Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:19](O)[CH3:20].C(Cl)CCl>ClCCl>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH2:19][CH3:20])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CCO
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenylacetic acid (24.65 g, 91 mmol) in dichloromethane (150 mL), was added 200 proof ethanol (10.63 mL, 181 mmol), EDC (34.7 g, 181 mmol) and 4-(N,N-dimethylaminopyridine (DMAP, 14.39 g, 118 mmol) at room temperature. The solution was stirred at RT over night, washed with 2 N HCl and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4, and the solvent was removed under vacuum to provide 26 g (96%) of the title compound.
Reaction SMILES: [C-]#N.[Na+].C(O)(=O)C.[C:8](#[N:10])C.[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH:24]=[O:25])[N:17]=[C:16]1[N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:12]#[C:13][CH3:14]>C(OCC)(=O)C>[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH:24]([C:8]#[N:10])[OH:25])[N:17]=[C:16]1[N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:12]#[C:13][CH3:14]
Reactant: CC#N
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OC
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(O)C#N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.200 g of sodium cyanide and 0.010 ml of acetic acid were added to a 15 ml acetonitrile solution of t-butyl 4-[1-(2-butynyl)-5-methoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 16 hours. 100 ml of ethyl acetate was added to the solution, and the mixture was washed twice with 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.274 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).
Reaction SMILES: [CH2:1]([N:3]([CH2:61][CH3:62])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:40])[N:20]([CH3:39])[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:41]2[CH:46]=[C:45]([C:47](=[O:60])[NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[CH:44]=[CH:43][N:42]=2)[CH:5]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:61]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:40])[N:20]([CH3:39])[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:41]2[CH:46]=[C:45]([C:47](=[O:60])[NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:57])([F:59])[F:58])[CH:51]=3)[CH:44]=[CH:43][N:42]=2)[CH:5]=1)[CH3:62]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 1-(3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)phenyl)-2-methyl-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate (1.17 g) in DCM (20 mL) was added TFA (20 mL). The mixture was stirred for 1 hour, concentrated and lyophilized to give a think brown syrup. MS (ES, m/z): 808.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9](N2[C@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of (4R)-3-[(2R)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (1.58 g, 5.35 mmol) in 45 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (4.9 mL, 42.8 mmol) followed by LiOH (449 mg, 10.7 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (31 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.97 g (5.27 mmol, 98%) of (2R)-2-(4-chlorophenyl)propanoic acid; [α]D=−64.8° (C=1.05, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–10.8 (br, 1 H), 7.32–7.23 (m, 4 H), 3.72 (q, 1 H, J=7.3 Hz), 1.50 (d, 3 H, J=7.3 Hz); ESMS m/e: 183.2 (M−H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10]COCC[Si](C)(C)C)[CH3:2].[Li]C(C)(C)C.[C:24](=[O:26])=[O:25]>C1COCC1.CCOCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:24]([OH:26])=[O:25])[C:5]=1[OH:10])[CH3:2]
Reactant: O=C=O
Reactant: CCOc1ccncc1OCOCC[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccnc(C(=O)O)c1O
Reaction time: 0.75 h

Procedure:
A stirred solution of 11 (2.9 g) in THF (50 mL) under an argon atmosphere was cooled to ≦−70° C. To this was slowly added t-BuLi (8 mL, 1.5M pentane solution) while keeping the reaction temperature at ≦−66° C. After the addition was complete, the mixture was stirred at ≦−70° C. for 45 minutes and then poured into a slurry of crushed dry ice in ether. The resulting mixture was stirred until it reached room temperature, then the solvents were evaporated. THF (25 mL) and 4N HCl (15 mL) were added to the residue and the resulting mixture was stirred at room temperature for two hours. At the end of this period, the insoluble material was filtered, washed with a small volume of THF and air dried to give the title compound as a white solid (1.05 g). Preparation of 6-Bromo-3-benzyloxy-4-methoxypyridine-2-carboxylic Acid (16) and its Acid Chloride (3) (See Scheme 4). a. Preparation of Methyl 4,6-Dibromo-3-hydroxypyridine-2-carboxylate (14).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([O:24][C:26](=[O:28])[CH3:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC(OC(C)=O)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 57 %

Procedure:
To a solution of methyl-3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate (1.7 g.) in pyridine at 0° C. was added acetic anhydride (2.7 ml). The reaction was stirred for four days at room temperature. The solvent was removed in vacuo and the remaining oil was purified by HPLC on silica gel using a hexanes/ethyl acetate in 9:1 ratio as an eluent (1.1 g., 57% yield).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:17][C:18]1[C:31]([F:32])=[C:30](F)[C:29]([F:34])=[C:28]([F:35])[C:19]=1[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21]>N1C=CC=CC=1>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:30]2[C:29]([F:34])=[C:28]([F:35])[C:19]([C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21])=[C:18]([F:17])[C:31]=2[F:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: CC(=O)NC1CCNC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(N2CCC(NC(C)=O)C2)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To 2.62 g (20.4 mmol) of 3-acetamidopyrrolidine dissolved in 50 mL of pyridine and cooled to 0° C. was added 2.06 g (20.4 mmol) of triethylamine and 5.24 g (18.6 mmol) of ethyl 2,3,4,5,6-pentafluorobenzoylacetate, from step 2 above. The solution was stirred at 0° C. for 1 hour, then at room temperature overnight. The solvent was removed by evaporation under vacuum and the residue was dissolved in chlorform, which was washed with 0.5N HCl and 5% potassium carbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was further dried by adding and distilling off ethylene dichloride, chloroform and methylene, followed by further drying under vacuum. The crystalline residue was washed with hexane and dried to afford 6.8 g of the title compound as a tan solid, mp 90°-92° C. MS M/Z: 391 (M+H). IR (CDCl3): 1635, 1680, 1740 cm-1. NMR (CDCl3) d: 1.26 (m, 3H), 2.00 (m, 5H), 2.22 (m, 2H), 3.54 (m,1H), 3.77 (m, 2H), 3.85 (m, 1H), 3.98 (m, 1H), 4.22 (m, 2H), 5.75 (m, 1H). Analysis calculated for C17H18F4N2O4 : C, 52.31; H, 4.65; N, 7.18. Found: C, 52.47; H, 4.67; N, 7.33.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cn1
Reaction time: 24 h
Yield: 80 %

Procedure:
2-Bromo-5-hydroxypyridine (3 mmol) is dissolved in DMF (2.5 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min benzylbromide (1.1 eq.) is added and the reaction solution is stirred 24 hours. The reaction solution is pored into water and extracted with methyltert.-butyl ether. The combined organic layers are dried over Na2SO4 and the solvent is removed in vacuo. 5-Benzyloxy-2-bromo-pyridine is obtained after column chromatography as brown oil in a yield of 80%. HPLC (method C): 2.01 min; LC-MS (method A): 1.97 min, 264.00 (MH+).
Reaction SMILES: [C:1]([N:5]1[C:9]2[NH:10][C:11](=[O:14])[CH:12]=[CH:13][C:8]=2[C:7]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>CC(O)=O>[Br:19][C:12]1[C:11](=[O:14])[NH:10][C:9]2[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=[C:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:8]=2[CH:13]=1
Reactant: BrBr
Reactant: CC(C)(C)n1nc(C2CCC2)c2ccc(=O)[nH]c21
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2cc(Br)c(=O)[nH]c21
Reaction time: 0.25 h
Yield: 16.6 %

Procedure:
To a stirring solution of 1-tert-butyl-3-cyclobutyl-1,7-dihydro-pyrazolo[3,4-b]pyridin-6-one (1.0 g, 4.1 mmol) in AcOH (10 mL) was added bromine (236 uL, 4.6 mmol) dropwise. After 15 min, the resulting solid was collected and washed with hexanes. The solution was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification of the resulting material was accomplished by flash chromatography, using a Biotage® column, eluting with a gradient of 10%, 20% EtOAc/hexanes. The product-containing fractions were collected and concentrated to give the title compound (220 mg, 16% yield) as a tan solid. LRMS m/z (APCl) 322, 324 (M−1); 500 MHz 1H NMR (CDCl3) δ 12.5 (bs, 1H), 8.09 (s, 1H), 3.66 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 2.45-2.34 (m, 4H), 2.15-1.92 (m, 2H), 1.76 (s, 9H).
Reaction SMILES: [CH3:1][Mg]Br.CC[O:6][CH2:7][CH3:8].C1(C#N)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>O1CCCC1>[C:7]([C:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)(=[O:6])[CH3:1]
Reactant: C[Mg]Br
Reactant: CCOCC
Reactant: N#Cc1nccc2ccccc12
Solvent: C1CCOC1
Product: CC(=O)c1nccc2ccccc12
Temperature: 0 °C
Yield: 62 %

Procedure:
Methyl magnesium bromide in ether (8.1 ml, 24.3 mmole) is dissolved in 16 ml tetrahydrofuran in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution is cooled to 0° C., is diluted with 8 ml diethyl ether, and is treated with 1-isoquinoline carbonitrile (3.0 g, 19.5 mmole). The reaction is warmed to reflux for one hour, is cooled to 0° C., and is quenched with 20 ml 6 M hydrochloric acid. The reaction mixture is warmed to 50° C. for two hours, is cooled, and is poured into 75 ml 2N sodium hydroxide. The mixture is extracted with 3×80 ml ethyl acetate and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to a crude amber oil. The crude material is chromatographed over 150 g silica gel (230-400 mesh), eluting with 10% acetone/hexane, while collecting 22 ml fractions. Fractions 16-26 are combined and concentrated to provide 2.1 g (62%) of 1-acetylisoquinoline.
Reaction SMILES: [C:1]([O:9][CH2:10][O:11][CH2:12][N:13]1[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]1=[O:15])(=O)C1C=CC=CC=1.C([CH:24]([CH2:30]C)[O:25][P:26]([OH:29])([OH:28])=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:44](OCC)(=O)[CH3:45]>C1C=CC=CC=1>[CH2:44]([O:29][P:26]([CH2:1][O:9][CH2:10][O:11][CH2:12][N:13]1[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]1=[O:15])([O:25][CH2:24][CH3:30])=[O:28])[CH3:45]
Reactant: CCOC(C)=O
Reactant: Cc1cn(COCOC(=O)c2ccccc2)c(=O)[nH]c1=O
Reactant: CCC(CC)OP(=O)(O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: c1ccccc1
Product: CCOP(=O)(COCOCn1cc(C)c(=O)[nH]c1=O)OCC
Temperature: 85 °C

Procedure:
To a solution of 1-[(benzoyloxy)methoxymethyl]-thymine (2.9 g, 10 mmol) and diethyl phosphonomethanol (1.85 g, 11 mmol) in benzene (180 mL) was added trimethylsilyl trifluoromethanesulfonate (0.05 mL) via a syringe under nitrogen. The solution was heated at 85° C. for 20 min. After cooling to room temperature, ethyl acetate (50 mL) was added and washed with aqueous bicarbonate, brine dried (MgSO4), filtered and concentrated in vacuo. The resultant yellow oil was purified by silica gel column chromatography using CH2Cl2 /5% MeOH as an eluent to give the title compound as a white oil: yield 980 mg (30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[CH3:22][O:23][C:24](=[O:28])[C@@H:25]([CH3:27])[NH2:26].C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:26][C@@H:25]([C:24]([O:23][CH3:22])=[O:28])[CH3:27])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 80 °C
Yield: 65.4 %

Procedure:
To ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (100 mg, 339 μmol, see Example 2) and D-alanine methyl ester hydrochloride (71 mg, 509 mmol) was added 1,4-dioxane (339 μL) and N-ethyl-N-isopropylpropan-2-amine (177 μL, 1018 μmol). The reaction was then heated at 80° C. for 16 hours. The resulting reaction mixture was evaporated to give the title compound (78 mg) as an amorphous solid after purification via preparatory LC. MS m/e=352 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[N:3]=1.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34].C(N(CC)CC)C>CN(C=O)C>[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([C:2]2[C:7]([S:8][CH3:9])=[C:6]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:5]=[C:4]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:24])=[CH:20][CH:21]=3)[N:3]=2)[CH2:38][CH2:37]1)(=[O:35])=[O:34]
Reactant: CSc1c(Cl)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1c(N2CCOCC2)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCN(S(C)(=O)=O)CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 1-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea (120 mg, 0.26 mmol.), 1-methanesulfonyl-piperazine (65 mg, 0.39 mmol, 1.5 eq.), triethylamine (40 mg, 0.39 mmol, 1.5 eq.), and DMF (4.0 ml) was added to the reaction vessel and flushed with argon. The reaction mixture was stirred at 80° C. for 5 hrs and then dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and NH4Cl(aq), the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified with flash chromatography on silica gel (Hexane/EtOAc 1:1) to give a pale yellow solid of 77.2 mg (50.3%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])/[CH3:4].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])/[CH3:4])=[CH:20][CH:19]=1)[CH3:29]
Reactant: CC(C)=CCC/C(C)=C\COc1ccc(C(=O)O)cc1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(/C)CCC=C(C)C)cc1
Yield: 30 %

Procedure:
In a manner identical to Example 15, 4-neryloxybenzoic acid (1.64 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.84ml), thereby yielding 0.69 g (30%) of the aimed compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][S:17]([NH2:20])(=[O:19])=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2/[CH:14]=[N:20]/[S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1noc(-c2ccc(Br)cc2)c1/C=N/S(C)(=O)=O

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (2 g, 7.5 mmol) was mixed with methanesulfonamide (0.714 g, 7.5 mmol) and p-toluenesulfonic acid monohydrate (0.010 g, 0.053 mmol) in toluene. The reaction was heated to reflux for 24 hours with Dean-Stark apparatus in place. Upon cooling the product precipitated from the reaction mixture and was isolated by filtration to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][C:21]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:19]([O:18][CH3:17])[CH:20]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
A mixture of 4-chloro-7-fluoro-6-methoxy-3-quinolinecarbonitrile (500 mg, 2.11 mmol), 3,4,5-trimethoxyaniline (515 mg, 2.81 mmol) and pyridine hydrochloride (270 mg , 2.33 mmol) in 20 mL of 2-ethoxyethanol is heated at reflux for 4 hours then cooled to room temperature. The reaction mixture is poured into aqueous sodium bicarbonate and stirred at room temperature for 15 minutes. The solid is collected by filtration and partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ethyl acetate and diethyl ether provides 512 mg of 7-fluoro-6-methoxy-4-[(3,4,5-trimethoxyphenyl)amino]-3-quinolinecarbonitrile, mp 215-217° C.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:20]([OH:22])=O)=[N:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=12)C1C=CC=CC=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:20]([C:10]2[C:9]([OH:8])=[C:13]3[C:14](=[O:19])[NH:15][CH2:16][CH2:17][CH2:18][N:12]3[N:11]=2)=[O:22])=[CH:26][CH:25]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)c1nn2c(c1OCc1ccccc1)C(=O)NCCC2
Product: O=C(NCc1ccc(F)cc1)c1nn2c(c1O)C(=O)NCCC2
Reaction time: 0.17 h

Procedure:
The title compound was prepared from 3-benzyloxy-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid using a procedure similar to that found in Example 13, Step 3, except that 4-fluorobenzylamine was used in place of 4-fluoro-N-methylbenzylamine and the reaction time totaled 10 minutes. Purification by reverse phase chromatography was not necessary. 1H NMR (400 MHz, CDCl3) δ 7.26-7.22 (m, 7H), 7.01-6.96 (m, 2H), 6.15 (br s, 1H), 5.30 (s, 2H), 4.57-4.55 (d, 2H), 4.46-4.43 (t, 2H), 3.16-3.11 (m, 2H), 2.20-2.13 (dt, 2H); ES MS (M+1)=409.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[Cl:9][C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:20][NH:21][C:22](=[O:35])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:25]=2)[CH2:15]1.CO>CC(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:20][NH:21][C:22](=[O:35])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:1])[S:31]([CH3:34])(=[O:32])=[O:33])[CH:25]=2)[CH2:15]1
Reactant: CS(=O)(=O)Nc1cccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1cccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1)S(C)(=O)=O
Yield: 32.1 %

Procedure:
Potassium carbonate (0.035 g) and iodomethane (0.015 ml) were added to a stirred solution of Example 139 (0.115 g) in acetone (1 ml), and stirring was continued at 22° C. for 72 h before a further portion of iodomethane (0.003 ml) was added. After stirring for a further 24 h, more iodomethane (0.003 ml) and potassium carbonate (0.007 g) were added, and the mixture stirred for a further 48 h. The mixture was applied in two equal portions to two ion exchange cartridges (2 g Isolute SCX, pre-conditioned with methanol). Elution with methanol (3 column volumes) followed by 10% 0.880 ammonia in methanol (2 column volumes), and evaporation of the first basic fraction from each elution in vacuo gave the title compound as a pale yellow gum (0.038 g).
Reaction SMILES: [Na].Br[C@H:3]([CH2:7]O)[C:4]([OH:6])=[O:5].[CH3:9][CH:10]([SH:12])[CH3:11].C[OH:14]>C[O-].[Na+]>[OH:14][C@@H:3]([CH2:7][S:12][CH:10]([CH3:11])[CH3:9])[C:4]([OH:6])=[O:5]
Reactant: CO
Reactant: O=C(O)[C@H](Br)CO
Reactant: CC(C)S
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Product: CC(C)SC[C@H](O)C(=O)O
Reaction time: 2 h

Procedure:
Sodium (7.09 g, 308 mmol) in methanol (100 ml) was added over 35 min to a stirred solution of (R)-2-bromo-3-hydroxypropanoic acid (25.5 g, 151 mmol) in methanol (200 ml) at -25°. The temperature was allowed to reach 10° and the mixture stirred for a further 2 h. 2-Propanethiol (11.4 ml, 240 mmol) in sodium methoxide solution, prepared from sodium (5.68 g, 247 mmol) and methanol (100 ml) was added to this suspension (240 ml, 120 mmol) at -5°. After 16 h at room temperature the solvent was evaporated and the residue dissolved in water/ether/conc. hydrochloric acid to a final pH of approximately 1. The organic phase was separated and the aqueous phase re-extracted with ether (×2). The combined organic extracts were dried (Na2SO4) and the solvent evaporated to give the sub-title compound (18.56 g).