Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[F:11].[C:12]([O:16][C:17]([NH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][C@@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(F)c1CN1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Bromomethyl)-1-fluoro-3-methoxybenzene (3.19 g, 14.57 mmol), (R)-3-(tert-butoxycarbonylamino)piperidine (3.0 g, 12.67 mmol), and K2CO3 (2.63 g, 19.01 mmol) were taken up in DMF (25 mL) in a 50 mL flask. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL, ×2), dried over MgSO4, filtered, and the solvent evaporated in vacuo. The residue was purified by flash chromatography (6-50% EtOAc/hexanes) to give (R)-tert-butyl 1-(2-fluoro-6-methoxybenzyl)piperidin-3-ylcarbamate. MS ESI calc'd. For C18H22FN2O3 [M+1]+ 339. found 339.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:18]([CH3:19])[CH2:17][O:16][CH2:15][C:14]1=[O:20])[C:5]([O:7]CC)=[O:6].[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:18]([CH3:19])[CH2:17][O:16][CH2:15][C:14]1=[O:20])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(N2C(=O)COCC2C)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1COCC(=O)N1c1ccc(C(=O)O)cc1Cl

Procedure:
Prepared analogously to Example 31b from ethyl 3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoate with lithium hydroxide in THF and water.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[Br:14][C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1>C(O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccc(Br)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Reaction time: 72 h
Yield: 91.7 %

Procedure:
A solution of diethyl methylmalonate (87 g) in absolute ethanol (100 ml) was added to a pre-formed solution of sodium (11.5 g) in ethanol (400 ml) under argon. A hot solution of p-bromobenzylbromide (125 g) in absolute alcohol (200 ml) was added rapidly with vigorous stirring, which was continued for 3 days and the solid so formed was removed by filtration. The filtrate was evaporated and the residue dissolved in ethyl acetate (11), washed with brine (250 ml), dried (MgSO4) and evaporated. The residual oil was distilled under vacuum to give diethyl (4-bromophenyl)methylmalonate (150.7 g) b.p. 130-133/0.03 mm Hg; 1H NMR (d6 -DMSO): 1.33 (t, 6H), 1.4 (s, 3H), 3.27 (s, 2H), 4.30 (q, 4H), 7.23 (d, 2H), 7.6 (d, 2H),
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[CH3:26][S:27]([CH2:30][C:31](O)=[O:32])(=[O:29])=[O:28]>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][C:31](=[O:32])[CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Yield: 86.1 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-2-methanesulfonyl-acetamide (103 mg, 84%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and methanesulfonyl acetic acid (55 mg, 0.4 mmol) following the general procedure T.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].Br[CH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)Cc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(Cc1ccccc1F)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
N-Ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide (0.381 g, 1.327 mmol) and methyl 2-(bromomethyl)benzoate (0.334 g, 1.460 mmol) were dissolved in acetonitrile (10 ml) and potassium carbonate (0.367 g, 2.654 mmol) was added. The mixture was stirred at 65° C. for three hours. When N-ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide was consumed, PS-trisamine (0.3 eqv) was added and the solution was stirred overnight at room temperature. The polymer was filtered off and acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of water, dried (MgSO4) and the solvent was removed by evaporation to give 0.545 g of methyl 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (yield 94.3%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.[CH3:34]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][CH:23]=[N:24][C:16]=3[NH:15][C@H:13]([C:4]2[N:3]=[C:2]([CH3:34])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:12])[CH3:14])=[CH:27][CH:28]=1
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
(S)-9-(4-Methoxybenzyl)-N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9H-purin-6-amine (1) (2.0 g, 4.2 mmol, 1.0 eq), methylboronic acid (277 mg, 4.62 mmol, 1.1 eq), Pd (PPh3)4(485 mg, 0.42 mmol, 0.1 eq) and Na2CO3(1.34 g, 12.6 mmol, 3.0 eq) were suspended in a mixture of 1,4-dioxane (30 mL) and water (10 mL). The resulting mixture was degassed and back-filled with argon three times and then stirred at reflux under argon for 16 h. The mixture was allowed to cool to RT, concentrated in vacuo and the residue was purified by column chromatography on silica gel (1-3% MeOH-DCM) to afford the product, (S)-9-(4-methoxybenzyl)-N-(1-(8-chloro-1-methylisoquinolin-3-yl)ethyl)-9H-purin-6-amine (168). Compound 168 was then converted to compound 169 using the analogous procedures for the synthesis of 151 in Example 91 except that pyridin-3-ylboronic acid was used in place of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The PMB group of compound 169 was then subsequently deprotected using Method L to afford compound 170. ESI-MS m/z: 382.2 [M+H]+.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O)(O)(=O)=O.[NH2:16][OH:17].[OH-].[Na+]>O>[CH:1](=[N:16][OH:17])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ON=CC=Cc1ccccc1
Temperature: 3 °C
Yield: 70 %

Procedure:
53.3 grams of cinnamaldehyde (0.40 mols) was added to a solution of 39.1 grams of hydroxylamine sulfate (0.48 mols) in 79.5 grams of water. The mixture was cooled in an icewater bath to 3° C. Then a solution of 17.7 grams of NaOH (0.44 mol) in 17.7 grams of water was added over a period of 25 minutes. The formed cinnamaldehyde oxime precipitated. The reaction mixture was warmed to roomtemperature and the crude product was filtered. After recrystallization from toluene pure cinnamaldehyde oxime was obtained as white crystals. Yield: 70%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCBr)C1c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A suspension comprising 9.96 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, 5.4 ml of 1,4-dibromobutane and 2.07 g of potassium carbonate in 60 ml of dimethylformamide was heated at 50° C. under stirring for 2.5 hours. The mixture was then cooled to room temperature, poured into 400 ml of water and extracted with diethyl ether. The ethereal extracts were then dried on anhydrous sodium sulfate and evaporated to dryness to give an oil which was purified by flash chromatography on silica gel columns, employing first chloroform and then chloroform: ethyl acetate 97:3 by volume as eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:15]=1.[Cu][C:17]#[N:18]>N1C=CC=CC=1>[C:17]([C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:15]=1)#[N:18]
Reactant: CN1CC(=O)Nc2ccc(Br)cc2C1=O
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: CN1CC(=O)Nc2ccc(C#N)cc2C1=O

Procedure:
15.0 g of 7-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5 (1H)-dione and 7.5 g of copper (I) cyanide (freshly prepared) are mixed well in a mortar and heated from 165° to 195° with 7.2 ml of dry pyridine (freshly distilled over potassium hydroxide) under argon over a period of 3 hours. After cooling to 150°, the solid mass is dissolved in about 250 ml of boiling dimethylformamide. The mixture is left to cool, poured into 800 ml of ice-water and extracted three times with 500 ml of chloroform each time. The organic extracts are washed with 250 ml of 2N hydrochloric acid and three times with 500 ml of water each time, dried in the presence of active carbon and evaporated. The residue is dissolved in about 1 l of methanol. The solution is concentrated to a volume of 250 ml, treated with active carbon and cooled to 5°. The precipitated material is filtered off under suction and dried, there being obtained 7-cyano-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione as white crystals of melting point 256-258°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[O:26]=[S:23]1[CH2:24][CH2:25][N:20]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[C:6]=3[N:7]=[C:2]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:3]=2)[CH2:21][CH2:22]1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4cccnc4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4cccnc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-4-(1-oxido-thiomorpholino)-8-(3-picolylamino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 227°-229° C.) and piperazine.
Reaction SMILES: [Br-:1].[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N:48]1[C:52]([CH2:53]O)=[CH:51][C:50]([C:55]([F:58])([F:57])[F:56])=[N:49]1>>[Br:1][CH2:53][C:52]1[N:48]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[Cl:41])[N:49]=[C:50]([C:55]([F:58])([F:57])[F:56])[CH:51]=1
Reactant: OCc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1cc(CBr)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dry 250 mL flask was charged with triphenylphosphonium dibromide (6.3 g, 14.9 mmol) and a solution of [2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-methanol (3.54 g in 100 mL of CH2Cl2) was added portionwise. The reaction was stirred at room temperature for 2 h then was washed into a separatory funnel with water and CH2Cl2. The CH2Cl2 was separated, dried (MgSO4), and concentrated in vacuo. The crude bromide was purified by silica gel flash chromatography (Jones Flashmaster, 70 g Silica gel, gradient elution from 100% hexanes to 10% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo to afford 5-bromomethyl-1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole as a colorless oil, yield: 2.74 g (64% for both steps); 1H NMR (400 MHz, CDCl3): δ 7.35-7.55 (m, 4H), 6.70 (s, 1H), 4.21 (br s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:20]=[CH:19]2.[CH:33]1[CH:38]=[CH:37][C:36]([O:39][C:40](OC2C=CC=CC=2)=[N:41][C:42]#[N:43])=[CH:35][CH:34]=1>CC(O)C.C1COCC1>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:8]3[C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:4]#[C:3][CH2:2][NH:1][C:40](=[N:41][C:42]#[N:43])[O:39][C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH:6]=4)[N:11]=[CH:10][N:9]=3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N#CN=C(NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)Oc1ccccc1
Reaction time: 8 h
Yield: 49.6 %

Procedure:
[6-(3-Amino-prop-1-ynyl)-quinazolin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (280 mg, 0.663 mmol) is treated with diphenyl cyanocarbonimidate (163 mg, 1.031 equiv.) in a mixture of i-PrOH (12 ml) and THF (4 ml). Stir mixture overnight, then concentrate to dryness and chromatograph on silica (EtOAc/hexanes) to obtain 186.3 mg (49.6%) of pure desired product.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]1.[C:16](#N)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].ICC>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]1
Reactant: CC#N
Reactant: COC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Product: CCN1CCC(OC)(c2cccc(F)c2F)C1
Temperature: 110 °C
Yield: 27 %

Procedure:
A mixture of 3-(2,3-difluorophenyl)-3-methoxypyrrolidine (0.4 g, 1.87 mmol), acetonitrile (5 ml), sodium carbonate (0.52 g, 3.74 mmol) and iodoethane (0.28 g, 1.87 mmol) was heated at 110° C. in a sealed tube under microwave irradiation for 10 minutes. Water (30 ml) was added and the aqueous phase was extracted with ethyl acetate (2×50 ml), the combined organic phases was dried (MgSO4) and evaporated to give the crude product (0.45 g). Purification by flash chromatography (ethyl acetate/methanol 1:1) and by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.12 g, 27%). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 94-98° C. MS m/z (rel. intensity, 70 eV) 241 (M+, 5), 226 (54), 211 (27), 141 (50), 71 (bp).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14](N(C)C)=[O:15])[CH2:10]1.[C:19]1(C)C=CC=CC=1.C[Mg]Br.Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14](=[O:15])[CH3:19])[CH2:10]1
Reactant: CN(C)C(=O)C1=NOC(c2c(F)cccc2F)C1
Reactant: Cc1ccccc1
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Product: CC(=O)C1=NOC(c2c(F)cccc2F)C1
Temperature: -5 °C

Procedure:
To a 1 L flask equipped with a thermometer and addition funnel was added 5-(2,6-difluorophenyl)-4,5-dihydro-N,N-dimethyl-3-isoxazolecarboxamide (i.e. the product of Step A) (80.0 g, 0.31 mol) and toluene (320 mL). The reaction mixture was cooled to −5° C., and methyl magnesium bromide (3.0 M in tetrahydrofuran, 120 mL, 0.36 mmol) was added dropwise while maintaining the temperature between −10 and −5° C. When gas chromatography analysis of the reaction mixture showed about 2% of 5-(2,6-difluorophenyl)-4,5-dihydro-N,N-dimethyl-3-isoxazolecarboxamide remaining, the reaction mixture was poured into a stirred solution of concentrated hydrochloric acid (80 mL) and water (320 mL) while maintaining the temperature between 10 and 30° C. The organic layer was separated, washed with saturated aqueous sodium chloride solution (80 mL), and then concentrated under reduced pressure. The resulting oil was crystallized from hexanes (100 mL), collected by filtration, washed with hexanes, and dried in a vacuum oven overnight at 23° C. to provide the title compound as a waxy, off-white solid (65 g), melting at 47-50° C.
Reaction SMILES: CCOP(S)(OCC)=S.[Br:10][C:11]1[CH:12]=[C:13]([C:17](=O)[CH:18]=[CH:19][C:20]([OH:22])=O)[CH:14]=[CH:15][CH:16]=1.BrC1C=C(C(=O)CC(SP(OCC)(OCC)=S)C(O)=O)C=CC=1.O.[NH2:48][NH2:49]>C(O)C>[Br:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[CH:19][C:20](=[O:22])[NH:48][N:49]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C=CC(=O)c1cccc(Br)c1
Reactant: NN
Agent: CCOP(=S)(OCC)SC(CC(=O)c1cccc(Br)c1)C(=O)O
Agent: CCOP(=S)(S)OCC
Solvent: CCO
Solvent: O
Product: O=c1ccc(-c2cccc(Br)c2)n[nH]1
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
1.12 g (0.006 mole) of O,O-diethyldithiophosphoric acid were added, at room temperature, to a suspension of 1.28 g of 4-(3-bromophenyl)-4-oxo-2-butenoic acid in 10 ml of ethanol, and then the mixture was stirred for 10 minutes. Formation of 4-(3-bromophenyl)-2-diethoxyphosphinothioylthio-4-oxobutanoic acid was confirmed by thin layer chromatography but the compound was not separated from the reaction mixture. 0.3 g (0.006 mole) of hydrazine monohydrate was added to the reaction mixture, which was then stirred overnight at room temperature. At the end of this time, the crystals which had precipitated were collected by filtration and washed with ethanol to give 0.48 g of the desired 6-(3-bromophenyl)-3(2H)pyridazinone. The filtrate was concentrated and then subjected to column chromatography through silica gel eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give a further 0.48 g of the product, a total of 0.96 g (yield 76%) of the product, melting at 202°-204° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:25](O)(=[O:27])[CH3:26].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:25](=[O:27])[CH3:26])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CC3CCNCC3)ccc2n1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reaction time: 8 h

Procedure:
4-(2-chloro-6-(piperidin-4-ylmethyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (40 mg) was added to a pre-stirred (15 minutes) solution of acetic acid (5 eq), 1-Hydroxybenzotriazole (HOBt, 1.2 eq.), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.5 eq.), DIPEA (5 eq) in N,N-Dimethylformamide (DMF, 0.9 mL). The reaction was stirred overnight then extracted with Ethyl Acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of 1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:32]=[O:33]>O1CCCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH:32]=[O:33])[C:9]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To 2,4-difluoro-phenyl)-carbamic acid tert-butyl ester (123, 1.41 g, 6.17 mmol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at 78° C. were added n-butyllithium (2.50 M in hexane, 2.59 mL) for 30 min. Lithium diisopropylamide (2.0 M in hexane, 3.4 mL) was added to the reaction. After 35 min, N,N-dimethylformamide (1.05 mL, 0.0136 mol) was added to the reaction mixture. The reaction was allowed to cool to room temperature overnight. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography, eluting with 20% ethyl acetate in hexane to provide compound 124.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[C@H:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:12][C:13](=[O:16])[CH2:14][NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C=C(Cl)C(Cl)=CC=1[O:34][C:35](=O)[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CN1CCOCC1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:24])[C@H:11]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:12][C:13](=[O:16])[CH2:14][NH:15][C:35](=[O:34])[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 6.1 parts glycyl-L-phenylalanine benzyl ester hydrochloride, 7.0 parts N-t-butoxycarbonylglycine 2,4,5-trichlorophenyl ester and 1.8 parts N-methylmorpholine in 150 parts methylene chloride is stirred overnight at room temperature. The solvents are then removed by evaporation under reduced pressure to yield the crude tripeptide. Purification by low pressure column chromatography affords pure N-t-butoxycarbonylglycylglycyl-L-phenylalanine benzyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.Cl[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[O:29][CH:30]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[O:29][CH:30]=[C:26]([CH2:25][S:19][C:15]3[C:16]([C:17]#[N:18])=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=4)[C:12]([C:22]#[N:23])=[C:13]([O:20][CH3:21])[N:14]=3)[N:27]=2)=[CH:36][CH:35]=1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
400 mg (1.222 mmol) of 4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile together with 306 mg (1.344 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 410 mg (4.888 mmol) of sodium bicarbonate in 8 ml of DMF are stirred at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 10.4 mg (1.6% of theory) of the target compound.