Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].C([O:13][C:14](=O)[CH:15]([CH3:19])[C:16](=O)[CH3:17])C>CCO.CC(O)=O>[OH:13][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:16]([CH3:17])[C:15]=1[CH3:19]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N#Cc1ccnc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nn(-c2cc(C#N)ccn2)c(O)c1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile (134 mg, 1 mmol, PREPARATION 2) and 2-methyl-3-oxo-butyric acid ethyl ester (158 mg, 1.1 mmol) in EtOH (5 mL) and AcOH (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (CH2Cl2) to afford the title compound (100 mg, 47%) as an orange solid. [M+H] Calc'd for C11H10N4O, 215; Found, 215.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:22])(C)(C)C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)C.[Zn]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:22])[NH:13]2
Reactant: CC(C)(C)O
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Yield: 97 %

Procedure:
4-(2,3-difluoro-phenyl)-1H-indole 6c (744 mg, 3.25 mmol) was dissolved in 12 ml of ethanol under stirring, and added successively with tert-butanol (21 ml), glacial acetic acid (6.4 ml) and pyridinium tribromide (3.12 g, 9.7 mmol) at room temperature. Upon completion of the addition, the reaction mixture was stirred for 3 hours, added with glacial acetic acid (16 ml) and zinc dust (1.1 g, 16.25 mmol), and stirred for another 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was added with ethyl acetate (30 ml), washed successively with water (10 ml), saturated sodium bicarbonate solution (10 ml) and saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d (780 mg, yield 97%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([CH2:27]Br)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:26][C:22]1[C:23]([F:25])=[CH:24][CH:19]=[CH:20][C:21]=1[CH2:27][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Fc1cccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2F)CCCC1=O
Temperature: 25 °C
Reaction time: 73 h
Yield: 70.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-2,3-difluorotoluene (1.01 g, 4.8 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL DMF was stirred at room temperature for 73 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, saturated NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 1.04 g (70%) of the 9-[(2,3-difluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.4 (d, 1H, J=8 Hz), 7.35 (d, 1H, J=8 Hz), 7.15-6.9 (m, 5H), 6.35 (t, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.25 (m, 2H). IR (KBr, cm−1) 1719 and 1650. MS (ES) m/e 368, 370.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.CO.[C:12](=O)(O)[O-:13].[Na+].C(=O)=O>O>[CH3:12][O:13][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(Cl)nc(Cl)n1
Temperature: 3 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
36.8 g (0.2 mol) of cyanuric chloride are added in the course of 2 hours, at 0°-5° C., to a mixture of 200 ml of methanol, 25 ml of water and 33.6 g (0.4 mol) of sodium bicarbonate. The reaction mixture is stirred, first for one hour at about 3° C. and then for about 30 minutes at 30° C., until the evolution of CO2 has ceased. The white suspension is washed with 100 ml of water and the product is filtered off and dried at 60° C. in a drying cabinet. Recrystallisation from hexane yields 19.6 g of 2-methoxy-4,6-dichloro-1,3,5-triazine with a melting point at about 90° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[O:9])=[C:6]([CH3:10])[N:5]=[CH:4]1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[C:6]([CH3:10])[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1cnc(C)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a 0° C. solution of 1-ethyl-4-methyl-1H-imidazole-5-carbaldehyde (806 mg, 5.8 mmol) in anhydrous methanol (55 mL) was added sodium borohydride (500 mg, 13.2 mmol). The reaction mixture was stirred at room temperature overnight. Water (30 mL) was added. The mixture was evaporated. The resultant residue was treated with EtOAc (50 mL). The solution was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (1-ethyl-4-methyl-1H-imidazol-5-yl)methanol (754 mg, 93% yield). The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[C:18]([CH:19]=[O:20])=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[N:22]=3)[CH:16]=[CH:15][N:14]=1)[CH:8]=[CH:7]2.C(Cl)Cl.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[C:18]([CH2:19][OH:20])=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[N:22]=3)[CH:16]=[CH:15][N:14]=1)[CH:8]=[CH:7]2
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ccc6cc(C(C)(C)C#N)cc(F)c6c5=O)c4C=O)nn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ccc6cc(C(C)(C)C#N)cc(F)c6c5=O)c4CO)nn(C)c3=O)cc2C1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
In a 25 mL round-bottomed flask, 2-(8-fluoro-2-{3-formyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl -propionitrile (800 mg, 1.35 mmol, 1.0 equiv.) was combined with dry DCM (25 ml) and dry methanol (5 mL) to give a light yellow solution. The reaction mixture was cooled to 0° C. and sodium borohydride (91.8 mg, 2.43 mmol, Eq: 1.8) was added. The reaction mixture was stirred at 0° C. for 40 min. and then was quenched with 2 mL saturated NH4Cl with stirring for 5 min. The reaction mixture was poured into 100 mL H2O and extracted with DCM (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude foam was taken up in 20 mL DCM and 15 mL methanol. To this mixture was added 200 mg of 10% Pd/C (Degussa brand). The reaction mixture was stirred at room temperature for 2 h. The solid was removed by filtration and washed several times with 10% methanol in DCM. The combined filtrate and washes were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 4% MeOH holding gradient as each peak came off). Center cut fractions were concentrated to give a glass, which was triturated with ether to afford 2-(8-fluoro-2-{3-hydroxymethyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-proprionitrile as an off-white solid. (M+H)+=596 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6 H) 2.52 (s, 3 H) 2.94 (t, J=5.67 Hz, 2 H) 3.65 (d, J=2.27 Hz, 2 H) 3.90 (s, 3 H) 4.05-4.22 (m, 3 H) 4.42-4.60 (m, 2 H) 5.85 (s, 1 H) 6.66 (dd, J=7.55, 1.89 Hz, 1 H) 7.22 (dd, J=12.46, 1.89 Hz, 1 H) 7.35 (d, J=7.55 Hz, 1 H) 7.53 (d, J=1.89 Hz, 1 H) 7.62 (d, J=4.91 Hz, 1 H) 7.92 (s, 1 H) 7.99 (s, 1 H) 8.68 (d, J=4.91 Hz, 1 H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:3]1.Cl[CH2:39][CH2:40][N:41]=[C:42]=[O:43].CC(C)([O-])C.[K+]>C1COCC1.O>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([N:1]3[CH2:39][CH2:40][NH:41][C:42]3=[O:43])[CH2:3][N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C=NCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N2CCNC2=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-amino-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1-carboxylate (124 mg) was dissolved in THF (4 ml), chloroethyl isocyanate (24 μl) was added, and the mixture was stirred at room temperature for 1 hr. Potassium tert-butoxide (40 mg) was added and the reaction mixture was stirred at room temperature for 7 hr and further at 60° C. for 5 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (10:90-100:0) and concentrated under reduced pressure to give the object compound (70.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[CH2:13]([O:15][C:16](=[O:24])[N:17]([CH2:21][CH2:22]Br)[CH2:18][CH2:19]Br)[CH3:14].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]1([CH2:22][CH2:21][N:17]([C:16]([O:15][CH2:13][CH3:14])=[O:24])[CH2:18][CH2:19]1)[CH2:6]2
Reactant: CCOC(=O)N(CCBr)CCBr
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC1)Cc1cc(OC)ccc1C2=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
To a stirred solution of 5-methoxy-1-indanone (1.0 g, 6.17 mmol) and bis-(2-bromo-ethyl)-carbamic acid ethyl ester (1.87 g, 6.17) in DMF (10 mL) at 50° C. was added NaH (0.370 g, 15.4 mmol) by small portions. After being stirred at 50° C. for 16 hr, the reaction was cooled to ambient temperature. The reaction was diluted with 15 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column (gradient of 85:15 to 60:40 heptane/ethyl acetate over 30 min) to give the title compound (590 mg, 1.945 mmol). MS calculated for C17H22NO4 304.4. found (ESI) m/z 304.2 (M+H)+, retention time 1.56 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](O)[CH2:14][CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[O:7]1[CH2:13][CH2:14][CH2:15][O:16][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(C2OCCCO2)ccc1O
Yield: 85.3 %

Procedure:
A mixture of 8 g of 4-hydroxy-3-nitrobenzaldehyde, 16 g of 1,3-propanediol, a catalytic amount of pyridinium p-toluenesulfonic acid and 250 ml of toluene was azeotropically dehydrated with heating under reflux. The reaction mixture was cooled, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from toluene-n-hexane to obtain 9.2 g of 4-(1,3-dioxan-2-yl)-2-nitrophenol.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].[O-]CC.[Na+].CN([CH:12]=[C:13]1[CH2:17][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:15][C:14]1=O)C>C(O)C.C(OCC)(=O)C>[N:3]1[C:14]2[CH2:15][NH:16][CH2:17][C:13]=2[CH:12]=[N:4][CH:2]=1
Reactant: CN(C)C=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1ncc2c(n1)CNC2
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of formamidine hydrochloride (190 mg) in anhydrous ethanol (25.0 mL) under nitrogen were added sodium ethoxide (21% wt in ethanol, 1.2 mL) and 4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one (300 mg, prepared as described for Step B, Intermediate 4). The mixture was refluxed at 80° C. for 8 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic layer was washed sequentially with 5% aqueous citric acid solution and brine, dried over anhydrous sodium sulfate, filtered, concentrated. The crude residue was deprotected by treatment with 4N methanolic hydrogen chloride for 2.5 h. The mixture was concentrated and the residue purified by chromatography on a Biotage® system (silica, gradient 15% to 25% of 10% concentrated ammonium hydroxide in methanol/dichloromethane) to give the title compound. LC-MS=243.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]1=[NH:9].[Cl:10][C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([N:9]=[C:3]2[N:4]([CH3:8])[C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: CN1CC(=O)N(C)C1=N
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CN1CC(=O)N(C)C1=NC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6.35 g (0.050 mole) of 1,3-dimethyl-2-iminoimidazolidin-4-one, 7.85 g (0.050 mole) of 3-chlorophenylisocyanate and 75 ml of dry tetrahydrofuran is stirred at room temperature for four hours. The solution is evaporated in vacuo and the residue is crystallized from acetonitrile. Two recrystallizations from acetonitrile - ether gives pure product, 1-(3-chlorophenyl)-3-(1,3-dimethyl-4-oxo-2-imidazolidinylidene)urea, m.p. 134°-137° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([CH3:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([CH3:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)C
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (265 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a brown foam (330 mg, 67%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:9]1[CH2:10][N+:11](=[O:15])[CH:12]=[CH:13][CH:14]=1)[C:7]#[N:8]>CO.O>[CH3:3][O:4][N:5]=[C:6]([C:9]1[CH2:10][N:11]([OH:15])[CH2:12][CH2:13][CH:14]=1)[C:7]#[N:8]
Reactant: CON=C(C#N)C1=CC=C[N+](=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=C(C#N)C1=CCCN(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Sodium borohydride (0.13 g, 0.0034 mol) was added to a mixture of methanol (5 ml) and water (5 ml) at 0° C. To this was added dropwise a solution of α-(methoxyimino)-α-(1-oxopyridinium-3-yl)acetonitrile (D5) (0.2 g, 0.0011 mol) in methanol (30 ml) and water (5 ml). The mixture was allowed to warm to room temperature and stirred for a further 2 h. The mixture was evaporated to dryness and the residue partitioned between saturated aqueous potassium carbonate (25 ml) and chloroform(3×30 ml). The organic extracts were combined and dried (Na2SO4) then filtered and evaporated to dryness. The residue was subjected to column chromatography on silica gel eluting with 0-2% methanol/chloroform to give a solid which was recrystallised from ethyl acetate/pentane to afford the title compound (E2) as a white crystalline solid (0.135 g, 67%) m.p. 145°-147° C.
Reaction SMILES: CC(S([NH:7][C:8]1([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:11][O:10][CH2:9]1)=O)(C)C.[ClH:18].C(OCC)C>CO>[ClH:18].[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[C:8]1([NH2:7])[CH2:11][O:10][CH2:9]1
Reactant: CC(C)(C)S(=O)NC1(c2ncccn2)COC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NC1(c2ncccn2)COC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
To a yellow solution of 2-methyl-N-(3-(pyrimidin-2-yl)oxetan-3-yl)propane-2-sulfinamide (0.025 g, 0.098 mmol) in MeOH (1 ml) in a 10 ml round-bottomed flask was added a solution of HCl in diethyl ether (0.098 ml, 0.392 mmol, 4N). The reaction mixture was stirred at 0° C. for 10 min., and then concentrated at 25° C. The residue was washed with n-hexane and dried to give the titled product as a white solid (0.017 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 9.15 (bs, 2H), 9.01 (d, J=4.8 Hz, 2H), 7.64 (t, J=5.0 Hz, 1H), 5.00 (d, J=7.2 Hz, 2H), 4.87 (d, J=7.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)[N:3]=1.C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.[W]>[Br:28][CH2:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([CH3:20])[CH:16]=1)[O:12][C:4]1[C:5]([CH:9]([CH3:10])[CH3:11])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mixture of (2) (9.72 g, 31 mmol), NBS (5.56 g, 31 mmol), and benzoyl peroxide (0.756 g, 3.1 mmol) in carbon tetrachloride (60 ml) was refluxed for 3 hr. under a light of 500 W tungsten lamp. After cooling to room temperature, the reaction mixture was filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:19)) to afford 8 g (62%) of a white solid; m.p. 98-101° C.; 1H NMR (200 MHz, CDCl3) δ 1.41 (6H, d, J=7.2 Hz), 2.38 (3H, s), 3.59 (1H, m), 4.47 (2H, s), 6.86 (1H, s), 6.97 (1H, s), 7.13 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[NH:12][CH2:13][CH2:14][NH:15]3)=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[NH:12][CH2:13][CH2:14][N:15]2[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(c1cccc(Cl)c1)c1cccc2c1NCCN2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1cccc(Cl)c1)c1cccc2c1NCCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of (3-chlorophenyl)(1,2,3,4-tetrahydroquinoxalin-5-yl)methanone (50 g, 183 mmol) in DCM (200 mL) at 0° C. was added pyridine (17.79 mL, 220 mmol). Then CBZ—Cl (26.2 mL, 183 mmol) in DCM (1.0 mL) was added dropwise. The reaction mixture was warmed up to room temperature and stirred at room temperature for 3 h. The reaction mixture was washed with H2O, saturated NaHCO3, and brine, dried over Na2SO4, filtered, concentrated to give crude material. This crude material was purified via BIOTAGE®, eluted with 10% EtOAC/hexane to afford benzyl 5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1D (60 g, 147 mmol, 80% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.5 (1H, bs), 7.6 (1H, s), 7.45 (2H, m), 7.4 (7H, m), 7.25 (1H, m), 6.5 (1H, m), 5.2 (2H, m), 3.9 (2H, m), 3.6 (2H, m).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:10][CH:11]1[NH:12][CH2:13][CH2:14][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: CC1CNCCN1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(c2ccc(C=O)cc2)CCN1
Temperature: 120 °C
Yield: 69.9 %

Procedure:
To a solution of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol) in DMF (10 mL) was added 2-methylpiperazine (1.9 g, 19.3 mmol) and K2CO3 (2.7 g, 19.3 mmol). The reaction was heated at 120° C. for 6 hours, diluted with H2O, and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, to afford 4-(3-methylpiperazin-1-yl)benzaldehyde (2.3 g, 69%): 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 7.75 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 3.67-3.83 (m, 2H), 3.07-3.18 (m, 1H), 2.81-3.06 (m, 3H), 2.50-2.62 (m, 1H), 1.46-1.73 (br s, 1H), 1.15 (d, J=6.3 Hz, 3H). ESI MS m/z 205 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:16][CH2:15][C:13](=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].CCN(S(F)(F)[F:23])CC>C1COCC1>[C:2]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:16][CH2:15][C:13]([F:23])=[CH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CC=C(F)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
4-N-Boc-aminomethyl cyclohexanone (4.95 g, 21.8 mmol) was dissolved in 80 mL of THF. DAST (4.3 mL, 32.7 mmol) was added dropwise and the solution was stirred at 50° C. for 5 h. The solvent was concentrated and the product purified by silica gel flash chromatography using 3:1/hexanes:EtOAc as eluent. Yield: 1.62 g (30%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.36-1.42 (m, 1 H), 1.44 (s, 9 H), 1.70-1.80 (m, 2 H), 1.82-1.90 (m, 1 H), 2.09-2.17 (m, 1 H), 2.17-2.29 (m, 2 H), 3.04-3.11 (m, 2 H), 4.61 (s, 1 H), 5.11-5.15 (m, 0.5 H), 5.16-5.19 (m, 0.5 H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[N-:14]=[N+:15]=[N-:16].[Li+].O>CN(C=O)C>[N:14]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[N+:15]=[N-:16]
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOc1ccc([N+](=O)[O-])cc1
Yield: 96.9 %

Procedure:
A solution of 1.12 g (5.55 mmol) of 4-nitro 2-chloroethyl ether (Example 212) and lithium azide (544 mg, 11.1 mmol) in 3 mL of DMF was heated at 60° C. in an oil bath overnight under nitrogen atmosphere. The reaction was poured into water and extracted with ethyl acetate. The organics were washed with water and brine and dried over anhydrous magnesium sulfate and concentrated to give 1.12 g (97%) of the product: 1H NMR (200 MHz, CDCl3) δ8.18 (d, 2H, J=9Hz), 6.96 (d, 2H, J=9Hz), 4.21 (t, 2H, J=5Hz), 3.63 (t, 2H, J=5Hz).