Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH:36](Br)[CH2:37][CH3:38])[CH:30]=1>C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:35][CH:36]([CH2:37][CH3:38])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([OH:10])=[O:9])[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CCC(Br)Cc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(Cc1cccc(OC)c1)C(C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Phenylacetic acid (0.84 g, 6.07 mmol) was dissolved in THF (50 mL) and cooled in an ice bath. nBuLi (2.5 M in hexanes, 5.4 mL, 13.4 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h, then at room temperature for 5 h. HMPA (0.25 mL) was added, and the stirring was continued for another 30 min. Cooled in an ice bath, a solution of 3-(2-bromobutyl)phenyl methyl ether (53) (1.77 g, 7.28 mmol) in THF (10 mL) was added dropwise. The resulting mixture was allowed to warm up to room temperature and stir at room temperature overnight, then heated at 50° C. for 1 h. Cooled and quenched with 0.5 N NaOH (25 mL), the mixture was again heated at 50° C. for 1 h. After cooled to room temperature and extracted with ether, the aqueous layer was acidified with 5 N HCl and extracted with CHCl3. The extracts were combined and washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography over SiO2 with CH2Cl2:Acetone (8:1) to give 0.81 g (45%) of the title compound (54) as a colorless viscous oil. 1HNMR indicated it was a mixture of two diastereomers with a ratio of 2:1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C[O-].[Na+].CO.[CH:16]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(OC)(OC)OC>[CH:16]1([CH:22]=[CH:1][C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)=[O:3])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)c1cccc(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=C(C=CC1CCCCC1)c1cccc(O)c1
Reaction time: 0.67 h

Procedure:
A mixture of 3-hydroxyacetophenone on Wang resin (6.0 g, 5.52 mmol) was swelled in trimethyl orthoformate (60 mL) for 10 min. 25% NaOMe in MeOH (2.4 g, 11.0 mmol) was added and the mixture was stirred for 40 min. Cyclohexanecarboxaldehyde (1.9 g, 16.56 mmol) was added and stirring was continued for 40 min. The resin was filtered and washed with alternating MeOH and CH2Cl2 (×5) and dried under high vacuum overnight to give 6.62 g of 3-cyclohexyl-1-(3-hydroxyphenyl)-2-propen-1-one on Wang resin.
Reaction SMILES: [OH-].[Li+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][C:11]([O:13]C)=[O:12].Cl>O1CCCC1>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)CCC1CCCCO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCC1CCCCO1
Yield: 108.9 %

Procedure:
A 2M aqueous solution of lithium hydroxide (4 ml) was added to a solution of methyl 3-(tetrahydropyran-2-yl)propanoate (Preparation 25, 460 mg, 2.67 mmol) in tetrahydrofuran (16 ml) and the reaction mixture was heated under reflux for 10 h. The cooled reaction mixture was acidified with 2N aqueous hydrochloric acid to pH 1 and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a colourless oil (460 mg, 67%).
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][CH2:15][CH3:16]>>[CH2:18]([N:17]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCNCCCCCCNCCCC
Reactant: CCCCCCCCCC1CO1
Product: CCCCCCCCCC(O)CN(CCCC)CCCCCCN(CCCC)CC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and N,N'-dibutylhexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-butyl-2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = CH3 (CH2)3, X = (CH2)6, Z = H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[C:23]([CH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH2:35])=[NH:34])[CH:29]=[CH:30][CH:31]=1)#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:34]=[C:33]([NH:32][C:28]4[CH:27]=[C:26]([CH2:25][C:23]#[N:24])[CH:31]=[CH:30][CH:29]=4)[N:35]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N#CCc1cccc(NC(=N)N)c1
Solvent: O=[N+]([O-])O
Product: N#CCc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-cyanomethyl-phenyl)-guanidine nitrate were converted to I-78 (6%): HRMS Calcd. for C20H14ClN5O: 376.0965, Found 376.0994.
Reaction SMILES: [S:1]([C:5]1[N:6]=[C:7]2[N:11]([C:12]=1C(OCC)=O)[CH:10]=[CH:9][S:8]2)([CH3:4])(=O)=O.[CH2:18](S)[CH2:19]C>>[CH2:4]([S:1][C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[CH:9][S:8]2)[CH2:18][CH3:19]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)nc2sccn12
Reactant: CCCS
Product: CCCSc1cn2ccsc2n1

Procedure:
In a manner similar to the procedure in Reference Example 1, the oily title compound was prepared from ethyl 6-mesylimidazo[2,1-b]thiazole-5-carboxlate and n-propyl mercaptan. ##STR9## NMR(CDCl3)δ: 1.00(t, 3H), 1.43-1.90(m, 2H), 2.88(t, 2H), 6.83(d, 1H), 7.38(s, 1H), 7.47(s, 1H)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[C:12]([CH2:14][N:15]1[C:20]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=2[O:18][CH2:17][C:16]1=[O:26])#[N:13].[H-].[Na+]>S(=O)(=O)(O)O.O>[C:12]([CH2:14][N:15]1[C:20]2[CH:21]=[C:22]([N+:1]([O-:4])=[O:2])[C:23]([F:25])=[CH:24][C:19]=2[O:18][CH2:17][C:16]1=[O:26])#[N:13]
Reactant: N#CCN1C(=O)COc2cc(F)ccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 95.2 %

Procedure:
98% nitric acid (0.71 g) was added dropwise to acetic anhydride (11.3 ml) at a temperature of 0° C. Subsequently a few drops of concentrated sulfuric acid were added thereto as catalyst, and the mixture was stirred for a while at 0° C. 4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.06 g) was added little by little thereto and stirred continuously at 0° C. for 30 minutes. A solution consisting of sodium hydride (10 g) and water (88 ml), cooled previously to 0° C., was added dropwise at 0° C. to neutralize the reaction liquor. The liquor was extracted with methylisobutyl ketone, and the extraction liquor was washed with water and a table salt solution, then dried with anhydrous sodium sulfate. The solvent was distilled off to give the desired 4-cyanomethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.39 g). mp. 204°-206° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:57])C(=O)C1>CC#N>[Br:57][C:36]1[N:37]2[C:12]3[N:13]4[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]5[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=5[C:30]5[CH:43]=[C:34]([C:35]=1[N:42]=[C:38]2[CH:39]=[C:40]([CH3:41])[C:11]=3[C@H:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[CH:33]=[CH:32][CH:31]=5)[CH2:15][CH2:14]4
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Solvent: CC#N
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (50 mg, 0.074 mmol, 1 equiv) in MeCN (1.5 mL) was added NBS (13 mg, 0.074 mmol, 1 equiv). After 1 h, the reaction was concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (40 mg, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.29 (s, 1H), 6.97 (d, J=10.3 Hz, 1H), 6.85 (d, J=6.5 Hz, 1H), 4.58-4.37 (m, 2H), 3.82-3.66 (m, 4H), 3.64-3.55 (m, 1H), 3.46-3.38 (m, 1H), 2.47 (br. s., 3H), 2.30 (d, J=0.8 Hz, 4H), 1.98-1.69 (m, 8H), 1.66-1.48 (m, 4H), 1.31-1.26 (m, 7H), 1.24 (d, J=5.8 Hz, 8H), 1.15 (d, J=6.0 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:29])[C:19]([C:27]#[N:28])=[C:20]4[C:26]=3[O:25][CH2:24][CH2:23][NH:22][CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12.O=[C:31]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[C:26]4[O:25][CH2:24][CH2:23][N:22]([CH:31]5[CH2:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34]5)[CH2:21][C:20]=4[C:19]([C:27]#[N:28])=[C:18]([Cl:29])[CH:17]=3)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCNC3)c2ncnc(N)c12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CN(C(=O)OC(C)(C)C)C2)C3)c2ncnc(N)c12
Temperature: 60 °C
Yield: 35.7 %

Procedure:
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (0.030 g, 0.078 mmol) was dissolved in methanol (3.0 mL), and the tert-butyl 3-oxoazetidine-1-carboxylate (0.027 g, 0.16 mmol) and then sodium cyanoborohydride (0.0098 g, 0.16 mmol) were added. The reaction was heated to 60° C. for 3 hrs and then allowed to cool to room temperature. The reaction was diluted with ethyl acetate and washed with brine. The organic layer dried over magnesium sulfate and concentrated to give the crude product as an amber oil. The oil was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient at pH 10 to give tert-butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate (0.015 g, 35%). LCMS calculated for C26H32ClN8O3 (M+H)+: m/z=539.2; found: 539.2.
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:18]1([NH:17][C:2]2[C:7]3=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]3[CH:5]([CH3:16])[CH2:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Solvent: CO
Product: CC1CC=C(Nc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To 800 ml of methanol 100.0 g. (0.348 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 100 cm3 of aniline are added. The mixture is heated under stirring until a solution is obtained. The solution is cooled to room temperature and stirred for 2-3 days. The precipitated crystals are filtered and washed with methanol. 64.0 g. (61.4%) of 9-(phenyl-amino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained which melts at 172°-173° C. after recrystallization from methanol.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][N:10]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11]1.O>CS(C)=O>[CH3:9][N:10]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[C@@H:19]2[CH2:4][C@H:20]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11]1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nn(C)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (0.650 g, 15.6 mmol) in dimethyl sulfoxide (5.0 mL) was added a solution of trimethylsulfoxonium iodide (3.34 g, 15.6 mmol) in dimethyl sulfoxide (35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methyl-2H-indazol-4-yl)acrylate (3.00 g, 13.0 mmol) in dimethyl sulfoxide (30 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (1.10 g, yield 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:13][CH2:12]3)[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:13][CH2:12]3)[CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C12CC2
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)NCC21CC1
Yield: 52.7 %

Procedure:
A mixture of 6′ chloro-spiro[cyclopropane-1,3′-[3H]indol]-2′(1′H)-one (0.291 g, 1.5 mmol) and borane-dimethyl sulfide complex in THF (2 M, 3.0 mL) was heated at reflux under nitrogen for 2 h. The mixture was cooled and MeOH (3 mL) was added dropwise (caution!). The resulting mixture was heated at reflux for 2 h, then was cooled and solvent evaporated in vacuo. Chromatography (SiO2; gradient elution with 0-100% Et2O in petrol) gave the title compound (0.142 g). MS: [M+H]+=180.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.Cl.Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)N[C@@H](C)c1ccc(CCl)cc1
Agent: Cl
Product: CC(=O)N[C@@H](C)c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using (S)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=114-115° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:19][C:10]1[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:25])[CH:4]=2)[CH:9]=1)[CH2:29][CH3:30])[CH3:27]
Reactant: CCNCC
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Product: CCN(CC)Cc1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 9(4), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a slightly yellow oil (yield: 94.7%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[N:11]=[CH:12][S:13][C:14]=1[CH:15]=O)(=[O:9])=[O:8].[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH3:31]>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[C:23]([CH2:15][C:14]2[S:13][CH:12]=[N:11][C:10]=2[S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:8])=[O:9])=[C:22]1[CH3:31]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1scnc1S(=O)(=O)c1ccccn1
Product: COC(=O)Cn1c(C)c(Cc2scnc2S(=O)(=O)c2ccccn2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 42b using 4-(pyridine-2-sulfonyl)thiazole-5-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:3]([NH:5][C@@H:6]([CH3:20])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[O:4].[Cl:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:28][C:29]1[CH:30]=[C:31]([S:35]([NH:1][C@@H:2]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:3]([NH:5][C@@H:6]([CH3:20])[CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:17])([F:18])[F:19])=[CH:11][CH:10]=2)=[O:4])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@@H](N)CC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CC1CCCCC1)NS(=O)(=O)c1cccc(Cl)c1
Reaction time: 12 h

Procedure:
The product from step D (15.4 mg, 39.7 μmol) was added to a flask with DMAP (14.5 mg, 0.119 mmol) and dry DMF (0.5 mL). 3-Chloro-benzenesulfonyl chloride (8.37 mg, 39.7 μmol) was added as a solution in 0.5 mL of dry DMF dropwise over 3 minutes. The resulting solution was stirred for 12 hours and the volatiles were stripped off. The solids were taken up in methanol and purified by prep HPLC. Yield 15 mg, 67%. 1H NMR (CDCl3) δ(ppm): 7.9 (s, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.6 (d, J=8 Hz, 1H), 7.5 (t, J=7.9 Hz, 1H), 7.05 (d, J=8.3 Hz, 2H), 6.6 (d, J=8.9 Hz, 2H), 6.15 (s, 1H), 5.1 (s, 1H), 4.1 (m, 1H), 3.65 (m, 1H), 3.25 (dd J=4.7, 12.9 Hz, 1H), 3.1 (dd J=7.5, 12.7 Hz, 1H), 1.6 (m, 7H), 1.4 (m, 1H), 1.3 (m, 1H), 1.2 (d, J=8.4 Hz, 3H), 1.07 (m, 3H), 0.65 (m, 1H). C25H31CWF3N3O4S: LC/MS=562.2 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[CH:11]=[C:10]2[CH3:18]>N>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([Cl:3])[CH:11]=[C:10]2[CH3:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]c2ccc(Br)cc12
Agent: N
Product: Cc1cc(Cl)nc2ccc(Br)cc12

Procedure:
25 mL of phosphorus oxychloride was added to 2.7 g (11.34 mmol) of 6-bromo-4-methyl-1H-quinolin-2-one (Example 1b) and the reaction mixture was refluxed for 2 hours. After cooling, the mixture was added batchwise to 250 mL of 10% NH3 solution, and the precipitate formed was filtered off, washed with water, and dried in the circulating air dryer at 30° C. Yield: 2.7 g (93% of theoretical); C10H7BrClN (M=256.526); calc.: molpeak (M+H)+: 256/258/260 (BrCl); found: molpeak (M+H)+: 256/258/260 (BrCl); Rf value: 0.95 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[O:10][CH:9]=[C:8]([CH:11]=O)[CH:7]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:8]1[CH:7]=[C:6]([CH3:5])[O:10][CH:9]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: Cc1cc(C=O)co1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1coc(C)c1)CC(=O)O
Yield: 30.5 %

Procedure:
Sodium ethylate (16 g, 0.23 mol) was added under vigorous stirring to a solution of 5-methyl-3-furaldehyde (21 g 80% purity, 0.19 mol) and diethyl succinate (50 g, 0.286 mol) in ethanol (400 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 300 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 700 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture (1:1). Fractions with the target product were collected, evaporated in vacuum and crystallized from ether/hexane mixture, 1:3 to give the desired product 14 g (58 mmol, 31%) as yellow crystals.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(N4CCOCC4)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccc(N4CCOCC4)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-morpholin-4-yl-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (44 mg, 0.093 mmol), β-alanine (666 mg, 7.5 mmol) and NaOMe solution (11 mL, 5.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 32 mg of the title compound. MS: (+) m/z 529.34 (M+1).