Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH:18]1[CH2:28][CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]1([C:5]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[CH:4][CH2:3][CH2:2][N:18]2[CH2:28][CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: BrCCC=C(c1ccccc1)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCN(CCC=C(c2ccccc2)c2ccncc2)C1

Procedure:
1-Bromo-4-phenyl-4-(4-pyridyl)but-3-ene (1.0 g, 3.5 mmol), ethyl nipecotate (0.72 g, 4.6 mmol) and potassium carbonate (1.93 g, 14.0 mmol) in acetone (30 ml) were stirred at room temperature for 5 days. The reaction mixture was filtered, and evaporated to a residue which was purified by flash chromatography on silica gel (Merck Art 9385). Elution with dichloromethane/ethanol/25% ammonium solution (190:9:1) provided the title compound as an oil. T.l.c. rf=0.23 (SiO2, CH2Cl2 /EtOH/NH3 (190:9:1)).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[N:43]([CH3:47])[N:42]=[C:41]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:41]4[C:40]5[C:44](=[CH:45][CH:46]=[C:38]([Cl:37])[CH:39]=5)[N:43]([CH3:47])[N:42]=4)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(Cl)cc12
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(Cl)ccc21
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 79.4 %

Procedure:
In a round-bottomed flask 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (150 mg, 0.26 mmol) and 5-chloro-1-methyl-3-tributylstannanyl-1H-indazole (372 mg, 0.45 mmol) were dissolved in DMF (2.4 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and copper(I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2% MeOH) to isolate 137 mg (80%) of 2-(5-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:18]C=[N:16][C:15]=2C(OCC)=O)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.[BrH:24]>>[BrH:24].[NH2:16][CH2:15][C:14]([C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([OH:9])=[C:3]([OH:2])[CH:4]=1)=[O:18]
Reactant: CCOC(=O)c1ncoc1-c1cc(OC)c(OC)c([N+](=O)[O-])c1
Agent: Br
Product: NCC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
1.0 g of ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazolecarboxylate is treated with 10 ml of constant-boiling hydrobromic acid and stirred at 140° for 2 hours. After distillation of the excess hydrobromic acid, the yellow residue is recrystallized from ethanol/acetone. There is obtained 2-amino-3',4'-dihydroxy-5'-nitroacetophenone hydrobromide in the form of yellow crystals of m.p. >250° (dec.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[O:15]=[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[NH:17]1>C(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:24]2[CH2:23][CH2:22][CH:21]([N:20]3[C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[NH:17][C:16]3=[O:15])[CH2:26][CH2:25]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n1C1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 18 h
Yield: 87 %

Procedure:
Excess 3-Trifluoromethyl-benzenesulfonyl chloride and polystyrene-diisopropylethylamine resin (ca. 40 mg) were added to a 50 mM solution of 4-(2-keto-1-benzimidazolinyl)piperidine in methylene chloride-dimethyl formamide (9:1) (1 mL). The mixture was shaken 18 hours then scavenged with polystyrene-trisamine resin (ca. 33 mg) for another 18 hours. The reaction was filtered and evaporated to give 1-[1-(3-Trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (18.6 mg, 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:13]([CH2:20][O:21][CH2:22][CH3:23])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[CH3:24][S-:25].[Na+]>CN(C)C=O>[CH2:22]([O:21][CH2:20][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([S:25][CH3:24])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:12]=1)[CH3:23]
Reactant: C[S-]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3cc(SC)ccc3c2n1CCCOC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinoline (U.S. Patent Application Publication No. US 2004/0147543 Examples 163-175, 1.0 g, 2.64 mmol) and sodium thiomethoxide (0.185 g, 2.64 mmol) were dissolved in N,N-dimethylformamide (25 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then heated at 55° C. for 16 hours. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and sequentially washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 2-Ethoxymethyl-1-(3-methoxypropyl)-7-methylthio-1H-imidazo[4,5-c]quinoline was isolated as 1.1 g of a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH2:10]([NH:17][C:18]([NH2:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC(=O)C)(=O)C>>[CH2:10]([N:17]1[C:4](=[O:5])[CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:20][C:18]1=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(=O)NCc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1Cc1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (350 mg; 2.5 mmoles), benzylurea (389 mg; 2.6 mmoles) and acetic anhydride (2 ml) was heated with stirring at 100° C. for 1 hour. The solvent was evaporated under reduced pressure, and the residue was recrystallized from chloroform/hexane to give 500 mg (yield: 72%) of 3-benzyl-5-trifluoromethyldihydrouracil. The physical and spectral properties of this product completely agreed with those of the product obtained in Example 6.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:4][CH:3]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(CCc1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(CCc4ccccc4)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,3-diphenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C@H:2]([OH:32])[C@@H:3]1[C:9](=[O:10])[N:8]2[C@@H:4]1[CH2:5][C:6]([S:14][CH2:15][CH2:16][NH:17][C:18]([CH2:20][CH2:21][NH:22][C:23]([C@H:25]([OH:31])[C:26]([CH2:29][OH:30])([CH3:28])[CH3:27])=[O:24])=[O:19])=[C:7]2[C:11]([OH:13])=[O:12]>O>[CH3:1][CH:2]([OH:32])[CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[CH2:5][C:6]([S:14][CH2:15][CH2:16][NH:17][C:18]([CH2:20][CH2:21][NH:22][C:23]([CH:25]([OH:31])[C:26]([CH2:29][OH:30])([CH3:28])[CH3:27])=[O:24])=[O:19])=[C:7]2[C:11]([OH:13])=[O:12]
Reactant: C[C@H](O)[C@@H]1C(=O)N2C(C(=O)O)=C(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO)C[C@H]12
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SCCNC(=O)CCNC(=O)C(O)C(C)(C)CO)CC12

Procedure:
The dark brown powder of antibiotics OA-6129 B1 and B2 obtained in step (C) was dissolved in a small amount of distilled water, and charged onto a column (8×100 cm) of Biogel P-2 (registered trademark). The column was developed with distilled water. Active fractions (1.0 liter in total) were collected by bioassay and adsorbed on a column (4×40 cm) of QAE-Sephadex A-25 (registered trademark) which had been equilibrated with 0.01 M phosphate, p.H 8.4. The column was washed with 200 ml of 0.01 M phosphate buffer, pH 8.4, and eluted with a linear concentration gradient of sodium chloride from 0 to 4% in 3.0 liters of the phosphate buffer. The eluate was fractionated in 15 ml portions, and antimicrobially active fractions Nos. 51 to 70 (300 ml) were collected. The combined fractions were lyophilized to give yellowish brown powder of antibiotics OA-6129B1 and B2. The powder was dissolved in a small amount of distilled water, and 5 g of sodium chloride was added. The solution was adsorbed on a column (2×50 cm) of Diaion HP-20AG (registered trademark). The column was washed with 50 ml of 5% sodium chloride and then with 100 ml of distilled water and eluted by using a linear concentration gradient of acetone from 0 to 30% in a total volume of 1.0 liter. The eluate was fractionated in 10 ml portions, and monitored by bioassay. Active fractions Nos. 15 to 24 (100 ml) and active fractions Nos. 26 to 35 (100 ml) were collected and combined respectively. The former solution contained antibiotic OA-6129B1, and the latter antibiotic OA-6129B2. Lyophilization of these solutions gave 840 mg of yellowish powder of antibiotic OA-6129B1 and 470 mg of yellowish brown powder of antibiotic OA-6129B2, respectively.
Reaction SMILES: [C:1]1([CH:7]([CH2:12][C:13](O)=[O:14])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(C)C.Cl>C1COCC1.O>[C:1]1([CH:7]([CH2:8][CH2:9][OH:10])[CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: OCCC(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g (14.4 mmol) of 3-phenylglutaric acid were dissolved in 20 ml of abs. THF, the mixture was cooled to −10° C. and 31.7 ml (31.7 mmol) of a 1 M solution of lithium aluminium hydride in THF were added dropwise. During the addition, a further 50 ml of abs. THF were added. The resulting suspension was slowly warmed to RT and stirred at RT overnight. After cooling to 0° C., initially isopropanol and then a mixture of isopropanol and water (3:1) were carefully added dropwise. The resulting suspension was acidified by addition of 1 N hydrochloric acid and mixed with Celite. The mixture was filtered through Celite, the filter cake was washed with isopropanol and the filtrate obtained was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 2:1→1:1). This gave 1.9 g of the target product (73% of theory).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH3:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=S.Cl.C(O)(=[O:35])C>C(OCC)(=O)C.C(OCC)C>[ClH:1].[CH3:2][CH:3]([CH3:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=[O:35]
Reactant: CC(=O)O
Reactant: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2

Procedure:
Mercuric acetate (0.668 g) is added with stirring to a suspension of N-(3-methylbutyl)-10-[(2RS)-1-(1-pyrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (1 g) in acetic acid (20 cc), and the mixture is left to react for 5 hours 30 minutes at a temperature in the region of 20° C. The reaction mixture is diluted with ethyl acetate (150 cc) and distilled water (50 cc) and then treated with caustic soda (d=1.33) to pH 13. The organic phase is separated and the aqueous phase is extracted again with ethyl acetate (2×50 cc). The combined organic phases are washed with saturated aqueous sodium hydrogen carbonate solution (100 cc) and then with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.53 g) is purified by chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting successively with a mixture (97.5:2.5 by volume) (100 cc) of methylene chloride and methanol and then with a mixture (95:5 by volume) (200 cc) of methylene chloride and methanol and collecting 15-cc fractions. Fractions 12 to 34 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oil obtained is dissolved in ethyl acetate (10 cc) and a 3N solution (0.5 cc) of hydrochloric acid in ethyl ether is added. The solid formed is drained, washed with ethyl ether (2×2 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(3-Methylbutyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.37 g) is thereby obtained in the form of a pale yellow solid, m.p. about 100° C. (melts forming a paste), the NMR spectrum of which is identical to that of the product described below in Example 26.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH:33]=[CH:34][S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[S:35](/[CH:34]=[CH:33]/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:37])=[O:36])[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(N(C3CCN(Cc4ccccc4)CC3)S(=O)(=O)/C=C/c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
A mixture of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (0.10 g, 0.29 mmol), 2-phenyl-ethenesulfonyl chloride (87 mg, 0.43 mmol), and TEA (0.08 mL, 0.57 mmol) in CH2Cl2 (5 mL) was stirred at rt for 20 h. The reaction mixture was concentrated, and the residue was purified on silica gel (60-70% EtOAc/hexanes) to afford the title compound (138 mg, 92%). 1H NMR (500 MHz, CDCl3): 8.12 (s, 1H), 7.50-7.48 (m, 2H), 7.43 (s, 1H), 7.41-7.39 (m, 3H), 7.25 (d, J=6.8 Hz, 2H), 7.20 (t, J=7.0 Hz, 3H), 7.15 (d, J=7.9 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.86 (d, J=15.0 Hz, 1H), 4.13 (t, J=8.0 Hz, 2H), 3.98-3.40 (m, 1H), 3.41 (s, 2H), 3.20 (t, J=8.5 Hz, 2H), 2.87 (d, J=10.5 Hz, 2H), 2.20 (s, 3H), 2.06-2.02 (m, 2H), 1.88 (d, J=10.7 Hz, 2H), 1.61-1.55 (m, 2H). MS: exact mass calculated for C30H33N3O3S, 515.22; m/z found, 516.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=2[F:21])=[CH:10][C:9](=[O:22])[N:8]([CH3:23])[CH:7]=1)=[O:5])C.[OH-].[Na+]>CCO>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:11]2[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]([CH3:23])[C:9](=[O:22])[CH:10]=2)=[C:14]([F:21])[CH:15]=1)#[CH:20]
Reactant: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)OCC)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (0.67 mg, 2.13 mmol) was suspended in EtOH (20 mL), to which was added NaOH (0.26 g, 6.40 mmol). This mixture was stirred at 70° C. for 1 hour. The solvent was removed under reduced pressure. The residue was acidified with 1N HCl then the resulting precipitate was filtered and washed with water. The tan solid was dried under high vacuum pump to afford 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.56 g, 91%). 1H NMR [(CD3)2SO, 400 MHz] δ 13.31 (v br s, 1H), 9.79 (s, 1H), 8.51 (s, 1H), 7.49 (dd, J=10.1, 1.9 Hz, 1H), 7.44 (dd, J=8.4, 1.7, 0.8 Hz, 1H), 7.32 (dd, J=8.5 Hz, 1H), 5.61 (dd, J=0.7 Hz, 1H), 4.25 (s, 1H), 3.41 (s, 3H). Anal. Calcd for C15H11FIN2O3: C, 62.94; H, 3.87; N, 9.79. Found: C, 62.56; H, 3.78; N, 9.30.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C)C=O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[C:3]([C:12](=[O:23])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:2]([O:1][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:7]=1
Reactant: COc1ccc(CCC(=O)c2c(O)cc(OC)cc2OC)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OC)cc(OC)c1C(=O)CCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Then, 30 ml of dimethylformamide was added to 5.0 g of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone and 420 mg of sodium hydride, and the mixture was stirred at 0° C. for 1 hour. Then, 2.6 g of methyl α-bromoacetate was added to the mixture, and the mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour to effect a reaction. After the reaction, the reaction mixture was extracted with ethyl acetate and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel chromatography [230-400 mesh silica gel; eluting solvent=n-hexane/ethyl acetate (2/1)] and recrystallized from a mixed solvent of diethyl ether and n-hexane to obtain 5.3 g (yield=87.1%) of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a colorless plate.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=2)[CH:5]=1)(=[O:3])[NH2:2].CO.[OH-].[Na+].Cl>C1COCC1>[C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(OC)c(F)c3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)O)ccc4c3n2)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.1 %

Procedure:
A solution of methyl 4-carbamoyl-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-7-carboxylate (75 mg, 0.19 mmol) in a mixture of THF (3 ml), MeOH (1 ml) and 1 N aqueous sodium hydroxide (3.0 ml, 3.0 mmol) was stirred at room temperature for 24 hr. This was neutralized with 1 N aqueous HCl and the organic solvents were removed on the rotary evaporator. The residue was dissolved in water and acidified to about pH 3 with 1 N aqueous HCl. The mixture was chilled in an ice bath and the precipitate was collected by filtration and dried to give 4-carbamoyl-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid (70 mg) as a yellow solid. MS (ESI) m/z 380.0 (M+H). 1H NMR (DMSO-d6) δ ppm 11.87 (1H, s), 8.64 (1H, br. s.), 8.50 (1H, s), 8.41 (1H, s), 8.36 (1H, d, J=7.93 Hz), 8.11-8.21 (2H, m), 7.96(1H, br. s.), 7.87 (1H, d, J=8.24 Hz), 7.36 (1H, t, J=8.85 Hz), 3.95 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]2[NH:33][C:32]([CH:34]=O)=[CH:31][CH:30]=2)=[O:28])[CH2:23][CH2:22]1>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:32]4[NH:33][C:29]([C:27]([N:24]5[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]5)=[O:28])=[CH:30][CH:31]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: CN1CCN(C(=O)c2ccc(C=O)[nH]2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCN(C(=O)c2ccc(C=C3C(=O)Nc4ncnc(Nc5ccc(F)c(Cl)c5)c43)[nH]2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.2 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (66.4 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 101.5 mg (84%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.39 (br s, 1H, NH), 11.74 (br s, 1H, NH), 8.81 (br s, 1H), 8.28 (s, 1H), 7.76 (s, 1H), 7.75 (m, 1H), 7.53 (m, 1H), 7.39 (t, J=8.9 Hz, 1H), 6.91 (m, 1H), 6.74 (m, 1H), 3.70 (m, 4H, 2×CH2), 2.37 (m, 4H, 2×CH2), 2.21 (s, 3H, CH3). MS 482 [M++1].