Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:16][Mg]Br>O1CCCC1>[OH:6][CH:5]([C:4]1[CH:7]=[C:8]([O:11][C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH3:16]
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1C(C)O
Temperature: 25 °C

Procedure:
To 2-methoxy-5-(trifluoromethoxy)benzaldehyde (1.0 g, 4.5 mmol) in tetrahydrofuran (10 mL) at 0° C. was added a solution of methyl magnesium bromide in tetrahydrofuran (1.6 mL, 3M, 4.7 mmol). The solution was then warmed to room temperature and quenched with saturated aqueous ammonium chloride solution (50 mL). The suspension formed was extracted with ethyl acetate (2×100 mL) and the extracts were dried (MgSO4). Concentration in vacuo yielded the title compound as an oil (1.03 g, 4.4 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[O:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=3)[CH:3]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cc(Nc3cccc(N)n3)ncn2)cc1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (200 mg, 0.90 mmol) in dry DMF (2 mL) was added 4-methoxyphenol (168 mg, 1.3 mmol) and anhydrous K2CO3 (179 mg, 1.3 mmol). The reaction mixture was heated at 100° C. for 16 h under N2 atmosphere. It was then cooled and DMF removed under reduced pressure to give a yellowish gummy residue that was taken in EtOAc (10 mL). The solution was washed with water (5 mL) and brine (5 mL), was dried over Na2SO4 and was then concentrated under reduced pressure to get crude product. This was further purified by column chromatography (SiO2, 60-120, hexane/EtOAc, 5/5) to give N2-(6-(4-methoxylphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (160 mg, 59.2%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH3:5][C:6]1[CH:7]=[C:8]([N:13]2[C:17](=[O:18])[C:16](=[N:19][NH:20][C:21]3[C:22]([OH:36])=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)[CH:24]=[CH:25][CH:26]=3)[C:15]([CH3:37])=[N:14]2)[CH:9]=[CH:10][C:11]=1[CH3:12]>C(O)C.O1CCCC1>[CH3:12][C:11]1[CH:10]=[CH:9][C:8]([N:13]2[N:14]=[C:15]([CH3:37])/[C:16](=[N:19]/[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)[C:22]=3[OH:36])/[C:17]2=[O:18])=[CH:7][C:6]=1[CH3:5].[CH2:3]([NH2:4])[CH2:1][OH:2]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Solvent: CCO
Solvent: C1CCOC1
Solvent: NCCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Reaction time: 3 h

Procedure:
To a solution of ethanolamine (0.9 g) in ethanol (100 mL) was added a solution of 3′-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid (3 g), prepared as in Example 4, in tetrahydrofuran (40 mL) at about room temperature over about 30 to 40 minutes and stirred for about 3 hours at about room temperature. The mixture was filtered, washed with ethanol (25 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours. Yield: 3.7 g
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:24](=[O:48])[NH:25][C:26](=[O:47])[C:27]=2[C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=3)[CH:29]=2)=[N:15]1)(=O)=O.O>CC(N(C)C)=O>[CH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:45]=[CH:46][C:37]=1[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]([C:27]2[C:26](=[O:47])[NH:25][C:24](=[O:48])[C:23]=2[C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([CH2:13][CH2:12][CH2:11][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:15]=2)=[CH:29]1
Reactant: CS(=O)(=O)OCCCn1nc(C2=C(c3cn(-c4ccc5ccccc5c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: C1CCNC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1NC(=O)C(c2nn(CCCN3CCCC3)c3ccccc23)=C1c1cn(-c2ccc3ccccc3c2)c2ccccc12
Temperature: 65 °C
Yield: 18 %

Procedure:
Pyrrolidine (1 mL) was added to the 3-[1-[3-[(methylsulfonyl)oxy]propyl]-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione (0.5 g, 0.975 mmol) in DMA (10 mL). The mixture was heated to 65° C. for 3 h, then cooled to rt. Water (5 mL) was added, followed by extraction with EtOAc (3×50 mL). The organic layers were combined, washed with H2O and brine, then dried (Na2SO4) and evaporated in vacuo to a dark brown oil. The oil was purified by flash column chromatography (97:3:0.3; DCM:MeOH:NH4OH) to afford Compound 85 (0.1 g, 18%) as an orange flaky solid. Compound 85 was dissolved in excess dilute HCl, then frozen and lyophilized to give the hydrochloride salt. 1H NMR (CD3OD) δ 8.22 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.89 (m, 3H), 7.49 (m, 7H), 7.00 (m, 2H), 6.64 (t, J=7.5 Hz, 1H), 6.39 (d, J=8.1 Hz, 1H), 4.47 (t, J=6.2 Hz, 2H), 3.44 (m, 2H), 3.07 (t, J=7.4 Hz, 2H), 2.82 (m, 2H), 2.16 (m, 2H), 1.93 (m, 4H). ES-MS m/z 566 (MH+).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:16]([O:18][C:19](=[O:38])[CH:20]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:21](N1C2C=CC=CC=2N=N1)=[O:22])[CH3:17]>C1COCC1>[CH2:16]([O:18][C:19](=[O:38])[CH:20]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:21](=[O:22])[CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1=[O:15])[CH3:17]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)C(C(=O)n1nnc2ccccc21)C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C1CCCCC1=O)C1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a −78° C. cold solution of LDA (2 M solution in heptane/ethylbenzene/THF, 1.8 ml, 3.66 mmol) in THF (16.8 ml) under an argon atmosphere was added a solution of cyclohexanone (380 μl, 3.66 mmol; CAS Reg. No. 108-94-1) in THF (12.6 ml) within 10 min. The mixture was stirred for 1 h at −78° C. A solution of 3-benzotriazol-1-yl-2-cyclohexyl-3-oxo-propionic acid ethyl ester (1.05 g, 3.33 mmol) in THF (11.1 ml) was added and the solution was stirred at ambient temperature for 14 h. Ice water was added, the mixture was poured onto ice water/brine 1/1 and extracted two times with TBME. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (209 mg, 0.71 mmol; 21%) as yellow oil. MS: m/e=295.2 [M+H+].
Reaction SMILES: C([O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH3:16])[CH:6]=1)(=O)C>CO>[OH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH3:16])[CH:6]=1
Reactant: CC(=O)Oc1cc(-c2ccccc2)n(C)c1
Solvent: CO
Product: Cn1cc(O)cc1-c1ccccc1
Reaction time: 0.25 h

Procedure:
To a mixture of deoxygenated methanol (15.5 ml) and 3-acetoxy-1-methyl-5-phenylpyrrole (11) (1.3 g, 6.2 mmole), under argon, was added deoxygenated NaOH (2N, 12.5 ml). The reaction mixture was stirred in an ice-bath for 15 minutes. Then deoxygenated citric acid (2M, 7 ml) was added and the resulting mixture was stirred in an ice bath for 8 minutes. The reaction mixture was concentrated under reduced pressure, then 20 ml of water was added and was extracted twice with ethylacetate (EtOAc) (50 ml). The EtOAc layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give 3-hydroxy-1-methyl-5-phenylpyrrole (12) as an orange residue. Under argon, a cold solution of anhydrous THF (12.4 ml), pyridine (0.6 ml, 7.4 mmole, 1.2 eq) and trifluoroacetic acid (1.2 ml, 15 mmole, 2.4 eq) was added to the orange residue, followed immediately by the addition of a solution of freshly prepared N-tosyl-L-alaninyl chloride (1.2 g, 7.4 mmole, 1.2 eq) in anhydrous THF (12.4 ml). The resulting mixture was stirred for one hr at 0° C. Then the reaction was quenched by the addition of aqueous citric acid (1M, 5ml) and EtOAc (30 ml). After a brief mixing, the layers were separated and the organic layer was successively washed with saturated NaCl solution, twice with 5% NaHCO3 solution and again with saturated NaCl solution. The EtOAc extract was then dried over MgSO4, treated with Norit 211, filtered and concentrated under reduced pressure to give the crude product (13) as an orange residue. This was dissolved in hexane: EtOAc (1:1) (5 ml) and chromatographed on a column (SiO2, 100 g) by elution with hexane:EtOAc (7:3) to give 1 g of (13) as a thick light orange oil. A portion of this crude product was further purified by semi-preparative HPLC (column, IBM silica, 1 cm×25 cm; mobile phase, hexane:EtOAc 8:2; flow rate, 4.0 ml/min; pressure, 0.2 psi) to yield a honey color thick oil (13).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.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>[CH3:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)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: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cccc(-c2ccc(C(=O)Nc3ccc4cccnc4c3)cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.153 mmol) in toluene (2 ml) and ethanol (0.4 ml) under an argon atmosphere was added 3-methyl-phenylboronic acid (21 mg, 0.153 mmol), 2M sodium carbonate solution (0.15 ml) and tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.05 mmol). The reaction was heated at reflux for 18 h, then cooled to room temperature and diluted with EtOAc. The mixture was washed with sat. aq. sodium bicarbonate solution and water, dried over MgSO4 and concentrated to give the crude product which was purified by SPE column chromatography. Elution with 50% EtOAc in 40-60° C. petroleum ether gave the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.92 (dd, 1H), 8.19 (d, 1H), 8.13 (m, 3H), 8.01, (d, 2H), 7.86 (d, 1H), 7.75 (d, 2H), 7.46 (m, 2H), 7.36 (m, 2H), 7.25 (m, 1H), 2.46 (s, 3H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:71])([F:70])[C:25]1[CH:26]=[C:27]([C@H:35]2[O:39][C:38](=[O:40])[N:37]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:44][C:43]=3[C:52]3[C:57]([Cl:58])=[CH:56][CH:55]=[C:54]([C:59]4[CH:64]=[CH:63][C:62]([CH:65]([OH:67])[CH3:66])=[CH:61][C:60]=4[CH3:68])[CH:53]=3)[C@H:36]2[CH3:69])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[C:65]([C:62]1[CH:63]=[CH:64][C:59]([C:54]2[CH:53]=[C:52]([C:43]3[CH:44]=[CH:45][C:46]([C:48]([F:49])([F:50])[F:51])=[CH:47][C:42]=3[CH2:41][N:37]3[C@@H:36]([CH3:69])[C@@H:35]([C:27]4[CH:26]=[C:25]([C:24]([F:71])([F:70])[F:23])[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=4)[O:39][C:38]3=[O:40])[C:57]([Cl:58])=[CH:56][CH:55]=2)=[C:60]([CH3:68])[CH:61]=1)(=[O:67])[CH3:66]
Reactant: Cc1cc(C(C)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccc(Cl)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin Periodinane (58.3 mg, 0.137 mmol) was added to a solution of alcohol from Example 51 (82 mg, 0.115 mmol) in methylene chloride (5 ml) at room temperature. The resulting slurry was stirred at room temperature for 1 h. No starting material was seen by TLC (EtOAc/hexane 2:8). The solid was filtered. The filtrate was concentrated. The residue was purified by flash column on silica gel, eluting with EtOAc/hexane (20:80) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz): δ a mixture of 1:1 atopoisomers 7.90 (s, 1H), 7.89 (s, 1H), 7.84 (d, J=8 Hz, 1H), 7.72 (m, 4H), 7.62 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 0.5H), 7.46 (d, J=8.0 Hz, 0.5H), 7.40-7.34 (m, 2H), 7.26 (d, J=2.5 Hz, 0.5H), 7.21 (d, J=2.5 Hz, 0.5H), 5.62 (d, J=8.0 Hz, 1H), 5.02 (d, J=15.5 Hz, 0.5H), 4.83 (d, J=16.0 Hz, 0.5H), 4.08 (d, J=16.0 Hz, 0.5H), 4.01 (d, J=15.5 Hz, 0.5H), 3.99 (m, 0.5H), 3.90(m, 0.5H), 2.64 (s, 3H), 2.40 (s, 1.5H), 2.39 (s, 1.5H), 0.64 (d, J=6.5 Hz, 1.5H), 0.62 (d, J=6.5 Hz, 1.5H). LC/MS M+714.01.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=3[O:37][CH3:38])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3ccccc23)CC1
Reaction time: 16 h
Yield: 47.7 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and dimethylformamide (60 ml) was stirred at 90 C. for 16 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4) and concentrated to afford a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and ethyl acetate-diethylamine (2%), as eluent. Concentration of the appropriate fractions afforded 3.9 g of product as an off-white solid. Recrystallization from absolute ethyl alcohol afforded 2.6 g (33%) of 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-3-methoxyphenyl]ethanone, m.p.=102-104° C., as colorless needles.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[CH:9]2)([O-])=O>C(O)(=O)C.[Fe]>[C:17]1([S:14]([C:10]2[CH:11]=[N:12][C:13]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[NH2:1])(=[O:15])=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 8-nitro-3-(phenylsulfonyl)quinoline (3.70 g, 11.77 mmol) in acetic acid (40 ml) at 80° C. was added iron powder (3.29 g, 58.86 mmol) in portions over 5 mins. The resulting suspension was stirred for a further 30 mins. It was then cooled down to room temperature and filtered. The solid was washed with acetic acid and the collected filtrates concentrated. The residue was dissolved in CH2Cl2 and washed with ammonium hydroxide solution (25%), water and then dried over MgSO4. The organic layer was filtered and then evaporated to afford the title compound (3.20 g, 96%) as a yellow solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[C:17]([F:19])[S:16][C:15]=2[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](OCC)=[O:31])=[C:24]([CH3:35])[C:23]=2[CH3:36])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[C:17]([F:19])[S:16][C:15]=2[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][OH:31])=[C:24]([CH3:35])[C:23]=2[CH3:36])=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(OCc2sc(F)cc2-c2ccc(Cl)cc2)c(C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1c(CCCO)ccc(OCc2sc(F)cc2-c2ccc(Cl)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((3-(4-chlorophenyl)-5-fluorothiophen-2-yl)methoxy)-2,3-dimethyl phenyl)propanoate to give the desired product as off-white oil. 1H NMR (300 MHz, CD3OD) δ: 7.36-7.39 (m, 4H), 6.85 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.98 (s, 2H), 3.54 (t, J=6.3 Hz, 2H), 2.58-2.63 (m, 2H), 2.17 (s, 3H), 2.10 (s, 3H), 1.64-1.74 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H22ClFO2S, 403.1 (M−H). found 403.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.FC(F)(F)C(O)=O.[C@@H:32]12[CH2:38][C@@H:35]([NH:36][CH2:37]1)[CH2:34][O:33]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:36]3[CH2:37][C@H:32]4[CH2:38][C@@H:35]3[CH2:34][O:33]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1O[C@H]2CN[C@@H]1C2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(N3C[C@H]4C[C@@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Temperature: 140 °C
Yield: 70.1 %

Procedure:
To a Smith process vial containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.68 g, 1.9 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane trifluoroacetate (prepared starting from cis-1-Boc-4-hydroxy-D-prolinate, 3.1 mmol) in ethanol (14 mL) was added triethylamine (4 mL, 31 mmol). The mixture was heated in the microwave reactor for 10 minutes at 140° C. The precipitate was collected by Buchner filtration and washed successively with methanol, water, methanol, and diethyl ether. Solid was dried under house vacuum to provide (1R,4R)-5-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane as a pale yellow solid (0.56 g, 70%). MS (ES+): 421.1 (M+H)+
Reaction SMILES: B(Br)(Br)Br.[C:5]1([S:11]([NH:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=2)[CH2:16][C:17]([O:19][CH2:20]C)=[O:18])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO>ClCCl>[C:5]1([S:11]([NH:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of BBr3 in dichloromethane (1M) was added at −78° C. to a solution of 2.0 g of (8c) in 50 ml of dichloromethane. After stirring at room temperature for 3 hours, the solution was cooled to −78° C. and 100 ml of methanol were then added. The mixture was stirred at room temperature overnight and then concentrated.
Reaction SMILES: C1(C2C=C(C)C(N3CCN(C(C4C=NC(F)=CC=4C)=O)CC3)=NC=2)CC1.COC1C=CC(CN)=CC=1.[Cl:37]CCCS(Cl)(=O)=O.NC1N=CC(C(N2CCN(C3C(C)=CC(C4CC4)=CN=3)CC2)=O)=C(C)C=1.[CH:71]1([C:74]2[CH:75]=[C:76]([CH3:102])[C:77]([N:80]3[CH2:85][CH2:84][N:83]([C:86]([C:88]4[CH:89]=[N:90][C:91]([N:95]5[CH2:99][CH2:98][CH2:97][S:96]5(=[O:101])=[O:100])=[CH:92][C:93]=4[CH3:94])=[O:87])[CH2:82][CH2:81]3)=[N:78][CH:79]=2)[CH2:73][CH2:72]1>>[ClH:37].[ClH:37].[CH:71]1([C:74]2[CH:75]=[C:76]([CH3:102])[C:77]([N:80]3[CH2:81][CH2:82][N:83]([C:86]([C:88]4[CH:89]=[N:90][C:91]([N:95]5[CH2:99][CH2:98][CH2:97][S:96]5(=[O:100])=[O:101])=[CH:92][C:93]=4[CH3:94])=[O:87])[CH2:84][CH2:85]3)=[N:78][CH:79]=2)[CH2:73][CH2:72]1
Reactant: O=S(=O)(Cl)CCCCl
Agent: COc1ccc(CN)cc1
Agent: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Agent: Cc1cc(N)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Product: Cl

Procedure:
Using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (1.25 g) described in Preparation Example 140, 4-methoxybenzylamine (2 mL) and 3-chloropropane-1-sulfonyl chloride (0.55 ml) and by the reaction and treatment in the same manner as in Example 223, the title compound (950 mg) was obtained via (6-amino-4-methylpyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone and [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-methylpyridin-3-yl]methanone.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[O:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Br[CH2:23][CH:24]=[CH2:25].[In].Cl>C1COCC1.O.CCOC(C)=O>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]([OH:21])[CH2:25][CH:24]=[CH2:23])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: C=CCBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (5.1 g, 17 mmol) in THF (100 mL) and water (33.3 mL) was added 3-bromoprop-1-ene (2.86 mL, 33.9 mmol) followed by indium (3.89 g, 33.9 mmol). The reaction mixture was stirred for about 15 h at ambient temperature and then aqueous HCl (1 N, 150 mL) and EtOAc (150 mL) were added. The organic layer was separated, dried over anhydrous Na2SO4, filtered, coned in vacuo and purified by chromatography on silica gel eluting with 20-60% EtOAc in heptane to provide 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-ol (4 g, 69%) as a thick oil: LC/MS (Table 1, Method a) Rt=2.30 min; MS m/z: 344 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:13])[CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:13])[CH2:12][N:11]([CH2:21][CH3:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(Cl)c2)CNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN1CC(O)(c2cc(F)cc(Cl)c2)C1
Temperature: 120 °C
Yield: 60.1 %

Procedure:
A mixture of 3-(3-chloro-5-fluorophenyl)azetidin-3-ol (0.41 g, 2.03 mmol), potassium carbonate (0.56 g, 4.06 mmol) and iodoethane (0.31 g, 2.03 mmol) in acetonitrile (5 ml) was heated at 120° C. under microwave irradiation for 10 min. Water (50 ml) and ethyl acetate (50 ml) was added and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the crude product. Purification by flash column chromatography on silica gel (ethyl acetate) gave 0.28 g (60%) of the title compound. The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 166-168° C. MS m/z (relative intensity, 70 eV) 229 (M+, 1), 172 (23), 130 (24), 109 (33), 58 (bp).