Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.[CH:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35]>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Reactant: CCCCC=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCC=Nn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg), triethylamine (130 μl), valeraldehyde (81 μl) and methanol (4.2 ml) was stirred at 70° C. for 3.5 hrs. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (200 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)=[O:3].[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:14]1([C:2]([C:4]2[CH:13]=[CH:12][C:7]3[O:8][CH2:9][CH2:10][O:11][C:6]=3[CH:5]=2)([OH:3])[CH3:1])[CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc2c(c1)OCCO2
Reactant: Br[Mg]C1CC1
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1ccc2c(c1)OCCO2)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (8.42 mmol) of 1,4-benzodioxan-6-yl methyl ketone and 33.7 ml (16.84 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.12 g (59% of theory) of the title compound were obtained.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[NH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[C:1]1(=[O:5])[N:7]2[C:13]3[CH:12]([CH2:17][CH2:16][CH2:15][C:14]=3[CH:9]=[CH:8]2)[CH2:11][CH2:10][C:2]1=[O:3]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=C1CCC2CCCc3ccn(c32)C1=O
Reaction time: 4 h

Procedure:
To a solution of oxalic chloride (27.5 ml) in tetrahydrofuran (THF; 500 ml) which was subjected to refluxing with heating, was dropwise added a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (28.8 g) in THF (100 ml), which was thereafter subjected to stirring for 4 hours as such. After cooled, the solvent was distilled off and the residue was dissolved into carbon disulfide (600 ml), to which then only small portions of aluminium chloride (52.27 g) were added at room temperature with stirring and was further subjected to stirring for 4 hours. With removal of supernatant solution from the reaction mixture, ice-water was added to the residue, which was then extracted with chloroform. The organic layer was thoroughly washed with water, dried over anhydrous sodium sulfate and then the solvent thereof was distilled off.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:8]2O)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:15][C:13](=[O:14])[CH2:12][C:7]1[CH2:6][C:5]2[C:9]([CH:8]=1)=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2
Reactant: CO
Reactant: O=C(O)CC1Cc2ccc(Br)cc2C1O
Agent: O=S(=O)(O)O
Product: COC(=O)CC1=Cc2cc(Br)ccc2C1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
The product from Example 52B (1.35 g, 5 mmol) in methanol (12 mL) was treated with concentrated sulfuric acid (2 mL) and heated to gentle reflux. After 2 hours, additional sulfuric acid was added (1 mL) and heating was continued for another 2 hours. The mixture was concentrated under vacuum and the residue was diluted with water (15 mL). The mixture was cooled to 10° C., filtered, and the filter cake washed with water (5 mL) and dried to provide the title compound. 1H NMR (CDCl3) δ 3.42 (s, 2H); 3.55 (s, 2H); 3.74 (s, 3H); 6.65 (m, 1H); 7.22-7.31 (m, 2H), 7.44 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCCBr)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 2,3-dichloroanisole (89 g., 0.50 mole) and 6-bromohexanoylchloride (120 g., 0.59 mole) in methylene chloride (500 ml.) is cooled to 5° C. and treated with aluminum chloride (74 g., 0.56 mole) in portions during a one-half hour period. The reaction mixture is kept at 25° C. for 18 hours then poured into ice water (1 l.) containing hydrochloric acid (100 ml.) the organic phase is separated, washed with water, 2% sodium hydroxide and dilute hydrochloric acid. The methylene chloride is evaporated at reduced pressure. The crude product is dissolved in ether (200 ml.), dried over magnesium sulfate, filtered and treated with hexane (600 ml.) affording 2,3-dichloro-4-(6-bromohexanoyl)anisole which melts at 52°-53° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][CH:10]=1.[C:30](Cl)(=O)[CH3:31].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[N:14]=[C:30]([CH3:31])[O:16][N:15]=2)=[CH:17][CH:18]=1
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)no1
Reaction time: 4 h

Procedure:
100 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxybenzamidine are placed in 2 ml of toluene. 20 mg of acetyl chloride and 2 ml of pyridine are added, and heating is carried out for 4 hours at 120° C. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and washed with dilute hydrochloric acid and water. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.10).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:23]=O.O>CO>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: O
Solvent: CO
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a solution of the amine (4) (363 mg, 1.39 mmol) and 3,5-dimethoxybenzaldehyde (301 mg, 1.81 mmol) in methanol (10 mL) was added borane-pyridine complex (445 μL, 4.18 mmol) at 40° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (5) as a pale yellow solid (329 mg, Yield: 57%).
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]([CH3:12])[C:4]=2[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)Cl.CO>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([C:2]2[NH:7][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]([CH3:12])[C:4]=3[CH:3]=2)[CH2:22][CH2:21]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cn1ccc2c(=O)[nH]c(Cl)cc21
Solvent: ClCCl
Solvent: CO
Product: Cn1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)cc21
Temperature: 140 °C
Yield: 68.1 %

Procedure:
A mixture of 6-chloro-1-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (Intermediate G) (17 mg, 0.09 mmol) and 1-(2-fluorophenyl)piperazine (140 mg, 0.77 mmol) was heated at 140° C. in a sealed tube overnight. Flash chromatography (20/1 methylene chloride/methanol) afforded 6-[4-(2-fluoro-phenyl)-piperazin-1-yl]-1-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (20 mg, 65.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.1 (d, J=4.77 Hz, 4H) 3.2-3.3 (m, 4H) 3.6 (s, 3H) 5.8 (s, 1H) 6.3 (d, J=3.01 Hz, 1H) 6.9 (d, J=3.01 Hz, 1H) 7.0-7.0 (m, 1H) 7.1-7.2 (m, 3H) 10.6 (s, 1H). LC-MS calcd. for C18H20FN4O [(M+H)+] 327, obsd. 327.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][C:17]#[N:18])[C:6]1=[O:19])=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].Cl>O.CN(C=O)C>[CH3:32][C:31]([O:30][C:28](=[O:29])[CH2:27][C:5]1([C:3]([O:2][CH3:1])=[O:4])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][C:17]#[N:18])[C:6]1=[O:19])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C1C(=O)N(CC#N)C(=O)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CC(=O)OC(C)(C)C)C(=O)N(CC#N)C(=O)c2ccccc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a suspension of 2-(cyanomethyl)-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinoline carboxylic acid methyl ester (6.5 g, 25.19 mmol), K2CO3 (6.95 g, 50.38 mmol) and anhydrous DMF (100 mL) was added tert-butyl bromoacetate (6.1 mL, 37.79 mmol). After stirring at 85° C. for 3 hours, the mixture was poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/EtOAc 4/1) gave a white solid (8.5 g, 90.7%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([CH2:23][C:24]#[N:25])[CH:16]=1)[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[C:24]([CH2:23][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:5]=2[CH2:4][N:3]([CH2:1][CH3:2])[C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[CH:16]=1)#[N:25]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetonitrile and cyclopropanecarbonyl chloride. M+H is 417.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[NH:8][S:9](=[O:18])(=[O:17])[C:10]2[CH:16]=[CH:15][S:14][C:11]=2[C:12]=1[OH:13])=[O:5])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]([CH3:21])[S:9](=[O:17])(=[O:18])[C:10]2[CH:16]=[CH:15][S:14][C:11]=2[C:12]=1[OH:13])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)CC1=C(O)c2sccc2S(=O)(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1=C(O)c2sccc2S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.93 G. (7 mmol) of 3-ethoxycarbonylmethyl-4-hydroxy-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide are dissolved in 4 ml. of absolute dimethylformamide and added dropwise during 30 minutes at 0° C. to a stirred suspension of 0.185 g. (7.7 mmol) of sodium hydride in 2 ml. of absolute dimethylformamide. The mixture is stirred for a further 1 hour at room temperature. There are then added firstly 0.53 ml. (1.2 g.; 8.45 mmol) of methyl iodide and, after 30 minutes, a further 0.25 ml. (0.565 g; 4 mmol) of methyl iodide and the mixture is allowed to react for 1 hour. After distillation of the solvent, the residue is taken up in 30 ml. of 0.5-N hydrochloric acid and 30 ml. of methylene chloride, the organic phase is separated and the aqueous layer is back-extracted twice with a small amount of methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated. The crystalline residue is digested with a small amount of cold ethanol. There is obtained 3-ethoxycarbonylmethyl-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide of melting point 161°-163° C. (crystal transformation at 151°-152° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(NCc3ccc(F)c(F)c3)c2cc1OCC

Procedure:
In the manner of Example 61 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3,4-difluorobenzylamine gave the title compound as a tan solid, mp167-169° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(=O)([O-])O.[Na+].C(OC(N1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=O)C.Cl>C(#N)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 69.9 %

Procedure:
A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (200 mg, 0.73 mmol) and sodium hydrogen carbonate (80 mg, 0.95 mmol) in acetonitrile and water(2 mL each) was stirred under nitrogen at room temperature for 2 minutes. To the resulting solution was added N-ethoxycarbonylphthalimide (170 mg, 0.78 mmol). After 17 hours, the resulting solution was stirred with hydrochloric acid (2 mL, 4 N), and water (30 mL) at room temperature for 30 minutes. The resulting suspension was filtered and the solid was washed with water (2×25 mL), and then dried in a vacuum oven overnight (60° C., <1 torr) to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3dione as a solid (206 mg, 70% yield): mp, 151.0-152.0° C.; 1H NMR (CDCl3); δ 1.46 (t, J=6.9 Hz, 3H, CH3), 2.84 (s, 3H, CH3), 3.78 (dd, J=4.8, 14.4 Hz, I H, CHH), 3.84 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.54 (dd, J=10.1, 14.4 Hz, 1H, CHH), 5.90 (dd, J=4.8, 1 0.1 Hz, 1H, NCH), 6.83 (d, J=8.5 Hz, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.67-7.73 (m, 2H, Ar), 7.80-7.84 (m, 2H, Ar); 13C NMR (CDCl3) δ 14.63, 41.49, 48.84, 54.82, 55.89, 64.45, 111.43, 112.50, 120.43, 123.51, 129.56, 131.58, 134.17, 148.57, 149.63, 167.80; Anal Calcd for C20H21NO6S: C, 59.54; H, 5.25; N, 3.47. Found: C, 59.66; H, 5.28; N, 3.29.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 4-ethylaniline (2 g) and triethylamine (13.91 mL) in dichloromethane (40 mL) at 0° C. under nitrogen was treated dropwise with acetic anhydride (4.67 mL). The mixture was warmed to ambient temperature, then stirred for 16 hours at room temperature, then washed with (i) 10% citric acid (40 mL), (ii) water (40 mL) and (iii) brine (40 mL). The organic phase was dried over magnesium sulfate and then evaporated to give 4-ethyl-N-acetyl-aniline (2.36 g) as a pale orange solid which was used without further purification. LC-MS (METHOD B): RT=2.80 minutes; 164.2 (M+H)+. (b) 3-Methyl-4-isopropyl-N-acetyl aniline
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[C:10]1[CH3:22])=[O:4].[CH:26]1([C:29]2[CH:30]=[C:31]([C@@H:35]([NH2:37])[CH3:36])[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27]1>>[CH:26]1([C:29]2[CH:30]=[C:31]([C@@H:35]([NH:37][C:18]([C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:9]([CH2:8][C:7]3[CH:6]=[C:5]([CH:25]=[CH:24][CH:23]=3)[C:3]([O:2][CH3:1])=[O:4])[C:10]([CH3:22])=[C:11]4[CH3:21])=[O:20])[CH3:36])[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27]1
Reactant: C[C@H](N)c1cccc(C2CC2)c1
Reactant: COC(=O)c1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Product: COC(=O)c1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C5CC5)c4)ccc32)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 5, Example 35, using 1-(3-(methoxycarbonyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and (S)-1-(3-cyclopropylphenyl)ethanamine.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](N)=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[ClH:13].[OH2:14]>>[ClH:13].[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:14])=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: O
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Agent: Cl
Product: N=C(N)c1ccc(C(=O)O)cc1
Reaction time: 9 h

Procedure:
4-Amidinobenzamide (commercially available one, 7.8 g) is dissolved in water (200 ml), and thereto is added conc. hydrochloric acid (200 ml), and the mixture is stirred at a temperature below 100° C. for 9 hours. The mixture is cooled, and the precipitated crystals are collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:25]([CH3:26])[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:16]3[CH2:15][CH2:14][N:13]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:12]([CH3:11])[CH2:17]3)=[CH:24][CH:23]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(Cl)n1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Cl)n3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was dissolved in DCM (15 mL) and added to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.500 g, 1.57 mmol) and triethylamine (0.284 mL, 2.04 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature overnight and then washed with water (×2) and brine. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography. Elution with 20-60% EtOAc/pentane yielded the title compound as a yellow oil/solid (0.658 g). δH (CDCl3, 400 MHz) 7.56 (1H, m), 7.46 (1H, m), 7.17 (2H, m), 6.99 (2H, m), 4.16 (1H, br.s), 3.79 (1H, d), 3.50 (3H, s), 3.46 (1H, d), 3.32 (1H, d), 3.07 (1H, m), 2.69 (1H, d), 2.50 (1H, d), 2.08 (1H, m), 1.97 (1H, m), 1.46 (9H, s), 1.19 (3H, d). MS (ES): MH+ 459/461.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[S:40][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:37]=1.C(N(CC)CC)C.NCCN(CCN)CCN>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:41]([C:39]2[S:40][C:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=3)=[CH:37][CH:38]=2)(=[O:42])=[O:43])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: NCCN(CCN)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (15 mg, 0.038 mmol), prepared in Step A of Example 13a, 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (5 eq), and triethylamine (5 eq) in CH2Cl2 (1-2 mL) was stirred at room temperature for 72 h. Additional 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (5 eq) and triethylamine (5 eq) were added and the reaction was stirred for 24 h followed by addition of tris(2-aminoethyl)amine on polymer support. The reaction was stirred for 24 h and the resin was removed by filtration with the aid of CH2Cl2. The organic solution was washed sequentially with 5.5% aqueous HCl and saturated NaHCO3 solution. The organic solution was concentrated and was used in Step B without further purification.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 72.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-methylsulfonylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (101 mg, 0.23 mmol) in DMF (2.5 ml) was added hydrazine monohydrate (80%, 28 μl, 0.87 mmol, 3.8 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-methylsulfonylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (72 mg, 72%).
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6].[Li+].[OH-].CC(=O)OCC>O1CCOCC1>[C:23]([O:22][C:20]([NH:19][CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:5]([OH:6])=[O:4])[N:8]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1nc(CNC(=O)OC(C)(C)C)oc1-c1ccccc1
Agent: N#N
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1nc(C(=O)O)c(-c2ccccc2)o1
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butoxycarbonylamino-methyl)-5-phenyl-oxazole-4-carboxylic acid methyl ester (200 mg, 0.60 mmol) in dioxane (2.0 mL) was treated with 1N LiOH (2.0 mL). The resulting mixture was stirred for 1 h. EA (10 mL) was added and the organic phase was washed with 1N HCl (3 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=0.89 min, [M+H]+=319.17.