Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[CH:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][N:10]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:29](=O)[C:30]#[CH:31]>C1(C)C=CC=CC=1>[C:25]([O:24][C:22]([N:10]1[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:14][CH:9]1[C:2]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:31][CH:30]=[CH:29][N:1]=1)=[O:23])([CH3:27])([CH3:26])[CH3:28]
Reactant: CCOC(=O)/C=C(\N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: C#CC=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bis(1,1-Dimethylethyl) 2-[(1Z)-1-amino-3-(ethyloxy)-3-oxo-1-propen-1-yl]-1,4-piperazinedicarboxylate (may be prepared as described in Intermediate 4; 500 mg) in toluene (100 mL), propiolaldehyde (1.0 eq) was added at room temperature. After completion of addition, the reaction mixture was stirred for 2 h at room temperature and then heated to 90° C. Completion of reaction was followed by TLC. TLC showed disappearance of starting material in 5 h. Toluene was removed by vacuo then the residue was diluted with ethyl acetate (100 mL) and washed with water (2×50 mL) followed by brine solution (50 mL) and dried over anhydrous sodium sulphate, concentrated under vacuum to get 600 mg of crude product. The crude product was purified by column chromatography over 100-200 mesh silica gel by using 10%-30% ethyl acetate in pet ether as solvent, which yielded the title compound (200 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][S:13][C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17]>C(O)(C)C>[N+:16]([CH:15]=[C:14]([S:13][CH3:12])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([O-:18])=[O:17]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccccn1
Solvent: CC(C)O
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccccn1

Procedure:
A solution of 2-[(2-pyridyl)methylthio]ethylamine (from the dihydrobromide, 20.0 g; 60.6 mmoles) [prepared according to the procedure described in Belgian Pat. No. 779,775] and 1,1-bis(methylthio)-2-nitroethylene [prepared according to the procedure described in Chem. Ber., 100, 591 (1967) or Acta Chem. Scand., 21, 2797 (1967)] (10.0 g; 60.6 mmoles) in isopropyl alcohol (175 ml) was stirred at ambient temperature under a positive pressure of nitrogen for 16 hours then at reflux temperature for 2 hours to complete the reaction. The mixture was cooled in an ice-water bath and the product collected by filtration. Recrystallization from isopropyl alcohol with activated carbon treatment gave 1-nitro-2-methylthio-2-{2-[(2-pyridyl)methylthio]ethylamino}ethylene; mp 97°-99°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:30]3[S:34][C:33]([CH2:35]O)=[CH:32][CH:31]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.C1(P([N:59]=[N+:60]=[N-:61])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N:59]([CH2:35][C:33]1[S:34][C:30]([C:12]2[C:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)[CH:19]=4)[C:14]=3[N:10]([CH:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:11]=2)=[CH:31][CH:32]=1)=[N+:60]=[N-:61]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CO)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CN=[N+]=[N-])s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 382 (8.0 g, 13.2 mmol) in tetrahydrofuran (100 mL) was cooled to about 0° C. and diphenylphosphoryl azide (7.1 mL, 33.0 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7ene (4.9 mL, 33.0 mmol) were added slowly in the dark. After the addition was complete, the mixture was stirred for about 2 hours at ambient temperature in the dark. The mixture was basified by addition of potassium carbonate and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered, and concentrate. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (10:1) as eluent to provide the desired product. MS (ESI): m/z 632 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15](=[O:18])[CH2:16][CH3:17])[CH:7]=[CH:6]2.[Br-:19].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>>[Br:19][CH:16]([CH3:17])[C:15]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)=[O:18]
Reactant: [Br-]
Reactant: CCC(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: C[N+](C)(C)c1ccccc1
Product: COc1cc2ccc(C(=O)C(C)Br)cc2cc1OC
Yield: 84 %

Procedure:
From 1-(6,7-dimethoxy-2-naphthyl)-1-propanone and phenyl trimethyl ammonium tribromide through 2-bromo-1-(6,7-dimethoxy-2-naphthyl)-1-propanone (yield 84%; m.p. 122°-124° C.) which is then reacted with 4-(2-oxo-1-benzimidazolinyl)-1-piperidine followed by reduction with LiAlH4. Yield 55%; m.p. 246°-248° C. J=9.5 Hz.
Reaction SMILES: C(N(N=O)[C:9](=[O:38])[CH:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)C1C=CC=CC=1.O.[OH-].[Li+].OO.C(O)(=[O:48])C>O1CCCC1.O>[CH:32]1([CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:9]([OH:38])=[O:48])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N(Cc2ccccc2)N=O)C2CCCCC2)c(OC)n1
Reactant: CC(=O)O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Reaction time: 1 h

Procedure:
To a suspension of 12.1 g (22.02 mmol) N-benzyl-N-nitroso-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide in 65 ml tetrahydrofuran and 15 ml water were added dropwise over 20 min. a solution of 9.24 g (220 mmol) lithium hydroxide monohydrate in 45 ml (440 mmol) hydrogen peroxide and 30 ml water. The reaction mixture turned into a turbid solution and a slight temperature raise was observed (cooled temporarily using an ice-bath). After 1 h the pH of the mixture was adjusted to pH 4 using acetic acid. The resulting light yellow solution was extracted three times with ethyl acetate. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate solution, once with water and once with brine. The solution was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 200 ml tert-butyl methyl ether and partially evaporated until a precipitation formed. The suspension was cooled in the refrigerator for 30 min, then the solid was filtered off, washed with 50 ml ice-cold tert-butyl methyl ether and dried in high vacuum. White solid (99%). MS (Turbo Spray): m/z=432.2 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([O:10][CH3:11])[CH:3]=1.ClCCl.[CH2:15](N(CC)CC)[CH3:16]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.CCO>[CH:15]([C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([O:10][CH3:11])[CH:3]=1)=[CH2:16]
Reactant: CCN(CC)CC
Reactant: COc1cc(Cl)ncc1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: C=Cc1cc(OC)c(C#N)cn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A 20 mL microwave tube was charged with 6-chloro-4-methoxypyridine-3-carbonitrile (200.0 mg, 1.2 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (97.0 mg, 0.12 mmol), potassium vinyl trifluoroborate (318.0 mg, 2.37 mmol), and triethylamine (0.33 mL, 2.37 mmol), and EtOH (6 mL). The microwave tube was evacuated and filled with nitrogen (two times) and heated to 140° C. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The extracts were concentrated and chromatographed over a column of SiO2 (0-30% EtOAc/hexanes as eluent). Evaporation of the solvent yielded the title compound. 1H NMR (500 MHz, DMSO-d6), δ 8.65 (s, 1H), 6.89 (s, 1H), 6.83 (dd, J=10.7 Hz, 1H), 6.42 (d, J=7.3 Hz, 1H), 5.70 (d, J=10.6 Hz, 1H) 4.05 (s, 3H);
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6]1[CH:10]=[C:9]([C:11]([CH2:13][CH2:14][CH2:15][Cl:16])=O)[S:8][CH:7]=1>CO.Cl.O>[Cl:16][CH2:15][CH2:14][CH2:13][C:11](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[C:9]1[S:8][CH:7]=[CH:6][CH:10]=1
Reactant: O=C(CCCCl)c1cccs1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCCCl)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
Thiosemicarbazide (9.11 g, 0.1 mol) was added under nitrogen to a solution 4-chloro-2'-butyrothienone (16.2 mL, 0.1 mol) in 350 mL of methanol plus 27 mL 1N HCl plus 25 mL of water. After stirring at room temperature for approximately 2 hours, all of the solid had dissolved. The reaction was then stirred at room temperature for 24 hours (overnight). By TLC starting material remained. An additional 27 mL of 1N HCl was added and the reaction stirred at room temperature for 6 hours. The solid formed was removed by filtration and dried under high vacuum to give 14.87 g (57%) of the title compound as a brown solid, mp 120-122° C.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([F:32])=[CH:14][C:15]([F:31])=[C:16]([C:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=2)[CH:17]=1)=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:11][C:12]1[C:13]([F:32])=[CH:14][C:15]([F:31])=[C:16]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]2)[CH:17]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(NC(=O)OCc3ccccc3)c(F)cc2F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)c(F)cc2F)CC1
Reaction time: 72 h
Yield: 123.6 %

Procedure:
A mixture of tert-butyl 4-(5-{[(benzyloxy)carbonyl]amino}-2,4-difluorophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.60 g, 3.60 mmol) and 5% Pd/C (320 mg, 0.100 mmol) in ethyl acetate (25.0 mL) and methanol (25.0 mL) was hydrogenated at room temperature for 72 hours using hydrogen bomb (200 psi). The reaction mixture was filtered through Celite and washed with EtOAc/MeOH (1:1, 3×50 mL). The filtrate was concentrated in vacuo to afford tert-butyl 4-(5-amino-2,4-difluorophenyl)-1-piperidinecarboxylate (1.39 g, 100%). 1H NMR (400 MHz, CDCl3) δ 6.73 (t, 1H, J=10.6 Hz), 6.60-6.54 (dd, 1H, J=7.6, 6.57 Hz), 4.20 (br, 2H), 3.55 (s, 2H), 2.96-2.72 (m, 3H), 1.79-1.71 (m, 2H), 1.58-1.52 (m, 2H), 1.47 (s, 9H); ESMS m/e: 257.3 (M−56).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([Cl:18])[C:12]=3[C:11]([I:19])=[CH:10]2)[CH2:6]1)=O.C(=O)=O.CC(C)=O.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:18][C:17]1[C:12]2[C:11]([I:19])=[CH:10][N:9]([C@@H:7]3[CH2:6][C@H:5]([CH2:3][OH:2])[CH2:8]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COC(=O)[C@H]1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: OC[C@H]1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 45 °C
Reaction time: 0.83 h

Procedure:
To a solution of cis-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid methyl ester (2.15 g, 5.49 mmol) in CH2Cl2 (85 mL), cooled by dry ice/acetone, was added DIBAL (1M in toluene, 12.4 mL, 12.4 mmol) over 5 min. Note that the ester started precipitating at the low temperature; but upon adding the DIBAL solution, a clear, pale yellow solution formed. After 50 min, the dry ice/acetone bath was replaced with and ice/water bath. The reaction was quenched 2.5 h later by adding Na2SO4.10H2O. A very slow gas evolution occurred, even with vigorous stirring or sonication. MeOH (2 mL) was added at ambient temperature, and a precipitate slowly formed, which was filtered off and washed with 150 mL of 10% MeOH in CH2Cl2. The combined filtrate and washings were concentrated, the resulting solid was suspended in 80 mL of 10% MeOH/CH2Cl2, heated briefly to 45° C., and cooled to −20° C. overnight. The white solid was filtered off and dried in vacuo, yielding the title compound. The aluminum-containing precipitate was suspended in potassium sodium tartrate solution and extracted with CH2Cl2 (3×100 mL), the combined extracts were dried over MgSO4, filtered, and combined with the mother liquor of the white solid. This material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-7)→CH2Cl2:EtOAc 5:1 (8-32)→CH2Cl2:EtOAc 4:1 (33-43)] to give a second crop of the title compound. 1H NMR (CDCl3, 400 MHz): δ=1.79 (brs, 1H), 2.40-2.53 (m, 3H), 2.59-2.71 (m, 2H), 3.74 (brs, 2H), 5.13-5.23 (mc, 1H), 7.60 (s, 1H), 8.60 (s, 1H). MS (ES+): m/z 364.0/366.0 (100/40) [MH+]. HPLC: tR=2.9 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1S(=O)(=O)N(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CBr
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
Under nitrogen, a mixture of intermediate 45, 5-fluoro-2,N,N-trimethyl-benzenesulfonamide, (435 mg, 2.0 mmol) and N-bromosuccinimide (391 mg, 2.2 mmol) in CCl4 (20 mL) was stirred at 80-90° C. for 5 min. To this mixture was added 2,2′-azobisisobutyronitrile (AIBN, 100 mg) and stirring continued at 80-90° C. for 30 min. After cooling, the insoluble precipitates were filtered and the filtrate concentrated and purified by column chromatography (SiO2, CH2Cl2) to provide 440 mg (Yield 74%) of the title compound; 1H NMR (500 MHz, CDCl3) δ ppm: 2.87 (6H, s) 4.86 (2H, s) 7.28 (1H, dd, J=8.55, 2.75 Hz) 7.61-7.65 (2H, m); LC/MC m/z 296/298 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[O:26][CH2:27][O:28][C:21]=12>>[Cl:18][CH2:17][CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[O:26][CH2:27][O:28][C:21]=34)=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: Nc1ccnc2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Product: COc1cc2c(Nc3ccnc4c3OCO4)ncnc2cc1OCCCCl
Yield: 68 %

Procedure:
Using an analogous procedure to that described in Example 14, 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline was reacted with 4-amino-2,3-methylenedioxypyridine to give the title compound in 68% yield; NMR Spectrum: (DMSOd6) 2.26 (m, 2H), 3.83 (m, 2H), 3.96 (s, 3H), 4.28 (m, 2H), 6.12 (s, 2H), 7.15 (br d, 1H), 7.25 (s, 1H), 7.61 (d, 1H), 7.81 (s, 1H), 8.49 (s, 1H), 9.79 (br s, 1H); Mass Spectrum: M+H+ 389.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[N:10][CH:11]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH3:23][C:7]1[C:6]([CH2:4][OH:3])=[CH:11][N:10]=[C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:8]=1
Reactant: CCOC(=O)c1cnc(NCCCC2CCN(C)CC2)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1CO
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a 0° C. solution of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carboxylic acid ethyl ester (0.20 g, 0.63 mmol) in THF (6 mL) was added diisobutylaluminum hydride (1 M in hexanes; 1.25 mL, 1.25 mmol) dropwise. The mixture was warmed to rt over 1 h. The reaction was quenched with 1 M H2SO4 (2 mL). The mixture was neutralized with satd. aq. NaHCO3, and diluted with MeOH (2 mL), CHCl3 (10 mL), and satd. aq. sodium potassium tartrate (10 mL). The mixture was stirred vigourously until the layers separated. The organic layer was dried (Na2SO4) and concentrated to give the crude product (138 mg), which was used in the next step without further purification. 1H NMR (CDCl3): 8.07 (s, 1H), 4.52 (s, 2H), 3.42-3.33 (m, 2H), 2.88-2.74 (m, 2H), 2.41 (s, 3H), 2.23 (s, 3H), 1.93-1.83 (m, 2H), 1.72-1.53 (m, 4H), 1.35-1.16 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:4][CH:3]=1.[CH:29]1([Mg]Br)[CH2:31][CH2:30]1.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([C:24]([CH:29]2[CH2:31][CH2:30]2)([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: O=C(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)(C1CC1)C1CC1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a stirred solution of [10-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-a]benzimidazol-7-yl](cyclopropyl)methanone (67.1 mg, 0.154 mmol) in tetrahydrofuran (1 mL) was added a solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.0 M, 4.62 mL, 4.62 mmol) at 0° C. After 15 min, the reaction mixture was poured into a mixture of ethyl acetate and aqueous ammonium chloride. The organic phase was washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with a 0-25% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (48.2 mg, 0.101 mmol, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].C(#N)C.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: C1COCCN1
Reactant: Nc1nnc(Cl)cc1Br
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nnc(Cl)cc1N1CCOCC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
4-Bromo-6-chloropyridazin-3-amine (2.0 g, 9.6 mmol) was placed in an 8 mL vial equipped with a stir bar, and ACN (5 mL) and morpholine (8.3 mL, 96 mmol) were added. The mixture was stirred at 70° C. for 18 h. The reaction was cooled to rt, the suspension obtained was filtered, and the filtercake was washed with ACN (10 mL). The filtrate was concentrated under reduced pressure and the residue obtained was dissolved in DCM (50 mL) and washed with saturated NaHCO3 solution (2×30 mL). The aqueous washings were combined and extracted with DCM (3×30 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude residue was triturated with EtOAc (30 mL) then the solid was isolated by filtration to give compound 19a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H11ClN4O: 215.1 (M+H). found: 215.1.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[C:7]([Cl:24])=[CH:8][C:9]([F:23])=[C:10]([N:12]2[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]2=[O:22])[CH:11]=1)([OH:3])=[O:2].[CH2:25]([N:27]([CH2:29][CH3:30])O)[CH3:26]>O1CCCC1>[CH2:25]([N:27]([O:2][C:1]([CH2:4][S:5][C:6]1[C:7]([Cl:24])=[CH:8][C:9]([F:23])=[C:10]([N:12]2[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]2=[O:22])[CH:11]=1)=[O:3])[CH2:29][CH3:30])[CH3:26]
Reactant: CCN(O)CC
Reactant: O=C(O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Solvent: C1CCOC1
Product: CCN(CC)OC(=O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 72.5 %

Procedure:
In 20 ml of tetrahydrofuran, 1.85 g of 2-(5-carboxymethylthio-4-chloro -2-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione was dissolved, to which 0.97 g of N,N'-carbonyldiimidazole was added and the resultant mixture was stirred for 30 minutes at room temperature. To the resultant mixture, 0.53 g of N,N-diethylhydroxylamine was added, and the resultant mixture was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried with anhydrous magnesium sulfate, and evaporated to remove the solvent under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=5:1 to 3:1), which afforded 1.60 g of 2-[5-(N,N-diethylaminooxycarbonylmethylthio)-4-chloro-2-fluorophenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([O:11][C:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[CH2:1])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Oc1cccc(C=O)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cccc(OC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
m-Hydroxybenzaldehyde (819 mmol, 100.0 g) was placed in a 5 L 3-necked round bottom flask equipped with a mechanical stirrer and an argon gas inlet, to which was added THF (4.5 L). Potassium t-butoxide (834 mmol, 93.7 g) was slowly added to the solution over 3 min. After 15 min, di-t-butyl dicarbonate (834 mmol, 182.3 g) was added over 15 min. After 2.5 hr at room temperature the reaction mixture was poured into 4 L of water and the product was extracted with 2 L of a mixture of hexanes and ether (1:1). The organic layers were combined, washed with saturated NaCl (2 L), saturated NaHCO3 (1 L), and H2O (2 L), and dried over MgSO4 (ca. 100 g). The organic phase was filtered and condensed to give m-(t-butoxycarbonyloxy)benzaldehyde (792 mmol, 176 g) in 97% crude yield. Methyl(triphenyl)phosphonium bromide (848 mmol, 303 g) was placed in a 2 L 3-necked round bottom flask containing 1.5 L of THF. The mixture was cooled to 0° C. under nitrogen and potassium t-butoxide (830 mmol, 93.1 g) was added slowly to the mixture over 10 min. m-(t-Butoxycarbonyloxy)benzaldehyde (792 mmol, 176 g) was added and the mixture was stirred for another 6 h, upon which the solvent was removed on a rotary evaporator and hexanes (1.5 L) added. The mixture was stirred for 2 h and filtered through a small bed of silica. The hexane layer was concentrated to give 120 g of the crude product. Purification by column chromatography gave 85 g of pure m-(t-butoxycarbonyloxy)styrene (47% yield based on m-hydroxybenzaldehyde).