Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])/[C:5](/[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:6]/[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])/[C:5](/[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:31])=[N:6]/[O:7][C:8]([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)O/N=C(/c1ccc(F)c(Br)c1)c1ncccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)O/N=C(/c1ccc(F)c(Br)c1)c1c(O)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
A mixture of (Z)-2-(3-bromo-α-t-butoxyimino-4-fluorobenzyl)-3-hydroxypyridine (0.55 g), 70% m-chloro perbenzoic acid (0.74 g) and tetrahydrofuran (10 mL) was stirred overnight at room temperature. To the reaction mixture was added an aqueous solution of sodium sulfite. The reaction mixture was stirred for 30 minutes, and subjecting to extraction with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was crystallized from isopropyl ether, and recrystallized from ethanol-water to afford (Z)-2-(3-bromo-α-t-butoxyimino-4-fluorobenzyl)-3-hydroxypyridine 1-oxide (0.46 g) (compound 25).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11]#[N:12].C([O:15]CCO)C>C([O-])(O)=O.[Na+]>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11]([NH2:12])=[O:15]
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: CCOCCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: NC(=O)Cc1c(Cl)cccc1Cl

Procedure:
Alternative Conditions. To a solution of sodium (169 mg, 7.35 mmol) dissolved in 2-ethoxyethanol (7.0 mL) was added 2,6-dichlorophenylacetonitrile (1.40 g, 7.53 mmol) and (IV) (502 mg, 3.66 mmol), and the mixture was then stirred at reflux for 30 minutes. The resulting solution was diluted with aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The solvents were removed under reduced pressure, then chromatography of the residue on silica gel, eluting with 2-3% MeOH/CH2Cl2, gave firstly a mixed fraction, which on crystallisation from CHCl3 /light petroleum gave 2,6-dichlorophenylacetamide (165 mg): mp (MeOH/CH2Cl2) 211.5-213° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[CH:39]([O:38][C:36]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:37])([CH3:41])[CH3:40]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
General procedure for the syntheses of carbamates, pyridinamides, and sulfonamides. In a 16 mL reaction vessel was placed (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (42 mg, 0.1 mmol), triethylamine (90 μl) and DMF (1.5 mL) was added to completely dissolve the solid material. Isopropyl chloroformate (0.15 mL, 1.0M in toluene) was added to the solution and the mixture was stirred 30 min under N2 at room temperature. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was concentrated under vacuum and purified by preparative HPLC to give Compound A22, 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H), 1.89 (m, 2H), 1.93 (m, 2H), 3.07 (s, 3H), 3.63 (m, 2H), 3.67 (m, 2H), 4.94 (m, 1H), 5.61 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.40 (s, 1H), 10.18 (s, 1H). Exact mass calculated for C20H25N5O7S 479.15, found 480.4 (MH+).
Reaction SMILES: [C:1]1([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS([C:20]1[N:30]=[C:23]2[N:24]=[C:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[N:22]2[N:21]=1)(=O)=O>O1CCCC1>[CH3:29][C:25]1[CH:26]=[C:27]([CH3:28])[N:22]2[N:21]=[C:20]([O:10][CH2:9][CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11][CH2:12][OH:13])[N:30]=[C:23]2[N:24]=1
Reactant: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Reactant: OCCN(CCO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(OCCN(CCO)c3ccccc3)nc2n1
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
A mixture of N-phenyldiethanolamine (8.76 g, 48.3 mmol) and tetrahydrofuran (70 mL) was added to a 200 mL RBF under a nitrogen atmosphere with a magnetic stirring bar. Sodium hydride (60% dispersion in mineral oil) (1.93 g, 48.3 mmol) was added portion-wise (4×˜500 mg) over 10 minutes (Effervescence). The reaction was stirred for 10 minutes before 2-methanesulfonyl-5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine (9.1 g, 40.3 mmol) was added portion-wise (4×˜2.3 g) over 10 minutes (Effervescence). Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. The title compound eluted with retention time of 3.7 min. After 45 minutes the reaction was concentrated under reduced pressure then partitioned between dichloromethane (200 mL) and water (25 mL). The aqueous layer was extracted once more with dichloromethane (100 mL). The combined organic layer was washed with saturated aqueous NaCl (25 mL), dried (Na2SO4), filtered, and concentrated. The crude material was dissolved in ethyl acetate (80 mL) and extracted with 1 N HCl (80 mL) and 0.5 N HCl (10 mL). Solid NaCl was added (˜1-3 g) to the combined acidic extracts with stirring for 10 minutes. The pH was adjusted to basic with 5 N NaOH (˜23 mL) and a gummy precipitate formed. The aqueous layer was decanted into a separatory funnel, and the solid residue was rinsed with an additional 15 mL of water. The combined aqueous layers were extracted with dichloromethane (4×30 mL). The gummy precipitate was dissolved in an additional amount of dichloromethane (50 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient elution of 60-100% ethyl acetate in hexanes to afford the title compound as a white solid (8.62 g, 65% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.15 (m, 2H), 7.07 (s, 1H), 6.79 (d, 2H), 6.59 (t, 1H), 4.70 (t, 1H), 4.49 (t, 2H), 3.79 (t, 2H), 3.54 (q, 2H), 3.46 (m, 2H), 2.63 (s, 3H), 2.52 (s, 3H). EM (calc.): 327.2; MS (ESI) m/e: 328.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]([CH:35]2[CH2:38][C:37]([F:40])([F:39])[CH2:36]2)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[Cl:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>CN(C=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([CH:26]([CH:35]2[CH2:36][C:37]([F:40])([F:39])[CH2:38]2)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:20][C:19]=1[NH:18][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(c1ccc(Cl)c(N)c1)C1CC(F)(F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(C(CC(=O)OC(C)(C)C)C2CC(F)(F)C2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F

Procedure:
A solution of 76 mg (0.29 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 45 mg (0.13 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-(3,3-difluorocyclobutyl)-propanoate, 119 mg (0.31 mmol) of O-(1H-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and 0.51 ml of pyridine in 1 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was directly, without further work-up, separated into its components by preparative HPLC. This gave 19 mg (25% of theory) of the title compound as a colourless oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12](OCC)=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.O.[Cl-].[Ca+2].[Cl-]>C(OCC)C>[OH:13][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)cs1
Agent: O=C=O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: OCc1nc(-c2ccccc2)cs1
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 86.2 %

Procedure:
A solution of ethyl 4-phenylthiazole-2-carboxylate (Example 4B, 1.300 g, 5.57 mmol) in diethyl ether (60 mL) in a 500 mL flask under a nitrogen atmosphere was cooled to −40° C. (dry ice-water-calcium chloride bath) and treated with solid LiAH4 (0.40 g, 10.54 mmol) added all at once. The mixture was stirred at −40° C. over 2.5 h. The reaction was quenched by dropwise addition of ethyl acetate (1 mL), water (0.4 mL) followed by 15% aqueous sodium hydroxide (0.4 mL) and water (1.2 mL). The bath was then removed and the mixture was stirred at room temperature for 50 min. The solid formed was filtered and washed with ether (50 mL). The combined filtrate and washing was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Evaporation gave a yellow oil which was purified by silica gel chromatography (2.5×8 cm, elution toluene-ethyl acetate 9:1, 8:2 to 7:3). The resulting light yellow oil (0.931 g) was then distilled in vacuo (bp: 105-110° C./0.1 torr, bulb to bulb, air bath temperature) to provide the title material (0.918 g, 86%) of a colorless syrup. LC (Method C): 1.672 min. HRMS (ESI) calcd for C10H10NOS [M+H]+ m/z 192.0478, found 192.0508. 1H NMR (CDCl3, 400 MHz) δ ppm: 2.90 (br t, 1H), 5.02 (d, J=4.30 Hz, 2H), 7.31-7.38 (m, 1H), 7.39-7.45 (m, 2H), 7.46 (d, J=0.8 Hz, 1H), 7.85-7.92 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH2:31][CH2:32][CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])([C:26]([O:28]CC)=[O:27])[C:21]([O:23]CC)=[O:22])=[C:8]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[CH:7]=[CH:6]2.[OH-].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH2:31][CH2:32][CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])([C:26]([OH:28])=[O:27])[C:21]([OH:23])=[O:22])=[C:8]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[CH:7]=[CH:6]2
Reactant: CCOC(=O)C(CCCCCCCc1c(-c2ccc(OC)cc2)ccc2cc(OC)ccc12)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1
Yield: 106.7 %

Procedure:
Diethyl 2-[7-[6-methoxy-2-(4-methoxyphenyl)napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate (1.02 g, 1.5 mmol) was dissolved in ethanol (10 ml). To this solution, sodium hydroxide (1.2 g, 30 mmol) and water (1 ml) were added, and the resulting mixture was heated under reflux for 3 hours. Dilute hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to give 2-[7-[6-methoxy-2-(4-methoxyphenyl)napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)malonic acid (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH:17]([C:20](=O)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:19])[CH3:18]>>[CH2:25]([O:24][C:22]([C:21]1[C:20]([CH:17]([CH3:19])[CH3:18])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:23])[CH3:26]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCOC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 1 step A using (2-amino-5-chlorophenyl)(phenyl)methanone and ethyl 3-isopropyl-3-oxopropanoate as starting materials.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)/[CH:16]=[CH:17]/[C:18](OCC)=[O:19].O>C1COCC1>[F:11][C:12]([F:26])([F:27])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)/[CH:16]=[CH:17]/[CH2:18][OH:19]
Reactant: CCOC(=O)/C=C/c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OC/C=C/c1cccc(C(F)(F)F)c1
Yield: 50.7 %

Procedure:
12.29 ml of 1M diisobutylaluminum hydride solution in THF diluted with 20 ml of THF are introduced under argon and a solution of 1.00 g (4.095 mmol) of ethyl E-3-trifluoromethylcinnamate in 20 ml of THF is added dropwise. The mixture is subsequently stirred for 30 min. hydrolyzed with water, then extracted with dichloromethane, and the combined extracts are dried and concentrated. Column chromatography on silica gel (mobile phase: cyclohexane:ethylacetate:=7:3) yields in the first fraction 420 mg (50.7% of theory) of E-3-trifluoromethylcinnamyl alcohol which is employed further for the oxidation.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=[O:4].[ClH:25]>C(OCC)(=O)C.O1CCOCC1>[ClH:25].[CH3:1][N:2]([CH3:24])[C:3]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1(c2ccccc2)CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
900 mg (2.7 mmole) of N,N-dimethyl-1-t-butoxycarbonyl-4-phenylpiperidine-4-carboxamide (prepared as described in Preparation 1) were dissolved in 10 ml of ethyl acetate, and 5 ml of a 4 N solution of hydrogen chloride in dioxane were added, whilst ice-cooling. The mixture was then stirred at 0° C. for 1 hour. At the end of this time, the crystals which had deposited were collected by filtration, to give 690 mg (yield 95%) of the title compound as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[N:15]([N:27]=[C:28]([C:30]([O:32]CC)=[O:31])[CH:29]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:18]=2)=[N:7][CH:8]=1)#[N:2].O.[OH-].[Na+].Cl>COCCOC>[ClH:25].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[N:15]([N:27]=[C:28]([C:30]([OH:32])=[O:31])[CH:29]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:18]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc2c(NCCNc3ccc(C#N)cn3)nc(-c3ccc(Cl)cc3Cl)cn2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3nc(C(=O)O)cc23)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.16 mmol) of ester (Example 3) were dissolved in 5 ml of 1,2-dimethoxyethane, and 2.5 ml of water and 0.43 ml (0.4 mmol) of 1N sodium hydroxide solution were added. The solution was stirred at RT for 2 h. 20 ml of dilute hydrochloric acid (pH 3) were initially charged, and the reaction solution was slowly added dropwise. The mixture was stirred for another 30 min, and the product was filtered off and washed with diethyl ether. This gave, after drying under high vacuum, 70 mg (84% of theory) of the product as a solid.
Reaction SMILES: F.F.F.C(N(CC)CC)C.[B-](F)(F)(F)F.CCN([S+](F)[F:22])CC.[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33]O)[C:28]([CH:31]=[CH2:32])=[N:29][CH:30]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33][F:22])[C:28]([CH:31]=[CH2:32])=[N:29][CH:30]=1
Reactant: CCN(CC)[S+](F)F
Reactant: C=Cc1ncc(Cl)cc1CO
Agent: F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ncc(Cl)cc1CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
To a solution of triethylamine trihydrofluoride (Aldrich, 1.9 mL, 12 mmol) in DCM (30 mL) at −78° C., was added Xtalfluor-E (4.1 g, 18 mmol, Aldrich), followed by a solution of (5-chloro-2-vinylpyridin-3-yl)methanol (2 g, 12 mmol) in DCM (40 mL). The cold bath was removed and the reaction mixture was allowed to warm from −78° C. to rt over a period of 15 min. The reaction was quenched by the addition of aqueous saturated bicarbonate solution. After 15 min stirring at rt, the reaction mixture was diluted with EtOAc and water. The organic phase was separated and dried over MgSO4. The filtrate was absorbed onto a plug of silica gel and purified by chromatography through, eluting with a gradient of 5% to 45% EtOAc in hexane, to provide the title compound as colorless oil (1.22 g). LC/MS m/z=172.1 [M+H]+.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4](OC)(=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.O.Cl>CS(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([CH2:2][C:1]#[N:3])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: CC#N
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 60 °C
Yield: 79.7 %

Procedure:
To a solution of acetonitrile (15 g) in DMSO (25 mL) was added methyl p-anisate (25 g) and the mixture was stirred with heating at 60° C. for 1 hour. The reaction mixture was allowed to cool and cold water (100 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give 4-methoxybenzoylacetonitrile (21 g) as colorless crystals. To a solution of the obtained crystals in toluene was added hydrazine monohydrate (13 g) and the mixture was heated under reflux for 3 hours. The mixture was cooled and the precipitated crystals were collected by filtration to give 5-amino-3-(4-methoxyphenyl)pyrazole (22 g). Subsequently, the title compound was prepared from methyl butyrate, 2-chlorobenzaldehyde and 5-amino-3-(4-methoxyphenyl)pyrazole in the same manner as in Example 94.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:37])[O:28][C:29]=3[C:30]3[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:37])[O:28][C:29]=3[C:30]3[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid (2-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-yl)-amide (109 mg, 0.21 mmol) in dry THF (2.0 mL) was treated at 0° C. with TBAF (0.41 mL of a 1M solution in THF, 0.41 mmol). The reaction mixture was stirred at 0° C. for 45 min. The mixture was then diluted with EA (10 mL), washed with NaHCO3 (10 mL) followed by brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as a yellow oil. TLC:rf (19:1 CH2Cl2-MeOH)=0.23. LC-MS-conditions 02: tR=0.95 min; [M+H]+=409.78.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Cl)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39](B4OC(C)(C)C(C)(C)O4)[CH:38]=3)=[CH:34][CH:35]=2)[CH:30]=[N:29]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.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>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([C:33]4[CH:32]=[C:31]5[C:36](=[CH:35][CH:34]=4)[N:28]([CH3:27])[N:29]=[CH:30]5)[CH:42]=3)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(Cl)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cn1ncc2cc(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)ccc21
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 95 °C

Procedure:
The reaction mixture of (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (300 mg, 0.65 mmol), 1-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole (260 mg, 0.78 mmol), Pd(PPh3)4 (75 mg, 0.065 mmol), 2N K2CO3 (1.6 mL) in dioxane (5 mL) was heated at 95° C. for hours. After the reaction finished, the reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C33H36BrN3O3S: 634.2 (M+H+); Found: 634.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:17])[CH2:15][CH:14]2[NH:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1.[CH3:18][O:19][C:20]1[C:25]2[O:26][C@H:27]([CH2:30]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[C:25]2[O:26][C@@H:27]([CH2:30][N:16]3[CH:11]4[CH2:12][CH2:13][CH:14]3[CH2:15][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])([OH:17])[CH2:10]4)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccccc1C1(O)CC2CCC(C1)N2
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Product: COc1ccccc1C1(O)CC2CCC(C1)N2C[C@H]1COc2cccc(OC)c2O1
Yield: 70 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-(2-methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 70%, white solid.