Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:33][C:34]1[CH:35]=[CH:36][C:37]([N:43]2[N:47]=[CH:46][CH:45]=[N:44]2)=[C:38]([CH:42]=1)[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:39]([C:38]4[CH:42]=[C:34]([F:33])[CH:35]=[CH:36][C:37]=4[N:43]4[N:47]=[CH:46][CH:45]=[N:44]4)=[O:40])[CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(C)c(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(3,6-Dimethyl-pyrazin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 10) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C21H22FN7O, 407.45; m/z found 408.2 [M+H]+. 1H NMR (CD3OD): 8.05-7.84 (m, 2H), 7.66-7.24 (m, 4H), 4.59-3.44 (m, 7H), 3.04-2.31 (m, 6H), 2.09-2.96 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:16][CH2:17][CH2:18][CH:19]=[CH2:20]>CC(O)C>[BrH:16].[CH2:20]([N:6]1[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3][C:2]1=[NH:1])[CH2:19][CH:18]=[CH2:17]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: C=CCCBr
Solvent: CC(C)O
Product: Br
Product: C=CCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: 20 °C
Yield: 16.9 %

Procedure:
The procedure is as in Example 15, starting with 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and 4-bromo-1-butene (10.8 g) in 2-propanol (30 cc). The mixture is heated for 48 hours to boiling. After cooling of the mixture to a temperature in the region of 20° C., the precipitate is filtered off and then washed with 2-propanol (2×50 cc). 3-(3-Butenyl)-2-imino-6-trifluoromethoxybenzothiazoline hydrobromide (2.5 g), m.p. 202° C., is obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:24])[CH2:4][CH2:3]1.[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:23][O:22][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][C:17]=1[O:20][CH3:21])[N:10]([CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:36][C:34]3[CH:33]=[CH:32][C:29]4[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=4[N:35]=3)[CH2:3][CH2:4]1)[C:11](=[O:24])[CH:12]=[N:13]2
Reactant: COc1cc2ncc(=O)n(CCN3CCC(N)CC3)c2cc1OC
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1cc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2cc1OC
Yield: 68.6 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,7-dimethoxyquinoxalin-2 (1H)-one (Intermediate 156, 75 mg, 0.23 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (40 mg, 0.23 mmol), and sodium triacetoxy borohydride (150 mg, 0.69 mmol) were reacted as described according to Example 69 to give 78 mg (68%) of the free base of the product as a colorless solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 15 g (120.86 mmol) of p-fluorobenzaldehyde in 200 ml of DMF, 16.8 g (193.4 mmol) of morpholine and 33.36 g (241.7 mmol) of potassium carbonate are added successively at r.t. After being stirred for 8 h at 100° C., the reaction mixture is cooled to r.t., diluted with ice water and then the mixture is extracted with AcOEt and CH2Cl2. The combined extracts are concentrated under reduced pressure and purified by silica gel column chromatography (eluent: n-Hexane:AcOEt=5:1˜3:1) to give 4-morpholin-4-yl-benzaldehyde. 1H-NMR (400 MHz, CDCl3): 3.35-3.40 (m, 4H), 3.85-3.90 (m, 4H), 6.92 (d, 2H, J=8.56 Hz), 7.77 (d, 2H, J=8.56 Hz), 9.80 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH3:8].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:8][O:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COCOCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCOCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 100 °C

Procedure:
To a solution of 1-bromo-3-(methoxymethoxy)propane (0.46 g, 2.5 mmol) in anhydrous toluene (1.5 mL) was added triphenylphoshine (0.71 g, 2.7 mmol) under argon with stirring. The mixture was heated at 100° C. for 20 h and cooled to room temperature. The liquid was decanted and the solid residue was grounded with spatula, filtered and washed several times with ether. After drying overnight in vacuum dessicator colorless crystals of phosphonium salt A (0.98 g, 88%) could be used in the Wittig reaction without further purification. A: 1H NMR (500 MHz, CDCl3) δ 1.96 (2H, m, CH2—CH2—CH2), 3.31 (3H, s, O—CH3), 3.85 (2H, br t, J=5.6 Hz, CH2—CH2—O), 4.00 (2H, m, P—CH2), 4.60 (2H, s, O—CH2—O), 7.70, 7.79 and 7.86 (6H, 3H and 6H, each m, Ar—H); Anal. Calcd for C23H26O2PBr: C, 62.03, H, 5.88, Br, 17.94. Found: C, 61.87, H, 5.77, Br, 17.89.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[CH:15]=2)[N:11]=1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: NCCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)nc1NCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 54.8 %

Procedure:
A mixture of methyl 2,6-dichloronicotinate (53.3 g, 0.26 mol), 3-fluorophenethyl amine (37.3 mL, 0.29 mol), K2CO3 (72 g 0.52 mol) and NMP (150 mL) was stirred at 100° C. for 10 hrs. The mixture was diluted with ethyl acetate (2×300 mL) and washed with brine. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography using hexane-EtOAc (9:1) as eluant to give methyl 6-chloro-2-(3-fluorophenethylamino)nicotinate as an off-white solid (44 g, 54%). LRMS (M+H+) m/z 309.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][NH:27][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NCC(F)(F)F)s1
Yield: 68 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (56 mg, 68%) which was obtained as a white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](/B(O)O)=[CH:27]\[CH3:28].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:26]=[CH:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C/C=C/B(O)O
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CC=Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 61.6 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (600 mg, 1.34 mmol) and trans-1-propen-1-ylboronic acid (460 mg, 5.36 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0), (4.84% Pd, 285 mg, 0.13 mmol) and 2M aqueous solution of K2SO4 (2.68 mL, 5.36 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC and gave the pure product (142) as white solid (300 mg, 63%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C1C2CCCCC=2C=CC=1O.[N:34]1([CH2:41][CH2:42][O:43][C:44]2[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[N:34]1([CH2:41][CH2:42][O:43][C:44]2[CH:51]=[CH:50][C:47]([CH2:48][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:46][CH:45]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCNc1ccc(OC)cc1C1CCc2cc(O)ccc2C1
Reactant: O=Cc1ccc(OCCN2CCCCCC2)cc1
Agent: Oc1ccc2c(c1)CCCC2
Product: COc1ccc(NCCCc2ccc(OCCN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)c1

Procedure:
Synthesized from 6-(2-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol according to an analogous synthetic method to Example 36, 642-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (40 mg) and 4-(2-azepan-1-ylethoxy)benzaldehyde (202 mg) were used according to an analogous synthetic method to Example 38 to provide the title compound (32 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12]([CH3:16])([CH3:15])[C:13]#N)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(=[O:24])C1C=CC=CC=1.[F:26][C:27]([F:39])([F:38])[S:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>ClC1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[C:6]([N:11]3[C:12]([CH3:16])([CH3:15])[C:13](=[O:24])[N:35]([C:32]4[CH:31]=[CH:30][C:29]([S:28][C:27]([F:38])([F:26])[F:39])=[CH:34][CH:33]=4)[C:36]3=[O:37])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C#N)Nc1cccc2cnccc12
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Reactant: O=C(O)c1ccccc1
Solvent: Clc1ccccc1
Product: CC1(C)C(=O)N(c2ccc(SC(F)(F)F)cc2)C(=O)N1c1cccc2cnccc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 677.5 %

Procedure:
500 mg (2.4 mmol) of 2-(isoquinolin-5-ylamino)-2-methylpropionitrile, 1.6 mg (0.013 mmol) of benzoic acid and 526 mg (2.4 mmol) of 4-(trifluoromethylthio)phenyl isocyanate in 4 ml of chlorobenzene were refluxed for 2 days. The resulting mixture was filtered and the filtrate was evaporated to dryness. The intermediate imine was separated out by preparative HPLC chromatography (RP 18, acetonitrile, water, 0.01% TFA). 60 mg of the resulting product were stirred for 1 hour at 40° C. with 1N hydrochloric acid. The solvent was evaporated off and the residue was taken up in sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases were dried and the residue remaining after evaporation was purified by flash chromatography (SiO2, methylene chloride/methanol=98/2), to give 38 mg of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:21][N:22]([CH2:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=O)[O:26]1)[CH3:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>C(COC)OC.C1COCC1>[CH3:23][N:22]([CH2:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[O:26]1)[CH3:21]
Reactant: CN(C)CC1OC(=O)c2ccccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CN(C)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
To a solution of oxindole (205 mg, 1.54 mmol) in dimethoxyethane (4.0 ml) at room temperature was added 1.0M LiHMDS in THF (1.54 ml). After stirring for 10 minutes at room temperature, 3-dimethylaminomethyl-3H-isobenzofuran-1-one (235 mg, 1.23 mmol) in dimethoxyethane (0.5 ml) was added and the mixture was stirred rapidly for 1 hour. Additional 1.0M LiHMDS/THF (1.54 ml) was added. After 2 hours the reaction was quenched into 10% HCl (50 ml) and 25 ml water added. The aqueous layer was washed with EtOAc and then basified with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and rotary evaporated to provide a yellow solid. The yellow solid was chromatographed silica gel column (CHCl3 to 2.5% MeOH/CHCl3 gradient) and then recrystallized from MeOH to give 3-(3-dimethylaminomethy-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as yellow needles (92 mg, 24%).
Reaction SMILES: [OH-].[Na+].N(C(C)(C)C#N)=NC(C)(C)C#N.[C:15]([C:19]1([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][O:20]1)([CH3:18])([CH3:17])[CH3:16].[NH:31]1[CH:35]=[N:34][CH:33]=[N:32]1>CN1CCCC1=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][C:19]([CH2:21][N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)([OH:20])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:25][CH:26]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 120 °C
Yield: 85.4 %

Procedure:
4.15 g (0.103 mole) of sodium hydroxide and a spatula-tip of azo-bis-isobutyronitrile were added to a solution of 71.55 g (0.3 mole) of 2-tert.-butyl-2-(4-chloro-phenyl-ethyl)-oxirane in 10 ml of N-methylpyrrolidone. The mixture was heated to 120° C. and a solution of 20.7 g (0.3 mole) of 1,2,4-triazole was added dropwise in the course of 3 hours, with stirring. The mixture was then stirred at 120° C. for a further hour and then allowed to cool. Thereafter, it was worked up by a procedure in which the N-methyl-pyrrolidone was distilled off at a bath temperature of 100° C. under a pressure of 0.2 mbar and the residue which remained was washed with water and then dried and stirred with 150 ml of benzine. The solid product which deposited was filtered off and dried again. 78.9 g (85.8% of theory) of 1-(4-chloro-phenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-pentan-3-ol were obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH3:13][S:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:6][O:8][C:9]([C:4]1[N:22]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([S:14]([CH3:13])(=[O:15])=[O:16])=[CH:18][CH:19]=2)[C:6](=[O:8])[C:5]2[C:4]([C:9]=1[OH:10])=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)=[O:10]
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Product: COC(=O)c1c(O)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The present compound was synthesized according to the method shown in Reference Example 8 and using 4-chloro phthalic anhydride and 4-(methanesulfonyl)benzylamine.
Reaction SMILES: [K].[OH:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].[C:16](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.[K]>CC(C)=O>[CH3:16][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1O
Agent: [K+]
Agent: [K]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Yield: 80 %

Procedure:
2-Hydroxy-3-methoxy-6-nitrobenzaldehyde potassium salt was slurried in acetone (500 mL) containing potassium carbonate (50 g) and the suspension was treated with dimethylsulfate (18.5 mL) and heated to reflux for one hour. An additional aliquot (18.5 mL) of dimethylsulfate was then added and the mixture was heated overnight. After 24 hours the red color of the potassium salt was virtually absent. The salts were removed by filtration, the filtrate was concentrated and the residue was recrystallized from isopropanol to give the title compound 40.0 g (80% from 3) mp 109°-110° C.
Reaction SMILES: [CH3:1][C@@H:2](CCCC1C=CC=CC=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C@@H:2]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:6][CH3:7])[O:8][CH3:9]
Reactant: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Reactant: BrCCc1ccccc1
Product: COP(=O)(CC(=O)[C@@H](C)CCc1ccccc1)OC

Procedure:
(S)-Dimethyl (3-methyl-2-oxo-5-phenylpentyl)phosphonate was prepared in the same manner as the second alternative preparation of (S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) using the same sequence of reactions except that (2-bromoethyl)benzene was used instead of (3-bromopropyl)benzene. The crude product was purified by silica gel chromatography. Elution with ethyl acetate-heptane (50:50 v/v) afforded the title compound (460 mg) as a colorless oil; TLC Rf 0.14 (solvent system: 50:50 v/v ethyl acetate:heptanes); MS (ESI+) m/z 285.1 (M+H)+; 1H-NMR (CDCl3) δ 7.30-7.24 (m, 2H), 7.21-7.14 (m, 3H), 3.76 (d, J=14.65 Hz, 3H), 3.76 (d, J=8.06 Hz, 3H), 3.16-3.03 (m, 2H), 2.77 (q, J=6.84 Hz, 1H), 2.64-2.56 (m, 2H), 2.03 (ddt, 1H), 1.16 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=0.052/(0.01998 g/1.5 mL)(0.5)=+7.81° (c=1.33, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][O:5][N:6]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:14]([C:13]1[CH:12]=[C:11]([NH:10][C:7]([C:3]2[C:2]([CH3:1])=[N:6][O:5][N:4]=2)=[O:9])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: Cc1nonc1C(=O)O
Reactant: N#Cc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nonc1C(=O)Nc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
4-Methyl-1,2,5-oxadiazole-3-carboxylic acid (200 mg, 1.6 mmol) and bromotris(pyrrolydino)phophonium hexafluorophosphate was dissolved in a 1/1 mixture of DMF/DCM. To the mixture was added DMAP (120 mg, 0.95 mmol) and 3-amino-benzonitrile (184 mg, 1.6 mol) followed by N,N-diisopropylethylamine. The reaction mixture was stirred at rt overnight. The volatiles were removed in vacuo and the residue dissolved with chloroform and loaded onto a 40 g Silica ISCO cartridge eluting with 25%-50% EtOAc/Hexane to afford a white powder (25 mg). MF=C11H8N4O2; LCMS calculated for C11H9N4O2(M+H)+: m/z=229.1.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CCC2N=C(C3C=CC=CC=3)OC=2C)=[CH:10][C:9]=1[CH3:29])([CH3:6])[C:3]([OH:5])=[O:4].[H][H].[CH2:32](O)[CH3:33]>[Pd]>[CH2:32]([O:5][C:3](=[O:4])[C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:29])([CH3:1])[CH3:6])[CH3:33]
Reactant: [H][H]
Reactant: Cc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OC(C)(C)C(=O)O
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reaction time: 6 h

Procedure:
2-Methyl-2-{2-methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid (9.00 g, 26.3 mmol) in ethanol (250 mL) was treated with 5% Pd/C (1.25 g) and hydrogen (60 psi, rt, overnight). Additional 5% Pd/C (1.25 g) was added, and the reaction was continued for 6 h at 40° C. The mixture was filtered and concentrated to a tan oil (6.25 g). This oil contained 9 mol % of 2-(4-Hydroxy-2-hydroxymethyl-phenoxy)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:23])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[C:7](=O)[C:6]=2[CH:22]=1.C.OS(O)(=O)=O>O1CCOCC1.C(O)C.[Pd]>[OH:1][C:2]1[C:3]([OH:23])=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[CH2:7][C:6]=2[CH:22]=1
Reactant: COc1ccc(-c2coc3cc(O)c(O)cc3c2=O)cc1OC
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(C2COc3cc(O)c(O)cc3C2)cc1OC

Procedure:
6,7-Dihydroxy-3-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-one [Indian J. Chem. Sect. B 19B, 82 (1980) and Indian J. Chem. Sect. B 15B, 1049 (1977)] (25 g) in a mixture of dioxane and ethanol 1:1 (1250 ml) is hydrogenated for 8 days at normal pressure and room temperature over palladium 10% on active charcoal (2.5 g) in the presence of concentrated H2SO4 (2.5 ml). After filtration of the catalyst, the filtrate is evaporated under reduced pressure to a volume of about 50 ml and diluted with water till turbidity appears. After cooling the solution, a solid precipitates. It is filtered off and recrystallized from ethanol. The product is dried in vacuo to constant weight to yield 3,4-dihydro-6,7-dihydroxy-3-(3,4-dimethoxyphenyl)-2H-1-benzopyran, m.p. 153°.