Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH:10]([OH:12])[CH3:11])=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([O:17][C:15]([NH:14][CH2:13][CH:9]([CH2:8][NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:10]([O:12][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH3:11])=[O:16])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O[Si](C)(C)C(C)(C)C
Reaction time: 14 h
Yield: 91.6 %

Procedure:
To a stirred solution of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)butan-3-ol (90.00 g) in N,N-dimethylformamide (800 ml) were added imidazole (85.51 g) and t-butyldimethylsilyl chloride (61.53 g). The resulting mixture was allowed to stand at ambient temperature for 14 hours. The mixture was diluted with ethyl acetate (2.4 l), washed successively with water (1.6 l) and brine (1 l), and dried over magnesium sulfate. Removal of the solvents gave a residue, which was chromatographed on silica gel (1 l) eluting with a mixture of n-hexane and ethyl acetate (9:1-7:3, V/V) to give 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)-3-(t-butyldimethylsilyloxy)butane (115.40 g).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C1COCC1.O.[Cl-].[Cl-].[Zn+2].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>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:13])[CH2:1][CH3:2])=[CH:15][CH:16]=1)([O-:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC[Mg]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of 0.5M ZnCl2 in THF (60 mL, 30 mmol) in THF (20 mL) at room temperature was treated with 2M ethyl magnesium chloride in THF (15 mL, 30 mmol) dropwise via syringe, cooled with an ice bath for about 10 minutes, stirred at room temperature for 20 minutes, cooled to 0° C., and treated sequentially with Pd(PPh3)4 (1.73 g, 1.5 mmol) and a solution of 4-nitrobenzoyl chloride (6.12 g, 33 mmol) in THF (20 mL). The mixture was stirred at 0° C. for 40 minutes, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with saturated Na2CO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/ethyl acetate to provide 2.17 g (40%) of the desired product. Rf=0.6 (3:1 hexanes/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35](Cl)=[C:30]3[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:13][C:10]4[CH:11]=[CH:12][C:7]([N:6]5[C:2]([CH3:1])=[N:3][N:4]=[N:5]5)=[CH:8][CH:9]=4)=[C:30]3[CH:29]=[N:28]2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Cc1nnnn1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnnn1-c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 11.8 %

Procedure:
A mixture of 4-(5-methyl-tetrazol-1-yl)-phenol (Chembridge Corporation, San Diego, Calif., USA; 32 mg, 0.178 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.391 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to afford 4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 12%) as a white solid. Mass spectrum MH+=478.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:21]([O-:23])=[O:22])=[C:13]([CH:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH3:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:21]([O-:23])=[O:22])=[C:13]([C:15](=[O:20])[CH:16]=[C:17]([CH3:19])[CH3:18])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CC(O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)=CC(=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 81 %

Procedure:
In an analogous manner to the procedure of Example VI, 1.70 g (5.43 mmol) of 1-[5-(benzyloxy)-2-nitrophenyl]-3-methyl-2-buten-1-ol are reacted with 4.25 g (48.83 mmol) of manganese dioxide in 30 ml of dichloromethane to give 1.37 g (81%) of 1-[5-(benzyloxy)-2-nitrophenyl]-3-methyl-2-buten-1-one.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[C:24]([O:26][CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.O=S(Cl)Cl.[Na+].[I-].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[Cl-]>C(Cl)Cl.CCOC(C)=O>[CH3:27][O:26][C:24]1[C:23]([C:28]([F:30])([F:31])[F:29])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-methoxy-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 46) (86 mg, 0.2 mmol) by treatment with SOCl2 (0.044 mL, 0.6 mmol) in CH2Cl2 (2 mL) from 23° C. to reflux for 15 min, followed by evaporation to dryness. The crude chloride was dissolved in DMF (2 mL) and stirred with cat. amount of NaI and pyrrolidine (0.17 mL, 2.0 mmol) at 23° C. until tlc indicated complete conversion of the chloride. The reaction mixture was taken up in EtOAc, washed with water and brine, dried over Na2SO4. Removal of the solvent in vacuum left a yellow semisolid, which was purified by silica gel column chromatography. Obtained as a yellow solid (47 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:52])[C@H:26]([NH:34]C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[S:7].N1CCCCC1>CN1C(=O)CCC1.CCCCCC>[CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:52])[C@H:26]([NH2:34])[CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[S:7]
Reactant: CCc1cccc(C)c1C(=S)N[C@@H](Cc1ccc(NC(=O)[C@@H](Cc2cccnc2)NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)OC
Solvent: C1CCNCC1
Solvent: CCCCCC
Solvent: CN1CCCC1=O
Product: CCc1cccc(C)c1C(=S)N[C@@H](Cc1ccc(NC(=O)[C@H](N)Cc2cccnc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
N-[(2-ethyl-6-methylphenyl)thioxomethyl]-4-[[(2R)-2-(Fmoc-amino)-1-oxo-3-(pyridin-3-yl)propyl]amino]-L-phenylalanine methyl ester from example 26 (0.308 mmol, 224 mg) was treated with 25% piperidine in NMP (3 mL) and the solution was stirred at room temperature. Within 1 h, TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with hexane (25 mL) and the formed layers were separated. The bottom yellow layer was washed with hexane, then was diluted with water and extracted with ethyl acetate and THF (2:1, 3×25 mL). The combined extracts were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and the solvents were removed under vacuum. The resulting residue was dried under high vacuum to afford 126 mg (81%) of 4-[[(2R)-2-amino-1-oxo-3-(pyridin-3-yl)propyl]amino]-N-[(2-ethyl-6-methylphenyl)thioxomethyl]-L-phenylalanine methyl ester as an amorphous colorless solid. HR MS: Obs. mass, 505.2270. Calcd. mass, 505.2274 (M+H).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][S:33]([C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][S:33]([C:36]2[S:37][C:38]([C:13]#[C:12][C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]5[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=5)=[N:6][C:7]=34)=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[CH:27][CH:26]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCc1ccncc1)c1ccc(Br)s1
Product: O=S(=O)(NCc1ccncc1)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (pyridin-4-ylmethyl)-amide (example B.55) (167 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (96 mg, 33%). MS (ISN) 588.2 [(M−H)−]; mp 141° C.
Reaction SMILES: O[CH:2]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:3]([CH3:7])[C:4]([OH:6])=O.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[CH3:7][C@@:3]12[C:4](=[O:6])[CH2:11][C@@H:10]1[CH2:9][CH:8]=[CH:2]2
Reactant: C=CCCC(O)C(C)C(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: C[C@]12C=CC[C@H]1CC2=O
Reaction time: 3 h
Yield: 19.2 %

Procedure:
A mixed solution of 3-hydroxy-2-methylhept-6-enoic acid (5.45 g, 34.5 mmol), potassium acetate (7.0 g, 71.3 mmol), and acetic anhydride (30 mL) was stirred at room temperature for 1.5 hours and then stirred for 3 hours under conditions of heating to reflux. The reaction solution was left overnight, then diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil (810 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: ClCCCN1CCOCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CCCN2CCOCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Yield: 52 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 4-(3-chloro-propyl)-morpholine gave the title compound in 52% yield. ES-MS m/e (%): 494.6 (M+H+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=3[C:38]3[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=3)[CH:19]=2)(=[O:17])=[O:16])=[N:10][CH:9]=1.C=O.[Na]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:2][N:41]1[CH2:40][CH:39]=[C:38]([C:29]2[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:28]=2[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[CH:26]=[CH:27][C:18]([S:15]([NH:14][C:11]2[CH:12]=[CH:13][N:8]=[CH:9][N:10]=2)(=[O:17])=[O:16])=[CH:19]3)[CH2:43][CH2:42]1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3C3=CCNCC3)cccc2c1
Agent: C=O
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 182.3 %

Procedure:
To a round bottom flask charged with N-(pyrimidin-4-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide (EXAMPLE 48, 167.0 mg, 0.327 mmol) was added MeOH (3271 μl), then formaldehyde (265 μl, 3.27 mmol). The solution was maintained at rt for 15 min, then sodium triacetoxyhydroborate (693 mg, 3.27 mmol) was added portionwise. After 10 min, the reaction mixture was partitioned between ice and saturated NaHCO3 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (1×25 mL). The combined organic extracts were washed with brine (1×20 mL) and dried over Na2SO4 and concentrated under a vacuum. The residue was taken up in minimal MeOH and purified by reverse phase preparative HPLC (20 to 80% CH3CN:H2O (1% TFA modifier) over 15 min). Clean fractions were combined and concentrated to afford 5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate (190 mg, 0.298 mmol) as a off-white amorphous solid. 1H NMR (400 MHz, MeOH) δ ppm 1.98-2.47 (m, 2H) 2.49-2.90 (m, 4H) 3.08-3.28 (m, 1H) 3.37-3.58 (m, 1H) 3.64-3.90 (m, 1H) 5.68 (d, J=8.51 Hz, 1H) 7.16 (dd, J=6.36, 0.98 Hz, 1H) 7.54 (d, J=8.02 Hz, 1H) 7.58-7.69 (m, 2H) 7.70-7.85 (m, 3H) 7.94 (d, J=8.61 Hz, 1H) 8.18 (d, J=8.31 Hz, 1H) 8.30 (d, J=6.36 Hz, 1H) 8.60 (s, 1H) 8.72 (d, J=1.37 Hz, 1H); m/z (ESI, +ve ion) 525.2 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)Cl>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Oc1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Product: Oc1ccc(Br)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
3-Phenoxyphenol (700 mg, 3.8 mmol) was stirred at 0° C. in DCM (7 mL) and bromine (0.154 mL, 3.0 mmol) was added dropwise. The reaction was stirred at ambient temperature for 10 min and then the solvents removed in vacuo to afford a crude oil which was purified by preparative HPLC to afford, in order of elution, 4-bromo-3-phenoxyphenol (126 mg, 0.5 mmol, 16%) M.S. (ESI) (m/z): 263,265 [M−H]−; and 4,6-dibromo-3-phenoxyphenol (201 mg, 0.6 mmol, 39%) M.S. (ESI) (m/z): 341, 343, 345 [M−H]−
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[C:35]#[N:36])C>CCO.[OH-].[Na+]>[C:35]([C:8]1[CH:9]=[C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:37])=[O:3])#[N:36]
Reactant: CCOC(=O)CCc1ccc(OCCc2nc(-c3ccc(Oc4ccccc4)cc3)oc2C)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(Oc3ccccc3)cc2)nc1CCOc1ccc(CCC(=O)O)c(C#N)c1

Procedure:
A mixture of 2-(3-ethoxy-but-3-enyl)-5-hydroxy-benzonitrile (220 mg, 1.00 mmol), toluene-4-sulfonic acid 2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethyl ester (450 mg, 1.00 mmol; Preparation 6), and CsCO3 (978 mg, 3.00 mmol) in DMF (10 mL) was stirred overnight at 60° C. under an N2. The mixture was cooled, diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried (Na2SO4) and concentrated. The product mixture was purified by radial chromatography (10-70% EtOAc/hexanes) to give 3-(2-cyano-4-{2-[5-methyl-2-(4-phenoxyphenyl)oxazol-4-yl]ethoxy}phenyl)propionic acid ethyl ester (201 mg). A solution of this ester in EtOH (10 mL) and 5N NaOH (10 mL) was heated at 70° C. overnight, concentrated, acidified with 1N HCl, and extracted with EtOAc. The organic layer dried (Na2SO4) and concentrated to give the title compound (192 mg); MS [ES] m/z 469 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nc(N)c(C=O)c(Cl)n1
Product: CSc1nc(N)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.59 (s, 3H), 5.78 (br s, 1H), 7.11-7.32 (m, 2H), 7.42-7.58 (m, 2H), 8.65 (br s, 1H), 9.71 (s, 1H). LC MS (m/e)=264 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:18][C:19]([C:21]1[S:22][C:23]([CH3:27])=[C:24]([NH2:26])[CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.Cl>O1CCCC1.O>[CH2:11]([O:18][C:19]([C:21]1[S:22][C:23]([CH3:27])=[C:24]([NH:26][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1sc(C(=O)OCc2ccccc2)cc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(C(=O)OCc2ccccc2)cc1NC(=O)Cc1ccccc1
Reaction time: 18 h
Yield: 51.3 %

Procedure:
Phenylacetyl chloride (0.26 g, 1.7 mmol) was added to a stirred solution of 5-methyl-4-amino-thiophene-2-carboxylic acid benzyl ester (0.4 g, 1.6 mmol), prepared as described above in Step 2, and diisopropylethylamine (0.26 g, 2.0 mmol) in tetrahydrofuran (15 mL) under an inert atmosphere at room temperature. After 18 hours, the mixture was diluted with water (100 mL) and acidified with aqueous HCl. The precipitate was filtered off, rinsed with water, then ethanol, then ether, and dried to afford 0.3 g of 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid benzyl ester. Recrystallization of a sample from acetonitrile gave product with a mp 173-174° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:1][C:2]1([CH:8]=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CC1(CO)CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(C=O)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
Into a 100-mL 3-neck round-bottom flask, was placed a solution of (4-methyltetrahydro-2H-pyran-4-yl)methanol (compound 188.2, 300 mg, 2.30 mmol) in dichloromethane (15 mL). Dess-Martin reagent (1.17 g, 2.76 mmol) was added to the reaction. The reaction mixture was stirred for 2 h at room temperature, then quenched with 15 mL of water. The aqueous phase was extracted with 20 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 200 mg (68%) of the title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-])=O)[CH:9]=[C:8]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)C.C1(C)C=CC=CC=1.C[O-].[Na+]>O1CCCC1.[C].[Pd]>[O:3]=[C:4]1[CH2:6][N:7]2[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:9][C:10]3[C:15]2=[C:14]([CH:13]=[CH:12][CH:11]=3)[NH:16]1
Reactant: CCOC(=O)Cn1c(C(=O)OCC)cc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc3c2n1CC(=O)N3
Yield: 85.7 %

Procedure:
Ethyl 1-ethoxycarbonylmethyl-7-nitro-1H-indole-2-carboxylate (2.11 g, 6.59 mmol) was subjected to catalytic reduction in the presence of 10% palladium-carbon (0.20 g) in tetrahydrofuran (70 ml) at ordinary temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. Toluene (100 ml) and sodium methoxide (0.35 g, 6.48 mmol) were added to the residue, and the resulting mixture was heated under reflux for 2 hours. Then, the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/8) to obtain ethyl 2,3-dihydro-2-oxo-1H-pyrrolo[1,2,3-de]quinoxaline-5-carboxylate (1.38 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=O)[C:19]=3[CH:18]=2)[C:14]([CH3:29])=[CH:13][N:12]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([NH2:47])[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)C>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH:38]([NH:47][C:26]([C:25]2[C:19]3[CH:18]=[C:17]([C:15]4[C:14]([CH3:29])=[CH:13][N:12]=[C:11]([Cl:10])[N:16]=4)[S:21][C:20]=3[CH:22]=[CH:23][CH:24]=2)=[O:28])[C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[CH:44][CH:43]=1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)O)cccc2s1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(Cl)ncc4C)cc23)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
Diisopropylethylamine (1.80 mL, 10.3 mmol) is added to a stirred suspension of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid (3.00 g, 9.84 mmol) in anhydrous dichloromethane (100 mL) at 0° C. under nitrogen to form a solution, then followed by the successive addition of C,C-bis-(4-methoxyphenyl)-methylamine (2.51 g, 10.3 mmol) and powdered 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4.56 g, 10.3 mmol). The resultant mixture is allowed to stir at 0° C. for 1 hour, then at room temperature for 3 hours. Diethyl ether (50 mL) is added in small portions to the mixture, the mixture is stirred for another 10 minutes before filtration. After vacuum drying at 35° C., the crude title compound (5.19 g) is obtained as a tan solid. It is used without further purification.