Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[NH2:18][OH:19].[OH-].[K+].CO>C1COCC1>[OH:19][NH:18][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: COC(=O)C=CC=CCSc1ccc(Cl)cc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C=CC=CCSc1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of the 6-(4-chlorophenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.44 g, 1.64 mmol) in distilled THF (9.0 mL) containing 50% aqueous hydroxylamine (1.0 ml, 15.2 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 2.6 mL, 2.6 mmol) over a period of 30 minutes. After stirring at 0° C. for 1 h, distilled water (9.0 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (3×30 mL) and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (0.21 g, 48%) as a pale brown powder, mp 120-122° C. (decomp).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC>O1CCCC1>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([B:16]([OH:17])[OH:15])=[CH:5][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of p-trifluoromethylbromobenzene (814.8 g) and triisopropoxyborane (681.0 g) in tetrahydrofuran (6300 mL) is cooled to −78° and n-butyllithium (2.5 m in hexanes, 1448 mL) is added over 30 minutes at a temperature below −60° to yield p-trifluoromethylphenylboronic acid.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][CH2:10][C:11]([O:13][C:14](C)(C)C)=[O:12])[CH2:5][CH2:4]1>CO>[ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CO
Product: COC(=O)CO[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrochloric acid gas is piped for an hour over a solution of 59.4 g of tert.butyl (trans-4-aminocyclohexyl)oxyacetate in 500 ml of methanol, cooled in an ice bath, and then the mixture is stirred overnight at ambient temperature. It is evaporated to dryness, the residue is triturated with acetone and the solid is suction filtered and dried.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Yield: 78.4 %

Procedure:
To a suspension of sodium hydride (29.5 g of 60% oil dispersion, washed free of oil with hexane) in diethyl carbonate (88 mL, 0.726 mol) at room temperature under argon was added dropwise over 30 minutes p-fluoroacetophenone (50.0 g, 0.362 mol). Ethanol (0.1 mL) was added during the addition to initiate the reaction. After 2/3 of the ketone had been added, white solid had separated and Et2O (600 mL) was added to facilitate stirring. When the addition was complete the mixture was refluxed for 3 hours. The mixture was then placed in an ice bath, and the reaction was quenched by the dropwise addition of water (100 mL) and 5% KHSO4 solution (100 mL). The mixture was acidified with 10% H2SO4, the organic phase separated and washed with saturated NaHCO3 and saturated NaCl solutions, dried (MgSO4) and evaporated. The residue was distilled in vacuo to give title compound (59.66 g, 78%) as a colorless liquid, bp 115°-118° C. (1 mmHg).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1.[Cl:14][C:15]1[CH:34]=[CH:33][C:18]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26](O)=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)=[C:17]([F:35])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C=O)C.O>[Cl:14][C:15]1[CH:34]=[CH:33][C:18]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:5][CH2:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=4)=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)=[C:17]([F:35])[CH:16]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cc1cc(CO)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
Thionyl chloride (0.3 ml) was added to a solution of 4-hydroxymethyl-2-methylpyridine (240 mg, 1.9 mmol) in toluene (10 ml) and the mixture stirred at ambient temperature for 2 hours. The volatiles were removed by evaporation, the residue azeotroped with toluene and dried under vacuum to give crude 4-chloromethyl-2-methylpyridine hydrochloride which was used directly. This product was then added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (510 mg, 1.6 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (1.4 g 10 mmol) in DMF (8 ml) for 90 hours. The mixture was diluted with water and the precipitated solid collected by filtration, washed with water and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-methyl-4-pyridyl)methoxy)quinazoline (290 mg, 43%), a sample was recrystallised from ethyl acetate/hexane.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[CH2:29][C:30]1([CH3:34])[CH2:33][O:32][CH2:31]1>CN(C)C=O.O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:29][C:30]2([CH3:34])[CH2:33][O:32][CH2:31]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: CC1(CCl)COC1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1(C)COC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 244A (0.75 g, 2.31 mmol) in N,N-dimethylformamide/tetrahydrofuran (1:4, 20 mL) were added potassium tert-butoxide (0.39 g, 3.46 mmol), tetrabutylammonium iodide (0.09 mg, 0.23 mmol) and commercially available 3-(chloromethyl)-3-methyloxetane (TCI, 0.28 g, 2.31 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled, diluted with ethyl acetate (20 mL) and quenched with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (1×25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.24 (s, 3H), 1.33 (s, 9H), 3.77 (s, 3H), 4.19 (d, J=6.1 Hz, 2H), 4.38 (s, 2H), 4.69 (d, J=6.1 Hz, 2H), 7.10 (d, J=9.2 Hz, 1H), 7.29 (s, 1H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.58 (d, J=2.7 Hz, 1H); MS (ESI+) m/z 409 (M+H)+; Anal. Calculated for C20H25ClN2O3S: C, 58.74; H, 6.16; N, 6.85. Found: C, 58.92; H, 6.04; N, 6.84.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.S(Cl)(Cl)=O.CN(C)C=O.[CH:23]1([CH:26]([NH2:28])[CH3:27])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.O.O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:28][CH:26]([CH:23]1[CH2:25][CH2:24]1)[CH3:27])=[O:9]
Reactant: CC(N)C1CC1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(NC(=O)c1cc(Cl)ccc1[N+](=O)[O-])C1CC1
Reaction time: 15 h
Yield: 75 %

Procedure:
A mixed liquid comprising 25 g of 5-chloro-2-nitrobenzic acid, 25 ml of toluene, 22.2 g of thionyl chloride and 0.1 ml of dimethylformamide was refluxed with heating for 1 hour to prepare acid chloride. 18.0 g of triethylamine was added to a mixed solution comprising 13.75 g of 1-cyclopropylethylamine and 375 ml of tetrahydrofuran and cooled with ice. The above prepared acid chloride was dissolved in 30 ml of toluene and dropwise added under cooling with ice. After completion of dropwise addition, reaction was carried out at room temperature for 15 hours. After completion of the reaction, the reaction mixture was poured to water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 25 g of the pale yellow desired product (melting point: 137 to 141° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.C=C1O[C:20](=[O:21])[CH2:19]1>C1(C)C=CC=CC=1.O>[CH3:8][N:7]([CH2:6][C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:20](=[O:21])[CH3:19]
Reactant: C=C1CC(=O)O1
Reactant: CNCc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N(C)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolved in toluene was 3.1 g (0.02 mole) of 4-chloro-N-methyl-benzylamine, followed by an addition of a catalytic amount of pyridine and a further dropwise addition of 1.8 g (0.022 mole) of diketene at room temperature. After stirring the reaction mixture at room temperature for 3 hours, it was poured in water and then extracted with toluene. Subsequent to purification, N-methyl-N-(4-chlorobenzyl)acetamide was obtained in an oily form.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[C:27]([C:38]([F:41])([F:40])[F:39])=[N:28][N:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])[CH:30]=3)=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[C:32]1([CH3:37])[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:29]1[CH:30]=[C:26]([CH2:24][NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:43])=[O:4])[CH2:12][CH2:11]3)=[CH:14][CH:15]=2)=[O:42])[C:27]([C:38]([F:41])([F:39])[F:40])=[N:28]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cn(-c4ccccc4C)nc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-n1cc(CNCCC(=O)Nc2ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc2)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (52.6 mg, 1.3 mmol) was added to trans-[4-(4-{3-[(1-o-tolyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (75 mg, 0.13 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH of 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was stirred with acetonitrile and filtered. The filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified. Accordingly, the desired compound (70 mg, 96%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]1)([C:38]#[CH:39])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:39]#[C:38][C:36]([N:40]3[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]3)([CH3:37])[CH3:35])[S:17][C:10]=12
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: C#CC(C)(C)N1CCC(CO)CC1
Product: CC(C)(C#Cc1cc2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)c2s1)N1CCC(CO)CC1
Yield: 22.9 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 20 mg, 0.0338 mmol) and (1-(2-methylbut-3-yn-2-yl)piperidin-4-yl)methanol (12.3 mg, 0.0676 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.63) eluting with 20% MeOH/DCM. The compound required a second purification by preparative TLC (0.5 mm thickness, Rf=0.11), eluting with 15% MeOH in EtOAc, to obtain product of adequate purity. The product was obtained as a beige powder (5 mg, 23%). HPLC: 99% purity (254 nm); LCMS (APCI−): 100% purity, 220 nm, m/z 643 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.49 (d, J=5 Hz, 1H), 8.23 (s, 1H), 7.78 (m, 1H), 7.56 (s, 1H), 7.45 (m, 2H), 7.27 (m, 2H), 7.07 (t, J=9 Hz, 2H), 6.53 (d, J=5 Hz, 1H), 3.53 (d, J=6 Hz, 2H), 3.22 (br s, 2H), 2.31 (br s, 2H), 1.82 (m, 4H), 1.62 (m, 10H), 1.36 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO[C:6]([C:8]1[N:12]2[C:13]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:14]=3[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH2:17][C:11]2=[N:10][N:9]=1)=[O:7]>O1CCOCC1.CO>[CH3:1][N:2]([CH3:3])[C:6]([C:8]1[N:12]2[C:13]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:14]=3[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH2:17][C:11]2=[N:10][N:9]=1)=[O:7]
Reactant: CNC
Reactant: COC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
10 ml of a 20% solution of dimethylamine in dioxane is added at 25° to a solution of 0.705 g (0.002 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxylic acid methyl ester in 10 ml of methanol. After 24 hours, the reaction mixture is concentrated by evaporation, and the residue crystallised from ethyl acetate/petroleum ether to obtain N,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, M.P. 180°-181°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Reaction time: 2 h

Procedure:
12.7 g of 3-(4-bromophenyl)-1-[4-[2-(ethoxycarbonyl)-ethyl]-phenyl]-imidazolidin-2-one, 300 ml of tetrahydrofuran, 100 ml of water and 23.6 ml of 4N sodium hydroxide solution are stirred overnight at ambient temperature. The precipitate is suction filtered, suspended in 1 liter of water, acidified with concentrated hydrochloric acid and stirred for 2 hours. It is then suction filtered, washed with water and dried at 60° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.[F:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([OH:29])[C:18](=[O:28])[NH:19][C:20]=3[C:24]([O:26]C)=O)[C:15]2=[O:30])=[CH:11][CH:10]=1.Cl>C1COCC1.C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([OH:29])[C:18](=[O:28])[NH:19][C:20]=3[C:24]([N:2]([CH3:3])[CH3:1])=[O:26])[C:15]2=[O:30])=[CH:31][CH:32]=1
Reactant: COC(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−10° C.) solution of dimethylamine (2M in THF, 0.002 g, 0.035 mmol) was slowly added trimethylaluminum (2M in toluene, 0.002 g, 0.035 mmol) and stirred for 30 minutes at room temperature. The reaction mixture was cooled to −10° C. and methyl 6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.004 g, 0.012 mmol, Example 1, Step 8) in THF (5 mL) was added. The reaction stirred at room temperature for 2 hours, then transferred via syringe to a solution of 1:1 CH2Cl2:0.5 N aq. HCl at 0° C. and stirred for 1 hour. The product mixture was separated, and the aqueous was extracted three times with CH2Cl2. The aqueous layer was treated with saturated Na2CO3 solution to pH 5 and extracted three times with CH2Cl2 again. The organic combined extracts were dried with Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.Cl>C(O)C>[ClH:1].[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cc1cccc(Cl)c1N
Agent: Cl
Solvent: CCO
Product: Cc1cccc(Cl)c1Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
2-Chloro-6-methylaniline (0.46 g) and 2-chlorobenzimidazole (0.5 g) were mixed in a flask and then kept at 170° C. for 30 min. After cooling, the residue was dissolved out of the flask with 1 N HCl and 10% ethanol at boiling heat. The material dissolved out was then stirred at RT for 30 min, then the insoluble material was filtered off with suction and the filtrate was evaporated. The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). The clean fractions were combined, the acetonitrile was stripped off, the residue was adjusted to pH 10 with potassium carbonate solution, extracted three times with EA, and then the combined phases were dried, filtered, and concentrated. The residue was taken up using HCl/water and freeze-dried. 227 mg of the title compound were obtained.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)C.[ClH:30]>O1CCOCC1>[ClH:30].[C:25]1([CH3:28])[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][N:8]3[CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(Oc2ccc(OC[C@@H]3CCCN3CCCC(=O)O)cc2)cc1
Temperature: 60 °C
Yield: 97 %

Procedure:
4-[(S)-2-(4-p-Tolyloxy-phenoxymethyl)-pyrrolidin-1-yl]-butyric acid ethyl ester (348 mg, 0.875 mmol) was taken into a mixture of concentrated HCl and Dioxane (1:1, 3 mL). The reaction was heated at 60° C. for 5 h. The reaction was concentrated to dryness under vacuum, and then dried in a vacuum oven at 50° C. for 12 h. The title product (346 mg, 0.853, 97% yield) MS; m/z 405.92, found 370 (M-35HCl); 1H NMR (400 MHz, DMSO-d6) δ1.78-1.8 (m, 2H), 1.90-2.05 (m, 3H), 2.21-2.26 (m, 1H), 2.27 (s, 3H), 2.36-2.40 (m, 1H), 3.10-3.16 (m, 2H), 3.47-3.49 (m, 1H), 3.61-3.70 (m, 1H), 3.86-3.10 (2H), 4.27-4.37 (m, 2H), 6.83-6.49 (m, 2H), 6.96-7.04 (m, 4H), 7.14-7.17 (m, 2H), 10.55 (s, 1H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH:5]=1)([O-])=O.[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([OH:29])=[O:28])=[N:22][CH:21]=[CH:20]2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:13]1([C:11]([NH:10][C:6]2[CH:5]=[C:4]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23]([C:27]([OH:29])=[O:28])=[N:22][CH:21]=[CH:20]4)[CH:9]=[CH:8][N:7]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(O)c1nccc2cc(O)ccc12
Reactant: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1nccc2cc(Oc3ccnc(NC(=O)C4CC4)c3)ccc12
Temperature: 20 °C

Procedure:
Cyclopropanecarboxylic acid (4-nitro-pyridin-2-yl)-amide (200 mg, 0.965 mmol), 6-hydroxy-isoquinoline-1-carboxylic acid (183 mg, 0.965 mmol), and potassium carbonate (267 mg, 1.93 mmol) are stirred in dimethylsulphoxide (10 mL) at 90° C. for 24 h. After cooling to 20° C., the dimethylsulphoxide is partially evaporated under reduced pressure, water is added, the solution is carefully acidified with trifluoroacetic acid and the resulting solution is purified using a MPLC reverse phase chromatography (Merck LiChroprep® RP-18, acetonitrile/water 0.1% trifluoroacetic acid) to afford the title compound as a solid. M-H, 348.1; HPLC tR: 3.29 min.
Reaction SMILES: C(O)(=[O:10])C=CC1C=CC=CC=1.[CH:12]1([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.NCCC[Si](OC)(OC)OC>>[CH:21]1([NH:20][C:19]([NH:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:10])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CO[Si](CCCN)(OC)OC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
40 g of cinnamic acid and 50 g of dicyclohexylcarbodiimide were added to a 1 L round 3-necked flask equipped with a dropping funnel and a cooler, and also 600 mL of toluene newly distilled from sodium ketyl was added thereto, and the resultant mixture was refluxed to yield a homogeneous solution. After about 30 minutes, 48 g of 3-aminopropyltrimethoxysilane was dropped over 30 minutes through the dropping funnel. The resultant reaction mixture was refluxed for 4 hours, and then toluene was removed by vacuum distillation without contacting with moisture. Dicyclohexyl urea formed in a remaining solution was removed by filtration to yield a product. The resultant product was determined using FT-IR and thin layer chromatography. Yield of the resultant product is about 30 g.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5](F)=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8].Cl[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][C:30]=1F)[C:21](NS(C)(=O)=O)=[O:22]>>[C:20]12([CH2:21][O:22][C:3]3[CH:4]=[CH:5][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[CH:14][C:2]=3[Cl:1])[CH2:28][CH:29]3[CH2:5][CH:6]([CH2:14][CH:18]([CH2:30]3)[CH2:19]1)[CH2:7]2
Reactant: CS(=O)(=O)NC(=O)c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Product: CS(=O)(=O)NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 3-chloro-4-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.34 g, 52%): 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.04-7.94 (m, 2H), 7.25 (d, J=8.5 Hz, 1H), 3.72 (s, 2H), 3.36 (s, 3H), 1.99 (br, 3H), 1.71-1.66 (m, 12H); MS (ES−) m/z 396.1, 398.1 (M−1).