothiophene-2-carboxylic acid ethyl ester (123 mg, 0.56 mmol) using Method C to give the title compound.