Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.[I-:33].[Na+].I>CC(C)=O>[I:33][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccccc1-c1cc(I)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To N-(6-chloro-4-o-tolylpyridin-3-yl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (460 mg, 0.97 mmol, example 12) in acetone (3 mL) was added sodium iodide (1.17 g, 7.8 mmol) and hydriodic acid (170 μL, 1.07 mmol). The reaction mixture was heated to reflux for 4 hours. Acetone was evaporated and acetonitrile (3 mL) was added and the reaction mixture heated again to reflux. After 16 hours, the reaction mixture was carefully neutralized with saturated aqueous NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. Filtration and removal of volatiles under reduced pressure afforded a brown solid. The desired compound was isolated by flash chromatography on silica gel (50% EtOAc in n-hexane) as an amber oil (324 mg, 59%).
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])=[O:10])=[CH:7][CH:6]=1)(=O)C.Cl>O1CCCC1>[OH:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])=[O:10])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C(=O)Sc2cc(Cl)c(Cl)cc2Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Sc1cc(Cl)c(Cl)cc1Cl)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
S-(2,4,5-Trichlorophenyl) 4-(acetoxy)thiobenzoate (10 g) in tetrahydrofuran was treated with 25 ml of 5.6M hydrochloric acid and stirred at room temperature overnight. The solvents were evaporated in vacuo to give a product which was purified by column chromatography (silica; ethyl acetate-hexane mixtures as eluant) to afford the title compound (5.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=2[N:7]=1.[OH:22][CH:23]1[CH2:26][CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:24]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:22][CH:23]2[CH2:24][CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:26]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)nc(Cl)nc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(Oc2nc(Cl)nc3c2c(C#N)cn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (481 mg, 1.4 mmol) in THF (12 mL) was added a 1:1 cis:trans mixture of tert-butyl (3-hydroxycyclobutyl)carbamate (see Radchenko et al., Journal of Organic Chemistry, 75(17):5941-5952 (2010)) (288 mg, 1.54 mmol) and KHMDS (419 mg, 2.1 mmol). The reaction solution was stirred at rt for 1 hr. The reaction was quenched with brine (5 mL), then partitioned between EtOAc (120 mL) and water (30 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4 and evaporated to give a light yellow gum. The gum was purified using flash chromatography eluting with a gradient of 0%-40% EtOAc in heptanes. The product fractions were combined and evaporated to afford the title compound (508 mg, 73 yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1H) 7.27-7.52 (m, 1H) 5.63 (s, 2H) 5.04-5.60 (m, 1H) 3.73-4.32 (m, 1H) 3.53-3.69 (m, 2H) 2.88 (m, J=9.35, 6.91, 6.91, 3.02 Hz, 1H) 2.50-2.56 (m, 2H) 2.13-2.28 (m, 1H) 1.46 (d, J=4.78 Hz, 9H) 0.92 (t, J=8.06 Hz, 2H) 0.00 (d, J=1.51 Hz, 9H). m/z (APCI+) for C22H32ClN5O4Si 440.0 (M−tBu+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@:8]([CH3:22])([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.CC(C[AlH]CC(C)C)C.C(O)C.Cl>C1(C)C=CC=CC=1.C(O)C.O>[CH3:22][C@@:8]12[CH2:7][CH2:6][C:5]3[CH:4]=[C:3]([OH:2])[CH:20]=[CH:19][C:18]=3[C@H:17]1[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]2[CH2:10][CH2:11][C@@H:12]1[OH:21]
Reactant: COc1ccc2c(c1)CC[C@@]1(C)[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@H]21
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@@]12CCc3cc(O)ccc3[C@H]1CC[C@@]1(C)[C@H]2CC[C@@H]1O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 99.2 %

Procedure:
74 mg of 3-methoxy-8β-methyl-estra-1,3,5(10)-trien-17β-ol was dissolved in 3 ml of anhydrous toluene, cooled to 0° C. and mixed carefully under argon with 0.6 ml of DIBAH. The reaction mixture was slowly refluxed, and it was kept at this temperature for 3.5 hours. Then, it was cooled again to 0° C., the solution was mixed in succession with 2 ml of ethanol, 2 ml of ethanol-water mixture (v/v=1/1) and 2 ml of semi-concentrated hydrochloric acid and extracted several times with ethyl acetate. The collected organic phases were washed neutral with water, dried with magnesium sulfate and evaporated to the dry state in a vacuum. 70 mg (99%) of colorless crystals with a melting point of 168-170° C. was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.[C-:26]#[N:27].[Na+].C(=O)(O)[O-].[K+].O>CS(C)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:26]#[N:27]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCC#N
Yield: 97.6 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (5.00 g, 14.0 mmol), sodium cyanide (852 mg, 16.8 mmol), and potassium bicarbonate (1.70 g, 16.8 mmol) were combined and vigorously stirred in DMSO (50 mL) at 50° C. for 2 h, then overnight at 25° C. The mixture was then poured into H2O (50 mL) and extracted with Et2O (2×50ML). The organic layer were combined then washed with H2O (50 mL), sat. NaCl (50 mL), dried over NaCl. The solvent was removed in vacuo to provide 2.90 g (98%) of product as a white powder: 1H NMR (400 MHz, CDCl3) δ 7.93 (m, 2 H), 7.39 (m, 3 H), 2.81 (t, 2 H), 2.71 (t, 2 H), 2.35 (s, 3 H); MS (EI) 213.1 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH:7]([CH3:36])[C@H:8]([C:13](=[O:35])[NH:14][C@H:15]1[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:34])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][CH:7]([C@H:8]([C:13](=[O:35])[NH:14][C@H:15]1[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:34])[CH2:9][CH:10]([CH3:11])[CH3:12])[C:6]([OH:37])=[O:5]
Reactant: CC(C)C[C@@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O)C(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O)C(C)C(=O)O

Procedure:
Alternatively, the less polar stereoisomer of (3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo- [10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester prepared in Example 5D above (15 mg) was taken up in CH2Cl2 (2.4 mL) and TFA (0.6 mL) and the resulting mixture was stirred at room temperature for 4 hrs. The solvent was removed under reduced pressure at 35° C. Then ethyl acetate was added and the solution was washed with water (3×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Recrystallization from ethyl acetate/petroleum ether gave (3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid as a white solid (7 mg), MS: 456.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH2:21][C:22]#[CH:23])=[CH:18][C:17]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[N:16]1.ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:49])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH2:21][C:22]#[CH:23])=[CH:18][C:17]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:33])([F:31])[F:32])=[N:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCNc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: C#CCNc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 74.6 %

Procedure:
0.17 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-(2-propynylamino)-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 80 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.13 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-(2-propynylamino)-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])=[N+]=[N-].[H][H]>[Ni].O1CCOCC1.C(O)C>[NH2:1][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)(=[O:16])=[O:15])=[CH:12][CH:13]=1)=[O:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(=O)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Agent: [Ni]
Solvent: CCO
Solvent: C1COCCO1
Product: NCC(=O)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Yield: 55.8 %

Procedure:
A mixture of 12 g of 2-azido-4'-(m-chlorophenylsulfonyl)acetanilide and 8 ml of Raney nickel in 150 ml of p-dioxane and 50 ml of ethanol was hydrogenated in a Parr shaker with an initial pressure of 30 psi of hydrogen for 2 hours. The mixture was filtered through a celite pad and the volatiles removed from the filtrate. The residue was crystallized from p-dioxane, giving 6.2 g of the desired product, mp 195°-196° C.
Reaction SMILES: C[SiH](C)C1C=CC=CC=1[SiH](C)C.[CH3:13][N:14]([CH3:27])[C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:27][N:14]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1)[CH3:13]
Reactant: COC(=O)c1ccc(C(=O)N(C)C)cc1
Agent: C[SiH](C)c1ccccc1[SiH](C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CN(C)C)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 20-mL eggplant flask equipped with a three-way cock and a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with argon atmosphere. Into the flask, iron complex A (1.0 mg, 0.002 mmol) was admitted as catalyst and dissolved in toluene (0.5 mL). To the solution, 1,2-bis(dimethylsilyl)benzene (475 μL) was added through a syringe, and N,N-dimethyl-4-methoxycarbonylbenzamide (207 mg, 1.0 mmol) was added. The solution was stirred at 100° C. for 30 minutes. Toluene was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (10/1) as developing solvent, obtaining N,N-dimethyl-4-methoxycarbonylbenzylamine (162 mg, 0.84 mmol, 84%). The results are shown as Entry 3 in Table 5. The resulting amine was identified for geometry by 1H and 13C-NMR spectroscopy and IR spectroscopy.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](Cl)=[O:4].[N+:26]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][OH:32])([O-:28])=[O:27].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([O:32][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[N+:26]([O-:28])=[O:27])=[O:4]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1[N+](=O)[O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Perfluorooctanoyl chloride (21.6 g, 0.05 mol) was added slowly with stirring to a solution of 2-nitrobenzyl alcohol (7.65 g, 0.05 mol) and triethylamine (5.2 g, 0.05 mol) in 100 ml benzene. During the addition, the temperature was allowed to rise to 50° C. and the triethylamine hydrochloride began to precipitate. After the addition was complete, the reaction was stirred an additional 30 minutes. The reaction was filtered and the filtrate evaporated in vacuo to give an oil which crystallized on cooling in an ice bath (m.p. 34°-35° C.). Benzene washings of the material retained on the filter paper gave a second fraction of oil which crystallized on cooling. Total yield was 11.97 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]#[N:6]
Reactant: COc1ccc(C=NO)c(OC)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(C#N)c(OC)c1

Procedure:
2,4-Dimethoxybenzoic acid is reacted with hydroxylamine to form 2,4-dimethoxybenzaldoxime. 2,4-Dimethoxybenzaldoxime is reacted with diphosphorus pentoxide to form 2,4-dimethoxybenzonitrile. 2,4-Dimethoxybenzonitrile is reacted with boron trichloride to form 2,4-dihydroxybenzonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][O:17][C:18](=[O:21])[NH:19][NH2:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:20][NH:19][C:18]([O:17][CH3:16])=[O:21])[C:7]=2[CH:15]=1)#[N:2]
Reactant: COC(=O)NN
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: COC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
A similar procedure to Reference Example 5 was performed using 6-cyano-3,4-epoxy-3,4 dihydro-2,2-dimethyl-2H-1-benzopyran and methylcarbazate, and as a result, trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-methoxycarbonylhydrazino)-2H-1-benzopyran-3-ol was obtained, m.p. 174°-175° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: C([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([NH2:17])(=[O:16])=[O:15])=O)C1C=CC=CC=1.CO>[Pd].C(O)=O>[CH:9]([NH:11][CH2:12][CH2:13][S:14]([NH2:17])(=[O:16])=[O:15])=[O:8]
Reactant: NS(=O)(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: NS(=O)(=O)CCNC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
In a reaction flask, 10.3 g of 2-benzyloxyformamidoethylsulfonamide, 10% Pd/C (3.0 g) and 600 ml of methanol were added. The mixture was stirred at room temperature overnight under hydrogen atmosphere, added with 35 ml of formic acid, stirred for 30 min, filtered, and concentrated under a reduced pressure to obtain 5.6 g of oily product, yield 93%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([C@@H:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:38][CH2:39][N:40]([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])[CH:31]=3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[NH:61][S:62]([CH3:65])(=[O:64])=[O:63])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[Si:54]([O:53][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:61][S:62]([CH3:65])(=[O:63])=[O:64])[CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([C@@H:37]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH2:38][CH2:39][N:40]([CH:41]([CH3:43])[CH3:42])[CH:44]([CH3:46])[CH3:45])[CH:31]=2)=[CH:24][CH:25]=1)([C:57]([CH3:60])([CH3:58])[CH3:59])([CH3:56])[CH3:55]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Temperature: 90 °C

Procedure:
N-{2-(benzyloxy)-5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(3-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}propoxy)phenyl]ethyl}amino)ethyl]phenyl}methanesulfonamide (Preparation 9, 100 mg, 0.11 mmol) was dissolved in ethanol (10 ml) and ammonium formate (68 mg, 1.07 mmol) and 10% palladium hydroxide on carbon (20 mg) added. The stirred reaction was heated at 90° C. for 2 hours, cooled to room temperature and filtered through Arbocel™, the filtrate was collected and the solvent removed in vacuo to furnish the title compound as a yellow glass, 98 mg.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[CH:15]([NH:16][C:17](=[O:27])[CH2:18][S:19]([CH2:22][C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:20])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:29]([S:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1)[CH2:30][CH2:31][S:32](=[O:35])(=[O:34])[NH2:33])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(#N)C>[F:26][C:23]([F:24])([F:25])[CH2:22][S:19]([CH2:18][C:17]([NH:16][CH:15]1[C:14](=[O:28])[N:13]2[C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH:29]([S:36][C:37]3[NH:41][N:40]=[N:39][N:38]=3)[CH2:30][CH2:31][S:32](=[O:34])(=[O:35])[NH2:33])[CH2:10][S:11][C@H:12]12)=[O:27])(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 3 h

Procedure:
The ester is dissolved in acetonitrile and trifluoroacetic acid is added. The solution is stirred for three hours, then evaporated to dryness to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[CH2:10][C:9](=[O:11])[NH:8][C:5]3=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1Cc2cc(-c3cccc(F)c3)cnc2N1
Reaction time: 24 h
Yield: 150.6 %

Procedure:
A mixture of 4 (16.63 g, 78.5 mmol), 3-fluorophenylboronic acid (16.47 g, 117.7 mmol), Pd(PPh3)2Cl2 (2.73 g, 6.60 mmol), LiCl (9.95 g, 0.23 mol), 1.0 M aqueous Na2CO3 solution (196 mL, 0.196 mol) in EtOH (470 mL)—toluene (470 mL) was refluxed overnight. More Pd(PPh3)2Cl2 (1.30 g, 3.14 mmol) was added and reflux was continued for 24 h. The mixture was cooled, and the organic layer was separated and washed with brine (100 mL). The washings were combined with the aqueous layer and extracted with AcOEt (4×400 mL). Combined extracts were washed with brine, added to the organic layer and dried with MgSO4. The solution was concentrated to dryness in vacuum to give 26.98 g of brown semisolid, which was triturated with ether:hexane=1:1 (2×500 mL). The residue was dried in vacuum to afford 5 (16.85 g, 94%) as tan solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 2H), 7.08 (dddd, J=8.4, 8.2, 2.4, 0.9 Hz, 1H), 7.22 (ddd, J=10.0, 2.4, 1.7 Hz, 1H), 7.30 (ddd, J=8.1, 1.7, 0.9 Hz, 1H), 7.43 (ddd, J=8.2, 8.1, 6.0 Hz, 1H), 7.69 (s, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.98 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:12])([F:11])[F:10])=[N:6][C:7]=1I.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:12])([F:11])[F:10])=[N:6][C:7]=1[C:13]#[N:14]
Reactant: CN(C)C=O
Reactant: Nc1ccc(C(F)(F)F)nc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1nc(C(F)(F)F)ccc1N
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 86.31 %

Procedure:
12.5 g (0.434 mol, 1 eq) of 5-amino-6-iodo-2-(trifluoromethyl)pyridine was dissolved in 125 mL of dry DMF and degasified with nitrogen for 5 min. 6.1 g (0.519 mol, 1.2 eq) of zinc cyanide and 5 g (0.1 eq) of Pd(PPh3)4 were added and heated at 100° C. for over night. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The crude product obtained was purified by 60-120 silica gel using 15% of ethyl acetate in pet ether to get 7 g (86.31%) of pale yellow solid. 1H NMR (CDCl3, 400 MHz): 4.85 (2H, bs), 7.25 (1H, d), 7.62 (1H, d). MS 188 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[S:9]1[CH:13]=[CH:12][C:11]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10]1
Reactant: OB(O)c1ccsc1
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Oc1cccnc1-c1ccsc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
2-Bromopyridin-3-ol (100 mg, 0.58 mmol), 3-thiophenyl boronic acid (88 mg, 0.69 mmol), sodium carbonate (184 mg, 2.07 mmol) and Pd2(dppf)2Cl2 (94 mg, 0.12 mmol) were dissolved in dimethoxyethane/water of 1 mL/1 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2-(thiophene-3-yl)pyridin-3-ol (50 mg, 48%).