Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[C:3]=1[C:4]([O-:6])=O.[Li+].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:55]1([N:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[NH:61][CH2:60][CH2:59]2)[CH2:57][CH2:56]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:4]([N:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:58]([CH:55]3[CH2:57][CH2:56]3)[CH2:59][CH2:60]2)=[O:6])=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)[O-])c(Cl)n1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution of 120 mg (0.355 mmol) lithium 2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinate in 3 mL dry N,N-dimethylformamide was added 0.30 mL (1.773 mmol) N-ethyldiisopropylamine and 163 mg (0.425 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N;N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 74 mg (0.425 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (Example 8, intermediate a). The reaction mixture was stirred for 18 hours at room temperature and evaporated. The residue was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 100:0) to provide 45 mg (26%) of the title compound as a light yellow foam (30%). MS (ESI): m/z=488.07 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br)[C:5]([O:7][CH3:8])=[O:6].O.C[N+]1([O-])CC[O:22]CC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[O:22])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Reactant: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CON=C(C(=O)OC)c1ccccc1C=O
Yield: 58.1 %

Procedure:
20 g (0.070 mol) of methyl 2-(bromomethyl)phenylglyoxylate O-methyloxime, 32 g (0.237 mol) of N-methylmorpholine N-oxide monohydrate and 300 ml of CCl4 are mixed and heated to reflux. After refluxing for 9 hours, the mixture is filtered, and the organic phase is washed with water and with 2 N hydrochloric acid, dried and concentrated. The residue is recrystallized from pentane. 9.0 g of product (58%) are obtained as colorless crystals.
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]([C:17]([F:20])([F:19])[F:18])([C:13]([F:16])([F:15])[F:14])[CH2:8][CH:9](I)[CH2:10]O>N1C=CC=CC=1>[F:6][C:7]([C:17]([F:18])([F:19])[F:20])([C:13]([F:14])([F:15])[F:16])[CH2:8][CH:9]=[CH2:10]
Reactant: OCC(I)CC(F)(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCC(F)(C(F)(F)F)C(F)(F)F

Procedure:
According to another embodiment, the reducing agent can include POCl3, pyridine and/or a mixture of POCl3 and pyridine. For example, the RF-intermediate 4,5,5,5-tetrafluoro-4-(trifluoromethyl)-2-iodopentan-1-ol can be reacted to form the RF-intermediate 4,5,5,5-tetrafluoro-4-(trifluoromethyl)pent-1-ene in the presence of a mixture of POCl3 and pyridine. This reaction can be performed while maintaining the temperature of the mixture between from about 0° C. to about 5° C., for example.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][CH:16]([CH2:18]Cl)[CH3:17]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:16]([Cl:15])=[CH2:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cl)COc1ccc(Cl)cc1
Yield: 92.5 %

Procedure:
To a mixture of 4-chlorophenol (6.1 g, 47.4 mmol) and potassium carbonate (13.1 g, 94.7 mmol) in acetone (200 mL), 2,3-dichloropropane (6.6 mL, 71 mmol) was added. After heating to reflux the reaction mixture for 48 hours, the reaction mixture was cooled and filtered. The residue was washed with more acetone and the combined filtrates were concentrated in vacuo. The crude pale brown liquid (11.5 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 85/15) to give 1-(4-chlorophenoxy)-2-chloro-2-propene (8.9 g, 98%) as a white liquid: Anal. Calc'd. for C9H8OCl2: C, 53.23; H, 3.97. Found: C, 53.09; H, 3.95.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:18]1[C:25](Cl)=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:20][C:19]1[N:18]=[C:25]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:17])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14](=[O:16])[C:15]=3[C:2]=2[NH2:1])[N:24]=[C:22]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:17])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14](=[O:16])[C:15]=3[C:2]=2[NH2:1])[N:21]=1
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1c(-c2nc(Cl)nc(-c3ccc4c(c3N)C(=O)c3ccccc3C4=O)n2)ccc2c1C(=O)c1ccccc1C2=O
Reaction time: 2 h

Procedure:
A dispersion of 22.3 parts of 1-aminoanthraquinone in 200 ml of nitrobenzene was brought to 100° C. and additioned with 9.22 parts of cyanuryl chloride and successively brought to 190° C. for 2 hours. The reaction mixture was filtered at a temperature of 150° C. and the cake was washed several times with methanol and then with n-heptane and was dried in an oven at a temperature of 110° C. About 23 parts of 2-chloro-4,6-bis-(1-aminoanthraquinonyl)-s-triazine were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].S(Cl)(Cl)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][CH:11]=[C:10]([S:14]([Cl:13])(=[O:16])=[O:15])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1c[nH]c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C

Procedure:
2-(4-chlorophenyl)imidazole (6 g., 0.034 mole) was added portionwise at room temperature with stirring to chlorosulfonic acid (30 ml.). The mixture was heated 2 hours at 100° and cooled to room temperature. Thionyl chloride (3 g.) was added and the mixture again heated for 2 hours at 100°. After cooling to room temperature the mixture was added cautiously to ice and water. A semi-solid separated and was extracted with ether. The ether layer was dried and concentrated to yield 2-(4-chlorophenyl)-4-chlorosulfonylimidazole (1.3 g., 0.005 mole).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.BrCC1CCCCO1>>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, (S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 144-146° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (dd, J=5.1, 0.6 Hz, 1H), 7.73 (ddd, J=7.8, 7.5, 1.5 Hz, 1H), 7.33-7.27 (m, 2H), 7.22 (ddd, J=7.7, 7.7, 1.3 Hz, 1H), 7.17 (dd, J=7.4, 0.9 Hz, 1H), 7.03 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.29 (s, 1H), 5.26 (d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.22-4.18 (m, 2H), 4.15-4.11 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.4, 155.3, 148.6, 144.8, 142.0, 138.4, 138.2, 132.2, 129.0, 124.0, 123.7, 123.3, 122.3, 121.1, 111.8, 109.7, 99.5, 80.3, 64.6, 64.0, 58.2, 45.5; MS (ES+) m/z 387.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH:8](Br)[CH3:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[Br:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH:8]([N:32]2[CH2:31][CH2:30][N:29]([S:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)(=[O:28])=[O:27])[CH2:34][CH2:33]2)[CH3:9])=[N:6][CH:7]=1
Reactant: CC(Br)c1ncc(Br)c(=O)[nH]1
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(=O)[nH]3)CC2)cc1
Yield: 53.4 %

Procedure:
In a round bottom flask containing 5-bromo-2-(1-bromo-ethyl)-3H-pyrimidin-4-one (1.0 g, 3.5 mmol) in acetonitrile (30 ml) was added KI (0.9 g, 5.3 mmol), K2CO3 (1.2 g, 5.3 mmol), and (1-(4-Methoxy-benzenesulfonyl)-piperazine (983 mg, 3.5 mmol). The reaction was heated at reflux for 12 hours. The solution was concentrated under reduced pressure. The residue was partitioned between water (10 ml) and dichloromethane (15 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue purified by column chromatography (ethyl acetate: hexanes 1:1) to give 5-bromo-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-pyrimidin-4-one (Yield 854 mg, 53%). 1H NMR (400 MHz, CDCl3): δ 1.28 (d, J=7.0 Hz, 3H), 2.62-2.49 (m, 4H), 3.00-2.94 (m, 4H), 3.84 (s, 3H), 4.05 (q, 1H, J=7.0 Hz), 6.97 (d, J=11.8 Hz, 2H), 7.62 (d, J=11.8 Hz, 2H), 8.11 (s, 1H). MS m/z calc. 457.3, found (ESI); 457.2 (M+1)+. Retention time 2.50 minutes.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](O)=[O:28])=[CH:23][NH:24]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27]([N:12]3[CH2:11][CH2:10][CH:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:15])[F:16])[CH2:14][CH2:13]3)=[O:28])=[CH:23][NH:24]2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Product: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2C(F)(F)F)CC1

Procedure:
Following general procedure I, the coupling of (commercially available) 4-(2-trifluoromethyl-phenyl)-piperidine (described herein) with 6-chloro-1H-indole-3-carboxylic acid gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[NH2:5].C[Al](C)C.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=[C:21]2[CH3:23])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: Nc1ccc(CN2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(CN3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.1 %

Procedure:
A mixture of 3-fluoro-4-(morpholinomethyl)aniline (0.21 g, 1.00 mmol), anhydrous CH2Cl2 (10 mL) and trimethylaluminum (4.5 mL, 4.5 mmol, 1.0 M in heptane) was stirred at rt for 20 min under N2, followed by the addition of a solution of methyl 3-acetaminocrotonate (0.19 g, 1.20 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 10 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2. The combined organic phases were washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (0.105 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[OH:11].[CH3:12]C(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[CH3:12][C:5]12[CH2:6][CH2:7][CH:8]=[CH:9][C:10]1=[CH:1][C:2](=[O:11])[CH2:3][CH2:4]2
Reactant: OC1CCc2ccccc2C1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC12CCC=CC1=CC(=O)CC2

Procedure:
1,2,3,4-Tetrahydro-2-napthol is reduced according to Preparation 9. The resulting diene is cyclopropanated with Simmons-Smith reagent, oxidized with Jones reagent, then the cyclopropane ring opened with acid to form dienone 4.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:5][C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7].N1C=CC=CC=1.C(Br)(Br)(Br)[Br:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:34][CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:5][C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7]
Reactant: CC(C)(C)OC(=O)NNC(=O)CC(CCO)c1cccc(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NNC(=O)CC(CCBr)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
tert-Butyl N′-[5-hydroxy-3-(3-trifluoromethylphenyl)pentanoyl]hydrazinecarboxylate (2.0 g) was dissolved in methylene chloride (53 mL). Pyridine (1.29 mL), carbon tetrabromide (2.64 g) and triphenylphosphine (2.1 g) were added at room temperature, followed by stirring for 30 minutes. The reaction solution was partitioned with water and ethyl acetate. Then, the organic layer was washed with saturated ammonium chloride aqueous solution and a saturated sodium bicarbonate aqueous solution and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 50%) to obtain the title compound (1.6 g).
Reaction SMILES: O[C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>ClCCl>[Cl:23][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(c2ccccc2)=C1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a suspension of 3-hydroxy-4-phenyl-1H-pyrrole-2,5-dione (25.0 g, 0.13 mol) in dichloromethane (600 mL) under nitrogen was added DMF (36 mL). The suspension was cooled to ice temperature and treated with oxalyl chloride (40.0 g, 0.32 mol). The reaction mixture was subsequently refluxed overnight. After cooling to room temperature silica gel was added and the reaction mixture evaporated to dryness and subjected to flash chromatography (hexane:EtOAc 80:20). Trituration with dichloromethane, filtration and drying gave 17.6 g (64%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.96-7.89 (m, 2H), 7.88-7.77 (bs, 1H), 7.55-7.45 (m, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[CH:7]=[N:8][CH:9]=[CH:10][C:2]2=3)=[O:16])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(=O)Cl)cc1Cl
Reactant: c1cc2c(cn1)OCCN2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCOc3cnccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
In a 10 ml flask, 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (60 mg, 0.441 mmol) and 3-chloro-4-methoxy-benzoyl chloride (108 mg, 0.529 mmol) were dissolved in dichloromethane (3 ml). Triethylamine (0.12 ml, 0.881 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate:n-hexane=1:1. The fractions containing the product were collected and evaporated to obtain white solid (134 mg, 99.8%).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([NH:10][C:11]3[C:16](Cl)=[C:15]([CH2:18][CH3:19])[N:14]=[CH:13][N:12]=3)[CH2:6][CH2:5]2)[O:3]C1.[ClH:21]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:21][C:11]1([NH:10][CH:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]2)[CH:16]=[C:15]([CH2:18][CH3:19])[N:14]=[CH:13][NH:12]1
Reactant: CCc1ncnc(NC2CCC3(CC2)OCCO3)c1Cl
Reactant: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC1=CC(Cl)(NC2CCC(=O)CC2)NC=N1

Procedure:
70 g (0.235 mol) of 4-(5-chloro-6-ethylpyrimidin-4-ylamino) cyclohexanone ethylene ketal (starting material for Example C) were stirred at 50° C. for 8 hours in a mixture of 250 ml of tetrahydrofuran and 250 ml of 2N hydrochloric acid. For work-up, the mixture was diluted with 250 ml of toluene, and the organic phase was extracted by stirring with sodium carbonate solution and water. Stripping off the solvent mixture gave 53.4 g (90% of theory) of product, which can be reacted without further purification.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:26]=[C:27]([N+:29]([O-])=O)[CH:28]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl.[Zn]>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:26]=[C:27]([NH2:29])[CH:28]=1)[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cc(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
2.52 g (38.5 mmol) Zn were suspended in 6 mL methylene chloride (dry, distilled), 0.9 mL (15.7 mmol) acetic acid were added and the suspension was cooled to 0° C. A solution of 0.7 g (1.93 mmol) nitrobenzoate 12 in 2 mL methylene chloride was added by syringe. After 2 h of stirring, TLC (hexanes/ethyl acetate, 7:3, Rf=0.4) indicated complete conversion of starting material. Zn was filtered off and the filtrate was concentrated, taken up in ethyl acetate and washed with aqueous NaHCO3 three times, then with brine. After drying with MgSO4 and evaporation, an orange-brown oil was obtained, which was purified by column chromatography (hexanes/ethyl acetate, 7:3) to afford 310 mg (48%) of a yellow oil. 1H NMR (CDCl3) δ 7.50-7.27 (m, 10H), 7.12 (dd, J1=1.3 Hz, J2=2.2 Hz, 1H), 7.02 (dd, J1=1.3 Hz, J2=2.2 Hz, 1H), 6.49 (t, J1=2.2 Hz, J2=2.2 Hz, 1H), 5.38 (s, 2H, PhCH2), 5.03 (s, 2H), 3.69 (s, 2H, PhCH2).
Reaction SMILES: [O:1]([CH:8]1[CH2:12][CH2:11][N:10]([C:13](Cl)=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>O1CCCC1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:13]([N:10]1[CH2:11][CH2:12][CH:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:14]
Reactant: O=C(Cl)N1CCC(Oc2ccccc2)C1
Reactant: CN(C)CCN
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCC(Oc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
A stirred solution of 0.088 mole of crude 3-phenoxy-1-pyrrolidinecarbonyl chloride in 100 ml of tetrahydrofuran was cooled to 0° C., treated with 7 g (0.088 mole) of pyridine (to remove any benzyl chloride contaminant), warmed to ambient temperature (1 hr.) and treated with 15.5 g (0.176 mole) of N,N-dimethylethylenediamine at a rapid drop rate. The reaction was slightly exothermic and after 2 hours, the mixture was filtered to remove a fine silvery precipitate (hydrochloride of the diamine) and concentrated in vacuo to a dark oil. The oil was partitioned between isopropyl ether and water, the isopropyl ether phase separated and the aqueous portion extracted with 100 ml of isopropyl ether. The isopropyl ether extracts were combined and concentrated in vacuo to give an amber oil, 5 g. The aqueous phase was extracted with 3×50 ml of benzene, the extracts combined, washed with 20 ml of water, dried over magnesium sulfate and concentrated in vacuo to a dark oil, 12 g. This residue partially crystallized overnight and was recrystallized 2 times with charcoal treatment, first from isopropyl ether/ligroin, then from isopropyl ether (cooled in a refrigerator) to give 4.1 g of white crystalline product which after drying at 64° C. under reduced pressure for 18 hours weighed 3.9 g, m.p. 72°-73° C. The residue from the original isopropyl extracts (5 g) was combined with the filtrate from above and upon reworking, gave an additional 4.3 g of product, m.p. 71°-73° C. The fraction with m.p. 72°-73° C. was submitted for elemental analysis and testing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cc(Cl)nc(Cl)c1
Yield: 76.5 %

Procedure:
2,6-Dichloro-4-pyridinamine (10 g, 61.3 mmol) (Aldrich) and triethylamine (10.69 ml, 77 mmol) were combined in dichloromethane (DCM) (75 ml) and cooled in an ice-bath. 2,2-dimethylpropanoyl chloride (8.30 ml, 67.5 mmol) (Aldrich) in DCM (15 ml) was added drop wise and the mixture stirred whilst allowing to warm up overnight producing a clear dark orange solution. LCMS showed good conversion to product. The solution was washed with water and sat. NaHCO3 (100 ml each), dried with Na2SO4, filtered and concentrated to yield a dark orange solid. The crude product was taken up in the minimum of DCM and applied to a 320 g Companion XL silica column and eluted with 0% EtOAc in cyclohexane for 2 CVs then 0-15% EtOAc in cyclohexane over 12 CVs then held at 15% for 2 CV. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (11.59 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:13][CH2:14][C:15](Cl)=[O:16]>ClCCl>[Cl:13][CH2:14][C:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CCl)N1CCOCC1

Procedure:
Utilize a Quest 205 Parallel Synthesizer and to a mixture of morpholine (2.6 g, 30 mmol), dichloromethane (45 mL) and 2M K2CO3 slowly add chloroacetylchloride (3.73 g, 33 mmol) in dichloromethane (10 mL). Agitate the reaction overnight and filter off the organic layer. Extract the aqueous with dichloromethane (20 mL) and add it to the previously collected organic layer. Dry the organic phase (MgSO4) and concentrate under vacuum to obtain the title compound.