Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:25]1([NH2:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CCOC(C)=O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:31][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NN1CCOCC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NN1CCOCC1
Temperature: -60 °C
Yield: 32.6 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.250 g), morpholin-4-amine (0.072 g, 1.0 eq.) and EtOAc (10 mL). The solution was cooled to −60° C. and treated with T3P (50% in EtOAc; 0.63 mL, 1.5 eq.) and DIPEA (0.24 mL, 2.0 eq.) under a nitrogen atmosphere. The progress of the reaction was followed by TLC analysis using 10% MeOH:CH2Cl2 as mobile phase and visualization under UV light. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc (3×15 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.35 g of a crude solid. Purification (Combi-flash, elution with 3% MeOH:CH2Cl2) afforded 100 mg (yield: 33%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-morpholinoacrylamide. 1H NMR (400 MHz, DMSO-d6) δ=9.52 (s, NH exchange, 1H), 8.51 (s, 2H), 8.28 (s, 1H), 7.38-7.42 (m, 1H), 6.50-6.53 (d, J=10.4 Hz, 1H), 5.84-5.86 (d, J=10.4 Hz, 1H), 3.63 (s, 4H), 2.87 (s, 4H); LCMS for C17H16F6N5O2 [M+H]+ 436.33; found 436.18 (RT 2.64 min, purity: 100%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[C:17]([Cl:38])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:31]([N:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:16][C:17]=1[Cl:38])[C:23](=[O:30])[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CN(Cc2ccccc2)C(=O)Cc2cccs2)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NS(=O)(=O)c1ccccc1-c1ccc(CN(Cc2ccccc2)C(=O)Cc2cccs2)c(Cl)c1
Yield: 127516.5 %

Procedure:
510 mg of 4′-{[benzyl-(2-thiophen-2-ylacetyl)amino]methyl}-3′-chloro-biphenyl-2-sulfonic acid t-butylamide and 110 μl of anisole are allowed to stand at RT for 18 h in 3 ml of trifluoroacetic acid. The volatile constituents are then removed in vacuo, the residue is taken up in 5 ml of toluene and volatile constituents are again removed in vacuo. 586 g of a colorless oil are obtained, which is used further without purification.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.C[N:19]1CCO[CH2:21][CH2:20]1.C(Cl)(=O)OCC.C(N)C>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([NH:19][CH2:20][CH3:21])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
25 g of Boc-D-Leu-OH.H2O was dissolved in 200 ml of THF. The solution was cooled to -20° C. 11 ml of N-methylmorpholine and 9.56 ml of ethyl chlorocarbonate were added to the solution. After 5 min, 12.9 g of a 70% aqueous ethylamine solution was added thereto and the mixture was stirred at about -5° C. for 2 h. After concentration, the residue was dissolved in ethyl acetate and washed with an aqueous NaHCO3 solution and water successively. After concentration to dryness, 24.5 g of Boc-D-Leu-NHC2H5 was obtained.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[F-].[K+].[F:21][C:22]1[N:27]=[C:26]2[O:28][C:29]3[C:34]([C@@:35]4([CH2:39][O:38][C:37]([NH2:40])=[N:36]4)[C:25]2=[CH:24][C:23]=1I)=[CH:33][C:32]([C:41]1[C:42]([F:47])=[N:43][CH:44]=[CH:45][CH:46]=1)=[CH:31][CH:30]=3.C[Si](C)(C)[C:51]#[C:52][C:53]1([CH3:57])[CH2:56][O:55][CH2:54]1>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.[Cu]I.CN(C=O)C>[F:21][C:22]1[N:27]=[C:26]2[O:28][C:29]3[C:34]([C@@:35]4([CH2:39][O:38][C:37]([NH2:40])=[N:36]4)[C:25]2=[CH:24][C:23]=1[C:51]#[C:52][C:53]1([CH3:57])[CH2:56][O:55][CH2:54]1)=[CH:33][C:32]([C:41]1[C:42]([F:47])=[N:43][CH:44]=[CH:45][CH:46]=1)=[CH:31][CH:30]=3
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1nc(F)c(I)cc12
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: CC1(C#Cc2cc3c(nc2F)Oc2ccc(-c4cccnc4F)cc2[C@@]32COC(N)=N2)COC1
Temperature: 100 °C
Yield: 66.5 %

Procedure:
A vial charged with Pd(Ph3P)4 (0.035 g, 0.030 mmol), copper(I) iodide (5.80 mg, 0.030 mmol), 18-crown-6 (0.12 g, 0.46 mmol), potassium fluoride (0.035 g, 0.61 mmol), (S)-2-fluoro-7-(2-fluoropyridin-3-yl)-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.15 g, 0.31 mmol, prepared as described in Method BB34), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.077 g, 0.46 mmol) was treated with 1.5 mL DMF, capped under argon, and was heated to 100° C. for 2 h. The reaction mixture was purified directly by column chromatography [0-100% (95:5 EtOAc/MeOH)/hexanes] yielding (S)-2-fluoro-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.095 g, 0.206 mmol, 67.7% yield). MS m/z=461.0 [M+H]+. Calculated for C25H18F2N4O3: 460.43.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]([CH3:19])[CH2:16][CH:17]=[CH2:18])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6])C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:19][CH:15]1[CH2:16][CH:17]=[CH:18][CH2:1][N:4]([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)(=[O:6])=[O:7])[CH2:14]1
Reactant: C=CCC(C)CN(CC=C)S(=O)(=O)c1ccccn1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC1CC=CCN(S(=O)(=O)c2ccccn2)C1
Yield: 82.9 %

Procedure:
Pyridine-2-sulfonic acid allyl-(2-methyl-pent-4enyl)-amide (1.2 g, 4.3 mmol) was diluted in CH2Cl2 (100 ml). After carefully degass by Ar, Grubbs catalyst (0.35 g, 0.43 mmol) was added under Ar protection. The mixture was then refluxed for 2 h before the reaction mixture was concentrated by rotary evaporation. The product was purified by column chromatography (5%–20% EtOAc/hexanes) to give the title compound (0.9 g, 83% yield): MS (M+H+):253.2; 1H-NMR (400 Hz, CDCl3): d=8.70(d, 1H), 8.0–7.75(m, 2H), 7.5(m, 1H) 5.79–5.60(m, 2H), 4.00(d, 2H), 3.65(dd, 1H), 3.22(dd, 1H), 2.30–2.05(m, 3H), 0.96(d, 3H)
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([N+:38]([O-])=O)[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:33]=[CH:32][C:17]([CH2:18][N:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>O.CCO.CO.[Fe]>[NH2:38][C:36]1[CH:35]=[CH:34][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:33]=[CH:32][C:17]([CH2:18][N:19]5[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]5)=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cc2)CC1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
Compound 453 (5.4 g, 9.56 mmol), iron powder (1.602 g, 28.69 mmol) and NH4Cl (0.78 g, 14.34 mmol) were placed in a mixture of H2O (24mL) and EtOH (48 mL). The reaction mixture was heated to reflux for 5 h. It was then cooled to RT, diluted with MeOH and filtered through a pad of celite. The filtrate was concentrated to dryness and the residue was dissolved in dichloromethane, washed with aqueous NaHCO3 and brine, dried over Na2SO4, and filtered. The filtrate was concentrated to dryness to give compound 454 as white solid (4.2 g, 83% yield). LCMS: 535 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[C:9]([CH2:14][OH:15])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:3]([C:8]1[C:9]([CH:14]=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(OC)c1cccnc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCC(CC)(OC)c1cccnc1C=O
Reaction time: 16 h
Yield: 78.9 %

Procedure:
Activated MnO2 (0.458 g, 5.26 mmol) was added to a stirred solution of [3-(1-ethyl-1-methoxy-propyl)-pyridin-2-yl]-methanol (0.110 g, 0.526 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 16 h, and then filtered through a celite cake. The filtrate was concentrated by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2), affording 3-(1-ethyl-1-methoxy-propyl)-pyridine-2-carbaldehyde as yellow oil (0.086 g, 46%). 1H NMR (CDCl3) δ 0.71 (t, 6H, J=7.5 Hz), 1.83-2.09 (m, 4H) 3.16 (s, 3H), 7.37 (dd, 1H, J=7.7, 4.8 Hz), 7.62 (dd, 1H, J=7.8, 1.5 Hz), 8.65 (dd, 1H, J=4.8, 1.5 Hz), 10.57 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[C:21]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:30]1([N:26]2[CH2:27][CH2:28][CH2:29][N:23]([C:21]([C@@H:9]3[CH2:10][C@H:11]([O:13][C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[CH2:12][NH:8]3)=[O:22])[CH2:24][CH2:25]2)[CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H]1C[C@H](Oc2ccc(F)cc2)CN1)N1CCCN(C2CCC2)CC1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (2S,4S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(4-fluoro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (969 mg, 2.09 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (2 mL). After 1 h, the mixture was concentrated and the residue purified by FCC to give the desired product (665 mg, 88%). MS (ESI): mass calcd. for C20H28FN3O2, 361.22; m/z found, 362.5 [M+H]+. 1H NMR (CDCl3): 6.95-6.90 (m, 2H), 6.78 (dd, J=9.0, 4.3 Hz, 2H), 4.79-4.74 (m, 1H), 3.88 (ddd, J=9.1, 6.3, 6.3 Hz, 1H), 3.81-3.69 (m, 1H), 3.58-3.47 (m, 2H), 3.47-3.37 (m, 2H), 3.08-2.76 (m, 3H), 2.59-2.28 (m, 5H), 2.00 (dd, J=16.1, 7.7 Hz, 2H), 1.95-1.72 (m, 5H), 1.69-1.53 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].[CH:15]([NH:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([N:18]([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])=[O:5]
Reactant: CC(C)NC(C)C
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(C)C
Yield: 56.1 %

Procedure:
The compound of Example b (2.47 g, 10 mmol), diisopropyl amine (2.23 g, 22 mmol), and toluene (25 mL) were combined according to General Method E2. The crude product was recrystallized from ethanol/water to afford 1.75 g of the title compound as a white solid, a 58% yield. m.p. 96°-97.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:15]([O:19][C:20](=[O:31])[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:15]([O:19][C:20](=[O:31])[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:26][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
Entire reaction was performed under dry air using syringe septa technique. 4 Å molecular sievies were added to a stirred solution of 3-chloro-4-(trifluoromethyl)phenylboronic acid (0.021 mol, 2 eq) and [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert butyl ester (0.011 mol, 1 eq) in dry DCM (105 ml) at ambient temperature in a flame dried flask flushed with dry air. The reaction was stirred for 15 min. After that, copper (II) acetate (0.011 mol, 1.01 eq), triethylamine (0.053 mol, 5 eq) and pyridine (0.053 mol, 5 eq) were added in succession and the reaction was stirred for 50 hours. The reaction mixture was sequential washed with 0.5 M HCl (4×250 ml), water (3×150 ml) and brine (1×150 ml). Organic layers were combined, dried over Na2SO4/MgSO4, filtered and evaporated. Crude product was purified on Biotage SP1 Snap Si 100; 40 ml/min in the gradient of EtOAc in cyclohexan: 0-30% in 25 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product {2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.703 mmol, yield=34%, purity=89%). [M+H]+=360.22 1H NMR (300 MHz, CDCl3) δ/ppm 1.42 (s, 9H), 2.75-2.84 (m, 2H), 3.31-3.43 (m, 2H), 4.55 (br. s., 1H), 6.84-6.90 (m, 1H), 6.94-7.01 (m, 2H), 7.02-7.06 (m, 1H), 7.18-7.23 (m, 3H), 7.55-7.61 (m, 1H)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N+:7]([O-:34])[CH:8]=[CH:9][C:10]=1[C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][C@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccncc1OCOC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc[n+]([O-])cc1OCOC
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a dichloromethane solution (0.1 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(3-{[(methyloxy)methyl]oxy}-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added 3-chloroperoxybenzoic acid (1 eq.). The resulting colorless solution was stirred at RT for 13 h. The reaction was then quenched with sat. aq. NaHSO3 and 1 N aq. NaOH. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15](C3C=CC=CC=3Cl)=[O:16])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC([C:55]1[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=1)=O>>[C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:29])([F:30])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=3)=[O:16])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3Cl)nc2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccc(Cl)cc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 2-[5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl]-1-(2-chloro-phenyl)-ethanone (example 47), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(4-chlorophenyl)ethanone and isolated as light yellow solid. MS (m/e): 435.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc2ccccc2n1
Product: FCc1cccc(C#CCCn2cc3ccccc3n2)n1
Yield: 16.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (204 mg, 1.07 mmol) and 2-but-3-ynyl-2H-indazole (183 mg, 1.07 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 50 mg (0.18 mmol, 17%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C@@H:10]1[O:41][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:12][C@H:11]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C@@H:10]1[OH:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C)OCC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A solution of diethyl (((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (3.3 g, 4.72 mmol, 1.0 equiv) in DCM (50 mL) was cooled to 0° C., and a mixture of trifluoroacetic acid and water (3.3 mL/0.33 mL) was added. The reaction mixture was then stirred at room temperature for 16 hours. The mixture was then sequentially washed with saturated aqueous sodium bicarbonate solution (120 mL) and water (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product thus obtained was purified by silica gel chromatography, eluting with 70% EtOAc in petroleum ether to give diethyl (((2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxytetrahydro-2H-pyran-2-yl)methyl)phosphonate as a white solid (2.1 g, 76%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 15H), 4.66-4.56 (m, 3H), 4.52 (s, 2H), 4.41-4.31 (m, 2H), 4.18-4.00 (m, 4H), 3.87-3.70 (m, 4H), 3.67 (td, J=4.1, 1.5 Hz, 1H), 2.24-2.17 (m, 1H), 2.14 (d, J=6.9 Hz, 1H), 1.82-1.67 (m, 2H), 1.34-1.28 (m, 6H). MS (ESI positive ion) m/z: 585.0 (M+1); calc for C32H41O8P 584.3.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[CH:20]1[C:30]2[CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[CH2:26][NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[CH:20]1[C:30]2[CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[CH2:26][N:25]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.7 %

Procedure:
To a solution of 0.27 g (1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 2 ml of tetrahydrofuran is added 0.20 g (1 mmol) of 6,11-dihydro-5H-dibenz[b,e]azepine and 0.20 g of triethylamine. The mixture is stirred at room temperature for 3 hours and the solvent removed under vacuum. To the residue is added 1N HCl and the mixture extracted with ethyl acetate (20 ml) and the extract washed with saturated NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated. The residue is triturated with ether-hexane and filtered to give 0.47 g of a white solid: Mass Spectrum; EI 433 (M+1); EI-high resolution 432.1842.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[C:11]([OH:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[OH:14])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=O)=[CH:24][CH:23]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[O:14][C:7]3[CH:8]=[C:9]([OH:13])[CH:10]=[C:11]([OH:12])[C:6]=3[C:4](=[O:5])[C:3]=2[O:2][CH3:1])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COCC(=O)c1c(O)cc(O)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COc1c(-c2ccc(F)cc2)oc2cc(O)cc(O)c2c1=O
Temperature: 25 °C
Yield: 81.9 %

Procedure:
Under nitrogen atmosphere, 2-methoxy-1-(2,4,6-trihydroxyphenyl)ethanone (60 mg, 303.03 mmol), anhydrous potassium carbonate powder (250.9 g, 1.82 mmol), TBAB (tetrabutyl ammonium bromide, 145.9 mg, 454.52 mmol) and 4-fluorobenzoyl chloride (95.8 mg, 606 mmol) were dissolved in toluene (1200 mL), and refluxed for 6 hours. After cooling, toluene was removed, and then water (500 mL) was added. The aqueous solution was extracted with dichloromethane. The combined organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. A brown residue was obtained after removal of solvent. The residue was dissolved in a 5% potassium carbonate aqueous solution and heated to reflux for 2 hr. After cooling to ambient temperature, the mixture was acidified to pH 6 with 1N HCl solution, and extracted with dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate, and the solvent was removed. The crude product was purified by silica gel column chromatography (eluent:ethyl acetate/petroleum ether, 1:5) and recrystallized in ethanol to give the desired compound (75 g, yield 81.9%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[S:3])[NH2:2].[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](=O)[CH2:23]Br)=[CH:20][CH:19]=1)[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=3)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3][CH:23]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOC(=O)c1cccc(C(N)=S)c1
Reactant: CCOc1ccc(C(=O)CBr)cc1
Product: CCOC(=O)c1cccc(-c2nc(-c3ccc(OCC)cc3)cs2)c1
Yield: 59 %

Procedure:
In the same manner as in Example 74, ethyl 3-thiocarbamoylbenzoate was reacted with 4-ethoxyphenacyl bromide to obtain ethyl 3-[4-(4-ethoxyphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 59%. Pale yellow prisms. Melting point: 108 to 110° C.