Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.[CH:30]1[CH:31]=[CH:32][C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.NC1C=CC=CC=1>CN(C=O)C>[NH:36]([C:16](=[O:18])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=2[CH:14]=1)[C:34]1[CH:35]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cc2ccc(CC(=O)O)cc2s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: CCOC(=O)c1cc2ccc(CC(=O)Nc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
[2-(ethoxycarbonyl)-1-benzothien-6-yl]acetic acid (0.2 g, 0.757 mmol), EDCI (0.22 g, 1.15 mmol) and HOBt (0.16 g, 1.18 μmmol) were stirred in DMF (6 mL) for 10 minutes before adding aniline (85 mg, 0.913 mmol). The solution was stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue partitioned between H2O-EtOAc. The aqueous phase was extracted with further portions of EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Et2O was added and the resulting beige solid collected by filtration to give the product. 1H NMR (DMSO-d6) δ 10.21 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.42 (dd, J=8.4, 1.2 Hz, 1H), 7.27 (t, J=7.2 Hz, 2H), 7.01 (t, J=7.2 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.78 (s, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
To a solution of ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (200 mg, 0.51 mmol) in toluene (10 mL) at −78° C. was added DIBAH (2.0 mL) in toluene dropwise. The resulting solution was stirred at rt, quenched with 1N HCl (0.5 mL). The organic layer was washed with 1N HCl (5 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (50% EtOAc in hexane) to give the product (62 mg, 38% yield). LC-MS m/z 317.0 (MH+), retention time: 2.75 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl>>[ClH:1].[CH:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[C:2]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:12]
Reactant: C1CNCCN1
Reactant: CC(=O)Nc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Agent: Cl
Product: CC(=O)Nc1cccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)c1
Yield: 37 %

Procedure:
N-[3-(2-chloro-3-formyl-indol-1-yl)phenyl]-acetamide is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford N-{3-[3-Formyl-2-(piperazin-1-yl)-indol-1-yl]phenyl}-acetamide hydrochloride (37% yield) as a cream solid. ESI/MS 363 (M+H); RT 2.2 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[F:21][C:22]([F:39])([F:38])[O:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][C:32]([CH3:37])=[C:33]([CH2:35]I)[N:34]=2)[CH:27]=[CH:28][CH:29]=1>>[F:39][C:22]([F:21])([F:38])[O:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][C:32]([CH3:37])=[C:33]([CH2:35][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:34]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2cccc(OC(F)(F)F)c2)nc1CI
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(OC(F)(F)F)c4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-trifluoromethoxyphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 64 of molecular weight 519.52 (C27H28F3NO6), MS(ESI): 520.20 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[N:8]([CH:11]1[CH:14]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[NH:13][C:12]1=[O:24])=[N+:9]=[N-:10].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O>[Si:25]([N:13]1[CH:14]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:11]([N:8]=[N+:9]=[N-:10])[C:12]1=[O:24])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: [N-]=[N+]=NC1C(=O)NC1CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCOC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (0.2 mol) is added dropwise to an ice-cold stirred solution of 3-azido-4-(2-trifluoroacetoxyethyl)-azetidin-2-one (0.2 mol) and t-butyldimethylsilyl chloride (0.2 mol) in dimethylformamide (100 ml). The resulting mixture is stirred for 10 min. in the cold and for 10 min at room temperature, and then evaporated under vacuum to remove DMF. The residue is taken up to methylene chloride, washed with water and brine, dried with magnesium sulfate, and evaporated under vacuum to provide N-(t-butyldimethylsilyl)-3-azido 4-(2-trifluoroacetoxyethyl)-azetidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[N:12]3[N:29]=[CH:30][C:31]([CH:32]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(O)C.[NH:37]1[CH2:43][C:41](=[O:42])[NH:40][C:38]1=[O:39].N1CCCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]3)[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:43]4[C:41](=[O:42])[NH:40][C:38](=[O:39])[NH:37]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=O)cnn23)CC1
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 80 °C
Yield: 67 %

Procedure:
To the reaction flask, tert-butyl 4-(5-(3-chlorophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate (811 mg, 1.7 mmol) was added to ethanol (6.3 mL) along with hydantoin (172 mg, 1.7 mmol) and piperidine (170 μL, 1.7 mmol). The reaction was heated at 80° C. for 12 hours then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water and cold ethanol. The material was dried under vacuum overnight. The product, tert-butyl 4-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate, was recovered as a red solid in 67% yield after further purification by recrystallization from ethyl acetate/hexanes. LCMS (M+1=553)
Reaction SMILES: [OH-].[Li+:2].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[C:18]([C:19]3[C:20]([O:25][CH3:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([F:27])[CH:10]=2)=[C:6]([O:30][CH3:31])[CH:5]=1>C1COCC1>[Li+:2].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[C:18]([C:19]3[C:20]([O:25][CH3:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][C:12]([C:13]([O-:15])=[O:14])=[C:11]([F:27])[CH:10]=2)=[C:6]([O:30][CH3:31])[CH:5]=1
Reactant: COC(=O)c1cc(-c2cccnc2OC)c(Oc2ccc(Cl)cc2OC)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1Oc1cc(F)c(C(=O)[O-])cc1-c1cccnc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 149.9 %

Procedure:
Aqueous lithium hydroxide solution (1M, 0.57 mL, 0.57 mmol) was added to a solution of methyl 4-(4-chloro-2-methoxyphenoxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoate (Preparation 16, 0.0477 mg, 0.114 mmol) in THF (2.3 mL) and stirred for 72 hours at room temperature under a nitrogen atmosphere. The reaction was then concentrated in vacuo to afford the title compound as a white solid (0.070 g).
Reaction SMILES: [NH3:1].[CH3:2][CH:3]([CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:23])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:4][C:5](Cl)=[O:6]>O1CCCC1>[CH3:2][CH:3]([CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:23])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:4][C:5]([NH2:1])=[O:6]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CC(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CC(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To 100 ml of a tetrahydrofuran solution containing 1 g of ammonia, 9.5 g of the compound obtained in step (d) above was added dropwise at 0° to 5° C., and the mixture was stirred at room temperature for 30 minutes. The liquid reaction mixture was extracted with n-hexane, and the extract was washed with water and dried. The solvent was removed by distillation and the obtained oily substance was purified by column chromatography using silica gel to obtain 5.6 g of the intended compound in the form of an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:13]1[CH:22]=[C:21]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:25])[C:20]([N+:32]([O-:34])=[O:33])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].[CH2:35]([S:37]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])[CH3:36]>O>[CH2:35]([S:37]([C:40]1[CH:45]=[CH:44][C:43]([O:46][C:13]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:25])[C:20]([N+:32]([O-:34])=[O:33])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:42][CH:41]=1)(=[O:39])=[O:38])[CH3:36]
Reactant: CCS(=O)(=O)c1ccc(O)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Oc2cc(NC(=O)c3ccccn3)c([N+](=O)[O-])cc2C(=O)OC)cc1
Temperature: 80 °C
Yield: 82.2 %

Procedure:
3.5 g of potassium carbonate was added to a dimethylformamide (110 ml) solution of 6 g of methyl 2-fluoro-5-nitro-4-[(2-pyridinylcarbonyl)amino]benzoate and 3.48 g of 4-(ethylsulfonyl)phenol obtained in Reference Example 2, and stirred under heat at 80° C. for 30 minutes. The reaction liquid was restored to room temperature, poured into 300 ml of water, and the formed solid was taken out through filtration. This was dried under reduced pressure to obtain 7.46 g of the entitled compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][CH:25]([Cl:29])[C:26](Cl)=[O:27]>>[Cl:24][CH:25]([Cl:29])[C:26]([NH:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1)=[O:27]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)C(Cl)Cl
Yield: 37 %

Procedure:
Using compound (3S,3 aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1 (3H)-one (the product of step (e) in Example 1) (40 mg, 0.178 mmol) and 2,2-dichloro acetyl chloride (27.6 mg, 0.188 mmol) as starting materials, preparation following the method as described in Example 1(f) afforded white solid 20 mg, yield: 37%.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[Cl:11][CH:12]([CH:1]([OH:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCl
Reactant: COc1ccc(C=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cl)C(O)c1ccc(OC)cc1

Procedure:
Condensation reaction between p-anisaldehyde and methyl chloroacetate was effected in tetrahydrofuran at -78° C. in the presence of lithium diisopropylamide, and the methyl 2-chloro-3-hydroxy-3-(p-methoxyphenyl)propionate obtained was separated into anti isomer (a mixture of (2R, 3R) isomer and (2S, 3S) isomer) and syn isomer (a mixture of (2R, 3S) isomer and (2S, 3R) isomer) by silica gel chromatography (solvent: n-hexane/ethyl acetate=3/1). NMR of these isomers was measured to determine anti isomer and syn isomer. When these isomers were analyzed by high performance liquid chromatography by use of a chiralcel OJ 4.6 mmφ×250 mm manufactured by Dicel Chemical Industries, LTD. (mobile phase: n-hexane/i-propanol=7/3, flow rate: 1.0 ml/min, column temperature: 40° C.), a retention time of the anti isomer was 9.2 minutes and 9.9 minutes, and a retention time of the syn isomer was 11.7 minutes and 13.9 minutes.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](=O)[CH:27]=[CH2:28])[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][NH:31][NH2:32].O1CCCC1>C(OCC)(=O)C>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26]3[CH2:27][CH2:28][N:31]([CH3:30])[N:32]=3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CNN
Reactant: C=CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(CC2CN=C(c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)S2)=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of N-methyl-N-{2-[5-(2-oxobut-3-en-1-yl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (250 mg), methylhydrazine (0.050 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 3 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the insoluble substance was filtered off, and the filtrate was concentrated. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=3:7-5:5), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (156 mg, yield: 59%) as colorless needle crystals. MS:474(MH+). melting point 149-150° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].Cl.O[C@H:12]1CCN[C@@H:13]1C(OCC)=O>>[CH3:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: CCOC(=O)[C@H]1NCC[C@@H]1O
Reactant: C[C@H]1CCN[C@@H]1C(=O)O
Agent: Cl
Product: CCOC(=O)[C@H]1NCC[C@@H]1C

Procedure:
The title compound was prepared from (3S)-3-methyl-L-proline, using the methods used to prepare ethyl(3S)-3-hydroxy-L-prolinate hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.8 Hz, 3H) 1.2 (t, J=6.8 Hz, 3H), 1.6 (m, 1H), 2.1 (m, 1H), 2.3 (m, 1H), 3.2 (m, 2H), 3.8 (m, 1H), 4.2 (m, 2H), 4.7 (m, 1H), 9.0(s, 1H), 10.4 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10]Br.[NH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: N#Cc1ccc(Br)c(CBr)c1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)c(CN2CCSCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-(bromomethyl)benzonitrile (0.95 g, 3.46 mmol) in DMF (13.40 ml) was added thiomorpholine (0.417 ml, 4.15 mmol) and potassium carbonate (0.573 g, 4.15 mmol). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was poured onto water and extracted with EtOAc (×2). The organic extractions were combined, washed with brine (×3), dried (MgSO4) and evaporated to give a yellow oil. This was purified by flash silica chromatography (Biotage column) (eluent=25% ether/isohexane) to give the sub-title compound as a colourless oil. Yield: 0.951 g
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26]>C(O)CCC>[CH3:1][N:2]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: OCCOCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN(CCOCCOCCO)c1ccccc1

Procedure:
A mixture of freshly distilled N-methylaniline (116 g, 1.1 mol), potassium carbonate (175 g, 1.25 mol), sodium iodide (4 g, 0.025 mol), 2-[2-(2-chloroethoxy)ethoxy]ethanol (168 g, 1 mol), and 900 mL of butanol was heated at reflux for 72 hours under nitrogen with vigorous stirring. After cooling and filtration the butanol was evaporated at reduced pressure to leave a tan oil. The oil was fractionally distilled in vacuo, yielding 150 g (63%) as a colorless oil, bp 190°-191° C. (0.13 mm).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([S:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13]
Reactant: Sc1ccccc1Cl
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1cc(Sc2ccccc2Cl)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 64.1 %

Procedure:
To 5 ml of chloroform were added 0.95 ml of diisopropylethylamine, 0.5 g of 4-(2-butynyloxy)-6-chloropyrimidine, and 0.42 g of 2-chlorothiophenol, followed by stirring at room temperature for 7 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.51 g of 4-(2-butynyloxy)-6-(2-chlorothiophenoxy)pyrimidine (the present compound (142)).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C1C=C[C:9]2N(O)N=[N:12][C:10]=2[CH:11]=1>CN(C=O)C>[CH:3]([NH:12][CH:10]([CH3:9])[CH3:11])([CH3:4])[CH3:2].[NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: On1nnc2ccccc21
Solvent: c1cc[nH]c1
Solvent: CN(C)C=O
Product: CC(C)NC(C)C

Procedure:
Chloropyrrolotriazine (1) (compound 3 of Scheme 9) can be reacted with an aniline (1a) (e.g., compound 1 of Scheme 11) in anhydrous DMF at rt to afford compound (2). Reaction of compound (2) with an aq. base such as NaOH with heating affords compound (3). Compound (3) can be reacted with an amine R2NH2 in the presence of a coupling reagent, such as HOBt, with or without a base such as diisopropylamine, in an organic solvent, such as DMF to afford compound (4). Compound (4) can be reacted with hydrogen in the presence of a catalyst, such as Pd/C, in an organic solvent, such as MeOH to afford compound (5). Reaction of compound (5) with an isocyanate in an organic solvent, such as DCE affords compound (6).
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH:4]1O)#[N:2].Cl.C(OCC)(=O)C.C(OC(C)C)(C)C>N1C=CC=CC=1>[C:1]([C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH:4]=1)#[N:2]
Reactant: COc1cccc2c1CCC(C#N)C2O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: COc1cccc2c1CCC(C#N)=C2

Procedure:
A mixture of the compound obtained in step (iv) above (16.2 g, 0.079 mol) and POCl (30 ml, 0.32 mol) in pyridine (200 ml) is heated for 3 hours to 120° C. ext.. The reaction mixture is then cooled and made acidic by the dropwise addition of 2N HCl. The solution is treated with ethyl acetate, the organic phase is recovered, washed with a saturated sodium bicarbonate solution and then with water. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness yielding the compound indicated in the title [9.8 g); m.p. 47°-49° C. (isopropyl ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.N1C=CC=CC=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(F)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
5 g (40.1 mmol) of 3-fluoro benzaldehyde, 8.38 g (2 eq.) of malonic acid, and 0.34 g (0.1 eq.) of piperidine were added to 9.52 g (3 eq.) of pyridine and stirred at room temperature for about 1 hour. After heating it to 80° C., the mixture was stirred for 12 hours. After the reaction, the resulting solution cooled to room temperature and was slowly added with 1M HCl until it was titrated to about pH 4. The resulting powder was filtered and washed with water, and then dried in a vacuum oven. (Yield: 84%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[I:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH2:22].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:22][C:21]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:19]([I:18])[CH:20]=1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: Cc1ccc(N)cc1I
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccc(C)c(I)c2)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 3-fluoro-4-methyl benzoic acid (1.15 g, 7.44 mmol) in CH2Cl2 (50 mL) and DMF (2 drops) was cooled to 0° C. under argon and treated with oxalyl chloride (0.71 mL, 8.18 mmol) dropwise. The mixture was warmed to r.t. and stirred for 1 h. In a separate flask, 3-iodo-4-methyl aniline (2.60 g, 11.16 mmol), K2CO3 (1.54 g, 8.93 mmol) and pyridine (4 drops) were suspended in CH2Cl2 (10 mL). The mixture was cooled to 0° C. under argon and the acid chloride reaction mixture was slowly added. Upon complete addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 days. The resultant solid was filtered off and the reaction mixture was diluted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. Diethyl ether was added and the impurities were filtered off, affording the title compound as a brown solid. 1H-NMR (400 MHz, d6-DMSO) δ: 10.24 (1H, s), 8.32 (1H, d), 7.77 (3H, m), 7.46 (1H, t), 7.32 (1H, t), 2.35 (3H, s), 2.32 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[N:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1cnc(I)nc1
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: [K+]
Solvent: C1COCCO1
Product: Fc1ccccc1-c1ncc(Br)cn1
Temperature: 110 °C
Yield: 71.4 %

Procedure:
A mixture of 5-bromo-2-iodopyrimidine (2.58 mmol, 0.500 g), 2-fluorophenylboronic acid (3.87 mmol, 0.542 g), 2M aqueous solution of K2CO3 (7.76 mmol, 3.9 ml), Pd(PPh3)4 in dioxane (12 ml) was heated at 110° C. overnight. The solvent was evaporated and the solid residue was extracted between water and ethyl acetate. The organic phase was evaporated and the crude residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 0.466 g (yield 56%) of the expected product.