Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.ClC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]3=[C:17]([CH2:31][OH:32])[CH:16]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Agent: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(CO)c12
Yield: 55 %

Procedure:
At 0° C. to a solution of 3.00 g of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetra-hydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 50 ml of dry tetrahydrofurane were added 1.2 ml of Hünig's base, followed by slow addition of 0.7 ml of ethyl chlorformate. After 30 min at 0° C. the resulting suspension was filtered. Under argon atmosphere to the filtrate were added 290 mg of sodium borohydride and 15 ml of water. After 2 h at 0° C. sat. aqueous ammonium chloride solution was added. The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether. The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. 1.60 g (55%) of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:13]1[CH:12]=[C:11]([CH2:22][NH:23][CH3:24])[CH:10]=[C:9]1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:16])=[O:15]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccco2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1-(2-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (193 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 127 mg, 77%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:4]1.[CH2:16]([S:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1)[CH2:17][CH2:18][CH3:19]>CN(C=O)C>[CH2:16]([S:20][C:21]1[N:22]=[C:23]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:4]2)[CH:24]=[CH:25][N:26]=1)[CH2:17][CH2:18][CH3:19]
Reactant: NS(=O)(=O)c1c[nH]c2ccccc12
Reactant: CCCCSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSc1nccc(-n2cc(S(N)(=O)=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
NaH (147 mg, 3.67 mmol, 60% dispersion) was added to a solution of 1H-indole-3-sulfonic acid amide (600 mg, 3.06 mmol) in DMF (5 mL) at 0° C., and stirred for 15 min. 2-Butylsulfanyl-4-chloro-pyrimidine (682 mg, 3.36 mmol) was added, and washed down with additional DMF (2 mL). The reaction mixture was allowed to warm to RT, and stirred overnight under N2. The reaction mixture was then poured into water, extracted with hot EtOAc, washed with water, brine, and filtered. The mixture was concentrated to half volume, heated on a steam bath, and allowed to crystallize. The resulting white solid was filtered off, washed with DCM, and air-dried to provide 1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indole-3-sulfonic acid amide (868 mg, 71.4% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[Cl:13])(=[O:3])[CH3:2].[OH-].[K+].[F:16][C:17]([F:24])([F:23])[C:18]([F:22])=[C:19]([F:21])[F:20]>CN(C)C=O>[C:1]([NH:4][C:5]1[C:6]([Cl:13])=[CH:7][C:8]([O:12][C:19]([F:21])([F:20])[CH:18]([F:22])[C:17]([F:24])([F:23])[F:16])=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(Cl)cc(O)cc1Cl
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(Cl)cc(OC(F)(F)C(F)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 20 h

Procedure:
47 g of 4-acetylamino-3,5-dichlorophenol together with 154 g of 90% potassium hydroxide solution and 130 ml of dimethylformamide are stirred in an autoclave. 75.8 g of hexafluoropropylene are then pressed into the closed autoclave. The mixture is stirred for 20 hours at 70° C. under the pressure developing in the autoclave. After cooling, the mixture is concentrated by rotary evaporation and the residue is dissolved in methylene chloride. The resultant solution is washed with water, dried over Na2SO4 and concentrated. The crude product obtained as residue is chromatographed through a column of silica gel (length: 1 m; diameter: 10 cm) eluted with an 11:1 mixture of toluene and acetone, affording 4-acetylamino-3,5-dichloro-1-(1,1,2,3,3,3-hexafluoropropyloxy)benzene in the form of pale yellow crystals (m.p.: 113°-115° C.), 26 g of which are kept for 10 hours under reflux with 110 ml of ethanol and 35.6 ml of 37% hydrochloric acid. The reaction mixture is then concentrated, diluted with ice/water and made weakly alkaline. The product is extracted from the mixture with methylene chloride. The organic extract phase is washed with water, dried over Na2SO4 and concentrated. The residue is purified by distillation, thus affording the title compound of the formula ##STR12## as a colourless liquid with a boiling point of 91°-96° C./0.001 torr.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[K+].[N+:12]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-:27])=[O:26])[C:16]=1Cl)([O-:14])=[O:13].Cl>CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:16]2[C:17]([N+:25]([O-:27])=[O:26])=[CH:18][C:19]([C:21]([F:24])([F:22])[F:23])=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Nc1ncc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
In 20 ml. of dimethylformamide, 1.65 g. of 2-amino-3,5-dichloropyridine was dissolved and 1.0 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, 2.7 g. of 2,6-dinitro-4-trifluoromethylchlorobenzene was added at 30° C. during 5 minutes and the reaction was continued for about 3 hours. The reaction mixture was acidified with conc. HCl and the product was extracted with methylenechloride. The extracted layer was washed with water and dehydrated. The solvent was distilled off and the product was separated by a silica gel column with an eluent of toluene and the solvent was distilled off to obtain 2.8 g. of the object compound having the melting point of 85° to 87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[F:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)ccc1NC(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a mixture of methyl 2-amino-5-fluorobenzoate (alfa) (16.9 g, 100 mmol) and isobutyryl chloride (21.2 g, 200 mmol) in dry tetrahydrofuran was added triethylamine (40.4 g, 400 mmol) at 0° C., then the mixture was stirred at room temperature overnight. After removal of the solvent under reduced pressure, the mixture was suspended in water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was recrystallized from ethyl acetate/petroleum ether (5:1, 150 mL) to give the title compound as white solid (12.3 g, 51.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1Cl
Temperature: 105 °C

Procedure:
57 g (363.96 mmol) of 2-chloro-5-methylanisole is dissolved in 800 ml of carbon tetrachloride and mixed at room temperature with 69.9 g (393.08 mmol) of N-bromosuccinimide. After 174.6 mg of benzoyl peroxide is added, it is refluxed for five hours (bath temperature 105° C.). The reaction mixture is suctioned off via a glass fiber filter, rewashed, and the solution is spun in in a rotary evaporator. 83.6 g (97.5%) of the desired product (contains traces of starting material and dibromide), which is incorporated in crude form into the next stage, is obtained.
Reaction SMILES: [F:1][C:2]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:63]([CH2:65][C:66](O)=[O:67])#[N:64]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:66](=[O:67])[CH2:65][C:63]#[N:64])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1)nn2[C@@H]1CCCNC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.1 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-[4-(2,3-difluorophenoxy)-phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.71 mmol, 1.00 equiv) in dichloromethane (30 mL), HATU (400 mg, 1.05 mmol, 1.5 equiv), triethylamine (220 mg, 2.17 mmol, 3.0 equiv), and 2-cyanoacetic acid (90 mg, 1.06 mmol, 1.5 equiv). The resulting solution was stirred for 10 h at 25° C. and then washed with water and brine. The organics were dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (10/1) gave 240 mg (69%) of 3-[(3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14](OCC)=[O:15])=[CH:10][CH:9]=2)[O:5][C:4](=[O:21])[C:3]=1[S:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH4-].[Li+]>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:19][CH:20]=2)[O:5][C:4](=[O:21])[C:3]=1[S:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCO)cc2)cc(O)c1SCCc1ccccc1
Reaction time: 8 h

Procedure:
To a tetrahydrofuran (7 mL) solution of [4-[4-hydroxy-2-oxo-3[(2-phenylethyl)thio]-2H-pyran-6-yl]-phenoxy]acetic acid, ethyl ester (0.30 g, 0.70 mmol) was added 2.0M lithium borohydride (0.5 mL, 1.00 mmol). The reaction was stirred overnight. The reaction was then quenched by addition of 1N hydrochloric acid (2.0 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated and washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 50% ethyl acetate/hexanes to 100% ethyl acetate as the eluent. m.p. 123-125° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2H), 2.97 (t, 2H), 3.37 (m, 2H), 4.07 (t, 2H), 4.92 (bs, 1H), 6.68 (s, 1H), 7.09 (d,2H), 7.19 (m, 5H), 7.75 (d, 2H).
Reaction SMILES: C1(C=[N:8][CH:9]2[C:17]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:26])[CH2:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)C=CC=CC=1.O.NN>C(O)C>[NH2:8][CH:9]1[C:17]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=C1Nc2ccccc2C12Cc1ccccc1C2N=Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC1c2ccccc2CC12C(=O)Nc1ccccc12
Temperature: 25 °C

Procedure:
To a slurry consisting of 1,3-dihydro-1-[(phenylmethylene)amino]-spiro[2H-indene-2,3'-[3H]indole]-2'(1'H)one (13.8 g), and absolute ethanol (300 ml) was added hydrazine hydrate (13.9 ml). The resulting mixture was heated at reflux for 3 hours, cooled to room temperature and the resulting precipitate removed by filtration. The mother liquor was concentrated and the resulting oil solidified upon addition of ethyl acetate-hexane. The resulting solid was recovered by filtration. Additional product was obtained from the mother liquor as above. Recrystallization from ethyl acetate afforded 1-amino-1,3-dihydrospiro[2H-indene-2,3'-[3H]-indol]-2'(1'H)one, m.p. 195°-197° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH:8]([C:26](C)(C)[O:27][SiH2]C(C)(C)C)[CH2:9][O:10][C:11]1[C:18]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([O:24][CH3:25])[CH:12]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:6][CH2:7][CH:8]([CH2:26][OH:27])[CH2:9][O:10][C:11]1[C:18]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([O:24][CH3:25])[CH:12]=1
Reactant: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)C(C)(C)O[SiH2]C(C)(C)C)c(-c2cccs2)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
Ex-50C: To a solution of 4-[3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-50B, 0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol) and the mixture was stirred at rt for 30 min. The reaction was diluted with ethyl acetate (50 mL) and washed with a 50% ammonium chloride solution (1×30 mL), water (2×30 mL), brine (1×30 mL), dried over sodium sulfate and concentrated to a crude yellow solid. Silica gel chromatography afforded 0.37 g (99%) of the expected 4-(3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde as a pale yellow solid, 90% yield, mp 144–145° C. 1H-NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 8.10 (s, 1H), 7.38 (dd, 1H, J=3.6, 1.5 Hz), 7.30 (dd, 1H, J=5.1, 1.5 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.59 (s, 1H), 4.35 (d, 2H, J=6.0 Hz), 4.02 (t, 4H, J=4.8 Hz), 3.96 (s, 3H), 2.33 (pentet, 1H, J=6.0 Hz), 1.89 (t, 2H, J=4.8 Hz). MS (ESI) m/z=323 ([M+H]+, 100%). Anal. Calcd. for C16H18O5S: C, 59.61; H, 5.63; S, 9.95. Found: C, 59.34; H, 5.75; S, 9.82.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[F:15].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl.O>[CH2:25]([O:24][C:22]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[F:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
(3R,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (300 mg, 1.374 mmol) was taken up in DCM (8 mL) and a solution of sodium bicarbonate (346 mg, 4.12 mmol) in water (1 mL) was added. The reaction mixture was cooled to 0° C. and benzyl chloroformate (0.235 mL, 1.649 mmol) was added dropwise. The reaction was stirred at 0° C. for 30 min, then brought to room temperature and stirred overnight. The reaction mixture was diluted with DCM and water, and the organic layer was collected. The aqueous layer was re-extracted with DCM and the organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography, eluting with 0-30% EtOAc/Hex. The fractions were combined and concentrated to give (3R,4S)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-fluoropiperidine-1-carboxylate (450 mg) as a colorless glass.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.C(C1C=C[C:33](C)=[N:34]C=1)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>[C:33]([C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1)#[N:34]
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Reactant: CCc1ccc(C)nc1
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: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1C#N
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 94 %

Procedure:
2.0 g (4.2 mmol) of 3-(4-bromo-5-ethylsulfonylamino-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione, 0.3 g of zinc cyanide and 0.5 g of tetrakis(triphenylphosphine)palladium were added to 10 g of 5-ethyl-2-picoline and the mixture was stirred at 80° C. under an argon atmosphere for 3.5 hours. After the reaction was completed, 94% of the title compound was detected as the relative area value in liquid chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCCC1
Yield: 27.4 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and piperidine (0.38 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 1-[(4-bromophenyl)sulfonyl]piperidine (0.13 g) was provided after purification. HRMS: calcd for C11H14BrNO2S+H+, 304.00014; found (ESI, [M+H]+), 304.0009. HPLC purity 99.2% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.BrC[CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42]CC)=O>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=5)=[C:18]4[O:42][CH2:40][CH2:39][CH2:38][CH2:37][CH3:36])=[CH:13][C:12]=3[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C=CCOC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Reactant: CCOC(=O)CCCCCBr
Product: C=CCOC(=O)c1ccc(-c2ccc3cc(C(=O)OCC)c(C45CC6CC(CC(C6)C4)C5)cc3c2OCCCCC)cc1
Yield: 108.9 %

Procedure:
Following the procedure of Example 12(a), but reacting 3 g (6.8 mmol) of allyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 2.3 g (10.2 mmol) of ethyl 6-bromohexanoate, 2.15 g (55%) of the expected compound were obtained, which compound had a melting point of 116°-7° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH2:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[N:28]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH2:26][CH3:27])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: CCNCCN(C)C
Product: CCN(CCN(C)C)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with N′-ethyl-N,N-dimethyl-ethane-1,2-diamine gives “A91”; method 1: HPLC/MS: 1.08 min, [M+H]=433;
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.S(Cl)(Cl)=O.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:1][C:2]1[S:3][C:4]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:5]([CH3:7])[N:6]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1csc(Cl)n1
Solvent: O=S(Cl)Cl
Product: Cc1nc(Cl)sc1S(=O)(=O)Cl
Temperature: 120 °C
Reaction time: 48 h
Yield: 42.7 %

Procedure:
2-Chloro-4-methyl-thiazole (33 g, 180 mmol) was added dropwise to a solution of thionyl chloride (32.7 mL, 451 mmol) and chlorosulfonic acid (60.2 mL, 902 mmol). The reaction mixture was stirred for 48 h at 120° C., cooled then poured onto ice-water and extracted 3 times with CH2Cl2, dried over Na2SO4, filtered, and concentrated to give a crude liquid. The product was isolated by simple distillation (17 mbar at 85-95° C.) to give 2-Chloro-4-methyl-thiazole-5-sulfonyl chloride (17.85 g, 43%) as a light-yellow liquid. MS (ISP) 233.0[(M+H)+].
Reaction SMILES: [C:1]([NH:4][C@@:5]1([C:26]([NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:9][C@@H:8]([CH2:10][N+:11]([O-])=O)[CH2:7][C@@H:6]1[CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)(=[O:3])[CH3:2].C(OCC)(=O)C.C(O)C>O1CCCC1.[Ni]>[C:1]([NH:4][C@@:5]1([C:26]([NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:9][C@@H:8]([CH2:10][NH2:11])[CH2:7][C@@H:6]1[CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:24])([CH3:25])[O:18]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)C[C@@H](C[N+](=O)[O-])C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)C[C@@H](CN)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
To a stirring solution of (1S,2S,4S)-1-acetamido-N-(tert-butyl)-4-(nitromethyl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)cyclopentanecarboxamide (0.907 g, 2.0 mmol) in a mixture of tetrahydrofuran (20 mL), ethyl acetate (15 mL), and ethanol (5 mL) under nitrogen was added Raney nickel (1.2 g). The reaction mixture was then purged with hydrogen and stirred under an atmosphere of hydrogen at room temperature for 6 h. At the end of this period, the mixture was purged with nitrogen, then carefully through Celite®. After rinsing the filter cake with ethyl acetate the combined filtrate was concentrated in vacuo to afford the subject compound (0.841 g, 99%) as a white solid. NMR (CDCl3): δ 6.98 (br s, 1 H), 6.93 (br s, 1 H), 2.55-2.70 (m, 3 H), 2.44 (m, 1 H), 2.24 (m, 1 H), 1.91 (m, 3 H), 1.50-1.65 (m, 3 H), 1.20-1.45 (m, 4 H), 1.26 (s, 9 H), 1.66 (s, 12 H), 0.60-0.75 (m, 2 H). MS (M+1): 424.4.