Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[O:32])=[CH:29][C:28]=3[O:43][CH3:44])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CN1C(=O)C(F)(F)CN(CCOc2ccccc2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CCOc1ccccc1)CC(F)(F)C(=O)N2C
Yield: 0 %

Procedure:
The mixture of 0.08 g (0.22 mole) of 2-chloro-7,7-difluoro-5-methyl-9-(2-phenoxy-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-304), 0.070 g (0.26 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.062 g (0.33 mole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-20:80) gave 0.051 g of give 4-[7,7-difluoro-5-methyl-6-oxo-9-(2-phenoxy-ethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid (I-304).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[C@H:32]([NH:33][C:34](=[O:82])/[C:35](/[C:57]4[N:58]=[C:59]([NH:62]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:60][CH:61]=4)=[N:36]\[O:37]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:31](=[O:83])[N:13]3[C:14]=2[C:15]([O:17]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:16])[CH2:4][O:3]1.Cl.O>C(O)=O>[NH2:62][C:59]1[S:60][CH:61]=[C:57](/[C:35](=[N:36]/[OH:37])/[C:34]([NH:33][C@@H:32]2[C:31](=[O:83])[N:13]3[C:14]([C:15]([OH:17])=[O:16])=[C:9]([CH2:8][S:7][C:5]4[CH2:4][O:3][C:2](=[O:1])[CH:6]=4)[CH2:10][S:11][C@H:12]23)=[O:82])[N:58]=1
Reactant: O=C1C=C(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)CO1
Agent: Cl
Solvent: O=CO
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSC4=CC(=O)OC4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
Diphenylmethyl 3-(2,5-dihydro-2-oxofuran-4-ylthiomethyl)-7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetamido]ceph-3-em-4-carboxylate (744 mg) was dissolved in 98-100% formic acid (13 ml) and 1N hydrochloric acid (0.65 ml) and water (0.65 ml) were added. The mixture was stirred at room temperature for 30 mins and then concentrated hydrochloric acid (0.52 ml) was added. After stirring for a further hour the solvents were removed on a rotary evaporator. A mixture of toluene and tetrahydrofuran was evaporated from the residue twice, and the residue triturated with ether. The solid was filtered off, and washed with ether. The solid was suspended in water and the pH adjusted to 2.6 with 0.1N sodium hydroxide, the mixture was stirred for a further 30 mins, occasionally adjusting the pH to 2.6. The solid was then filtered off, washed with cold water and dried under vacuum to give the title compound (128 mg) as an off-white solid. υmax (KBr) 1773, 1735, 1670, and 1629cm-1. δH [(CD3)2SO] 3.49 (1H, d, J 18.0Hz), 3.72 (1H, d, J 18.1Hz), 4.10 (1H, d, J 13.2Hz), 4.18 (1H, d, J 13.2Hz), 4.97 (2H, s), 5.18 (1H, d, J 4.8Hz), 5.79 (1H, dd, J 4.8 and 8.0Hz), 6.11 (1H, s), 6.67 (1H, s), 9.51 (1H, d, J 8.1Hz), 11.40 (1H, s). [mass spectrum: +ve ion (thioglycerol) MH+ 498].
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:12]([C:21](=[O:38])[NH:22][CH2:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:11]([CH2:39][O:40][CH2:41][CH2:42]Cl)[NH:10][C:9]=1[CH3:44])=[O:7])#[N:2].[I-].[Na+].[N-:47]=[N+:48]=[N-:49].[Na+].C(OCC)(=O)C>CC(O)C.CN(C=O)C>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:12]([C:21](=[O:38])[NH:22][CH2:23][CH2:24][CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:11]([CH2:39][O:40][CH2:41][CH2:42][N:47]=[N+:48]=[N-:49])[NH:10][C:9]=1[CH3:44])=[O:7])#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCCl)N1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCN=[N+]=[N-])N1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
270 mg (0.430 mmol) of 6-(2-chloroethoxy) methyl-4-(3-chlorophenyl)-5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid (2-cyanoethyl) ester was dissolved in 3 ml of 2-propanol. 600 mg (0.400 mmol) of sodium iodide was added thereto and stirred at 60° C. for 20 hours. After the solvent was evaporated under reduced pressure, sodium iodide separated by adding dichloromethane was taken by filtration. The filtrate was concentrated under reduced pressure and stirred together with 33.0 mg (0.490 mmol) of sodium azide at 50° C. for 6 hours in 2 ml of DMF. After adding ethyl acetate, the reaction mixture was washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH:1]1([C:6](O)([CH2:23][C:24]2[O:25]C(C)(C)[O:27][C:28](=[O:30])[CH:29]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:11]([F:22])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4([C:20]#[N:21])[CH2:16][CH2:17][CH2:18][CH2:19]4)=[C:11]([F:22])[CH:10]=3)[CH2:23][C:24](=[O:25])[CH2:29][C:28](=[O:30])[O:27]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CCCC3)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCCC1

Procedure:
The title compound was prepared analogously to step 4 from Example A(97) where 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile (from step 2 below) was substituted in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (CDCl3) δ: 1.18–1.74 (m, 16 H), 1.92–2.17 (m, 2 H), 2.5–2.52 (m, 1 H), 2.66–2.68 (m, 2 H), 2.77 (s, 2 H), 3.43 (s, 2 H), 6.89–6.94 (m, 2 H), 7.33–7.37 (m, 1 H). MS (ESI): 398 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:11]2[NH:34][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:12]=2)[CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: [NH4+]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1F
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 5-[3-fluoro-4-(methylsulfanyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (127 mg) in acetic acid (2 mL) was added ammonium acetate (377% mg), and the mixture was stirred at 110° C. for 2 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (98.8 mg, yield 81%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].O=O>CO>[CH3:9][O:8][C:6](=[O:7])[C@@H:5]([CH3:10])[NH:4][C:1](=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: O=O
Solvent: CO
Product: COC(=O)[C@@H](C)NC(C)=O

Procedure:
A solution of methyl 2-acetamidoacrylate (22 mg, 0.15 mmol) and the catalyst (I) (1 mg, 0.0015, 1 mol %) in degassed methanol (1 ml) was prepared under exclusion of oxygen in a GC-vial. The vial was placed in a 50 ml Parr reactor which was purged with hydrogen and charged to 3.41 MPa (500 psi). After hydrogenation of the mixture overnight, the solvent was evaporated to give the (R)-N-acetylalanine methyl ester (complete conversion, 62.8% ee).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].[NH3:12].Cl>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][S:8]([NH2:12])(=[O:10])=[O:9]
Reactant: N
Reactant: O=S(=O)(Cl)CCc1cccs1
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)CCc1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of crude 2-thiophen-2-yl-ethanesulfonyl chloride (25 g) in THF (400 ml) was treated with sat. aq. ammonia (60 ml) at 0° C. The mixture was stirred at rt for 16 h before it was neutralised with 25% aq. HCl (60 ml). Bulk of the THF was evaporated. The aq. solution was extracted twice with EA. The organic phase was washed with water and evaporated. The remaining oil was purified by chromatography on silica gel eluting with heptane:EA 1:1. The product was further purified by recrystallisation from diethyl ether/pentane to give 2-thiophen-2-yl-ethanesulfonic acid amide (8.46 g) as off-white crystals. 1H-NMR (300 MHz, CDCl3): 3.36–3.50(m, 4H), 4.54(s br, 2H), 6.89–6.92(m, 1H), 6.95(dd, J=3.5, 5.1, 1H), 7.20(dd, J=1.1, 5.0, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][O:4][C:3]=1[C:10](OC)=[O:11].[BH4-].[Na+]>CO>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][O:4][C:3]=1[CH2:10][OH:11]
Reactant: COC(=O)c1occ(C)c(=O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1coc(CO)c(C)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
3,5-Dimethyl-2-methoxycarbonyl-4-pyrone 3 (R=Methyl) (294 mg, 1.62 mmol) and sodium borohydride (154 mg, 4.07 mmol) were dissolved in methanol (10 ml) and the resulting solution stirred at room temperature for 45 minutes. Silica gel (5 ml) was added and the solvent evaporated. The residue was applied to a pre-packed chromatography column assembled from silica gel (45 ml) in dichloromethane: ethyl acetate (1:1, v/v). Elution with firstly dichloromethane: ethyl acetate (1:1, v/v), then ethyl acetate, then methanol: ethyl acetate (1:3, v/v) gave 3,5-dimethyl-2-hydroxymethyl-4-pyrone 4 (230 mg, 92%) as a white solid. 1H-NMR (CDCl3) δ 1.93 (s, 3H), 2.01 (s, 3H), 4.60 (s, 2H), 7.71 (s, 1H); selected IR (cm-1, nujol) 3150-3500 (br, s), 1653 (s); Ms (APCI+) m/z (%) 155 (MH+, 100).
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:10])[CH2:5][O:6][CH2:7][CH2:8][OH:9].[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>C1COCC1.O>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:9][CH2:8][CH2:7][O:6][CH2:5][CH:4]([F:10])[F:3])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: OCCOCC(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Reaction time: 0.17 h
Yield: 112.5 %

Procedure:
To a cooled (0° C.) solution of 4.6 N sodium hydroxide (20.6 mL) was slowly added 2-(2,2-difluoroethoxy)ethanol (4 g, 31.7 mmol) in THF (10 mL) at a rate that maintained the temperature below 5° C. The mixture was stirred for 10 minutes, and TsCl (6.1 g, 32 mmol) in THF (10.6 mL) was slowly added at a rate that maintained the temperature below 5° C. The mixture was stirred for 30 minutes below 5° C., and then diluted with water. The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layers were washed with aqueous NH4Cl (30 mL), then with brine (30 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the crude product, which was purified by silica column chromatography (elution with PE:EtOAc=4:1) to give the title compound (10 g, yield 81.9%). 1H-NMR (CDCl3, 400 MHz): δ 7.78 (d, J=8.4 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 5.77 (ttt, J=4, 5.52 Hz, 1H), 4.16 (t, J=4.4 Hz, 2H), 3.74 (t, J=4.8 Hz, 2H), 3.62 (dt, J=4, 14 Hz, 2H), 2.44 (s, 3H).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][N:5]=1)=O.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]1>CCO>[CH3:26][S:23]([CH2:22][CH2:21][CH2:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[C:8]1[CH:7]=[CH:6][N:5]=[C:4]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]2)[N:9]=1)(=[O:25])=[O:24]
Reactant: NC1CCC(CO)CC1
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(CO)CC2)n1
Yield: 49.1 %

Procedure:
1-(2-Methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (5.0 g, 13 mmol) and (4-amino-cyclohexyl)-methanol hydrochloride (2.46 g, 19 mmol) were heated at reflux in EtOH (100 mL) under N2 for 16 h. The reaction mixture was then cooled, the suspension filtered, the filtrate volume reduced by half, diluted with EtOAc and washed with water, dried over sodium sulfate, filtered and concentrated until precipitate formed. This suspension was filtered, and the filtrate concentrated again until precipitation, and the suspension filtered, and both precipitates were combined and solvent removed in vacuo to yield (4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanol (Compound 214, 2.93 g), as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[N:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1C=CC=CC=1>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[N:8]=1
Reactant: BrP(Br)Br
Reactant: OCc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: c1ccccc1
Product: Clc1nc(N2CCOCC2)c2sc(CBr)nc2n1
Temperature: 25 °C

Procedure:
To a solution of (5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methanol 56 (100 mg, 0.4 mmol) in benzene (3.0 mL) at 0° C. was added PBr3(30 μL, 0.4 mmol). The reaction was heated at reflux for 1 hour. After cooling to room temperature the reaction was quenched by the addition of water. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude 4-(2-(bromomethyl)-5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 57 did not require further purification (x mg, x %). MS (Q1)×(M)+
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:3]1.C(N(CC)CC)C.[C:29]1([C:35](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.C1COCC1>[OH:7][C@H:6]1[C@H:2]([NH:1][C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:3][N:4]([C:8](=[O:21])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[CH2:5]1
Reactant: N[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)N1C[C@@H](O)[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.2 %

Procedure:
1-((3R,4R)-3-Amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (1.0 g) was dissolved in chloroform (30 mL) and THF (10 mL), followed by addition of triethylamine (0.55 mL) and triphenylmethyl chloride (1.4 g), and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=4:1-2:1) to obtain 1-((3R,4R)-3-hydroxy-4-(tritylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (1.1 g).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([C:14]([CH3:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl[C:18]1[C:23]([C:24]#[N:25])=[C:22]([NH:26][CH3:27])[C:21]([N+:28]([O-:30])=[O:29])=[CH:20][CH:19]=1.[NH4+].[Cl-]>CS(C)=O>[CH2:12]([O:11][C:9](=[O:10])[C:8]([C:18]1[CH:19]=[CH:20][C:21]([N+:28]([O-:30])=[O:29])=[C:22]([NH:26][CH3:27])[C:23]=1[C:24]#[N:25])([CH3:7])[C:14](=[O:15])[CH3:16])[CH3:13]
Reactant: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(NC)c1C#N
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
To a stirred solution of potassium t-butoxide (24.3 g, 206 mmol) in DMSO (500 mL) was added ethyl 2-methylacetoacetate (34.3 g, 233 mmol), dropwise over 5 min. The temperature rose to 30° C. 6-Chloro-2-methylamino-3-nitrobenzonitrile (43.6 g, 190 mmol) was added in portions over 15 min. The temperature rose to 40° C. The solution was stirred for 1 h with no external heating or cooling. The mixture was poured into 10% NH4Cl (500 mL), and extracted with EtOAc (2×500 mL). The combined extracts were washed with water (2×250 mL) and brine, and evaporated. MeOH (200 mL) was added to the residue and stirred for 1.5 h. The yellow solid was filtered, washed with cold MeOH (25 mL) and dried to give 2-(2-cyano-3-methylamino-4-nitrophenyl)-2-methyl-3-oxobutyric acid ethyl ester (36.2 g, 60%), mp 87-91° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:3]=1.[ClH:34].[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41].C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:34].[CH3:17][C:14]1([CH3:16])[C:13]2[CH2:12][CH2:11][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:9][C:8]=2[C:7]2[C:2]([O:1][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][N:36]([CH3:43])[CH3:35])=[CH:3][C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][C:6]=2[O:15]1
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN(C)C)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1

Procedure:
The above-titled compound was prepared according to the method of Example 8 by reacting equimolar quantities of {[10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridin-2-yl]acetyl}urea and 4-(dimethylamino)butyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[C:16]1([NH2:23])[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>CN(C)C=O>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:23][CH:3]=[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[NH:6][C:5]2=[O:15])=[CH:17][CH:18]=1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: Nc1ccc(N)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(NC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (203 mg, 1.0 mmol) in N,N-dimethylformamide (2.5 mL) is added 1,4-phenylenediamine (108 mg, 1.0 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to ambient temperature, product precipitated out of solution. The product is recovered by filtration, rinsing with diethyl ether, and drying to yield 205.9 mg 4-[(4-Amino-phenylamino)-methylene]-4H-isoquinoline-1,3-dione.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][C:24](Cl)=[O:25])[CH3:20]>C1C=CC=CC=1>[CH2:1]([N:8]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:24](=[O:25])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1NCc1ccccc1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)N(Cc1ccccc1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
52 g of N-benzyl-N-(2-nitro-5-chlorophenyl) amine and 35.5 g of (chloroformyl)acetic acid ethyl ester in 500 ml benzene are refluxed for 15 hours. The reaction is cooled, washed with dilute aqueous sodium bicarbonate, dried and the solvent evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[CH2:18][O:19][C:20]1[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:21]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[CH2:18][O:19][C:20]1[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:22]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:21]=1
Reactant: CCOC(=O)CCc1cc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2cc(CCC(=O)O)n(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A mixture of ethyl 3-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (830 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionic acid (490 mg, yield 62%), which was then recrystallized from acetone-isopropyl ether. melting point: 137–138° C.