Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[C:6]([N:11]([CH3:20])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:21]1[S:22][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:24][N:25]=1.Cl.C([N:33]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.N>O1CCCC1.C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[C:10]2[C:5](=[C:6]([N:11]([CH3:20])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:21]1[S:22][CH:23]([CH2:26][C:27]([NH2:33])=[O:29])[CH2:24][N:25]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(c1cccc2c(F)c(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cccc2c(F)c(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a solution of (2-{3-fluoro-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (97.2 mg) in tetrahydrofuran (2 mL) and acetonitrile (2 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (48 mg) and 1-hydroxybenzotriazole monohydrate (39 mg), and the mixture was stirred at room temperature for 1 hr. Aqueous ammonia (28%, 2 mL) was added, and the mixture was stirred at room temperature for 30 min, and diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluate:ethyl acetate), and the obtained solid was recrystallized (ethyl acetate-diisopropyl ether) to give the title compound (50.1 mg, yield 53%) as a colorless solid. melting point 204-205° C.
Reaction SMILES: C1C([C:7]2[C:16](=O)[C:15]3[CH:14]=[CH:13][C:12](O)=[CH:11][C:10]=3[O:9][CH:8]=2)=CC=C(O)C=1.C(N(C(C)C)CC)(C)C.ClC[O:31]C.C(=O)(O)[O-].[Na+]>CCOC(C)=O.CCCCCC.ClCCl.O>[O:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:7][C:8]1=[O:31]
Reactant: COCCl
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=c1ccc2ccccc2o1
Temperature: 8 °C
Yield: 228.6 %

Procedure:
A total of 329 g (1.29 mol) of 97% daidzein (from LLC Laboratories) was mixed with 4.5 L of dichloromethane in a 12 L 4-neck round bottom flask equipped with a thermocouple, overhead stirrer, heating mantle, addition funnel and nitrogen line. The resulted white suspension was chilled to 8° C., and a total of 655.8 g (5.07 mol, 3.9 eq.) of diisopropylethylamine (DIEA) was added to the pot. After 20 min a total of 373 g (4.63 mol, 3.59 eq.) of chloromethylmethyl ether (MOM-Cl) was added to the mixture via an addition funnel at 8° C. An ice bath was removed, replaced with a heating mantle and allowed to warm up to room temperature within 2 hours. The pot temperature was maintained at 40° C. and reaction was kept (usually overnight) at this temperature until daidzein and mono-MOM intermediate disappeared according to TLC (Rf=0.23 for daidzein, 0.38 for mono-MOM and 0.62 for bis-MOM-daidzein in EtOAc/hexane=1:1). The resulted clear brown solution was cooled to room temperature, and slowly poured under agitation on a cold mixture of 4 L of water, 1 kg of ice, 1 L of saturated sodium bicarbonate and 3 L of dichloromethane, which was prepared in a 20 L plastic bucket equipped with a powerful overhead stirrer and thermocouple. The pH of the resulted solution must stay basic during this work up to avoid degradation of the product. The organic phase was separated, and aqueous was back extracted with dichloromethane (2×1 L). The organic layers were combined, washed with water (2×3 L), sodium bicarbonate (3 L) and dried over sodium sulfate (500 g). The solvent was removed under reduced pressure to give 431 g (97% yield) of the product as a yellow solid. This material was purified by crystallization from 3.5 L of hot (56° C.) ethyl acetate followed by filtration and consequent washes with EtOAc/hexane=3:1 (2 L). Separated solid was dried overnight at 35° C. in a vacuum oven to yield 340.6 g (77% isolated yield) of bis-MOM-daidzein as a white solid. A second crop (a total of 66.31 g of the product) was isolated from a mother liquor to give a bis-MOM-daidzein in the 91.78% combined yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:13]([O:15][C:16](=[O:21])[C@H:17]([CH2:19][SH:20])N)[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16]([C@@H:17]1[CH2:19][S:20][C:5]([C:4]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=2[O:2][CH3:1])=[N:6]1)=[O:21])[CH3:14]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: COc1ccc(C#N)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H]1CSC(c2ccc(OC)cc2OC)=N1

Procedure:
2,4-Dimethoxybenzonitrile, (R)-cysteine ethyl ester and about 5 equivalents of triethylamine are refluxed in ethanol for about 6-8 hours to obtain ethyl-2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylate.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]1([C@H:9]([NH2:31])[C:10]([N:12]2[CH2:16][C:15]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])=[CH:14][C@H:13]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][CH2:2][C:3]([NH:31][C@@H:9]([CH:6]1[CH2:8][CH2:7]1)[C:10]([N:12]1[CH2:16][C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][C@H:13]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:11])=[O:4]
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reaction time: 0.5 h

Procedure:
Bromoacetyl bromide (49 μL, 0.56 mmol, 1.1 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 181 mg, 0.511 mmol, 1 equiv) and N,N-diisopropylethylamine (107 μL, 0.613 mmol, 1.20 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was allowed to stir for 30 minutes. The reaction mixture was partitioned between water (70 mL) and dichloromethane (2×60 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 2-bromo-N-{(1S)-1-cyclopropyl-2-[(2S) (2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}acetamide (25-1) as a pink foam. LRMS m/z (M+H) 477.3 found, 477.1 required.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:13])[C:11]=1[CH3:12])=[CH:8][C:7]([S:14](Cl)(=[O:16])=[O:15])=[CH:6][CH:5]=2.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>O>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:13])[C:11]=1[CH3:12])=[CH:8][C:7]([S:14]([OH:16])=[O:15])=[CH:6][CH:5]=2
Reactant: Cc1oc2ccc(S(=O)(=O)Cl)cc2c(=O)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: Cc1oc2ccc(S(=O)O)cc2c(=O)c1C
Temperature: 75 °C
Reaction time: 0.75 h
Yield: 81.1 %

Procedure:
2,3-Dimethyl-4-oxo-4H-chromene-6-sulphonyl chloride (obtained as described in J. Org. Chem., 1956, page 1104) (3.05 g, 11.2 mM) was added in small portions to a vigorously stirred solution of sodium hydrogen carbonate (1.88 g, 22.4 mM) and anhydrous sodium sulphite (2.54 g, 20.2 mM) in water (14 ml) at 75° C. When the addition was complete, the mixture was vigorously stirred at 75° C. for 45 minutes. The clear solution was allowed to cool to ambient temperature, diluted to 20 ml with water, and acidified with 2M hydrochloric acid at 0° C. The precipitated solid was collected by filtration, washed with a minimum of cold water, and air dried to give 2,3-dimethyl-4-oxo-4H-chromene-6-sulphinic acid as a white solid (2.16 g). This acid was converted to its sodium salt by addition of a methanolic solution of sodium methoxide [prepared from sodium (0.12 g) and methanol (100 ml)], and evaporation of the solution. The resultant sodium salt, obtained as a cream solid, was used immediately without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=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.COCCOC.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1N
Temperature: 90 °C

Procedure:
A DME/water solution (40 mL, 3/1) containing methyl 2-amino-5-bromobenzoate (2.5 g, 12.3 mmol), K2CO3 (4.0 g, 24.6 mmol), 4-(trifluoromethoxy)phenyl boronic acid (3.8 g, 18.5 mmol) and Pd(PPh3)4 (0.712 g, 0.62 mmol) was heated at 90° C. under an argon atmosphere. After approximately 1 hour the solution was cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was washed with water, brine and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.12 (d, J=2.2 Hz, 1H); 7.57 (d, J=8.5 Hz, 2H); 7.52 (dd, J=2.2, 8.5 Hz, 1H); 7.28 (d, J=8.5 Hz, 2H); 6.77 (d, J=8.5 Hz, 1H); 5.84 (broad s, 2H); 3.94 (s, 3H). LCMS1 3.91 min. (M+H)=312
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15]Br)[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2].[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15][P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)CCN(C)C(C)=O)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CCN(C)C(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
16.0 g (45.8 mmol) of 6-(N-acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 50.3 ml (183.3 mmol) of triisopropyl phosphite (90%) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate/isopropanol (7:2 ). 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[C:41]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21
Reaction time: 5 h

Procedure:
To 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 103, 0.438 g), diisopropylethylamine (0.26 ml), and dimethylamino-pyridine (0.018 g) in THF (20 ml) is added benzoyl chloride (0.19 ml). After stirring for 5 hr, additional benzoyl chloride (0.20 ml) is added. The reaction is stirred at 20°-25° for 2 hr, then stored over the weekend in the freezer. It is then stirred again at 20°-25° for 24 hr, after which the THF solvent is removed under reduced pressure and replaced with dichloromethane. After stirring for a final 7 hr, the reaction is partitioned between dichloromethane and aqueous sodium bicarbonate. The phases are separated and the organic phase is filtered through sodium sulfate, concentrated, and the crude product chromatographed on silica gel (300 ml) eluting with ethyl acetate/dichloromethane (20/80). The appropriate fractions are pooled and concentrated to give the product which is recrystallized from dichloromethane and hexane to give the title compound, mp 234.5°-235.5°; MS m/z at 401; IR (mineral oil) 1660, 1502, 1366, 786 and 1247 cm-1 ; NMR (CDCl3) 1.21, 2.20, 5.32, 6.98, 7.3-7.5 and 8.19 δ.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:19][CH:20]=[CH:21][CH2:22][CH2:23]CCCCCCCCCCC>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CC=CCCCCCCCCCCCCC
Reactant: CCCCCCCCC=CCCCCCCCC
Product: C=CCCCCCCCCCCCCCCCCCCCCC
Reaction time: 5 h

Procedure:
Following the procedure outlined in Example 6, 142 g. (0.56 mole) of 9-octadecene and 82 g. (0.37 mole) of 2-hexadecene were reacted at a reaction temperature of 100° C. After 5 hours and with a throughput of 200 ml. of olefin mixture per hour, 7.4% by weight of tricosene was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:37][C:38]([O:40][CH3:41])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH3:41][O:40][C:38](=[O:39])[CH:37]=[C:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)C=C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 60.5 %

Procedure:
A solution of N-benzyloxycarbonyl-4-piperidinone (5.0 g, 21.4 mol) and methyl (triphenylphosphoranylidene)acetate (10.0 g, 30.0 mmol) in benzene (100 mL) was heated at 75° C. for 48 h. The reaction was concentrated, diluted with ether, the precipitate filtered off, and the rinsate concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 20 to 60% ethyl acetate:hexanes to give the title compound (5.25 g). MS: m/z=290.1 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2Cl)(=O)C>CC(O)C>[CH2:1]([NH:8][C:16]1[C:15]2[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([OH:12])[CH:14]=2)[N:19]=[CH:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: COc1cc2ncnc(NCc3ccccc3)c2cc1O
Temperature: 25 °C
Yield: 75.9 %

Procedure:
Benzylamine (1.28 g, 12.0 mmol) was added into a mixture of compound 0105 (1.0 g, 4.0 mmol) and 2-propanol (50 ml). The reaction mixture was then stirred at reflux for 3 hours. The mixture was cooled to room temperature and the resulting precipitate was isolated. The solid was then dried to give the title compound 0701-85 as a yellow solid (854 mg, 76%): LCMS: 282 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:17])([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=2)[O:5][C:4](=[O:18])[C:3]=1[O:19]CC1C=CC=CC=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[OH:19][C:3]1[C:4](=[O:18])[O:5][C:6]([CH3:17])([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=2)[C:2]=1[OH:1]
Reactant: CC(C)Cc1ccc(C2(C)OC(=O)C(OCc3ccccc3)=C2O)cc1
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC(C)Cc1ccc(C2(C)OC(=O)C(O)=C2O)cc1
Yield: 82.9 %

Procedure:
Hydrogenolysis of 800 mg (2.3 mmol) of 4-hydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided 500 mg (84% yield) of 3,4-dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone as a light yellow crystalline material: mp 135-150° C. dec. 1H NMR (acetone-d6) δ 7.40-7.17 (m, 4H), 2.46 (d, 2H, J=7.1 Hz), 1.87-1.82 (m, 1H), 1.82 (s, 3H), 0.87 (d, 6H, J=6.6 Hz). 13C NMR (acetone-d6) δ 169.5, 157.2, 142.4, 138.0, 129.8, 125.9, 117.9, 81.3, 45.3, 30.8, 24.5. 22.5. Anal Calcd for C15H18O4+0.25 H2O: C, 67.53; H, 6.99. Found: C, 67.78; H, 7.09.
Reaction SMILES: C(O[C@H]1CN(C2N=CC=CN=2)C[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1.[CH3:41][N:42]([CH3:69])[C:43]1[N:48]=[CH:47][C:46]([C:49]2[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]3[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][NH:60][CH2:59]3)=[N:53][C:54]=2[CH2:55][CH3:56])=[C:45]([CH3:68])[CH:44]=1>>[CH3:69][N:42]([CH3:41])[C:43]1[N:48]=[CH:47][C:46]([C:49]2[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]3[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][N:60]([C:36]4[S:37][CH:38]=[CH:39][N:40]=4)[CH2:59]3)=[N:53][C:54]=2[CH2:55][CH3:56])=[C:45]([CH3:68])[CH:44]=1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Reactant: Brc1nccs1
Agent: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromo-1,3-thiazole and 5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 7.99, 7.23, 6.53, 6.46, 5.20, 4.92, 4.29, 4.02, 3.78, 3.58, 3.42, 3.13, 2.71, 2.53, 2.12, 1.33–1.27, 1.16; IR (diffuse reflectance) 2970, 2931, 2872, 2350 (w), 1606 (s), 1537 (s), 1489 (s), 1393 (s), 1372, 1360, 1347, 1343, 1338, 1210, 1122 cm−1 HRMS (ESI) calcd for C25H35N7OS+H1 482.2702. found 482.2699.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:24].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH2:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:24])[CH2:15][CH2:14]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: Cc1c(OC2CCNCC2)ccc2ccccc12
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(OC2CCN(CCCC(=O)c3ccc(F)cc3)CC2)ccc2ccccc12

Procedure:
A solution of 3.47 g of (12.5 mmole) of 4-(1-methyl-2-naphthalenyloxy)piperidine, 2.63 g (13.1 mmole) of 4-chloro-1-(4-fluorophenyl)-1-butanone, 5.2 g (52 mmole) of potassium bicarbonate and a pinch of potassium iodide in 60 ml of toluene is heated at reflux for 80 hours. The mixture is partitioned between toluene and water and the organic phase washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 4-[4-(1-methyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][N:39]=[CH:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:38]=[N:39][N:40]=[CH:41]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2cnnc2)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acid tert.-butyl ester (Example H11) (345 mg, 1.2 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (207 mg).
Reaction SMILES: [OH-:1].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4]>>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:4])=[O:1])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: [OH-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
From N-Boc-D-cHyp(Tosyloxy)-OMe (5.27 mmol, 2.50 g), powdered KOH (13.2 mmol, 0.74 g), and 4-nitrophenol (13.2 mmol, 1.83 g), held at reflux for 6 days, the 4-nitrophenyl ether of D-trans-hydroxyproline methyl ester (0.39 g, 20%, m.p. 154-155° C.) was obtained after purification by column chromatography (silica gel, ethyl acetate/hexane mixtures). Impure fractions (1.14 g) accounted for the low yield relative to L-hydroxyproline derivatives above. Elemental analysis for C17H22N2O7: Calculated C, 55.74; H, 6.05; N, 7.65. Found: Calculated C, 55.71; H, 6.08; N, 7.69.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:8]=[C:7]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)NCc2ccccc2)nc(S(C)(=O)=O)nc1OCCO
Reactant: C1COCCN1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)NCc2ccccc2)nc(N2CCOCC2)nc1OCCO
Temperature: 45 °C
Reaction time: 48 h

Procedure:
Benzylsulfamic acid [6-(2-hydroxy-ethoxy)-2-methanesulfonyl-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide (85 mg) were dissolved in THF (2 ml) and morpholine (2 ml) was added. The reaction mixture was stirred at 45° C. for 48 hours, poured onto water, acidified with solid citric acid and extracted with EtOAc (2×). The combined EtOAc layers were washed with 10% citric acid solution and with brine, dried over magnesium sulfate, filtered and the solvent was evaporated. The crude product was purified by chromatography on plates with toluene/EtOAc=1/1 to give benzylsulfamic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (Example 205) (60 mg). LC-MS: tR=4.69; [M+H]+=532.15.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]1[N:16]=[C:17]2[C:22](=[N:23][CH:24]=1)[N:21]=[CH:20][N:19]([CH3:25])[C:18]2=[O:26]>COCCO>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[N:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]=[CH:20][N:19]([CH3:25])[C:18]3=[O:26])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cn1cnc2ncc(Br)nc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: COCCO
Product: Cn1cnc2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2c1=O
Temperature: 100 °C
Yield: 91.4 %

Procedure:
To a stirred solution of 1-Boc-piperazine (18.9 g, 101.4 mmol) in 2-methoxyethanol (100 mL) was added 6-bromo-3-methyl-3H-pteridin-4-one (11.6 g, 48 mmol; see Example 16 (c) above) and the resulting suspension was heated for 3 hours at 100° C. The reaction was then cooled in an ice-water bath and the precipitate that formed was collected, washed with cold MeOH, and dried to afford 4-(3-methyl-4-oxo-3,4-dihydro-pteridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (15.2 g, 92%). 1H NMR (300 MHz, CDCl3) δ1.48 (s, 9H), 3.57-3.61 (m, 4H), 3.62 (s, 3H),3.78-3.82 (m, 4H), 8.07 (s, 1H), 8.56 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ28.38, 34.42, 44.40, 80.38, 130.64, 137.93, 145.53, 147.04, 152.91, 154.61, 160.89.