Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][CH2:41][S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[OH:48][C:47]1[CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])=[CH:15][CH:14]=2)[O:18][C:44](=[O:45])[C:43]=1[S:42][CH2:41][CH2:40][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(S(=O)(=O)c3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(phenylsulfonyl)acetophenone (2.50 g, 9.61 mmol), lithium bis(trimethylsilyl)amide (2.41 g, 14.42 mmol), chlorotrimethylsilane (1.83 mL, 14.42 mmol), THF (96 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 194-195° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 3.01 (t, 2 H), 6.87 (s, 1 H), 7.19 (m, 5 H), 7.68 (m, 3 H), 8.04 (m, 6 H), 12.05 (bs, 1 H).
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12]O)=[CH:9]2)=[N:4]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][N:37]3[C:33](=[O:43])[C:34]4[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:36]3=[O:38])=[CH:9]2)=[N:4]1)[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCn1cc2cc(CO)ccc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCn1cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (2-ethyl-2H-indazol-5-yl)methanol (step-2 of Example 13, 132 mg, 0.75 mmol) in THF (10 mL) was added triphenylphosphine (236 mg, 0.90 mmol) and phthalimide (132 mg, 0.90 mmol). The mixture was cooled to 0° C. Then, to the mixture was added 40% DEAD in toluene (0.30 mL, 0.75 mmol) and allowed to warm up to room temperature. The mixture was stirred at room temperature for 4 hrs. The reaction mixture was evaporated. The residual oil was purified by silica gel column chromatography (0-50% EtOAc in hexane) to give the titled compound as a mixture. The mixture was used next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:11](C(O)=O)=[C:10](O)[C:9]2[C:4](=[C:5]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:26])[C:9]2[C:4](=[C:5]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2c(-c3ccc(Cl)cc3Cl)nccc2c(O)c1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(Cl)c2ccnc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 230 °C

Procedure:
A solution of 2-methyl-3-carboxy-4-hydroxy-8-(2′,4′-dichlorophenyl)-1,7-naphthyridine (0.41 g, 1.2 mmole) in diphenyl ether (0.4 ml) is stirred and heated to 230° C. for 1.5 h. The solution is allowed to cool to r.t., and POCl3 (0.8 ml) is added. This mixture is heated to 100° C. for 2 h, then allowed to cool to r.t., and poured into 5% NaHCO3. This is extracted with EtOAc, the organic phase washed with brine, dried and concentrated. The product is purified by flash chromatography on silica gel to give the title compound D7.
Reaction SMILES: [C@H:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)[N:13]=1.[H-].[Na+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[C:24]([N:5]1[CH2:6][C@@H:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]1[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)[N:13]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c(N2CC3C[C@H]2CN3)nc(-c2ccncn2)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(N2CC3C[C@H]2CN3C(=O)c2ccccc2)nc(-c2ccncn2)cc1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a solution of 0.13 g (0.46 mmol) of (1S)-2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one in 3 ml of anhydrous dimethylformamide was added 24 mg (0.6 mmol) of sodium hydride and the resulting mixture was stirred at 0° C. for 15 min. There is added 0.07 ml (0.6 mmol) of benzoyl chloride and the resulting solution was stirred at 0° C. for 2h. Water was added to the mixture and the resulting solution extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 100/0 to 97/3 to give 90 mg (50%) of pure compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=O)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].Br[CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C(OC)=O.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[C:5]2[O:12][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc(C=O)c1O
Reactant: COC(=O)C(Br)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(Cl)cc2cc(-c3ccccc3)oc12
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A mixture of 3.0 g of methyl 5-chloro-3-formyl-2-hydroxybenzoate, 3.44 g of methyl α-bromophenylacetate, 8.28 g of potassium carbonate and 50 ml of dimethylformamide is heated at 70°-80° C. for 15 minutes and further heated at 100° C. for 10 minutes. After cooling, water is added to the mixture, and the aqueous mixture is acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is dissolved in 50 ml of ethanol, and 4.5 g of potassium hydroxide are added to the solution. The mixture is refluxed for 1 hour and then evaporated to remove solvent. Water is added to the residue, and the aqueous mixture is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated to remove solvent. 150 ml of xylene and 30 mg of p-toluenesulfonic acid are added to the residue and the mixture is refluxed for 1 hour. The reaction mixture is evaporated to remove solvent and the residue is dissolved in ethyl acetate. The solution is washed, dried and evaporated to remove solvent. The residue is crystallized from isopropyl ether to give 2.32 g of 5-chloro-2-phenylbenzofuran-7-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[C:36](=[O:40])[NH:35][CH2:34]5)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc2c(c1)CNC2=O
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc5c(c4)CNC5=O)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (70 mg, 0.17 mmol) and 5-aminoisoindolin-1-one (25 mg, 0.17 mmol) in dichloromethane (15 mL) were added the solution of 1-methyl-1H-imidazole (55 mg, 0.68 mmol) and EDCI (129 mg, 0.68 mmol) in dichloromethane (5 mL), the reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, then methanol (5 mL) was added, the precipitate was collected by filtration and washed with methanol (3 mL) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(1-oxoisoindolin-5-yl)piperidine-3-carboxamide (48 mg, 51.8%) as a brown solid. 1H NMR (300 MHz, DMSO): δ 10.29 (s, 1H), 9.64 (s, 1H), 8.84 (s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.64-7.53 (m, 3H), 7.33 (dd, 1H, J1=8.4 Hz, J2=1.8 Hz), 6.80 (brs, 1H), 4.81-4.63 (m, 2H), 4.33 (s, 2H), 3.68 (s, 3H), 3.59 (s, 3H), 3.14-2.92 (m, 2H), 2.65-2.60 (m, 1H), 2.04-2.00 (m, 1H), 1.81-1.69 (m, 2H), 1.49-1.45 (m, 1H). LC-MS: 545.9 [M+H]+, tR=1.42 min. HPLC: 99.69% at 214 nm, 99.44% at 254 nm, tR=4.87 min.
Reaction SMILES: [OH:1][C:2]([CH3:49])([CH3:48])[CH2:3][O:4][N:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]3[CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([O:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[C:31]([CH3:44])([CH3:43])[CH2:30]3)[N:21]=[C:20](Cl)[N:19]=2)[CH2:7][C:6]1([CH3:47])[CH3:46].[CH2:50]([CH2:52][NH2:53])[OH:51].[OH-].[Na+]>>[OH:1][C:2]([CH3:49])([CH3:48])[CH2:3][O:4][N:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]3[CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([O:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[C:31]([CH3:44])([CH3:43])[CH2:30]3)[N:21]=[C:20]([NH:53][CH2:52][CH2:50][OH:51])[N:19]=2)[CH2:7][C:6]1([CH3:47])[CH3:46]
Reactant: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of the intermediate prepared in Example 11 with ethanolamine and sodium hydroxide. The aqueous layer is removed, and the remaining layer is extracted with cyclohexane. Solvent is evaporated at reduced pressure, and the crude product is purified by flash chromatography on silica gel with 1:2 (v/v) hexane/ethyl acetate to afford 4.1 g of the title compound as a white solid, melting at 110-120° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[CH3:13][C:14]1[C:19]2[NH:20][C:21](=[O:23])[O:22][C:18]=2[CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[F:12][C:10]1[CH:11]=[C:3]([CH:4]=[C:5]([C:6]([C:16]2[CH:15]=[C:14]([CH3:13])[C:19]3[NH:20][C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)=[O:7])[CH:9]=1)[C:1]#[N:2]
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: N#Cc1cc(F)cc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
1.84 g (10.0 mmol) 3-cyano-5-fluoro-benzoic acid chloride, 1.49 g (10.0 mmol) 4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. Then the mixture was mixed with ice water. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:19]([NH:27][NH2:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:28]/[NH:27][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.36 to 1.39 (m, 4H), 1.69-1.75 (m, 2H), 3.73 (t, 2H), 3.87 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.98 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])/[CH:4]=[CH:5]/[C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1.[CH3:13][S:14][C:15]1[N:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH:17][N:16]=1>>[CH3:1][O:2][C:3](=[O:12])/[CH:4]=[CH:5]/[C:6]1[S:7][C:8]([C:17]2[CH:18]=[CH:19][N:20]=[C:15]([S:14][CH3:13])[N:16]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)/C=C/c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Product: COC(=O)/C=C/c1ccc(-c2ccnc(SC)n2)s1
Yield: 45 %

Procedure:
(E)-3-[5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-acrylic acid methyl ester was prepared analogous to Step A of Method D, using (E)-3-(5-bromo-thiophen-2-yl)-acrylic acid methyl ester and 2-methylsulfanyl-4-tributylstannanyl-pyrimidine. Yield: 45%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[CH:7]=[CH:6][C:5]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(Cl)CCl.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:12](=[O:14])[NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[CH:7]=[CH:6][C:5]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-((2S)-2-tert-Butoxycarbonylamino-2-carboxy-ethyl)-2-methoxycarbonylmethoxy-benzoic acid methyl ester of Step F (51 mg, 0.12 mmol) is stirred in CH2Cl2 (1.2 mL) at 0° C. under N2. EDC (24 mg, 0.12 mmol) is added and the reaction mixture is stirred for and additional 10 minutes. 4-Methoxybenzyl amine (0.18 μl, 0.14 mmol) is then added and the reaction is allowed to warm to RT overnight. The reaction is diluted with CH2Cl2 (25 mL) and is subsequently washed with 2N HCl (2×25 mL) and then saturated NaHCO3 (2×25 mL). The organics are then dried over MgSO4, filtered and and purified by flash column chromatography to provide 5-[(2S)-2-tert-butoxycarbonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)C.[ClH:33]>CO>[ClH:33].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(=O)[nH]c2cc(OCC3CO3)ccc12
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(=O)[nH]c2cc(OCC(O)CN3CCN(c4ccccc4)CC3)ccc12
Yield: 63 %

Procedure:
2.4 Grams of 4-methyl-7-(2,3-epoxypropoxy)carbostyril and 1.8 g of 4-phenylpiperazine are mixed with 30 ml of ethanol and heated for 3 hours under refluxing conditions. After cooling the reaction mixture, crystals thus precipitated are collected by filtration and washed with ether. The crude crystals thus obtained are dissolved in 50 ml of methanol and 3 ml of concentrated hydrochloric acid. The mixture then is concentrated under reduced pressure to dryness. The residue thus obtained is recrystallized from ethanol-ether to obtain 2.7 g (yield: 63%) of 4-methyl-7-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]carbostyril monohydrochloride in the form of colorless crystals with a melting point of 190°-191° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:16])[C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5]O.S(Cl)([Cl:19])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:16])[C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5][Cl:19]
Reactant: O=S(Cl)Cl
Reactant: CN(C)S(=O)(=O)c1c(Br)cc(CO)cc1Br
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1c(Br)cc(CCl)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of OBS02015 (3.93 g, 10.10 mmol) in anhydrous DCM (50 mL) was added thionyl chloride (1.11 mL, 15.15 mmol). The mixture was stirred at room temperature for 2 h and the volatiles removed in vacuo. The residue was re-dissolved and co-evaporated three times with DCM (3×20 mL) to give OBS02018 as a brown oil which solidified on standing (3.93 g, 96%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.83; 1H-NMR (270 MHz, CDCl3)=3.11 (6H, s), 4.46 (2H, s), 7.59 (2H, s). Dimethylsulfamic Acid 2,6-dibromo-4-{[(4-cyano-phenyl)-[1,2,4]triazol-4-ylamino]methyl}phenyl ester (OBS02019, STX740)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2′-Ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester (0,172 g, 0.5 mmol) and diisopropylethylamine (0.18 mL, 1.0 mmol) were combined in CH2Cl2 (2.5 mL) and cooled to 0° C. Benzyl chloroformate (0.1 mL, 0.7 mmol) was added, and the reaction was stirred for 1 hour. The mixture was purified by silica gel chromatography, and then further purified by preparative HPLC to give the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40]OC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[OH:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[C:63]([C:68]#[N:69])=[N:64][CH:65]=[CH:66][N:67]=2)=[CH:58][CH:57]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:55][C:56]3[CH:57]=[CH:58][C:59]([C:62]4[C:63]([C:68]#[N:69])=[N:64][CH:65]=[CH:66][N:67]=4)=[CH:60][CH:61]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1nccnc1-c1ccc(O)cc1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nccnc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1

Procedure:
The title compound 86 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 86A: 1H NMR (DMSO-d6): δ 8.96 (d, J=2.45 Hz, 1H), 8.76 (d, J=2.45 Hz, 1H), 8.02 (d, J=7.98 Hz, 2H), 7.90-7.93 (d, J=7.98 Hz, 2H), 7.78 (d, J=7.98 Hz, 1H), 7.67 (d J=7.67 Hz, 1H), 7.33-7.49 (m, 4H), 7.11-7.15 (m, 2H), 4.84 (s, 2H), 4.1 (t, J=6.29 Hz, 2H), 3.70-3.74 (m, 2H), 3.19-3.23 (m, 2H), 3.03 (t, J=5.83 Hz, 2H), 2.02-2.09 (m, 2H). ESI (+)/MS: 674 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([CH2:8][Cl:9])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH2:14]>C1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[CH2:8][Cl:9])=[O:7])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C=NC(=O)C(Cl)CCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: O=C(NC(=O)C(Cl)CCl)Nc1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Yield: 75.8 %

Procedure:
A solution of 17.0 g (0.1 mole) of 2,3-dichloropropionyl isocyanate in 50 ml of wash benzine was added dropwise to a solution of 16.0 g (0.1 mole) of 3,4-dichloroaniline in 150 ml of dry benzene at 0° to 5° C, while cooling. In the course thereof, the reaction product crystallized out. The mixture was stirred for a further hour at 20° C and was filtered, and the product was washed with petroleum ether and dried. 25 g of N-(3,4-dichlorophenyl)-N'-(2,3-dichloropropionyl)-urea of melting point 145° to 148° C, with decomposition, were obtained. The yield was 76% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13](Cl)=[O:14].C(N(CC)CC)C>O1CCOCC1>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: Nc1ccnc(Cl)c1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-3-fluoropyridin-4-ylamine (660 mg, 4.5 mmol), 2,6-dichlorobenzoyl chloride (1.43 mL, 2.10 g, 10.0 mmol) and triethylamine (1.53 mL, 1.11 g, 11.0 mmol) in dioxane (12 mL) was heated under reflux for 18 hours then cooled to ambient temperature. The resultant mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered, dried and further purified by silica gel flash chromatography (0-25% EtOAc in pentane) to afford the title compound as a pink solid (1.17 g, 81% yield). 1H NMR (300 MHz, CDCl3): δ 8.50 (t, J=5.3 Hz, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.83 (br s, 1H), 7.40-7.39 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:24][CH3:25])[CH3:23])=[CH:18][CH:17]=1)=[O:14]>CCO>[CH:22]([C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:13](=[O:14])[C:12]3[C:11](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:10]=[C:8]2[C:5]2[CH:4]=[N:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:17][CH:18]=1)([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=Cc1ccc(F)nc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(F)nc3)nc3ccccc3c2=O)cc1
Yield: 15 %

Procedure:
2-fluoro-5-formylpyridine (0.55 mmol) and anyhydrous CuCl2 (0.150 g, 1.10 mmol) were added to a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (0.205 g, 0.55 mmol) in anyhydrous EtOH (10 mL). After heating at reflux temperature for 2.5 hours, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 50% EtOAc in heptane, afforded the title compound as a white solid (15%). 1H-NMR (300 MHz, DMSO-d6): δ 8.17-8.33 (m, 2H), 7.87-8.02 (m, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.62-7.66 (m, 1H), 7.23-7.33 (m, 2H), 7.12-7.22 (m, 2H), 6.98-7.11 (m, 1H), 2.54-2.65 (m, 1H), 1.32-1.66 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 0.60 (t, J=7.4 Hz, 3H). MS (APCI) m/z: 374 (M+H)+.