Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]5[CH2:30][CH2:29][N:28]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1
Reactant: CN(C)C(=O)CCl
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(CC(=O)N(C)C)CC5)cc4)nc23)c1

Procedure:
2-(4-{4-[8-(3-Methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.150 g, 0.375 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.057 mL, 0.563 mmol) in a manner analogous to Example 313 to give product (0.065 g, 36%). MP=178-179° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.61 (s, 1H), 8.78 (d, 1H), 7.85 (d, 1H), 7.80 (s, 1H), 7.65 (m, 3H), 7.40 (m, 1H), 7.15 (m, 3H), 7.05 (m, 1H), 3.86 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.92 (m, 2H), 2.85 (s, 3H), 2.40 (m, 1H), 2.10 (m, 2H), 1.65 (m, 4H). MS=485 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[F:22][C:23]([F:42])([F:41])[C:24]1[CH:25]=[C:26]([C@H:34]2[O:38][C:37](=[O:39])[NH:36][C@H:35]2[CH3:40])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:36]2[C@@H:35]([CH3:40])[C@@H:34]([C:26]3[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=[C:24]([C:23]([F:22])([F:41])[F:42])[CH:25]=3)[O:38][C:37]2=[O:39])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester and (4S,5R)-5-(3,5-bis-trifluoromethyl-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:6]([CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:4].[CH:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH2:24]>O1CCCC1.O>[CH2:3]([C:5]1[N:6]([CH2:18][C:19]([CH3:22])([O:21][CH2:24][CH2:23][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:4]
Reactant: CCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2cnc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 30 mg, 0.74 mmol) was added to a stirred solution of 1-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (2.00 g, 7.43 mmol) in tetrahydrofuran (30 mL). After five minutes, methyl vinyl sulfone (1.60 g, 14.9 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours and a solid formed. A few drops of water were added to the mixture, which was then concentrated under reduced pressure to yield a solid that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 1.90 g of 2-ethyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][C:23]([CH3:26])=[CH:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].[BH4-].[Na+].CCOC(C)=O>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:11]1[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][CH2:16]1)[C:18]([CH:20]1[CH2:25][CH2:24][C:23]([CH3:26])=[CH:22][CH2:21]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)[C@H]1CC[C@H](O)CC1
Reaction time: 0.33 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohex-3-enecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (233 mg, 0.51 mmol) in THF (3 mL) and water (0.3 mL) was treated with sodium borohydride (19 mg, 0.48 mmol). After stirring for 20 min, water was added and the reaction mixture was extract twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (10% EtOAc:hexanes, 4 min, 10-70% EtOAc:hexanes, 12 min, 12 g column) afforded 130 mg (59% yield) of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-trans-cyclohexyl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:22][C:20]1[CH:19]=[C:18]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH:17]=[C:16]([C:15](=[O:32])[NH:14][CH:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][CH2:10]2)[CH:21]=1)[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: CCOC(=O)CCCCCBr
Product: CCOC(=O)CCCCCOc1cc(Oc2ccc(C#N)cc2)cc(C(=O)NC2CCC(NC(=O)OC(C)(C)C)CC2)c1
Yield: 86 %

Procedure:
Using 0.84 g (1.86 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 6-bromo-hexaanoic acid ethyl ester (0.41 g, 1.86 mmol) and following the procedure of Example 42(b) afforded 0.95 g of the required product. 1H NMR (DMSO-d6): δ 1.15 (3H, t), 1.25 (2H, m), 1.4 (9H, s), 1.45 (3H, m), 1.6 (2H, m) 1.7 (2H, m), 1.8 (4H, m), 2.3 (2H, t), 3.2 (1H, m), 3.7 (1H, m), 4.05 (4H, m), 6.72 (1H, d), 6.88 (1H, s), 7.12 (3H, m), 7.3 (1H, s), 7.84 (2H, d), 8.24 (1H, d).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:30][C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(F)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 68.5 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.0 g, 3.19 mmol), 2,4-difluoro-phenol (585 mg, 4.5 mmol), and potassium carbonate (882 mg, 6.38 mmol) in DMF (11 mL) was heated under microwave irradiation for 80 min at 150° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound C117 as a beige solid (890 mg, 69%). 1H NMR (CDCl3, 400 MHz) δ 1.19 (d, 6H), 1.66-1.76 (m, 2H), 1.86-1.95 (m, 2H), 2.11 (s, 3H), 3.30-3.40 (m, 2H), 3.63-3.73 (m, 2H), 4.86 (m, 1H), 5.26 (m, 1H), 6.80-6.91 (m, 2H), 7.09 (q, 1H), 7.19 (s, 1H). Exact mass calculated for C20H23F2N3O4 407.41, found 408.3 (MH+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[C:17]([O:21][CH3:22])(=[O:20])[C:18]#[CH:19].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C(OCC)(=O)C>CC(O)(C)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:22][O:21][C:17]([C:18]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:6]=2)[CH:19]=1)=[O:20]
Reactant: [N-]=[N+]=NCc1ccc(-c2ccccc2)cc1
Reactant: C#CC(=O)OC
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)nn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-Azidomethyl-biphenyl (145 mg, 0.5 mmol), methyl propiolate (44 mg, 0.5 mmol), copper(II) sulfate (17 mg, 0.1 mmol) and sodium ascorbate (103 mg, 0.5 mmol) in 3 mL tBuOH and 1 mL water was stirred at room temperature for 3 h. Ethyl acetate was added and the mixture was extracted with water. The organic layer was dried over MgSO4 and evaporated in vacuo to give the title compound which was used in the next step without further purification. LCMS (method A) RtA=1.964 min; [M+H]+=294.0.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C:10]([CH3:38])([CH3:37])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:36][CH2:35][C:19]2([O:24][CH2:23][CH2:22][N:21]([C:25]([C:27]3[N:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[S:30][CH:31]=3)=[O:26])[CH2:20]2)[CH2:18][CH2:17]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:32]([C:29]1[S:30][CH:31]=[C:27]([C:25]([N:21]2[CH2:20][C:19]3([CH2:35][CH2:36][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([CH3:38])([CH3:37])[CH:9]=[O:8])[CH2:17][CH2:18]3)[O:24][CH2:23][CH2:22]2)=[O:26])[N:28]=1)([CH3:34])[CH3:33]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCC(C)(C)CO)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCC(C)(C)C=O)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (0.048 mL) was added to a solution of (9-(7-hydroxy-6,6-dimethylheptyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 102, step c) (0.28 g) in DCM (15 mL) at 0° C. under argon and the mixture stirred for 5 min before addition of Dess-Martin periodinane (0.39 g). The reaction mixture was stirred at RT for 1 h then was quenched by addition of saturated sodium bisulfite solution (10 mL) and saturated sodium bicarbonate solution (10 mL) then ethyl acetate was added and the mixture stirred for 5 min. The layers were separated and the aqueous solution was extracted with ethyl acetate (×2). The combined organic solutions were washed with saturated sodium bicarbonate solution. Acetic acid (0.053 mL) was added to the organic phase which was then dried over sodium sulphate, filtered and evaporated in vacuo to afford the crude subtitled compound as a yellow oil. Yield 0.33 g.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.S([N:29]=[N+:30]=[N-])(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>C(#N)C>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([C:10]([S:11]([C:14]([F:16])([F:17])[F:15])(=[O:13])=[O:12])=[N+:29]=[N-:30])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)CS(=O)(=O)C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Crude p-toluenesulfonyl-trifluoromethanesulfonyl-methane (5 g, 0.017 mole) is dissolved in acetonitrile (200 ml) under nitrogen and the solution is cooled to 0° C. using an ice bath. Tosyl azide (16.3 g, 0.083 mole) and then triethylamine (4.6 ml, 0.063 mole) are added in one portion and the reaction mixture is stirred at that temperature for 24 h. After adding water (11), the mixture is extracted twice with dichloromethane (300 ml) and the combined organic phases are washed with 1 N HCl, saturated sodium bicarbonate and water. After drying over MgSO4 and removal of the solvent, the resulting yellow orange oil was chromatographed on silica gel using ethyl acetate/cyclohexane 1:5 as eluent, yielding p-toluenesulfonyl-trifluoromethanesulfonyl-diazomethane as a yellowish solid. The structure was confirmed by 1H/13C NMR and IR spectroscopy.
Reaction SMILES: Cl.CO[C:4](=[O:8])[CH2:5][NH:6][CH3:7].C1CCN2C(=NCCC2)CC1.[CH2:20]([N:27]=[C:28]=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([N:27]1[C:4](=[O:8])[CH2:5][N:6]([CH3:7])[C:28]1=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: S=C=NCc1ccccc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CN1CC(=O)N(Cc2ccccc2)C1=S
Yield: 99.9 %

Procedure:
To a solution of sarcosine methyl ester hydrochloride (0.56 g, 4.0 mmol) and DBU (0.60 mL, 4.0 mmol) in anhydrous ethanol added benzyl isothiocyanate (0.53 mL, 4.0 mmol). The resulting solution was heated at reflux 16 h, cooled, concentrated and chromatographed (silica gel, DCM) to give the title compound (0.88 g, quant.). 1H-NMR (CDCl3): δ 7.49–7.53 (2H, m), 7.28–7.35 (3H, m), 5.02 (2H, s), 4.03 (2H, s), 3.34 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]=[C:6]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH:6]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2]
Reactant: CCOC(=O)C=C(CCCCCCc1ccc2cccnc2n1)c1ccc(N)nc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(CCCCCCc1ccc2c(n1)NCCC2)c1ccc(N)nc1

Procedure:
A mixture of 28-5 (0.1 g, 0.3 mmol) and 10% Pd/C (0.1 g) in 10 mL methanol was purged with argon under vacuum and then treated under balloon hydrogenation conditions for 40 hr. It was filtered through a pad of celite. The solution was concentrated. The residue was purified by silica gel chromatography (100% CHCl3 to CHCl3 /MeOH 5:1) to afford the desired product 28-6 as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](B(O)O)[CH3:25].ClCCl>O1CCOCC1.O>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:4]1[CH:3]=[C:2]([CH2:24][CH3:25])[CH:7]=[CH:6][N:5]=1
Reactant: Fc1cccc(F)c1COc1cc(Br)ccn1
Reactant: CCB(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCc1ccnc(OCc2c(F)cccc2F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
A solution of 3.8 g (9.24 mmol, 73% purity) of 4-bromo-2-[(2,6-difluorobenzyl)oxy]pyridine (Example 145A) in 54 ml of 1,4-dioxane and 13 ml of water was degassed under argon for 10 minutes. The solution was admixed with 9.04 g (27.73 mmol) of caesium carbonate, 0.82 g (11.09 mmol) of ethylboronic acid (CAS: 4433-63-0) and 0.75 g (0.924 mmol) of (1,1)-bis(diphenylphosphino)ferrocenedichloropalladium(II) complex with dichloromethane (CAS: 95464-05-4). The reaction vessel was closed and the contents were stirred at 100° C. for 18 hours. The solvent was evaporated off and the residue was partitioned between water and ethyl acetate. The organic phase was removed and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane/ethyl acetate, gradient 0% to 5%), which gave 1.38 g (41% yield, 69% purity) of product.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][O:6][C:5](=[S:8])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH2:3]1.C(=O)([O-])O.[Na+].Cl[C:31]([O:33][CH3:34])=[O:32].O>C(#N)C>[CH3:1][C:2]1([CH3:24])[CH2:7][O:6][C:5](=[S:8])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]([C:31]([O:33][CH3:34])=[O:32])[S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])[CH2:3]1
Reactant: COC(=O)Cl
Reactant: CC1(C)COC(=S)N(Cc2ccccc2NS(=O)(=O)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)N(c1ccccc1CN1CC(C)(C)COC1=S)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 46.6 %

Procedure:
5,5-dimethyl-3-[2-(trifluoromethanesulfonylamino)benzyl]-[1,3]-oxazinan-2-thione (0.15 g, 0.39 mmol) and sodium hydrogen carbonate (0.05 g, 0.60 mmol) were suspended in acetonitrile (10 ml), added with methyl chloroformate (0.06 g, 0.60 mmol) and heated to reflux for three hours. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The solvent was evaporated under reduced pressure after the organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:l) to obtain 5,5-dimethyl-3-(2-[N-(methoxycarbonyl)-N-(trifluoromethanesulfonyl)amino]benzyl)-[1,3]-oxazinane-2-thione (0.08 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH2:12]([O:14][C:15](=[O:23])[CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:13].CCN(C(C)C)C(C)C.O>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:23])[CH2:18][CH2:19]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: CCOC(=O)CC1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC1CCN(c2nc(Cl)nc3[nH]ccc23)CC1
Yield: 95.4 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (188 mg, 1.00 mmol), 2-(4-piperidinyl)acetic acid ethyl ester (171 mg, 1.00 mmol) and DIEA (0.400 mL, 2.30 mmol) in dioxane (6 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, dried over Na2SO4, concentrated in vacuo to give ethyl 2-(1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)acetate (308 mg).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24]C)=[O:22]>CN(C=O)C>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: CCOC(=O)CCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCn1c2ccccc2c2ccccc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 51.7 %

Procedure:
To a round bottom flask fitted with reflux condenser containing carbazole (1.00 g, 5.98 mmol) and sodium hydride (60 wt. % in mineral oil, 0.29 g, 7.18 mmol), was added DMF (22 mL). After stirring at 50° C. for 20 min, ethyl 5-bromopentanoate (0.95 mL, 5.98 mmol) was added and the mixture stirred at 80° C. overnight. The reaction was quenched by addition of 5% aqueous NH4Cl (100 mL), transferred to a separatory funnel and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×20 mL), dried (Na2SO4) and concentrated. Purification by MPCC (0-40% gradient of ethyl acetate in hexane) afforded the title compound (0.87 g, 49%). 1H NMR (400 MHz, CDCl3): δ 8.14 (d, 2H, J=7.8 Hz), 7.51 (t, 2H, J=7.2 Hz), 7.43 (d, 2H, J=8.2 Hz), 7.27 (t, 2H, J=7.4 Hz), 4.35 (t, 2H, J=7.1 Hz), 4.13 (q, 2H, J=7.1 Hz), 2.35 (t, 2H, J=7.3 Hz), 1.98-1.91 (m, 2H), 1.79-1.72 (m, 2H), 1.25 (t, 3H, J=7.1 Hz). 13C NMR APT (100 MHz, CHCl3): δ 173.2 (up), 140.3 (up), 125.6 (down), 122.89 (up), 120.4 (down), 118.9 (down), 108.6 (down), 60.4 (up), 42.7 (up), 33.9 (up), 28.4 (up), 22.7 (up), 14.2 (down). ESI-HRMS (m/z): [M+H]+ calcd. for C19H21NO2, 296.1645. found, 296.1650.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=1[CH3:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[C:12]=2[CH3:21])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1c(Br)cccc1C(F)(F)F
Reactant: Cc1cnc(Cl)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1cccc(C(F)(F)F)c1C
Yield: 22.5 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.18 g, 5.9 mmol), 1-bromo-2-methyl-3-trifluoromethyl-benzene (0.33 g, 1.4 mmol), Pd2(dba)3 (0.12 g, 0.13 mmol), Xantphos (0.15 g, 0.25 mmol) and cesium carbonate (1.23 g, 3.8 mmol) were suspended in dioxane (8 mL) microwaved at 160° C. for 18 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.095 g, 25%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23]>ClCCl.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>[C:22]([NH:1][CH2:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1CN
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1COCCN1C(=O)OC(C)(C)C

Procedure:
To a solution of (S)-tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (commercially available, 0.62 g, 2.87 mmol) in dichloromethane (28.0 ml) were added sequentially pyridine (0.5 ml, 5.73 mmol) and acetyl chloride (0.25 ml, 3.44 mmol). After 30 min the reaction was diluted with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The resulting mixture was extracted with ethyl acetate (×3), and the combined organic layers were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting light yellow oil was purified by flash column chromatography (ISCO, SiO2, 0→10% methanol in ethyl acetate over 10 min) to afford (S)-tert-butyl 3-(acetamidomethyl)morpholine-4-carboxylate (0.741 g, yield: almost quantitative, INTERMEDIATE 86A STEP 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH2:11][C:10]([CH3:26])([CH3:25])[C:9]=2/[CH:27]=[CH:28]/[C@@H:29]2[O:34][C:33](=[O:35])[CH2:32][C@@H:31]([O:36][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:30]2)=[CH:4][C:3]=1[CH3:54].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[C:15](=[O:24])[C:16]4=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]4[C:18]3=[O:19])[CH2:11][C:10]([CH3:25])([CH3:26])[C:9]=2/[CH:27]=[CH:28]/[C@@H:29]2[O:34][C:33](=[O:35])[CH2:32][C@@H:31]([OH:36])[CH2:30]2)=[CH:4][C:3]=1[CH3:54]
Reactant: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC(=O)O3)C(C)(C)CC(N3C(=O)c4ccccc4C3=O)C2)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Product: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O)CC(=O)O3)C(C)(C)CC(N3C(=O)c4ccccc4C3=O)C2)ccc1F

Procedure:
In a manner similar to Scheme VIII, 44 (0.15 gm) was treated with tetrabutylammonium fluoride and HOAc and provided, after purification with SiO2 using 1:1 hexanes:EtOAc as eluent, 68 mg of the solid product.