Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:8]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[C:7]1=[C:30]=[O:31])(=[O:4])=[O:3].CO.[H][H]>[Pd].O1CCCC1>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][NH:9][C@@H:8]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[C:7]1=[C:30]=[O:31])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O[C@H]1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H](N2CCNC2=O)C1=C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@H]1CN[C@@H](N2CCNC2=O)C1=C=O
Yield: 82.1 %

Procedure:
A mixture of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)-carbonylpyrrolidine (30 g), 10% palladium on carbon (10 g), methanol (300 ml) and tetrahydrofuran (150 ml) was stirred for 5 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(2-oxoimidazolidin-1-yl)-carbonylpyrrolidine (14.92 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](NCC(OC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC([O:30][CH2:31][CH:32](C)[CH3:33])=O.[BH4-].[Na+]>O1CCCC1C([O-])=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11](/[CH:33]=[CH:32]/[CH2:31][OH:30])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])C1CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-n2ccc(/C=C/CO)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.5 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[E-2-(carboxy)ethenyl]-1H-pyrazole-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carboxyamide (1.0 g, 1.93 mmol) in 20 mL of tetrahydrofuran at-20° C. was added triethylamine (0.27 mL, 1.93 mmol) and iso-butyl chloroformate (0.25 mL, 1.93 mmol). This mixture was stirred for 30 min and then there was added sodium borohydride (0.22 g, 5.78 mmol) in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h and then was quenched with 10% aq HCl. After diluting with ethyl acetate, the organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 0.5 g (52%) of the title compound as a white powder. LRMS (ES+): 504.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH2:10][C@H:9]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[NH:34][N:33]=[N:32][N:23]=3)[CH:17]=2)[CH2:10][C@H:9]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(C#N)c2)C[C@H]1C(=O)N1CCSC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(-c3nnn[nH]3)c2)C[C@H]1C(=O)N1CCSC1

Procedure:
To a solution of Example 30A (300 mg, 0.67 mmol) in anhydrous DMF (4 mL) was added sodium azide (522 mg, 8.04 mmol) followed by ammonium chloride (428.8 mg, 8.04 mmol). The mixture was flushed with nitrogen, then exposed to microwave irradiation (20 W, 175° C.) for 15 minutes. The mixture was concentrated under reduced pressure to afford a brown oil. The brown oil was purified by RP-HPLC to provide the titled compound. MS (ESI) m/e 488 (M+H)+, 486 (M−H)−; 1H NMR (300 MHz, CD3OD) δ ppm 1.39 (s, 6 H) 1.47 (s, 3 H) 1.68 (m, 1 H) 1.94 (m, 1 H) 2.59 (m, 2 H) 3.02 (m, 1 H) 3.14 (m, 1 H) 3.23 (m, 1 H) 3.48 (m, 2 H) 3.79 (m, 2 H) 4.56 (m, 2 H) 4.72 (m, 1 H) 7.55 (t, 1 H) 7.82 (d, 1 H) 8.18 (dd, 1 H) 8.44 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1C=O.[CH3:14][O:15][CH:16](OC)[O:17][CH3:18]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH3:14][O:15][CH:16]([O:17][CH3:18])[C:3]1[C:2]([F:1])=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:7][C:6]=1[F:13]
Reactant: O=Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(OC)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Yield: 143.4 %

Procedure:
A solution of 2,6-difluoro-3-nitro-benzaldehyde (9.0 g, 48.1 mmol), p-toluenesulfonic acid monohydrate (183 mg, 0.962 mmol), trimethylorthoformate (3.5 ml, 32.4 mmol) and methanol (200 ml) was heated at reflux for 4 hours. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The resultant residue was dissolved in DCM (250 mL) and washed with a mixture of water (200 mL) and saturated NaHCO3 solution (50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to yield the title compound (10.83 g, 97%). 1H NMR (DMSO-d6, 300 MHz): 8.28 (1 H, ddd, J=9.34, 8.48, 5.51 Hz), 7.39 (1 H, td, J=9.34, 1.81 Hz), 5.66 (1 H, s), 3.40 (6 H, s).
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[CH2:16][CH2:15][CH2:14][CH2:13]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CC#N
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCC1

Procedure:
A solution of 4-bromobenzenesulphonyl chloride (0.5 g) and pyrrolidine (0.284 g) in acetonitrile (5 ml) were stirred at RT for 48 h then partitioned between ethylacetate and water. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with isohexane and filtered, yield 0.5 g.
Reaction SMILES: [Na].[N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]=1[NH:11][C:12]([O:14][CH3:15])=[O:13].[CH2:16]([Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])Cl)[CH3:17]>CN(C)C=O>[CH2:16]([Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])[N:11]([C:3]1[NH:2][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:17]
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Reactant: CC[Si](Cl)(CC)CC
Agent: [Na]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)N(C(=O)OC)c1nc2ccccc2[nH]1
Reaction time: 12 h

Procedure:
5 parts of the resulting sodium salt of methyl benzimidazolecarbamate are suspended in 15 parts of dimethylformamide and 3.9 parts of triethylchlorosilane are added, in portions, at room temperature. After stirring the mixture for 12 hours under nitrogen, the solvent is distilled off under reduced pressure, tetrahydrofuran is added to the residue, and the solution is filtered. The solvent is then distilled off, giving 2.7 parts of methyl N-triethylsilyl-benzimidazole-2-carbamate; decomposition point >120° C. (active ingredient No. 1).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]1.[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1>O1CCCC1.CCOCC>[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]([CH2:6][N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]2)([OH:20])[CH2:15]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: Cc1ccnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccnn1CC1(O)CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of nBuLi (12.48 mL) in tetrahydrofuran (40 mL) was added a solution of 1,5-dimethyl-1H-pyrazole (3.0 g) in tetrahydrofuran (3 mL) dropwise. After stirring for 1 hour, a solution of 3,3-dimethylcyclohexanone (3.94 g) in tetrahydrofuran (3 mL) was added dropwise, and the reaction was allowed to warm to 0° C. After stirring for 1 hour, the reaction mixture was diluted with ether (100 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography, eluting with a gradient of 3% to 25% ethyl acetate in hexanes, gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[C:12]([NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=1)(=[O:14])[CH3:13]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[O:9][CH2:21][C:19]1[N:20]=[C:16]([NH:15][C:12](=[O:14])[CH3:13])[S:17][CH:18]=1
Reactant: Cc1cc(Br)c(O)cn1
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(COc2cnc(C)cc2Br)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 270 mg (1.44 mmol) 4-bromo-6-methyl-pyridin-3-ol (Stage 40.4) in DMF (5 mL), 44.8 mg NaH (1.87 mmol) was added and this mixture was stirred for 1 h at rt. 301 mg (1.58 mmol) 2-acetamido-4-(chloromethyl)-1,3-thiazole (Apollo OR15549) was added and stirring was continued at rt for another 17 h. The reaction mixture was poured on water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to leave 350 mg of the title compound (white solid) considered sufficiently pure without further purification. LCMS: tR=1.36 min, M+H=342 (79Br), 344 (81Br) (method J).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[C:34](=[O:37])[CH2:35][CH3:36])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCNCCN2CCN(c3ccccc3)CC2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N(CCc1ccc([N+](=O)[O-])cc1)CCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of [2-(4-nitro-phenyl)-ethyl]-[2-(4-phenyl-piperazin-1-yl)-ethyl]-amine 27a (0.375 g, 1.05 mmol), Et3N (0.267 g, 2.64 mmol) in 25 mL of dry CH2Cl2 under nitrogen at 0° C. was added a solution of propionyl chloride (0.137 g, 1.48 mmol). The temperature was allowed to rise to room temperature, the mixture stirred for 2 h, and then washed with water. The aqueous layer was extracted with dichloromethane. The combined organic phase was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography over silica gel (EtOAc/Hex=9/1) to give 28a as a colorless oil: 0.39 g (89% yield). 1H NMR (CDCl3, 400 MHz): δ 1.16 (3H, t, J=7.2, CH3), 2.38 (2H, q, J=7.2, CH2), 2.51 (2H, t, J=7.2 Hz, CH2Ar), 2.62 (4H, t, J=4.8, (CH2)2N), 2.99 (2H, t, J=7.2, CH2—CH2NCO), 3.15-3.20 (4H, m, (CH2)2NHPh, 3.32 (2H, t, J=7.2, CH2—CH2Ar), 3.58 (2H, t, J=7.2, CH2NCO), 6.83-6.93 (3H, m, ArH), 7.23-7.28 (2H, m, ArH), 7.34 (1H, d, J=8.0, ArH), 7.38 (1H, d, J=8.8, ArH, 8.15 (1H, d, J=8.8, ArH), 8.18 (1H, d, J=8.4, ArH).
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:8][CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(CCNC)cc1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
To a solution of 0.907 g (2.95 mmol) of ethyl 4-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate in 10 mL of DCM at 0° C. was added 2.0 mL (26 mmol) of trifluoroacetic acid (TFA). The reaction was warmed to 22° C., stirred for 3 h and the solvents were then evaporated. The residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1 N NaOH which had been saturated with NaCl. The aqueous layer was back-extracted with ethyl acetate (6×50 mL) and the combined organics were dried (Na2SO4) and evaporated to give 2c as a colorless oil.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:10][C@@H:9]([NH2:8])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](COc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)COc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Dissolve (R)-2-(tert-butoxycarbonylamino)-3-phenoxy-propane (340 mg, 1.35 mmol) in DCM (80 mL), add trifluoroacetic acid (35 mL), and stir at 0° C. for 2 h. Evaporate and purify by SCX chromatography to give the title compound as a colorless oil (186 mg, 91%). MS (ES+) m/z: 151 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]Cl.C(#N)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[C:19]([I:23])[C:18]([O:21][CH3:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClI
Reactant: COc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CC#N
Product: COc1cc2c(cc1I)C1CCN(C(=O)OC(C)(C)C)CC1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
To a solution of 7-methoxy-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (500 mg, 2 mmol) in methanol (7 mL, 200 mmol) was added dropwise a solution of iodine monochloride (340 mg, 2.1 mmol) in 5 ml of methanol at RT. The mixture was stirred overnight at RT. After 18 h, the solvent was removed and the crude reaction mixture was treated with 50 mL of acetonitrile, di-tert-butyl dicarbonate (0.5 mL) and 10 mg of DMAP (10 mg). The mixture was stirred overnight at RT. After 18 h, solvent was removed and the crude product was purified by ISCO chromatography (Hexane:EtOAc 70:30) which was obtained as a syrup (321 mg, 45%). MS m/z 454 [M+H]+
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.IC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][C:32]=2[CH:33]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:34][C:32]=2[C:33]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: O=C(O)c1ccc(I)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(I)cc1

Procedure:
6.12 g of 4-iodobenzoyl chloride—prepared by reacting 4-iodobenzoic acid with thionyl chloride—and 5.42 g of 2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml of dichloromethane. The reaction was performed according to Example 10.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30]Cl.C(=O)([O-])O.[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[N:3]=1
Reactant: ClCc1ccccn1
Reactant: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(SCc3ccccn3)c2C#N)cc1
Reaction time: 2 h

Procedure:
9.28 g (30 mmol) of N-[4-(2-amino-3,5-dicyano-6-sulphanyl-4-pyridinyl)phenyl]-acetamide, 7.38 g (45 mmol) of 2-picolyl chloride hydrochloride and 10.08 g (120 mmol) of sodium hydrogen carbonate are stirred at room temperature in 100 ml of DMF. After 2 hours, 100 ml of water are added dropwise at from 40 to 50° C.
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:14]([OH:23])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)CO>>[C:1]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:14]([OH:23])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCC(=O)OCCO
Solvent: CCCCCCCC(=O)O
Solvent: OCCO
Product: CCCCCCCC(=O)OCCOC(=O)CCCCCCC

Procedure:
Three fractions containing 68.6 to 97.8% of 2-hydroxyethyl caprylate were obtained by heating caprylic acid (1.25 mol; 180 g) with ethylene glycol (8.27 mol; 513.5 g) to boiling temperature for 5 hours and gradual distillation; the overall yield of 2-hydroxyethyl caprylate was 61.3%. In addition to 2-hydroxyethyl caprylate, ethylene dicaprylate was formed from 21% of caprylic acid. In a similar experiment, the reaction mixture after 7 hours of heating was first extracted with benzene and the benzene extract with water, instead of direct distillation. Caprylic acid was consumed in 60.6% for 2-hydroxyethyl caprylate, whereas ethylene dicaprylate resulted from 21.5% of acid; distillation gave fractions of raw product containing 97.6 to 98.5% of 2-hydroxyethyl caprylate. Further procedure was carried out according to example 1.
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:26])([CH3:27])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)[C:38](=[O:39])[CH2:37][C:33]2[S:32][CH:36]=[CH:35][CH:34]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Reactant: O=C(Cl)Cc1cccs1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)Cc2cccs2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure E using 6-[(4-dec-1-ynylbenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and thien-2-ylacetyl chloride. HPLC, Rt: 6.1 min (purity: 82.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[C:29]([F:39])=[CH:30][C:31]([F:38])=[C:32]([S:34](Cl)(=[O:36])=[O:35])[CH:33]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[S:34]([C:32]2[CH:33]=[C:28]([Cl:27])[C:29]([F:39])=[CH:30][C:31]=2[F:38])(=[O:36])=[O:35])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2ccnc(OCc3ccccc3)n2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccnc(OCc3ccccc3)n2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Yield: 61.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 86a by using the 2-(benzyloxy)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.50 g, 1.42 mmol) prepared in Example 153a, 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.36 g, 1.57 mmol), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 1.71 mL, 1.71 mmol) and THF (5.0 mL), to yield the title compound (487.8 mg, 61%) as a colorless solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)C)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:41]=[C:42]([CH:48]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:50]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:39][C:40]1[CH:41]=[C:42]([CH:48]=[C:49]([C:2]2[C:10]3[C:9]([NH:11][CH2:12][C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:50]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44]
Reactant: CN(C)C(=O)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc(CNc3ncnc4c3c(-c3cc(O)cc(C(=O)N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 46 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with 3-hydroxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (92 mg, 0.32 mmol), sodium carbonate (33 mg, 0.32 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (31 mg, 0.04 mmol) and 3 ml 1,2-dimethoxyethane and 0.75 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 44 mg (46% yield, 89% purity) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](OCCCC)=[CH2:12].ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[OH-].[Na+]>ClC1C=CC=CC=1.O>[CH3:1][N:2]([C:9]([CH:11]=[CH2:12])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=COCCCC
Reactant: CN(C=O)c1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Product: C=CC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of N-methylformanilide (30 g), butyl vinyl ether (22.2 g) in 25 ml of clorobenzene under stirring at 10° C., a solution of bis-trichloromethylcarbonate (24.3 g) in 50 ml of clorobenzene is added dropwise in 2 hours. The reaction mixture is kept under stirring at room temperature overnight. Water (50 ml) is added, the mixture is cooled at about 5–10° C. and the pH is corrected to about 7 by adding sodium hydroxide 30% aqueous solution (50 ml). After separation of the phases, the aqueous layer is extracted with chlorobenzene (50 ml) and the combined organic layers are washed with water (20 ml) and evaporated under reduced pressure. To the residue tert-butyl methyl ether (50 ml) is added and the mixture is cooled at −15° C. for 1 hour. The precipitate is filtered on Buchner, washed twice with tert-butyl methyl ether (25 ml×2) and dried at 30–35° C. under vacuum overnight. 24.66 g of pure compound are obtained (69% molar yield)