Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O.[OH-].[Na+]>CC(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])/[C:7]#[N:8])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: CC(C)(C)CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 4-chloro-2-fluoro-benzyl cyanide (Oakwood) (1.70 g, 10.0 mmol) and 3,3-dimethyl-butyraldehyde (Aldrich) (1.0 g, 10.0 mmol) in iPrOH (20 mL) was added 2 N NaOH (2.0 mL) dropwise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was dried overnight in vacuum to give (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2.52 g, 100%) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:13]1([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Yield: 97 %

Procedure:
270 parts of β-naphthol, 175 parts of aniline and 5 parts of triphenyl phosphite are mixed and fused at 130° C. The reaction commences at an internal temperature of 190° C, with elimination of water. After 2 1/2 hours, internal temperature has reached 235° C and 34 parts of water have distilled off. 398 parts of N-phenyl-β-naphthylamine of melting point 100° - 102° are distilled, passing over at 230° C/15 mm Hg. This corresponds to a yield of 97% of theory.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH3:16]>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:16][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: FC(F)(F)c1cc(Cl)cc(C(F)(F)F)n1
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
A mixture of 4-chloro-2,6-bis(trifluoromethyl)pyridine (50 g, 0.20 mole) in concentrated ammonia (250 ml, density 0.88) and ethanol (250 ml) containing copper sulphate (ca. 0.5 g) was stirred and heated in a pressure vessel at 100°-120° C. for 5 hours. The mixture was cooled, extracted with methylene chloride and dried over MgSO4. The solvent was removed under reduced pressure leaving the title compound as a cream solid. The produt was recovered in a yield of 26 g, (56% of theoretical), m.p. 147°-149° C.
Reaction SMILES: [C:1](/[N:3]=[C:4](/[S-:7])\[S:5][CH3:6])#[N:2].[K+].Cl[CH2:10][C:11]([NH2:13])=[O:12].C[O-].[Na+].O>C(O)C>[NH2:2][C:1]1[N:3]=[C:4]([S:5][CH3:6])[S:7][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: CS/C([S-])=N\C#N
Reactant: NC(=O)CCl
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1nc(N)c(C(N)=O)s1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A mixture of potassium (Z)-methyl cyanocarbonimidodithioate (10.0 g, 58.7 mmol) and 2-chloroacetamide (6.04 g, 64.6 mmol) in ethanol (20 mL) was refluxed for 1 h. After cooling to ambient temperature, sodium methoxide (3.49 g, 64.6 mmol) was added to the mixture. The mixture was stirred at reflux for 3 hours. The mixture was cooled to ambient temperature and water (50 mL) was added. The precipitate formed was collected by filtration. The precipitate was further washed with water and dried in vacuo. The product was obtained as a yellow solid (3.372 g, 30%). 1H NMR (300 MHz, d6-DMSO) δ 6.96 (s, 2H), 6.89 (s, 2H), 2.64 (s, 3H); LC-MS: 190 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[O:44][C:45]([F:48])([F:47])[F:46])[CH2:5][NH:6][C:7]([C@H:9]1[CH2:14][N:13]([C:15]2[S:16][C:17]3[C:22](Cl)=[N:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[N:19][C:18]=3[N:27]=2)[CH2:12][CH2:11][N:10]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:8].C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[O:44][C:45]([F:48])([F:46])[F:47])[CH2:5][NH:6][C:7]([C@H:9]1[CH2:14][N:13]([C:15]2[S:16][C:17]3[CH:22]=[N:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[N:19][C:18]=3[N:27]=2)[CH2:12][CH2:11][N:10]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:40])[F:39])=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:8]
Reactant: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C4CC4)ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a mixture of the compound (49 mg) obtained in Step 6 and ammonium formate (42 mg) in ethanol (1.0 ml) was added 10% palladium carbon (25 mg) at 80° C. After stirring at 80° C. for 30 min, 10% palladium carbon (25 mg) was added. After stirring at 80° C. for 30 min, ammonium formate (42 mg) and 10% palladium carbon (25 mg) were added. After stirring at 80° C. for 30 min, 10% palladium carbon (25 mg) was added. After stirring at 80° C. for 30 min, the reaction mixture was allowed to return to room temperature, and the reaction mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:10) to give the title compound (29 mg).
Reaction SMILES: [NH2:1][C:2]1([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=2[O:26][CH3:27])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:16].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([C:2]2([NH:1][C:35](=[O:37])[CH3:36])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[NH:12][C:13](=[O:15])[CH3:14])[C:3]2=[O:16])=[C:18]([O:26][CH3:27])[CH:19]=1)([CH3:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2cccc(NC(C)=O)c2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2cccc(NC(C)=O)c2C1=O
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of N-(2-amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-indene-4-yl)acetamide (0.20 g, 0.54 mmol) in dichloromethane (10 mL) and was added triethylamine (0.23 mL, 1.6 mmol) and acetyl chloride (0.040 mL, 0.56 mmol) and then stirred for overnight. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (50% ethylacetate in hexane) to afford the title compound (210 mg, 95%).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:7]2=[CH:8][C:9]3[N-:13][C:12]4[C:14]([C@@H:56]([C:59]([O:61][CH3:62])=[O:60])[C:57](=[O:58])[C:11]=4[C:10]=3[CH3:63])=[C:15]3[N:19]=[C:18]([CH:20]=[C:21]4[N-:26][C:24](=[CH:25][C:5](=[N:6]2)[C:4]=1[CH3:64])[C:23]([CH:27]=[CH2:28])=[C:22]4[CH3:29])[C@@H:17]([CH3:30])[C@@H:16]3[CH2:31][CH2:32][C:33]([O:35][CH2:36]/[CH:37]=[C:38](/[CH2:40][CH2:41][CH2:42][C@@H:43]([CH2:45][CH2:46][CH2:47][C@@H:48]([CH2:50][CH2:51][CH2:52][CH:53]([CH3:55])[CH3:54])[CH3:49])[CH3:44])\[CH3:39])=[O:34].[Mg+2:65].CC(C)=[O:68]>>[CH3:1][CH2:2][C:3]1[C:7]2=[CH:8][C:9]3[N-:13][C:12]4[C:14]([C@@H:56]([C:59]([O:61][CH3:62])=[O:60])[C:57](=[O:58])[C:11]=4[C:10]=3[CH3:63])=[C:15]3[N:19]=[C:18]([CH:20]=[C:21]4[N-:26][C:24](=[CH:25][C:5](=[N:6]2)[C:4]=1[CH:64]=[O:68])[C:23]([CH:27]=[CH2:28])=[C:22]4[CH3:29])[C@@H:17]([CH3:30])[C@@H:16]3[CH2:31][CH2:32][C:33]([O:35][CH2:36]/[CH:37]=[C:38](/[CH2:40][CH2:41][CH2:42][C@@H:43]([CH2:45][CH2:46][CH2:47][C@@H:48]([CH2:50][CH2:51][CH2:52][CH:53]([CH3:55])[CH3:54])[CH3:49])[CH3:44])\[CH3:39])=[O:34].[Mg+2:65]
Reactant: CC(C)=O
Reactant: C=Cc1c(C)c2cc3nc(c4c5[n-]c(cc6nc(cc1[n-]2)C(C)=C6CC)c(C)c5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C
Agent: [Mg+2]
Product: C=Cc1c(C)c2cc3nc(c4c5[n-]c(cc6nc(cc1[n-]2)C(C=O)=C6CC)c(C)c5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C

Procedure:
To 100 g of dried chlorell were added 800 ml of acetone. The mixture was treated in the same manner as described in Example 1 whereby 0.190 g in total of chlorophyll A and chlorophyll B was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[CH:21]([CH3:22])[CH2:20][CH:19]([C:23]([NH:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:35][NH2:36]>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:21]([CH3:22])[CH2:20][C@H:19]([C:23]([NH:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:36][N:35]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CC(C(=O)NCc3ccccc3)CC2C)n1
Solvent: CCO
Solvent: O
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)C[C@H]2C)n1
Temperature: 100 °C

Procedure:
To a suspension of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide (360 mg total, 0.81 mmol) in EtOH (50 mL) at room temperature was added hydrazine monohydrate (2 mL) in one portion. The suspension was heated in an oil bath to 100° C. for 20 hours. LCMS showed there was still 40% starting material remaining. To the mixture was added 2 mL of hydrazine monohydrate, followed by heating to 100° C. for another 24 h. LCMS showed conversion complete. The mixture was cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo, and the resulting residue was taken up in 8 mL of water to form a suspension, which was briefly sonicated. The mixture was filtered. The solids collected were combined with another run starting with 190 mg of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide. The combined crude products were purified by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 75% A in CHCl3. A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3. Trituration of the purified material in a mixture of CHCl3 (2 mL) and hexane (8 mL), followed by drying under vacuum at 65° C. for 14 hours afforded the title compound (228 mg) as a beige powder. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.42 (d, J=6.1 Hz, 3H), 2.00-2.06 (m, 1H), 2.52-2.58 (m, 1H), 2.99 (s, 3H), 3.00-3.10 (m, 1H), 3.68-3.73 (m, 1H), 3.95-4.10 (bs, 1H), 4.21-4.33 (bs, 1H), 4.39-4.47 (m, 2H), 6.23 (s, 1H), 7.25-7.37 (m, 5H), 7.52 (dd, J=8.5, 1.1 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.85 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.N[C:32]1C=CC(C2C=C(C3C=CC=CC=3)N=C(OCCCCC(C)(C)C(OC)=O)C=2)=CC=1.CNC1C=CC(C2C=C(C3C=CC=CC=3)N=C(OCCCCC(C)(C)C(OC)=O)C=2)=CC=1>>[CH3:32][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)CCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Agent: CNc1ccc(-c2cc(OCCCCC(C)(C)C(=O)OC)nc(-c3ccccc3)c2)cc1
Product: CCOC(=O)CCCCCOc1cc(-c2ccc(NC)cc2)cc(-c2ccccc2)n1

Procedure:
When the procedure of Example 16 is followed and ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate is replaced with methyl 6-{[4 -(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}-2,2-dimethylhexanoate then the compound prepared is methyl 6-{[4-(4-methylaminophenyl)-6-phenyl-2-pyridyl]oxy}-2,2-dimethylhexanoate. (m.p.=77° C.)
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11]>S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: O=Cc1sccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: Brc1ccsc1C1OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Pyridinium tosylate (1 g., 4 mmoles) was added to a mixture of 3-bromothiophene-2-carboxaldehyde (2) (18.7 g., 97.9 mmole), ethylene glycol (22 mL., 24.8 g., 400 mmole) and dry toluene (100 mL). The mixture was refluxed and the water removed by a Dean-Stark trap. After 1 hour, TLC (10% EtOAC/hexane) showed the reaction was complete. The mixture was cooled to room temperature and partitioned between ether (100 mL) and water (100 mL) components. The organic layer was separated and extracted with water (3×50 mL) and then with a saturated solution of sodium bicarbonate (25 mL). The resulting extract was dried (MgSO4), filtered and evaporated in vacuo to leave 21.5 g, of crude product. This product was distilled to give 17.6 g of 3 -Bromo-2-(2-dioxolanyl)thiophene (3), bp: 86°-87° C./0.5 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Br)cn1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-amino-5-bromopyridine (6.92 g, 40 mmol) and 6.22 g (48 mmol) of diisopropylethylamine in 50 mL of chloroform was added dropwise to a solution of 8.19 g (48 mmol) of benzyl chloroformate in 20 mL of chloroform at about 0° C., with stirring. A voluminous white precipitate formed. After about 15 minutes, the mixture was filtered and the precipitate was washed three times with chloroform and dried to give 2.70 g of the title product, mp 184° C. (dec) (recrystallization solvent=2-propanol). 1H nmr (dimethylsulfoxide-d6): δ=10.48 (br s, 1 H), 8.37 (d, 1 H), 7.98 (d of d, 1 H), 7.81 (d, 1 H), 7.40 (m, 5 H), 5.17 (s, 2 H); ms (NH3Cl): m/z=307, 309 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([S:19][CH3:20])[CH:12]=1.[Na].C[OH:28]>O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([S:19]([CH3:20])=[O:28])[CH:12]=1
Reactant: COc1ccccc1OCCNC(C)Cc1ccc(OC)c(SC)c1
Reactant: CO
Agent: [Na]
Solvent: O
Product: COc1ccccc1OCCNC(C)Cc1ccc(OC)c(S(C)=O)c1

Procedure:
In 100 ml of a mixture of methanol and water (5:1) was dissolved 1.8 g of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole and after adding dropwise thereto 10.5 ml of an aqueous solution of 0.5M sodium metaperoiodate at 0° C., the mixture was stirred overnight at 4° C. The crystals formed were removed by filtratation and the filtrate was concentrated under reduced pressure and the residue formed was purified by a silica gel column chromatography (eluate: a mixture of chloroform and methanol (97:3 by volume ratio) to provide 722 mg of oily 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole. The product was dissolved in 10 ml of methanol and after adding thereto a solution of 252 mg of oxalic acid di-hydrate dissolved in 6 ml of methanol, the mixture was allowed to stand overnight at room temperature. The resulting crystaline material was recovered by filtration and recrystallized from ethanol to provide 700 mg of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole oxalate having a melting point of 172°-174° C.
Reaction SMILES: [Cl:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:4][C:3]1([Cl:6])[Cl:5].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[Cl:1][C:2]1([C:7]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[CH2:4][C:3]1([Cl:6])[Cl:5]
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1(Cl)CC1(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)C1(Cl)CC1(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 9.47 g (0.05 mole) of 1,2,2-trichlorocyclopropane carboxylic acid in 100 ml of reagent grade acetone was added 6.91 g (0.05 mole) of anhydrous potassium carbonate. To this stirred mixture was added 10.26 g (0.06 mole) of benzyl bromide diluted with a small volume of acetone. The reaction mixture was stirred overnight at room temperature and filtered with suction. The insoluble material was washed on the filter with additional acetone. The acetone wash solutions and the filtrate were combined and evaporated in vacuo to dryness. The resulting product residue was dissolved in 200 ml of diethyl ether and washed twice with water, once with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether solvent provided a straw-colored semi-viscous liquid which distilled at 145°-146° C./3 mm (5.31 g) identified as the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.F[C:25]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:33][C:32]1[C:25]([N:11]2[C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=3[C:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:10]2)=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]
Reactant: N#Cc1cccc(F)c1F
Reactant: COc1nccc2[nH]nc(-c3ccc(N4CCOCC4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1C#N
Yield: 77.4 %

Procedure:
A solution of 4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (355 mg), 2,3-difluorobenzonitrile (180 mg) and potassium carbonate in DMF (5 mL) was stirred at 100° C. for 2.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was washed with petroleum ether to give the title compound (380 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][C:24]([CH3:27])=[N:25][N:26]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:29][CH3:30].[OH-].[Na+].CN(C)C=O>O>[CH2:29]([N:26]1[N:25]=[C:24]([CH3:27])[S:23][C:22]1=[N:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH3:30]
Reactant: COc1ccc(N2CCN(c3ccc(Nc4nnc(C)s4)cc3)CC2)cc1
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)sc1=Nc1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Reaction time: 4 h
Yield: 25.3 %

Procedure:
A mixture of 10.6 parts of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-1,3,4-thiadiazol-2-amine, 0.5 parts of bromoethane, 4 parts of sodium hydroxide pellets and 188 parts of N,N-dimethylformamide was stirred for 4 hours at 40°-50° C. After the addition of water, the crystallized product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane, methanol, ethyl acetate and hexane (48:2:30:20 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 2.9 parts (25.3%) of N-(3-ethyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine; mp. 175.4° C. (int. 14). The second fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.5 parts (56.7%) of N-ethyl-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-1,3,4-thiadiazol-2-amine; mp. 186.8° C. (int. 15).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]1[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1>[Pd].CCO.O1CCOCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1=COC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: c1ccc(Nc2ccc(Oc3ncccc3C3CCCCO3)cc2)nc1
Reaction time: 24 h

Procedure:
A mixture of (±)-N-(4-(3-(3,4-dihydro-2H-pyran-2-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine (233 mg, 0.675 mmol) and palladium on carbon (wet) (71.8 mg, 0.067 mmol) in EtOH/dioxane was placed under an atmosphere of hydrogen gas and stirred for 24 hours. The mixture was then filtered through a cake of celite, washing with MeOH. The filtrate was concentrated and purified by silica gel chromatography, 10-100% acetone/hexanes, to give the title compound as a racemic mixture. MS (ESI, pos. ion) m/z: 348.0 (M+1). IC50 (uM) 0.149.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:39]([F:40])=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[C:25]([F:41])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:39]([F:40])=[CH:38][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]5)=[O:28])=[C:25]([F:41])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CCN1CCC(NC(=O)c2cc(F)c(N)cc2F)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN1CCC(NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)cc2F)CC1
Temperature: 110 °C
Yield: 54.2 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.33 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide (Intermediate 235; 102 mg, 0.36 mmol) and caesium carbonate (213 mg, 0.65 mmol) added to dioxane (5 mL) and the suspension bubbled with nitrogen for 10 minutes. tris-dibenzylideneacetonedipalladium (II) (18 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) were added and the mixture heated at 110° C. overnight. The mixture was filtered, and the filtrate loaded onto to an SCX-3 cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a light orange gum (99 mg, 55%).