Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>CCN(CC)CC.C1COCC1>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCNc1nc(N)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNc1nc(Cl)cc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the pyrimidine 18-2 (3.76 g, 21.8 mmol), pivaloyl chloride (10.7 mL, 87 mmol), Et3N (15.2 mL, 109 mmol) and THF (80 mL) were stirred at room temperature for 24 hours. A further 3 mL of pivaloyl chloride and 4 mL of Et3N was added and the mixture stirred for another 24 hours. The solution was poured into saturated Na2CO3, extracted with EtOAc (2×), washed with brine, dried (MgSO4) and filtered through a pad of silica gel. Removal of the solvent afforded an orange solid. Trituration with ether/hexane ˜20:1 and filtration provided the title compound 18-4 as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([N:20]1[CH2:23][CH:22]([OH:24])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([O:24][CH:22]1[CH2:23][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (2.57 mL, 33.3 mmol) and triethylamine (11.6 mL, 83.1 mmol) were added to a solution of commercially available N—BOC-3-hydroxy azetidine (4.8 g, 27.7 mmol) in tetrahydrofuran (100 mL) under nitrogen atmosphere at room temperature. The reaction liquid was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid at room temperature, and the mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to quantitatively obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)C1C=CC=CC=1.[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[K]>C1(C)C=CC=CC=1>[CH2:17]([O:24][C:25]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1CCNCC1
Agent: [K]
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 91 %

Procedure:
22.2 g(0.2 mol) of 4-aminomethyl-piperidine was dissolved in 250 ml of toluene and then 21.2 g(0.2 mol) of benzaldehyde was added thereto. The mixture was refluxed for 3 hours with Dean-stack and cooled down to 0° C., and then 34.2 g(0.2 mol) of benzylchloroformate was added thereto while stirring. After the mixture was stirred for 3 hours, 1N aqueous potassium hydrosulfate solution(220 ml) was added thereto at room temperature. The mixture was extracted three times with 200 ml of diethylether, and then the aqueous layer was basified with sodium hydroxide. The aqueous solution was saturated with sodium chloride and extracted three times with 100 ml of dichloromethane. The organic solution was dried over magnesium sulfate and distilled under reduced pressure to obtain 38 g(Yield 91%, Molecular weight 248) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5].[Cl-].[NH4+].CO.[H][H]>C1(C)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[C:18]([NH2:19])=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5]
Reactant: [H][H]
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c([N+](=O)[O-])c1Cl
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c(N)c1Cl
Temperature: 70 °C
Reaction time: 10 h

Procedure:
8.00 g (0.023 mol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N′-isopropyl-N′-methylsulfamide and 70 mg (6 mol %) of ammonium chloride in 33 g of toluene and 8 g of methanol were admixed with 0.19 g (0.15 mol %) of 10% Pd/C and hydrogenated with 5 bar of hydrogen with stirring at 70° C. After 10 h the solution was depressurized, the reaction mixture was filtered and the solvent was removed by distillation. This gave 6.4 g (89%) of the title compound in the form of a solid (m.p.: 147-149° C.).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[CH2:6]2.[C:12]([C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)([CH3:15])([CH3:14])[CH3:13]>CCOCC.Cl[Ni](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>[C:12]([C:16]1[CH:17]=[C:18]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH3:11])[CH2:6]3)[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC1=Cc2c(Cl)cccc2C1
Reactant: CC(C)(C)c1cc([Mg]Br)cc(C(C)(C)C)c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2c(cccc2-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-methylindene (6.1 g, 37 mmol) and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-Di-t-butylphenylmagnesium bromide (10 g, 37 mmol) as a Et2O solution was added to the solution and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 4.6 g (40%).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1>CC(=O)OCC.[Pd]>[CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=CC2(CCCC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCC2(CCCC2)CC1
Reaction time: 1.5 h

Procedure:
To a solution of spiro[4.5]dec-6-en-8-one (1.58 g, 10.5 mmol, prepared according to a literature procedure (N. R. Natale, R. O. Hutchins, Org. Prep. Proc. Int. 9 (1977) 103-108)) in EA (12 mL), Pd/C (75 mg, 10% Pd) is added. The mixture is stirred at it under 1 bar of H2 for 90 min before it is filtered over celite. The solvent of the filtrate is evaporated to give spiro[4.5]decan-8-one (1.56 g) as an almost colourless liquid; 1H NMR (CDCl3): δ 2.36 (t, J=7.0 Hz, 4H), 1.75 (t, J=7.0 Hz, 4H), 1.70-1.65 (m, 4H), 1.62-1.50 (m, 4H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[CH3:8][C:9]([CH:11]=[CH2:12])=[O:10].OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:4][CH2:8][C:9](=[O:10])[CH:11]=[CH:12]1)[CH3:2]
Reactant: CCC(C=O)CC
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCC1(CC)C=CC(=O)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
A mixture of 2-ethylbutyraldehyde (12.3 mL, 100 mmol), methylvinylketone (5.6 mL, 67.3 mmol) and H2SO4 (0.07 mL) is stirred at 40° C. overnight. Another portion of methylvinylketone (5.6 mL, 67.3 mmol) and H2SO4 is added and stirring is continued at 40° C. for 2 d. The yellow solution is diluted with chloroform and the solvent is removed again under reduced pressure. The crude product is purified by vacuum distillation to give 4,4-diethyl-cyclohex-2-enone (10.7 g) as a colourless oil; Kp11 mbar=88° C.; 1H NMR (CDCl3): δ 6.71 (d, J=10.0 Hz, 1H), 5.92 (d, J=10.5 Hz, 1H), 2.42 (t, J=7.0 Hz, 2H), 1.84 (t, J=7.0 Hz, 2H), 1.57-1.40 (m, 4H), 0.87 (t, J=7.6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[NH2:9][C:5]1[CH:4]=[C:3]([OH:12])[CH:2]=[CH:7][C:6]=1[F:8]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1cc(O)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-nitrophenol (3.20 g, 16.7 mmol) in methanol (60 mL) was added 20 wt % palladium hydroxide on carbon (1.60 g) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 8 hr under hydrogen atmosphere. After nitrogen replacement, triethylamine (2.32 mL, 16.7 mmol) was added to the reaction mixture, and the mixture was filtered through a kiriyama funnel. Saturated brine was added to the filtrate, and the mixture was extracted twice with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was recrystallized from diethyl ether/hexane to give the title compound (1.40 g, 66%) as pale-brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](S)=[N:8][C:7]=2[CH:12]=1.S(Cl)([Cl:15])=O>CN(C=O)C.ClCCl>[Cl:15][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2oc(S)nc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2oc(Cl)nc2c1
Temperature: 68 °C

Procedure:
To a mixture of 5-methoxy-benzooxazole-2-thiol (12.14 g, 0.07 mol) and thionyl chloride were added two drops of DMF. The mixture was stirred at 68° C. for forty minutes and the formation of gas had stopped. The mixture was diluted with dichloromethane, concentrated, and dried in vacuo to give the title compound as a green solid (14.31 g): 1H NMR (CDCl3, 200 MHz): δ=7.36 (m, 1H), 7.13 (m, 1H), 6.92 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[NH:23][S:24]([C:27]1[C:32]2=[N:33][S:34][N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.O[Li].O.O.Cl>O.C1COCC1>[N:35]1[S:34][N:33]=[C:32]2[C:27]([S:24]([NH:23][C:17]3[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=3[C:15]([NH:14][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=3)[C:3]([OH:37])=[O:2])=[O:36])(=[O:25])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=12
Reactant: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid methyl ester (55 mg, 0.079 mmol) in 2:1 water/THF (3 mL) was added LiOH-2H2O (7 mg, 0.158 mmol). The yellow solution was stirred for 2 h and then 20% aq. HCl (2 mL) was added. The mixture was extracted with EtOAc (3×). The organic layers were combined, dried (MgSO4), and concentrated to provide the desired product as a white solid (41 mg, 76%). HPLC: RT=9.77 min. MS (ESI−): mass calcd. for C22H15Cl2IN4O5S2, 677.3; m/z found, 676 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.22 (s, 1H), 8.33 (d, J=7.0, 1H), 8.12 (d, J=8.8, 1H), 7.98 (d, J=0.8, 1H), 7.70 (dd, J=8.6, 7.3, 1H), 7.33 (d, J=8.2, 1H), 7.22 (d, J=8.2, 1H), 7.02 (dd, J=8.2, 1.6, 1H), 6.93 (d, J=8.3, 1H), 6.73 (d, J=7.3, 1H), 4.99 (q, J=6.3, 1H), 3.31 (dd, J=14.2, 5.7, 1H), 3.20 (dd, J=14.2, 5.7).
Reaction SMILES: Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.[F:43][C:44]1[CH:70]=[C:69]([N+:71]([O-])=O)[CH:68]=[CH:67][C:45]=1[O:46][C:47]1[C:52]2=[C:53]([CH3:66])[C:54]([O:56][CH2:57][CH2:58][CH2:59][N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1>>[F:43][C:44]1[CH:70]=[C:69]([NH2:71])[CH:68]=[CH:67][C:45]=1[O:46][C:47]1[C:52]2=[C:53]([CH3:66])[C:54]([O:56][CH2:57][CH2:58][CH2:59][N:60]3[CH2:61][CH2:62][O:63][CH2:64][CH2:65]3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1
Reactant: Cc1c(OCCCN2CCOCC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCCN2CCOCC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Yield: 96.9 %

Procedure:
Following a procedure similar to that for the synthesis of Compound C of Example 36, 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(3-morpholinopropoxy)pyrrolo[2,1-f][1,2,4]triazine (31 mg, 0.072 mmol) was converted to the title compound (28 mg, 95%). MS(ESI+) m/z 402.3 (M+H)+.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:14][O+:15](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(Cl)Cl.O>[OH:15][CH2:14][C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N:1]=1
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A solution of 4-picoline-N-oxide (3.0 g, 27.52 mmol) in 90 ml of methylene chloride at room temperature is reacted with trimethyloxonium tetrafluoroborate (4.07 g, 27.52 mmol, 1.0 equiv.) for 1.5 h. The reaction mixture is concentrated directly at reduced pressure, the white solid dissolved in 60 ml of refluxing methanol and treated with ammonium persulfate (1.25 g, 5.50 mmol, 0.20 equiv.) in 5.5 ml of water with another addition of ammonium persulfate (0.625 g, 0.10 equiv.) in 2.5 ml of water 30 min later. After refluxing for an additional 40 min, the contents are concentrated at reduced pressure, treated with 75 ml of saturated brine plus 75 ml of water and finally 50 ml of 3N HCl. After stirring at room temperature for 1 h, the mixture is basified with 20 ml of 29% ammonium hydroxide, extracted 4 times with chloroform, dried the combined organic extracts with anhydrous Na2SO4 and concentrated in vacuo. Chromatography with 250 g of silica gel, packed and eluted with acetone-chloroform-methanol (1:2:2%), yielded 2.65 g (78%) of 2-hydroxymethyl-4-methylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[C:5]2[C:16]([F:19])([F:18])[F:17].P(Br)(Br)([Br:22])=O>>[Br:22][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([C:16]([F:19])([F:18])[F:17])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=[N+]([O-])c1c[n+]([O-])c2ccc(Cl)cc2c1C(F)(F)F
Product: O=[N+]([O-])c1c(Br)nc2ccc(Cl)cc2c1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of 3 (4.71 g, 16.1 mmol) and POBr3 (9.23 g, 32.2 mmol) were heated to 100° C. After 2 h, the reaction was cooled to rt and partitioned between EtOAc and H2O, adding ice when necessary. The mixture was stirred overnight to break up the solid materials. Et2O (100 mL) was added and the organic phase was removed. The remaining aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated to afford 5.5 g (96%) of the desired product which was used without further purification. An analytically pure sample was obtained by recrystallization (EtOH) to provide a fluffy off-white solid, mp 120° C. Rf 0.61 (10% Ethyl acetate-hexane). 1H NMR (CDCl3, 300 MHz) δ 8.16 (d, J=9.1 Hz, 1H), 8.16 (m, 1H), 7.92 (dd, J=2.2, 9.1 Hz, 1H); 19F NMR (CDCl3, 300 MHz) δ −57.63; 13C NMR (CDCl3, 75 MHz) δ 146.50, 137.35, 134.25, 131.88, 131.32, 124.45, 124.40, 122.44, 121.96, 118.76; IR (KBr) υmax 1606, 1588, 1552, 1492, 1426, 1382, 1361, 1308, 1283, 1219, 1180, 1169, 1157, 1134, 1097, 1023, 960, 846, 823, 792, 693, 661, 632 cm−1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][C:21]([N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
75 g of 2-methylaminoethanol and 101 g of triethyl amine are mixed with 1000 ml of absolute chloroform. 171 g of chloroformic acid benzyl ester are added dropwise to this solution at about 20° C. The mixture is stirred for 1 hour at room temperature, washed with water, diluted hydrochloric acid and again with water and dried over sodium sulphate. After evaporation of the solvent in vacuo 173 g of oil remain.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.Cl.[CH3:10][O:11][C:12](=[O:15])[CH2:13][NH2:14].C>O1CCOCC1>[N-:14]=[C:4]=[O:3].[CH3:10][O:11][C:12](=[O:15])[CH2:13][NH2:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: COC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
38.8 mL diphosgene is added dropwise over 1 hour to a mixture of 35 g glycine methyl ester hydrochloride and 0.4 g activated charcoal In 400 ml dioxane under N2. The reaction mixture warms to 80° C. during this time. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give pure glycine methyl ester isocyanate in ~70% yield (bp 60° C., 13 mm Hg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[OH:5].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16]>CC(OC)(C)C>[Br:12][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:15](=[O:16])[C:14]([F:21])([F:20])[F:13])[CH:11]=[CH:10][CH:9]=1
Reactant: NCCC(O)c1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Solvent: COC(C)(C)C
Product: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a cooled (0° C.) solution of 3-amino-1-(3-bromophenyl)propan-1-ol (24) (40 g, 173.8 mmol) in MTBE (250 mL) was added ethyl trifluoroacetate (28 mL, 234.7 mmol) over 7 min and the reaction mixture was stirred at room temperature for 50 min. Concentration under reduced pressure gave trifluoroacetamide 25 as a colorless oil. Yield (55.35 g, 98%): 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.51 (t, J=2.0 Hz, 1H), 7.41 (dt, J=7.6, 2.0 Hz, 1H), 7.25-7.32 (m, 2H), 5.46 (d, J=6.4 Hz, 1H), 4.55-4.60 (m, 1H), 3.20-3.23 (m, 2H), 1.75-1.82 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1)([OH:3])=[O:2].Cl.[CH3:14]O>>[CH3:14][O:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1)=[O:3]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CO
Agent: Cl
Product: COC(=O)c1n[nH]c2ccccc12

Procedure:
A solution of 3-carboxyindazole (2.0 g; 12.3 mmol) and conc.HCl (2 mL) in MeOH (50 mL) was heated at reflux overnight, concentrated, diluted with 2N NaOH (aq), and extracted with EtOAc. The extracts were rinsed with brine, dried (MgSO4), and concentrated to provide the desired product.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>O1CCOCC1.[Cu]>[CH3:10][C:9]1([CH3:11])[CH:3]2[CH:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: CC(C)=CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: C1COCCO1
Product: CC1(C)C2COC(=O)C21
Reaction time: 5.5 h

Procedure:
A solution of 3-methyl-2-butenyl diazoacetate (980 mg, 6.4 mmoles) in dioxane (15 ml) was added dropwise to a solution of bis[2-butoxy-α-[2-butoxy-5-(1,1-dimethylethyl)phenyl]-5-(1,1-dimethylethyl)-α-[(S)-1-[[2-hydroxyphenyl)methylene]amino]ethyl]benzenemethanolato (2-)]-copper (83 mg, 0.064 mmole) in dioxane (55 ml) at 110°. When the evolution of nitrogen started, the temperature was slowly lowered to 52°-3°. The addition took 5.5 hours, and the evolution of almost theoretical amounts of nitrogen was observed. After the addition was completed, the reaction mixture was stirred at 52°-3° for 2 hours, evaporated to dryness, and distilled under vacuum to afford 6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane enriched with the (1R,5S) isomer (500 mg). The optical rotation of the product was [α]D29 =-53.5° (CHCl3).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[N:4][CH:3]=1.[N:21]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:21]=[N:20][C:5]2=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To a solution of 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (6.55 g, 19.84 mmol) in acetic acid (15 mL) was added a solution of sodium nitrite (2.74 g, 39.7 mmol) in water (3 mL). After stirring at rt for 3 h, the solution was concentrated. The residue was taken with NaHCO3 (aq) and extracted with DCM. The organic layer was washed with NH4Cl (aq), dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography with EtOAc:hexane to provide 3.35 g (47%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) ppm 9.05 (s, 1H), 8.89 (d, 1H), 8.34 (d, 1H), 8.02 (d, 1H), 7.93 (s, 1H), 7.76 (dd, 1H), 7.53 (dd, 1H), 6.19 (s, 2H). LCMS (method B): [MH]+=343, tR=2.11 min.
Reaction SMILES: [CH2:1]([O:4][C:5](OCCC)=[N:6][NH:7][C:8]([O:10]C)=O)[CH2:2][CH3:3].[CH3:16][NH2:17]>CO.C(O)C>[CH2:1]([O:4][C:5]1[N:17]([CH3:16])[C:8](=[O:10])[NH:7][N:6]=1)[CH2:2][CH3:3]
Reactant: CN
Reactant: CCCOC(=NNC(=O)OC)OCCC
Solvent: CCO
Solvent: CO
Product: CCCOc1n[nH]c(=O)n1C
Temperature: 100 °C

Procedure:
693.6 g (94.4%) of methyl N′-dipropoxymethylenehydrazinecarboxylate (3 mol) were dissolved in 1752 g of methanol and admixed with 564.7 g (6 mol) of methylamine, dissolved in ethanol, and the mixture was heated in an autoclave at 100° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, the residue was taken up in water (880 ml) the mixture was extracted with methylene chloride and the extract was concentrated under reduced pressure. The crystals which precipitated out on cooling were filtered off and dried. This gave 383 g (71.2%, content 87.6%) of 5-propoxy-4-methyl-2,4-dihydro-1,2,4-triazol-3-one in the form of a solid. Melting point: 72.5-73.5° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:6])[CH3:2].C(#N)C>P([O-])([O-])([O-])=O>[CH2:1]([O:3][C@@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:6])[CH3:2]
Reactant: CCCCCCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CCCCCCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To hexyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)-propanoate (0.25 ml of a suspension containing 2 mg/ml in phosphate buffer 0.1M pH 7 and acetonitrile (amount indicated below)) was added the enzyme (amount indicated below) diluted in phosphate buffer 0.1M pH 7 (buffer volume such as total reaction mixture volume was 0.5 ml). The reaction mixture was shaken at room temperature and analysed at different times. The reaction mixture was analysed by the gradient HPLC method 1, and the chiral CE method 2.