Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6][C@H:7]([CH2:11][NH:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:8]([CH3:10])[CH3:9])[OH:4].C(=O)([O-])[O-].[Na+].[Na+].[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43].O>C(OCC)(=O)C>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:6][C@H:7]([CH2:11][NH:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:8]([CH3:9])[CH3:10])[OH:4])=[O:46]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The stirred solution of 0.030 g of tert-butyl (1(S)-(2-amino-1(S)-hydroxyethyl)-3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}4-methylpentyl)carbamate in 0.60 ml of ethyl acetate is admixed successively with 0.60 ml of 2M sodium carbonate solution and 0.012 ml of pivaloyl chloride and stirred at room temperature over 1 hour. The reaction solution is admixed with water and extracted with ethyl acetate (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.45 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.71 (gradient I)
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][CH:37]([CH3:43])[CH2:38][C:39]([NH:41][NH2:42])=O>CC1C=CC(C)=CC=1>[CH2:38]([C:39]1[N:26]2[C:21]3[CH:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:28][C:22]=3[O:23][CH2:24][C:25]2=[N:42][N:41]=1)[CH:37]([CH3:43])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: CC(C)CC(=O)NN
Solvent: Cc1ccc(C)cc1
Product: CC(C)Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Temperature: 150 °C
Yield: 6.6 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.410 mmol) and 3-methylbutanehydrazide (47 mg, 0.410 mmol) in p-xylene (1.5 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (15 mg, 5%). LCMS (Method D): RT=1.5687 min, M+1=552. 1H NMR (500 MHz, CDCl3): 7.80 (1H, s), 7.36-7.31 (5H, m), 7.30-7.27 (2H, m), 7.23-7.19 (2H, m), 5.57 (2H, s), 2.98 (2H, d), 2.54-2.41 (4H, m), 2.33-2.24 (1H, m), 2.13-2.01 (1H, m), 1.88-1.76 (1H, m), 1.44-1.26 (9H, bs), 1.11 (6H, d).
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[C:22]3[CH3:28])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[C:22]3[CH3:28])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]cc(C)c4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c[nH]c2ccc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(3-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate (80 mg, 0.21 mmol) in MeOH (10 mL) was added sodium hydroxide (52 mg, 0.29 mmol) and water (1 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The residue was dissolved in water (3 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(3-methyl-1H-indol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (45.8 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1.[C:18]([CH:21]=[C:22]=[O:23])(=[O:20])[CH3:19]>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:22](=[O:23])[CH2:21][C:18](=[O:20])[CH3:19])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1
Reactant: Nc1ccc(NCCCC2CCCO2)c(F)c1
Reactant: CC(=O)C=C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(NCCCC2CCCO2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a solution of 2-fluoro-N1-(3-(tetrahydrofuran-2-yl)propyl)benzene-1,4-diamine (260 mg, 1.09 mmol) in EtOAc (10 mL) was added acetyl ketene (110 mg, 1.31 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as yellow liquid (83 mg, 24%).
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[C:16]([S:17]([OH:19])=[O:18])=[CH:15][CH:14]=[C:13]([F:20])[C:9]=1[C:10]([OH:12])=[O:11].CI>CO.O>[F:7][C:8]1[C:16]([S:17]([CH3:1])(=[O:19])=[O:18])=[CH:15][CH:14]=[C:13]([F:20])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(F)ccc(S(=O)O)c1F
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 18 mmol sodium carbonate and 9 mmol 2,6-Difluoro-3-sulfino-benzoic acid in 30 ml of methanol was stirred at room temperature for 30 min, then heated to 60° C. 24 mmol of methyl iodide were added and the reaction mixture heated overnight at 60° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was discarded and the aqueous phase acidified by addition of concentrated hydrochloric acid. Extraction with ethyl acetate yielded the title compound as a slightly brownish solid. MS (m/e): 235.1 (M−H, 16%)
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.Cl[CH2:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[F:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[C:22]([O:21][CH2:20][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:31]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(OCCl)c1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.05 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.21 g of chloromethyl-3,4-difluorobenzoate was added, and the mixture was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.06 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3,4-difluorobenzoate (present compound (42)).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[CH3:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[CH:19][CH:18]=1)[CH3:22]
Reactant: CC(=O)Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCNc1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
N-[4-[4-(phenylmethyl)-1-piperazinyl]phenyl]acetamide is reduced with lithium aluminum hydride following standard chemical laboratory procedures to obtain the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1>C(Cl)Cl>[Cl:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N+:18]([O-:9])[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CCl)cn1
Solvent: ClCCl
Product: COc1ccc(CCl)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Chloro perbenzoic acid (mCPBA) (230 mg, 1.026 mmol) was added to a stirred, cooled 0° C. mixture of 5-(chloromethyl)-2-methoxypyridine (U1) (147 mg, 0.933 mmol) in CH2Cl2 (3731 μl). The reaction mixture was stirred at room temperature for 2 h. Another portion of mCPBA (150 mg) was added and stirred at room temperature for 4 h. A third portion mCPBA (150 mg) was added and the reaction was allowed to stir overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (first 0-30% EtOAc in hexanes to remove mCPBA and SM, then 0-20% MeOH in CH2Cl2 to wash product out) to provide 5-(chloromethyl)-2-methoxypyridine 1-oxide (U2) as a white solid. ES-MS [M+1]+: 174.1.
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].CCOCC.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>>[C:30]([O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:22]([CH3:24])[CH3:23])(=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reactant: CCCC(=O)Cl
Solvent: CCOCC
Product: CCCC(=O)Oc1ccc(C)cc1[C@H](CCN(C(C)C)C(C)C)c1ccccc1

Procedure:
A solution of 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenol (1.0 g) in butyryl chloride (5 ml) is heated under reflux for 90 min. Ether is added, and the precipitate of 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl butyrate hydrochloride is filtered off; mp 116-119° C. Anal Calcd for C26H37NO2.HCl: C, 72.28; H, 8.86; Cl, 8.21; N, 3.24. Found: C, 72.25; H, 8.71; Cl, 8.17; N, 3.25. [α]D (c=1, MeOH) +20°.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:16])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(C)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, grey solid (38 mg, 67%), MS (ISP) m/z=307.5 [(M+H)+], mp 245° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 10) (52 mg, 0.186 mmol) and commercially available 4-methoxy-phenylboronic acid (36.8 mg, 0.24 mmol).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].CO[C:10]([C:12]1([CH3:36])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH:26]([F:28])[F:27])[CH:21]=3)[NH:16][C:15]=2[CH:14]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[NH:13]1)=[O:11]>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6](=[O:7])[N:13]2[CH:14]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=3)[C:15]3[NH:16][C:17]4[C:22]([C:23]=3[CH2:24][C:12]2([CH3:36])[C:10]1=[O:11])=[CH:21][C:20]([O:25][CH:26]([F:28])[F:27])=[CH:19][CH:18]=4
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(OC(F)F)cc23)C(c2cccc(O)c2)N1
Reactant: O=C=NCCCCl
Product: CC12Cc3c([nH]c4ccc(OC(F)F)cc34)C(c3cccc(O)c3)N1C(=O)N(CCCCl)C2=O

Procedure:
The title compound is prepared analogously to the procedure described for example 22, using chloro propyl isocyanate and (1RS,3SR)-6-(1,1-difluoro-methoxy)-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester. MS: m/z (MH+)=490.0
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:6]1[N:7]=[C:2]2[CH:15]=[C:14]([Si:11]([CH3:13])([CH3:12])[CH3:10])[O:9][C:3]2=[CH:4][CH:5]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2oc([Si](C)(C)C)cc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a degased solution of 6-iodo-2-picolin-5-ol (855 mg; 3.64 mmol; 1.00 eq.) in triethylamine (20.00 mL) were added (trimethylsilyl)acetylene (1 g; 10.19 mmol; 2.80 eq.), cuprous iodide (90.07 mg; 0.47 mmol; 0.13 eq.) and dichlorobis(triphenyl phosphine)palladium(II) (229.82 mg; 0.33 mmol; 0.09 eq.). The solution was heated under reflux. After 3 h, the reaction was complete, and allowed to cool down to rt. The solution was filtered over celite (washed with AcOEt and MeOH). The solvents were removed. AcOEt and water were added and the combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the expected compound. The crude was purified by short flash chromatography using cyclohexane then AcOEt/Cyclohexane 20/80 to afford 603 mg of the desired compound as a solid (Intermediate 5.1). Amount: 603 mg; Yield: 81%; Formula: C11H15NOSi; HPLC Purity: 93.14%; HPLC (H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=2.17 min; 93.14%; 1H NMR (CDCl3) δ 7.65 (d, 1H, J=8.5 Hz), 7.10 (s, 1H), 7.06 (d, 1H, J=8.5 Hz), 2.67 (s, 3H), 0.36 (s, 9H); LC-MS: M/Z ESI: Rt (min) 1.89 min, 206.06 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]1[CH2:17][CH2:16][CH:15](O)[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH:15]1[CH2:16][CH2:17][N:13]([CH3:12])[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CN1CCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60 mL) is added 1-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0 g), and diethylazodicarboxylate (3.6 mL) and the mixture is stirred at room temperature under an atmosphere of argon for 1.5 hours. The solution is then concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous sodium hydroxide, water, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is chromatographed over silica gel (ethyl acetate then 10% methanol in dichloromethane is used as the eluant). Pooled product fractions are then recrystallized from hexanes to provide the desired product as a yellow solid. Using the above procedure and appropriate starting materials the following compounds were prepared:
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([OH:11])=[N:5][C:6]([F:10])=[C:7]([Cl:9])[CH:8]=1.CN(C)C=O.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C.O>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([O:11][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([Cl:9])=[C:6]([F:10])[N:5]=1)[CH3:24])[CH3:23]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1nc(F)c(Cl)cc1Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1nc(F)c(Cl)cc1Cl
Temperature: 118 °C

Procedure:
A solution was prepared by dissolving 1.84 grams (0.08 mole) of sodium metal in 140 milliliters of 28 percent ethanol. To this solution was added 14.6 grams (0.08 mole) of 3,5-dichloro-6-fluoro-2-pyridinol. The solution was warmed and 60 milliliters of N,N-dimethylformamide was added thereto. The solution was further heated to remove about 3/4 of the ethanol. To the remaining solution was added 15.5 grams (0.85 mole) of ethyl bromopropionate followed by an additional 40 milliliters of N,N-dimethylformamide. The mixture was refluxed at 118° C. for 20 minutes, cooled and poured into water. The mixture was extracted with hexane and the hexane thereafter removed by evaporation. The residue was distilled under reduced pressure and the ethyl[2-(3,5-dichloro-6-fluoro-2-pyridyloxy)]propionate was recovered as an oil in a yield of 17.7 grams (78.3 percent of theoretical) and had a boiling point at 2.4 millimeters of mercury at 127° C. Upon analysis, the product was found to have carbon, hydrogen, chlorine and nitrogen contents of 42.0, 3.1, 25.1 and 5.2 percent, respectively, as compared with the theoretical contents of 42.6, 3.6, 25.1 and 4.9 percent, respectively, calculated for the above named compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([C@H:30]4[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].C(Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]
Reactant: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1[C@H]1CC[C@H](O)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C1CCC(=O)CC1

Procedure:
A solution of trans-4-[4-(3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl]cyclohexanol (70.0 mg, 0.135 mmol), Dess-Martin periodinane (85.82 mg, 0.2023 mmol), NaHCO3 (22.66 mg, 0.2698 mmol) and DCM (4 mL, 70 mmol) was stirred at rt for 5 min. The material was extracted with DCM and sat. NaHCO3, and the organic layer was loaded onto silica gel for column chromatography, eluting with 2-4% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=517.11/519.08 (100/50) [MH+]. HPLC: tR=3.99 min (polar—5 min, ZQ3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39].[OH-].[Na+].O>CC(C)=O>[Cl:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: ClCCCCCBr
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCCl)cc2)cc1
Temperature: 25 °C
Yield: 113.7 %

Procedure:
4-(4-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (180 mg, 0.4 mmol), 1-bromo-5-chloropentane (0.39 ml, 2 mmol) and 2N aqueous sodium hydroxide solution (70 μl, 2 mmol) were dissolved in acetone (4 ml) and then refluxed for 6 hours. The reaction mixture was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 247 mg (yield: 97%) of the title compound as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: O=S(=O)(c1ccc(I)cc1)N1CCCC1

Procedure:
The title compound was prepared from 4-iodobenzenesulfonyl chloride and pyrrolidine using a similar procedure to that described for Description 30.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][N:10]([CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([Br:11])[CH:13]=1)[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: BrCc1cccc(Br)c1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1cccc(CN(Cc2cccc(Br)c2)c2ccc3[nH]cnc3c2)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 3-bromobenzylbromide (550 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.227 g (48.2%); MS m/z: 470.1/472.2/474.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.70 (s, 4H); 6.68-6.70 (m, 2H); 7.26-7.27 (m, 4H); 7.34 (d, 1H, 3J=8.6 Hz); 7.39-7.41 (m, 2H); 7.43 (s, 2H); 7.91 (s, 1H); 11.93 (br s, 1H); HPLC (METHOD [A]): rt 17.81 min (98.3%)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.C(OCC)(=O)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:16]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccoc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(-c3ccoc3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A mixture of tert-butyl 9-(3-furyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (190 mg, 0.602 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (131 mg, 86.2%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1])=[O:22]
Reactant: Cc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(OC(=O)C(C)(C)C)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a mixture of 100 g of 2-chloro-4-methylphenol, 92.3 g of triethylamine and 1 liter of anhydrous tetrahydrofuran was added dropwise 93.0 g of pivaloyl chloride at 5° to 10° C. under stirring over 1 hour. Then, after stirring at the same temperature for 3 hours, the reaction mixture was poured into ice water, which was extracted with diethyl ether. The organic layer was washed with 3% aqueous hydrochloric acid and then water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was distilled under reduced pressure, which afforded 155.3 g of 2-chloro4-methylphenyl 2,2-dimethylpropanoate as a colorless clear liquid. Yield, 97.7%.