Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]2)=[C:4]([NH2:17])[N:3]=1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][C:4]=3[NH2:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: Nc1nc(Cl)nc2c1ncn2C1C=CCCC1
Reactant: NC1CCCCC1
Solvent: CCO
Product: Nc1nc(NC2CCCCC2)nc2c1ncn2C1C=CCCC1
Yield: 77 %

Procedure:
A mixture of 2-chloro-9-(2-cyclohexenyl)-9H-adenine (300 mg., 1.2 mmole) and 1 ml. of cyclohexylamine in 3 ml. of ethanol is heated at 120°-125° C. for a period of 89 hrs. in a sealed tube and then evaporated in vacuo to give an oil. Purification of residual oil by column chromatography on silica gel affords 288 mg (77%) of 9-(2-cyclohexenyl)-2-cyclohexylamino-9H-adenine, m.p. 108°-111° C. IR (KBr): 3315, 3170, 2925, 2845, 1630, 1600, 1530, 1470, 1405 cm-1. UV: λmaxEtoH 224 nm(ε26,500), 259 nm(ε11,100), 291 nm(ε9,900). NMR(CDCl3): δ 0.9-2.3(16H,m), 3.75(1H,br.s), 4.95(1H,br.s), 5.4-6.2(2H,m), 7.42(1H,s).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[C:6]([Br:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:11]1[C:10]2[C:5](=[C:6]([Br:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:22])([F:1])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:12]=1
Reactant: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Br)c3n2)nc1
Temperature: 115 °C

Procedure:
To 2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-3H-quinazolin-4-one (0.19 g, 0.52 mmol) at rt were added DIEA (0.18 mL, 1.04 mmol) and POCl3 (3.5 mL, 76 mmol) and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and then was concentrated under reduced pressure. The residue was treated with toluene and concentrated to dryness twice. The residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL), and the separated EtOAc layer was diluted with EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL), brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-quinazoline as a brown viscous oil (207 mg, quantitative).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C@H:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35].[Br:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Br:41][C:42]1[CH:47]=[CH:46][C:45]([O:32][C@@H:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35])=[CH:44][CH:43]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COC(=O)[C@H](O)C(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](Oc1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
Diethylazodicarboxylate (17.5 ml) in dry toluene (60 ml) was added dropwise over 30 minutes to a cooled, stirred solution of triphenylphosphine (34 g), methyl (R)-2-hydroxy-3-methylbutanoate (17 g, J.Am. Chem. Soc., (1990), 112, 21, 7659) and 4-bromophenol (24 g) in dry toluene (180 ml). The resulting solution was stirred at room temperature for 30 minutes and was then concentrated under reduced pressure to approximately half the original volume. A mixture of isohexane (700 ml) was added and the mixture stirred at room temperature for 20 minutes. The solution was filtered to remove triphenylphosphine oxide and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with isohexane: dichloromethane (1:4) then (2:3) to give the sub-title compound as an oil (28 g).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:19][O:20]CC2C=CC(OC)=CC=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>C(O)C.FC(F)(F)C(O)=O.[Pd]>[OH:20][CH2:19][CH:7]([CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: [H][H]
Reactant: CCOC(=O)CCCCCOC(COCc1ccc(OC)cc1)Cn1ccnc1
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCCOC(CO)Cn1ccnc1
Temperature: 25 °C

Procedure:
A solution of ethyl 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoate (Example 4; 5.8 g 0.014 mol) in ethanol (20 ml) and trifluoroacetic acid (1 ml) containing a catalytic amount of 10% palladium on carbon (0.5 g) was stirred at room temperature under a hydrogen atmosphere. When hydrogen uptake had ceased the solution was filtered and the solvent was evaporated off under reduced pressure. The residue was treated with a saturated aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane. The extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (silica gel, chloroform to 5% ethanol in chloroform) to give ethyl 6-[2-hydroxy-1-(1H-imidazol-1-yl methyl)ethoxy]hexanoate as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:39](O)[CH:40]([OH:45])[CH2:41][CH2:42][CH2:43][OH:44].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:19]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:45][CH:40]([CH2:41][CH2:42][CH2:43][OH:44])[CH2:39][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCCC(O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CCCO)O1
Temperature: 25 °C

Procedure:
A mixture of dilinoleyl ketone (I, previously prepared as described in Example 1, 1.0 g, 2 mmol), 1,2,5-pentanetriol (crude, 0.25 g, 2 mmol) and pyridinium p-toluenesulfonate (100 mg, 0.4 mmol) in 150 mL of toluene was refluxed under nitrogen overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (3×40 mL), brine (50 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent gave a yellowish oily residual (1.1 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with 0-1% methanol in dichloromethane as eluent. This afforded 0.90 g of pure II as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21]>O.[Cu]>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)Cc1ccccc1I
Reactant: Fc1ccc(S)cc1Cl
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccccc1Sc1ccc(F)c(Cl)c1
Yield: 72 %

Procedure:
The thiophenol from the preceding experiment (34.5 g) is added at 50° C. to a solution of potassium hydroxide (40 g) in water (425 ml) and this mixture is stirred until it becomes homogeneous. Then, o-iodophenylacetic acid (55.0 g) and copper powder (2.0 g) are added and the mixture refluxed for 24 hours. While still warm, the solution is filtered with charcoal, the filtrate diluted with water and acidified with hydrochloric acid. The separated crude oily acid is extracted with benzene, the solvent evaporated and the residue crystallized from aqueous ethanol, yielding 45.2 g (72%) of 2-(3-chloro-4-fluorophenylthio)phenylacetic acid which in the pure state melts at 85°-87° C. (cyclohexane-hexane).
Reaction SMILES: C(OC([N:8]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH3:42])=[CH:36][CH:35]=1)[C:9]1[N:20]2[C:16](=[CH:17][CH:18]=[N:19]2)[N:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][N:13]2[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:41]([O:40][C:37]1[CH:36]=[CH:35][C:34]([NH:8][C:9]2[N:20]3[C:16](=[CH:17][CH:18]=[N:19]3)[N:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][N:13]3[C@H:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[CH:39][CH:38]=1)[CH3:42]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4ccnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Nc2c3c(nc4ccnn24)N([C@H]2CCCNC2)CC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
To a methylene chloride (4 mL) solution containing tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (0.693 mmol), trifluoroacetic acid (2 mL) was added with ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 16 hr. After the reaction, the reaction solution was poured into aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with PTLC {10% (2 mol/L ammonia/methanol)-methylene chloride} to obtain the title compound (97.0 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:5]2=[C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24](Cl)=[O:25].CO>ClCCl>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[N:7]=[CH:8][CH:9]=2)[NH:16][C:2]=1[CH3:1])=[O:25]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Cc1cc2ccnc(NC(=O)C3CC3)c2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: Cc1[nH]c2c(NC(=O)C3CC3)nccc2c1C(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
N-(2-Methyl-1H-pyrrolo[2,3-c]pyridin-7yl)cyclopropanecarboxamide (100 mg, 0.46 mmol) was added to a stirred suspension of aluminium chloride (620 mg, 4.65 mmol) in dry dichloromethane (5 mL) and the mixture was stirred at room temperature for about 1 hour under argon atmosphere. This was followed by drop wise addition of a solution of 2,6-dichlorobenzoyl chloride (194 mg, 0.93 mmol) in dichloromethane and stirring overnight at room temperature. After completion, methanol (10 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The residual mass was diluted with water and extracted with ethyl acetate. The combined organic layer was neutralized using aq. sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-[3-(2,6-dichlorobenzoyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (70 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][CH3:24])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39](OCC)[CH3:40])#[N:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][N:23]([CH3:24])[C:39](=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:30]#[N:31])[CH3:40])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C1=C(COCCNC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CCOC(C)=Nc1ccccc1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(COCCN(C)C(C)=Nc2ccccc2C#N)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 150 °C
Yield: 28.8 %

Procedure:
A mixture of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-methylaminoethoxymethyl)-1,4-dihydropyridine (2.5 g.), ethyl N-(2-cyanophenyl)acetimidate (1.1 g.) and p-toluenesulphonic acid (0.1 g.) was heated at 150° C. for 4 hours, cooled, and then dissolved in chloroform. The solution was washed with sodium bicarbonate solution, water and dried over sodium sulphate. Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform/hexane (1:1) gave the product as an oil (0.95 g.) which was used directly in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]([CH2:22][CH2:23][CH3:24])[C:19]([NH2:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:18]([CH2:22][CH2:23][CH3:24])[CH2:19][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCCC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(CN)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a stirred solution of the crude 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-propyl-3-phenylpropanamide in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (2.0 mL, 2.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 24 hr, the mixture was carefully quenched with MeOH, poured into brine (100 mL), extracted with ethyl acetate (2×100 mL), dried (Na2SO4) and concentrated to give 45 mg (94% yield, 3 steps) of 2((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)pentan-1-amine.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=3[S:22][C:6]=2[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH2:37])=[CH:34][CH:35]=2)[CH:30]=[N:29]1>>[F:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH:37][C:2]3[C:7]4[C:8]5[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=5[S:22][C:6]=4[N:5]=[CH:4][N:3]=3)=[CH:34][CH:35]=2)[CH:30]=[N:29]1
Reactant: CC(C)(C)OC(=O)N1CCCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CCCNC6)ccc32)c1
Yield: 63 %

Procedure:
The title compound was synthesized in analogy to Example 12A from tert-butyl 4-chloro-5,6,7,9-tetrahydro-8H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepine-8-carboxylate from Example 80A (200 mg, 0.59 mmol) and 1-(3-fluorobenzyl)-1H-indazol-5-amine from Example 8A (149 mg, 0.62 mmol) to yield 213 mg (77% purity, 63% yield), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSc1nccc(-c2cc3c(N)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Product: CSc1nccc(-c2cc3c(NC(=O)OCc4ccccc4)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1

Procedure:
Following a similar procedure to that described in example 245, but starting from 3-amino-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (obtained in example 123) and benzyl chloroformate, the desired compound was obtained.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[NH2:10][C:11]([NH2:13])=[O:12].C(OC(=O)C)(=O)C>CN(C)C=O>[F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][NH:13][C:11](=[O:12])[NH:10][C:4]1=[O:5]
Reactant: NC(N)=O
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 63.7 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (350 mg; 2.5 mmoles), urea (170 mg: 2.8 mmoles) and acetic anhydride (1 ml) in dimethyl-formamide (2 ml) was stirred at 100° C. for 40 minutes. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 290 mg (yield: 64%) of 5-trifluoromethyldihydrouracil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17](C)=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1.Cl[C:26]1C=C(C=CC=1)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([CH3:26])[N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2nc([S@@](=O)Cc3nc(C)cc(OC)c3C)[nH]c2c1
Temperature: 0 °C

Procedure:
(5)6-methoxy-2[[(4methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]1H-benzimidazole (16.2 g; 0.0492 mol)) is reacted with m-chlorobenzoic acid (13.6 g; 0.0537 mol) with CH2Cl2 acting as a solvent at a pH of 8.6. The pH is maintained by the presence of KHCO3 (5.6 g; 0.056 mol) acting as a buffer. The temperature is maintained at about 0° C. during the addition. Diluted NaOH is added to a pH above 12 and the CH2Cl2 phase is separated off. Dimethylformamide (4.7 g) is charged to the water phase and the pH is kept above 9, whereupon crystals a mixture of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole are formed. The crystals are filtered off and are washed with water and methanol at a temperature of about 0° C. The washed crystals are then dried under vacuum and are found to predominantly contain 6-methoxy-2-[[(4-methoxy-3,5dimethyl-2-pyridinyl)methyl]sulfinyl]1H-benzimidazole.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].[C:6]([C:14]1[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[C:6]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:2][CH3:1])[CH:15]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CO
Reactant: O=C(c1ccccc1)c1ccnc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Product: COc1cc(C(=O)c2ccccc2)ccn1
Reaction time: 1 h

Procedure:
While heating under reflux a 28% sodium methoxide methanol solution mildly, a mixture of 135 g of 4-benzoyl-2-chloropyridine and 150 ml of methanol was added dropwise thereinto over one hour, followed by heating under reflux for further 2 hours. After cooling as it was, the reaction solution was filtered to remove insoluble matters and the solvent was removed. To the residue was added an aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and then the solvent was removed, to give 130 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:7]1[N:8]([CH3:11])[C:9]2[C:5]([N:6]=1)=[C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cn1c(Br)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 60 °C
Yield: 85.2 %

Procedure:
To a suspension of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (5.08 g, 20.0 mmol) in acetonitrile (100 mL) was added N-bromosuccinimide (5.34 g, 30.0 mmol). The mixture was heated at 60° C. for 4 h. Cooled to rt, the contents were concentrated on a rotary evaporator. The remaining slurry was diluted with DCM and washed with a mixture of diluted Na2CO3 and NaHSO3 (2×), dried (Na2SO4), filtered and concentrated. The slightly orange solid was triturated with hot acetonitrile (˜70 mL). After cooled to room temperature (rt), the solid was collected with filtration and washed with acetonitrile. The filtrate was concentrated (to ˜30 mL) to yield a second crop. The product was dried in air then under vacuum to give 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (5.67 g, 85%). LCMS: M+H+=332.0, 334.0.
Reaction SMILES: [O-]CC.[Na+].C([S:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1)(=O)C.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>C(O)C>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][S:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1)[CH3:17]
Reactant: CC(=O)SC1C=CCCCC1
Reactant: CCOC(CBr)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CSC1C=CCCCC1)OCC
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of fresh sodium ethoxide prepared from 7.6 g (washed well gram-atom metallic sodium) in 200 ml of absolute ethanol was treated dropwise with 56.18 g (0.330 mole) of 3-acetylmercaptocycloheptene in 10 ml of absolute ethanol. The reaction was heated under reflux for 15 minutes and then cooled to room temperature. A solution of 49.69 ml (0.330 mole) of bromoacetaldehyde diethylacetal in 30 ml of absolute ethanol was added dropwise. The reaction mixture was heated under reflux for 2.0 hours and cooled. The precipitated sodium bromide was filtered and washed with absolute ethanol. The filtrate was concentrated and the residue partitioned between ether/brine. The aqueous phase was further extracted with ether. The organic extracts were pooled, dried over magnesium sulfate, and evaporated to afford 80.1 g (0.328 mole, 99%) of pure 3-[(2,2-diethoxyethyl)thio]-1-cycloheptene, as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([O:17]CC)(=O)[CH2:10][C:11]([O:13]CC)=O>>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][C:11](=[O:13])[CH2:10][C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=2)=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)CC(=O)OCC
Product: Cc1cccc(NC(=O)CC(=O)Nc2cccc(C)c2)c1
Temperature: 170 °C
Reaction time: 8 h

Procedure:
100 mmol m-toluidine and 50 mmol diethyl malonate were put together and stirred overnight at 170° C. The formed ethanol was distilled off directly (100 mmol≡6.6 mL) on a stream of nitrogen. N1,N3-di(3-methylphenyl)malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 9.5 g N1,N3-di(3-methylphenyl)malonamide (yield 67.3%, purity 97.2%) was obtained.