Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)(=[O:18])=[O:17])[C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].[CH3:35][OH:36]>>[CH3:35][O:36][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)(=[O:18])=[O:17])[C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]
Reactant: CO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C)cn1
Agent: [Na]
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OC

Procedure:
To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of 5-methyl-pyridine-2-sulfonic acid[6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide at RT and the mixture was refluxed for 5 days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Cl2. The organic layer was dried over Mg2SO4, concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120° C. to give the desired 5-methyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as white crystals. Melting point 225-226° C. ISN mass spectrum, m/e 478.2 (M-1 calculated for C23H21N5O5S1: 478).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:4][CH2:3]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCN(CCCC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-1-(4-phenyl-4-oxobutyl)piperidine (1.23 g. 0.005 m) was suspended in a solution of dichloromethane (10 mls) containing triethylamine (2 mls). Methanesulphonyl chloride (0.570 g, 0.005 m) in dichloromethane (5 mls) was added dropwise over 5 minutes and the reaction stirred overnight at room temperature. The solution was then washed with five aliquots of water and dried over magnesium sulphate. Evaporation yielded the free base in 90% purity. This was triturated in ethyl acetate and warmed. The mother liquor was decanted off and evaporated to yield the title compound m.pt 141.4° C. This was recrystallised from ethanolic HCl as the hydrochloride salt (0.510 g), m.pt 167.4° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2N(C3CCNCC3)C3C(SC=2C=1)=CC=CC=3.CC1(C)C(C)(C)OB([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[NH:64][C:65](=[O:67])[CH3:66])O1.N1C=CC=C(B(O)O)C=1>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.CN1C(=O)CCC1.O.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=4[NH:64][C:65](=[O:67])[CH3:66])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(Cl)ccc32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Agent: OB(O)c1cccnc1
Solvent: O
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1N2C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using an adaptation of the method described in Procedure 16, substituting 4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 2i, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide for 3-pyridyl boronic acid, Cp2Fe(PtBu2)2PdCl2 for Pd(PPh3)4 and a 5:1 mixture of dioxane:water for NMP, the title compound 4-[3-(2-acetylaminophenyl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 1j was obtained.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[S:9][C:8]([S:10]([NH:13][C@H:14]([CH:20]=[O:21])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])(=[O:12])=[O:11])=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[Cl:4][C:5]1[S:9][C:8]([S:10]([NH:13][C@H:14]([CH:20]([OH:21])[CH3:1])[CH:15]([CH2:16][CH3:17])[CH2:18][CH3:19])(=[O:12])=[O:11])=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: CCC(CC)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(C)O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of methylmagnesium bromide (1.4 M, 7.0 mL, 9.7 mmol) in toluene/THF (75:25) was added to a 0° C. solution of 5-chloro-N-[(S)-2-ethyl-1-formylbutyl]thiophene-2-sulfonamide (Example 221, 1.0 g, 3.2 mmol) in THF (30 mL). The mixture was warmed to 25° C. and after 2 h was quenched carefully with saturated aqueous ammonium chloride (25 mL). The mixture was extracted with EtOAc (3×25 mL). The organic extract was dried over Na2SO4, filtered and concentrated to give a colorless oil. The product was purified by column chromatography (Biotage), eluant: 1:4 EtOAc-hexane, to afford 5-chloro-N-[(S)-2-ethyl-1-(1-hydroxyethyl)butyl]thiophene-2-sulfonamide as a white solid (876 mg, 83%). The product is a diastereomeric mixture with a ratio of 3:7. mp 95-98° C. Anal. Calc'd for C12H20ClNO3S2: C, 44.23; H, 6.19; N, 4.30. Found: C, 44.25; H, 6.35; N, 4.29. Mass Spectrum (−ESI): 324 (M−H)−.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[CH:16]([C:22]1[CH:31]=[C:30]([O:32][CH3:33])[C:25]([NH:26][C:27](=[O:29])[CH3:28])=[C:24]([O:34][CH3:35])[CH:23]=1)CS(C)(=O)=O>CS(C)=O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:16][C:22]1[CH:31]=[C:30]([O:32][CH3:33])[C:25]([NH:26][C:27](=[O:29])[CH3:28])=[C:24]([O:34][CH3:35])[CH:23]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1NC(C)=O

Procedure:
A mixture of 3.78 g. of sodium methylate, 5.1 g. of β-anilino-propionitrile and 9.8 g. of 4'-[(1-hydroxy-2-(methylsulfonyl)-ethyl)]-2',6'-dimethoxy-acetanilide in 40 ml. of dimethylsulfoxide was stirred at 50° C. for 4 hours with the exclusion of moisture. The mixture was poured into 400 ml. of water and the resulting emulsion was extracted with three 500 ml. portions of ethyl acetate. The ethyl acetate extracts were washed with two 200 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-acetanilide having a melting point of 165°-167° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:15]=3[C:16]([NH:36][CH2:35][CH:34]([C:29]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=3)[CH3:37])=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(CNC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=12.51 min. MS (ESI−): mass calcd. for C22H16Cl4N4O3S2, 587.94; m/z found, 587/589/591 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.22 (s, 1H), 8.35 (d, J=7.0, 1H), 8.24 (d, J=8.8, 1H), 7.89 (s, 1H), 7.74-7.71 (m, 1H), 7.41 (d, J=8.2, 1H), 7.29 (d, J=2.0, 1H), 7.14 (s, 1H), 7.05 (dd, J=8.2, 2.0, 1H), 5.79 (s, 1H), 3.69-3.63 (m, 1H), 3.34-3.29 (m, 1H), 3.03-2.99 (m, 1H), 1.31 (d, J=7.0, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1Br.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1[O:23][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Br
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Oc1ccc(Br)cc1
Reaction time: 0.02 h
Yield: 98.4 %

Procedure:
To a solution of 2,3-dibromo-6-methoxybenzo[b]thiophene 1,1-dioxide (2.50 g, 7.06 mmol) in THF (100 mL) at room temperature was added 4-bromophenol (1.344 g, 7.77 mmol) and Cs2CO3 (6.90 g, 21.19 mmol). The reaction mixture turned green after ˜1 min of stirring. The mixture was stirred at room temperature for 18 h after which time the reaction was quenched with water and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide 2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (3.10 g, 6.95 mmol, 98% yield) as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm=3.83 (s, 3H), 6.92-7.03 (m, 3H), 7.25-7.35 (m, 2H), 7.39-7.50 (m, 2H).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH:3]([CH3:5])[CH3:4].Br[C:8]1[CH:9]=[C:10]([C@:15]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([F:34])[CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1[F:14]>CN1C(=O)CCC1.C1COCC1.CCOC(C)=O>[F:14][C:13]1[CH:12]=[CH:11][C:10]([C@:15]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([F:34])[CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][C:8]=1[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C[Zn+]
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(Br)c1
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1cc([C@](N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 75 °C
Yield: 18 %

Procedure:
To a solution of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(H) dichloride (8 mg, 0.01 mmol) in NMP (0.5 mL) was added isobutylzinc(II) bromide in THF (0.5 M, 0.7 mL, 0.35 mmol) followed by (S)-1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine, prepared as described Procedure 62, 5 and 6, (50 mg, 0.11 mmol) in anhydrous THF. The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed with sat. NH4Cl, dried over Na2SO4 and concentrated to yield (R)-1-(4-fluoro-3-isobutylphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine. LCMS: RT=3.62 min [M−NH2] 417 (Waters Sunfire-S5-C18 4.6×50 mm, eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:13][N:12]=1>O1CCOCC1.CC(OC)(C)C>[CH2:1]([O:7][C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: C=CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: C=CCCCCOc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
1.50 g (15 mmol) of 5-hexen-1-ol dissolved in 30 ml of dioxane were mixed with 600 mg (60%, 15 mmol) of sodium hydride and stirred at room temperature for 30 minutes. Addition of 1.7 g (7.5 mmol) of 2-chloro-4,5-diphenylpyrimidine was followed by stirring at room temperature for 6 hours. Taking up in MTBE and washing with saturated NaCl solution were followed by drying over sodium sulfate and evaporation. The residue was purified on silica gel with heptane/ethyl acetate (15:1). 1.93 g (77%) of the desired product were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])[CH:6]=[N:7][CH:8]=1)#[N:2].[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH3:13][NH:12][S:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1](=[NH:2])[O:14][CH2:15][CH3:16])(=[O:11])=[O:10]
Reactant: CNS(=O)(=O)c1cncc(C#N)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1cncc(S(=O)(=O)NC)c1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 5-cyano-N-methylpyridine-3-sulfonamide (0.1 g, 0.5 mmol) in ethanol was added sodium ethoxide (0.03 g, 0.55 mmol). After 2 h, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure to afford ethyl 5-(N-methylsulfamoyl)nicotinimidate (120 mg) as an off-white solid. The material was used without further purification. MS (ES+APCI) 244.0; LCMS retention time: 3.047 min (Method I).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH2:10](OC(OCC)OCC)C.C(OC(=O)C)(=O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[CH3:9][C:5]1[C:6]2[C:7]([NH:36][CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)=[N:8][CH:10]=[N:1][C:2]=2[O:3][CH:4]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: Cc1coc(N)c1C#N
Reactant: CCOC(OCC)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1coc2ncnc(NCCc3ccc(Cl)cc3)c12
Temperature: 135 °C

Procedure:
A mixture of 4.0 g of 2-amino-3-cyano-4-methylfuran, 3 cc of triethylorthoformate, and 0.05 cc of acetic anhydride was heated to 135° C. for three hours. Then 5 g of 2-(4-chlorophenyl)ethylamine, 5 cc of glacial acetic acid, and 3.2 g of sodium acetate were added to the reaction mixture. The temperature of the mixture was maintained at 135° C. for three additional hours, after which the mixture was cooled, treated with water and extracted with dichloromethane. The organic phase was then concentrated and washed with water. The solids were extracted from the organic phase with large volumes of ether, which were combined and concentrated to provide 1.07 g of product. M.P. 140° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH2:25][CH3:26])=[C:12]2[CH2:27][C:28]([NH2:30])=[O:29])C.[NH2:32][NH2:33]>C(O)C.O>[CH2:25]([C:13]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15]2[C:11]([C:12]=1[CH2:27][C:28]([NH2:30])=[O:29])=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([NH:32][NH2:33])=[O:3])=[CH:17][CH:16]=2)[CH3:26]
Reactant: NN
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(CC)n2Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCc1c(CC(N)=O)c2cc(OCCCC(=O)NN)ccc2n1Cc1ccccc1
Yield: 87 %

Procedure:
A mixture of 211 mg (0.05 mmol of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 1 mL of hydrazine in 5 mL of ethanol was heated to maintain reflux for 5 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was stirred with MeOH and the insoluble material filtered to give 177 mg (87% yield) of 2-ethyl-5-(4-hydrazino-4-oxobutoxy)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 176°-179° C.
Reaction SMILES: [CH2:1]([O:9][CH:10]([CH3:15])[CH2:11][CH2:12][CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[OH-].[Na+].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:14][CH2:13][CH2:12][CH2:11][CH:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:15])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CCCCCCCCOC(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 78.2 %

Procedure:
7 g of 4-octyloxypentanol, 4.34 g of p-toluenesulfonyl chloride, 1.8 g of pyridine and 10 ml of benzene were stirred under N2 stream at room temperature for 22 hours. Thereafter, 6.5 ml of hot conc. NaOH aqueous solution was added to the reaction mixture and stirred for 5 min. Then, the mixture was poured into cold 10%-hydrochloric acid and extracted with hexane. The hexane layer was washed successively with cold 5%-hydrochloric acid, saturated NaHCO3 aqueous solution and water and dried with anhydrous MgSO4. After removing the solvent by distillation, the product was treated with alumina column (hexane) to obtain 6.6 g of 4-octyloxypentyl p-toluenesulfonate.
Reaction SMILES: Br[CH2:2][C:3]1[S:12][C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=2[C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]2[S:12][C:6]3[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=3[C:4]=2[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: Nc1ncnc2sc(CBr)c(-c3ccc([N+](=O)[O-])cc3)c12
Solvent: CN(C)C=O
Product: CN1CCN(Cc2sc3ncnc(N)c3c2-c2ccc([N+](=O)[O-])cc2)CC1
Yield: 33.1 %

Procedure:
A mixture of Example 57A (330 mg) and N-methylpiperazine (0.3 mL, 2.71 mmol) in DMF (6 mL) was stirred at room temperature overnight and concentrated. The concentrate was absorbed on silica gel and purified by flash column chromatography with ethyl acetate followed by 12% methanol/dichloromethane to provide 115 mg the desired product. Rf=0.38 (12% methanol/dichloromethane).
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].[CH2:11]([Si:14](OC)([O:17][CH3:18])[O:15][CH3:16])[CH2:12][CH3:13].Cl>CCOCC>[CH3:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:3]=1[Si:14]([CH2:11][CH2:12][CH3:13])([O:17][CH3:18])[O:15][CH3:16]
Reactant: Cc1cccc(C)c1Br
Reactant: CCC[Si](OC)(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCC[Si](OC)(OC)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
A 500 mL round bottomed flask was charged with magnesium powder (2.1 g, 86 mmol, Aldrich) and ether (250 mL, Aldrich). 2-Bromo-m-xylene (9.0 mL, 68 mmol, Aldrich) was added over a 25 minute period. The contents were refluxed overnight (18 hours). The brown solution was cooled to room temperature and propyl-trimethoxysilane (17.8 mL, 101 mmol) was added over 20 minutes. A white precipitate formed. The contents were stirred at room temperature overnight (18 hours). The reaction was poured into 0.2N aqueous HCl (500 mL), the layers were separated and the product extracted into ether (3×150 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed via rotary evaporation (13.5 g crude). Distillation under reduced pressure (b.p. 57° C., 0.04 mm Hg) provided (2,6-dimethylphenyl)-propyl-dimethoxysilane (6.8 g, 28 mmol, 41% yield); C13H22SiO2 (Mw=238.40); 1H NMR (CDCl3) δ 7.2 (t, 1H), 7.0 (d, 2H), 3.6 (s, 6H), 2.5 (s, 6H), 1.4 (m, 2H), 1.0 (t, 3H), 0.9 (t, 2H); 13C NMR (CDCl3) δ 145.2, 131.0, 129.6, 128.0, 49.8, 23.4, 17.9, 16.7, 16.3; MS m/z (relative abundance) 238 (8), 195 (100), 165 (22), 133 (12), 119 (10), 105 (13), 91 (9), 59 (16).
Reaction SMILES: [CH2:1]([C:3]1[C:25]([F:26])=[CH:24][C:6]([O:7][C:8]2[CH:22]=[CH:21][C:11]([C:12]([N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:23])=[C:5]([O:27][CH3:28])[CH:4]=1)[CH3:2].[OH-:29].[K+].[CH2:31]([O:33]C(Cl)=O)[CH3:32]>C(#N)C>[C:28](=[O:29])([O:33][CH2:31][CH3:32])[O:27][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:25]([F:26])=[CH:24][C:6]=1[O:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)=[O:13])=[CH:10][C:9]=1[F:23]
Reactant: [OH-]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Reactant: CCOC(=O)Cl
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Oc1cc(CC)c(F)cc1Oc1ccc(C(=O)N2CCNC(=O)C2)cc1F
Reaction time: 1 h

Procedure:
To a solution of 4-[4-(4-ethyl-5-fluoro-2-hydroxyphenoxy)-3-fluorobenzoyl]piperazin-2-one (20 mg, 0.053 mmol; which may be prepared as described in D3) in acetonitrile (550 μL) was added KOH (3 mg, 0.053 mmol) followed by ethylchlorocarbonate (6 μL, 0.058 mmol). After 1 hour at room temperature, the mixture was quenched with water. The aqueous layer was extracted twice with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography on silica gel, using dichloromethane/methanol (95:5) as eluent. The title product was obtained as a white solid (11 mg, 46%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.[NH2:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23]([NH2:30])=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=1.C(O)(C(F)(F)F)=O>C(O)(C)C>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[N:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23]([NH2:30])=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: Nc1ccc2c(c1)Cc1cc(N)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Nc1ccc2c(c1)Cc1cc(N=Cc3ccc4c(c3)Cc3ccccc3-4)ccc1-2
Reaction time: 12 h

Procedure:
2-Fluorenecarboxaldehyde (49.5 mg, 0.25 mmol) was added to 2,7-diaminofluorene (50 mg, 0.25 mmol) in anhydrous isopropanol, under an N2 atmosphere and a catalytic amount of TFA. No heating was required. The reaction was run for 12 hours until a green precipitate was filtered, yielding 94.9 mg. of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19]CC)=O)[C:9]2=[O:27])=[CH:5][CH:4]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:9](=[O:27])[C:10]3[N:14]=[CH:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([OH:19])[C:11]=3[CH:12]=[CH:13]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=CNc1cccn(Cc2ccc(OC)cc2)c1=O)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(=O)n(Cc3ccc(OC)cc3)ccc2c1O
Reaction time: 0.5 h

Procedure:
Dowtherm A (50 ml) was heated to 250° C. in a 500 ml a 3-neck rbf equipped with a temperature probe, a stir bar and a reflux condenser. Diethyl 2-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (5.00 g, 12.5 mmol) was added in one portion. The mixture was stirred for 30 mins and then was rapidly cooled down using a stream of nitrogen. At around 140° C., a solid started to crash out. Once at RT, the mixture was diluted with hexanes (100 ml) and was allowed to stand overnight. The precipitate that formed was collected by suction filtration, washed with ether and dried to give ethyl 7-(4-methoxybenzyl)-4-hydroxy-8-oxo-7,8-dihydro-1,7-naphthyridine-3-carboxylate as a yellow solid. MS(M+H)+ 355.