Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[NH:19][N:18]=[N:17][N:16]=1.C(N(CC)CC)C.Cl[CH2:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[N:19]([CH2:28][C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[N:18]=[N:17][N:16]=1
Reactant: COc1cc2ncnc(-c3nnn[nH]3)c2cc1OC
Reactant: Cn1ccnc1CCl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(-c3nnnn3Cc3nccn3C)c2cc1OC
Temperature: 27.5 °C
Reaction time: 0.29 h
Yield: 35.2 %

Procedure:
Experimental Procedure: 50.0 ml of N,N-dimethyl acetamide and 5.0 g (0.019 mol) of 6,7-dimethoxy-4-(1H-tetrazol-5-yl)quinazoline were charged into a 250 ml of 4necked round bottom flask, connected to a mechanical stirrer, thermometer socket, condenser and addition flask under mild nitrogen atmosphere. 3.80 g (0.038 mol) of triethyl amine was added at 25-30° C. Stirred the mass for 15-20 min at 25-30° C. Reaction mass temperature was raised to 50-55° C. Maintained the mass temperature at 50-55° C. for 15-20 min. 2-chloro methyl -1-methyl-imidazole solution [2.50 g (0.019 mol) 2-chloro methyl -1-methyl-imidazole was dissolved in 25.0 ml of N,N-dimethyl acetamide] was added slowly at 50-55° C. for 30-45 min. Maintained the mass temperature at 50-55° C. for 15-20 min. Raised the mass temperature to 80-85° C. Maintained the mass temperature at 80-85° C. for 7-8 hours. N,N-dimethyl acetamide was completely distilled under vacuum. Crude compound was purified by the column chromatography by using hexane and ethyl acetate. Obtained pure compound weight 2.40 g (yield 35.2% by theory).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:15][O:16][C:17]1[C:25]([CH3:26])=[C:24]2[C:20]([C:21](=[O:27])[O:22][CH2:23]2)=[C:19]([O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:18]=1[CH2:35]/[CH:36]=[C:37](\[CH3:40])/[CH2:38]Br>CN(C=O)C>[CH3:34][O:33][CH2:32][CH2:31][O:30][CH2:29][O:28][C:19]1[C:18]([CH2:35]/[CH:36]=[C:37](\[CH3:40])/[CH2:38][CH:7]([P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:17]([O:16][CH3:15])[C:25]([CH3:26])=[C:24]2[C:20]=1[C:21](=[O:27])[O:22][CH2:23]2
Reactant: COCCOCOc1c(C/C=C(\C)CBr)c(OC)c(C)c2c1C(=O)OC2
Reactant: CCOC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2)P(=O)(OC)OC
Reaction time: 0.17 h

Procedure:
To a solution of ethyl dimethylphosphonoacetate (135 mg) in DMF (5 ml) at 0° was added 50% NaH/oil (33 mg), and the mixture stirred for 10 minutes. (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy7-methyl -3-oxoisobenzofuran-5-yl)-2-methylbut-2-enyl bromide (600 mg) was added at the same temperature and allowed to reach room temperature in 30 minutes. The reaction was poured onto water and extracted with EtOAc. The organic layers were washed with water, dried over sodium sulfate, and evaporated to give the crude product which was purified by flash chromatography (CH2Cl2 followed by EtOAc) to obtain ethyl (E)-6-(4-methoxyethoxymethoxy -1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-(dimethylphosphono) -4-methyl-4-hexenoate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:24](O)([CH3:27])([CH3:26])[CH3:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:9]
Reactant: COC(=O)CCCCC(=O)O
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCCC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of adipic acid monomethyl ester (4.8 g, 30 mmol) in DMF (30 mL), was added CDI (4.9 g, 30 mmol), and the resulting mixture was stirred under N2 at 40° C. for 1 hour. t-Butanol (4.4 g, 60 mmol) and DBU (4.6 g, 30 mmol) were added, and stirring proceeded at 40° C. for 70 hours. The mixture was poured into ether (100 mL), and this mixture was washed with 10% aq. HOAc (100 mL), 10% aq. K2CO3 (100 mL), and water (3×100 mL), dried (MgSO4), and evaporated, providing 5.1 g of hexanedioic acid tert-butyl ester methyl ester, in 78% yield; 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.59-1.67 (m, 4H), 2.21-2.26 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: I[C:2]1[CH:22]=[N:21][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH:10]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=3[F:20])[CH3:11])[C:4]=2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[O:31])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:22]=[N:21][C:5]4[NH:6][CH2:7][CH2:8][N:9]([CH:10]([C:12]5[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=5[F:20])[CH3:11])[C:4]=4[CH:3]=3)=[CH:34][CH:33]=2)=[O:31])[CH2:26][CH2:25]1
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(c1cc(F)c(F)cc1F)N1CCNc2ncc(I)cc21
Product: CC(c1cc(F)c(F)cc1F)N1CCNc2ncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)cc21
Yield: 2 %

Procedure:
7-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (30 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid (2% yield). LCMS: m/z=560.73 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.26 (8H, m), 2.44 (7H, m), 3.64 (4H, m), 7.38 (1H, m), 7.47 (4H, m), 7.61 (4H, m).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[C:15](O)=[C:16]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:17]([C:29]#[N:30])=[C:18]([CH3:28])[C:19]=1[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:13][C:14]1[C:19]([CH:20]=[CH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([CH3:28])[C:17]([C:29]#[N:30])=[C:16]2[C:15]=1[O:37][C:32]([C:33]([CH3:36])([CH3:35])[CH3:34])=[N:31]2
Reactant: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1C=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C=Cc2ccccc2)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Yield: 84.3 %

Procedure:
Toluene (3 ml), p-toluenesulfonic acid monohydrate (1.4 mg, 7.5 μmol) were added to N-(3-bromo-6-cyano-2-hydroxy-5-methyl-4-styrylphenyl)-2,2-dimethylpropionamide (I-14) (31 mg, 75 μmol), followed by refluxing with a Dean-Stark condenser for 2.5 hours. After cooling, saturated sodium bicarbonate water (30 ml) was added to the reaction liquid, the product was extracted with ethyl acetate (30 ml×2). The organic layer was washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain the entitled compound (25 mg, 84%) as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]([C:23]2[N:24]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[N:25]=[C:26]3[C:31]=2[CH:30]=[CH:29][CH:28]=[CH:27]3)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[C:9]([F:39])[CH:8]=1)([CH3:6])[CH3:5].[OH-].[Li+]>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([N:24]2[C:23]([N:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14](=[O:15])[NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:40])=[O:2])=[CH:8][C:9]=3[F:39])=[C:31]3[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]3)=[N:25]2)=[CH:33][CH:34]=1
Reactant: COC(=O)C(C)(C)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 2.2, 2-(4-{3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-3-cyclohexyl-ureido}-3-fluoro-phenyl)-2-methyl-propionic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as yellow solid. MS: m/e=549.3 [M+H+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>C(O)C.O>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:12]([O-:15])(=[O:14])=[O:13])[CH3:11].[Na+:16]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCS(=O)(=O)[O-]
Yield: 100 %

Procedure:
To a solution of ethyl 6bromohexanoate (61b) (2.48 g, 11.0 mmol) in ethanol (6 ml) a solution of sodium sulfite (2.16 g, 20.6 mmol) in water (9 ml) was added and the resulting mixture was refluxed for 1 hour. The reaction mixture was evaporated under reduced pressure and the obtained solid was extracted with boiling ethanol in Soxhlet extraction apparatus for 15–20 hours. The extract was evaporated and the residue was crystallised from ethanol-diethyl ether (1:10) giving the title compound (2.71 g, 99%) in a form of a white solid material. 1H NMR (DMSO-d6, HMDSO), δ: 1.05–1.78 (6H, m); 1.17 (3H, t, J=7.2 Hz); 2.26 (4H, t, J=7.5 Hz); 4.05 (2H, q, J=7.2 Hz).
Reaction SMILES: [CH3:1][C:2](=[CH:7][CH:8]=[CH:9][C:10]([CH3:23])=[CH:11][CH:12]=[C:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][C:16](=[O:21])[CH:15]=[C:14]1[CH3:22])[CH:3]=[CH:4][CH:5]=O.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][C:45](=[CH:47][CH:48]=[CH:49][C:50]([CH3:63])=[CH:51][CH:52]=[C:53]1[C:58]([CH3:60])([CH3:59])[CH2:57][C:56](=[O:61])[CH:55]=[C:54]1[CH3:62])[CH3:46].C[O-].[Na+]>CO>[CH3:62][C:54]1=[CH:55][C:56]([CH2:57][C:58]([CH3:60])([CH3:59])/[C:53]/1=[CH:52]\[CH:51]=[C:50](/[CH3:63])\[CH:49]=[CH:48]\[CH:47]=[C:45](/[CH3:44])\[CH:46]=[CH:5]\[CH:4]=[CH:3]\[C:2](\[CH3:1])=[CH:7]\[CH:8]=[CH:9]\[C:10](\[CH3:23])=[CH:11]\[CH:12]=[C:13]1/[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]([CH:15]=[C:14]/1[CH3:22])=[O:21])=[O:61]
Reactant: CC(C=CC=O)=CC=CC(C)=CC=C1C(C)=CC(=O)CC1(C)C
Reactant: CC(C)=CC=CC(C)=CC=C1C(C)=CC(=O)CC1(C)C
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: CC1=CC(=O)CC(C)(C)/C1=C\C=C(C)\C=C\C=C(C)\C=C\C=C\C(C)=C\C=C\C(C)=C\C=C1\C(C)=CC(=O)CC1(C)C

Procedure:
0.2 g. of 4,8-dimethyl-10-(4-oxo-2,6,6-trimethyl-2-cyclohexenylidene)-2,4,6,8-decatetraenal and 0.35 g. of 2,6-dimethyl-8-(4-oxo-2,6,6-trimethyl-2-cyclohexenylidene)-2,4,6-octatrien triphenylphosphonium bromide were dissolved in 6 ml. of methanol and treated with 0.2 g. of sodium methoxide at 0° for 4 hours. The precipitated dark violet solid was collected and recrystallized from benzene methanol to yield rhodoxanthin.
Reaction SMILES: C([O:8][C:9](=[O:23])[NH:10][C@@H:11]([CH3:22])[C@@H:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1)O)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[C:46]1[CH:47]=[C:48]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([O:62]C)=[O:61])=[CH:56][C:55]=2[CH3:64])[CH:49]=[CH:50][C:51]=1[O:52][CH3:53].[OH-].[Na+].Cl>CC(N(C)C)=O.C1COCC1>[Cl:21][C:16]1[CH:15]=[C:14]([C@H:12]2[O:23][C:9](=[O:8])[N:10]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=[CH:38][C:37]=3[C:46]3[CH:47]=[C:48]([C:54]4[CH:59]=[CH:58][C:57]([C:60]([OH:62])=[O:61])=[CH:56][C:55]=4[CH3:64])[CH:49]=[CH:50][C:51]=3[O:52][CH3:53])[C@H:11]2[CH3:22])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: C[C@H](NC(=O)OCc1ccccc1)[C@H](O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccc(F)c(Cl)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of benzyl[(1S,2R)-2-(3-chloro-4-fluorophenyl)-2-hydroxy-1-methylethyl]carbamate (51.4 mg, 0.152 mmol) in DMA (1.5 mL) was added NaHMDS (0.296 mL of a 1M solution in THF, 0.296 mmol). After 5 minutes, a solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (75 mg, 0.152 mmol) in DMA (2.5 mL) was added via cannula. After 5 minutes, saturated aqueous NaOH solution (3 mL) was added, and the mixture was allowed to warm to room temperature. After 3 hours, the mixture was acidified with 6 N HCl and concentrated. The residue was purified by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA) to afford 2″-{[(4S,5R)-5-(3-chloro-4-fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS=627.9 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.95-7.62 (m, 2H), 7.69-7.52 (m, 2H), 7.43-7.37 (m, 2H), 7.30-7.24 (m, 1H), 7.18-7.11 (m, 2H), 7.08-6.86 (m, 3H), 5.44 (d, J=8.0 Hz), 5.18 (d, J=8.0 Hz), 4.92-4.85 (m, 1H), 4.18 (d, J=15.5), 3.96 (d, J=15.5), 3.93-3.85 (m, 3H), 3.73-3.66 (m, 1H), 2.36 (s), 2.32 (s), 0.55 (d, J=6.6 Hz), 0.44 (d, J=6.6 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH2:20]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:19][CH:18]=[CH2:17]
Reactant: N#Cc1ccc(O)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCCOc1ccc(C#N)cc1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
4-Cyanophenol (30 g, 250 mmol) was mixed with K2CO3 (72.5 g, 525 mmol) and stirred for 60 minutes. 4-Bromo-1-butene (50 g, 370 mmol) was added dropwise. The reaction mixture was stirred at 60° C. overnight. The solids were filtered off and the solvents were evaporated. The residue was dissolved in DCM. and washed with 1 N NaOH. The organic layer was separated, dried (Na2SO4) and evaporated to give 37 g (58%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[N:15]=[C:16]([C:17]3[N:18](C(OC(C)(C)C)=O)[C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:3]=12.C([O-])(O)=O.[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[N:15]=[C:16]([C:17]3[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:3]=12
Reactant: CN1CCN(CCn2nc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCn2nc(-c3cc4ccccc4[nH]3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
A solution of tert-butyl 2-(4-chloro-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-1H-indole-1-carboxylate (29 mg, 0.051 mmol) in CH2Cl2 (3 mL) and trifluoroacetic acid (0.8 mL) was stirred at room temperature for 1 d. Solid NaHCO3 was added until no gas was evolved and sat. aq. NaHCO3 solution and CH2Cl2 was added. The layers were separated and the aqueous was extracted with CH2Cl2, the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was freeze dried from acetonitrile and water to provide Compound Im as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]([CH3:60])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C)C=O>[CH3:50][N:51]([CH3:60])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][N:57]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=5)=[O:49])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:56][CH2:55]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN(C)CCN1CCNCC1
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 25 h
Yield: 69.3 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added 1-(2-dimethylaminoethyl)piperazine (59.0 mg), followed by stirring at room temperature for 25 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, the residue was purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with diethyl ether:hexane=1:3 and dried under aeration to provide the titled compound as white powder (31.7 mg, 69.6%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)(=[O:12])(=[O:11])[NH2:10]>>[CH:1](=[N:17][C:16]1[CH:18]=[CH:19][C:13]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(N=Cc2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using benzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 91%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH:14]([N:13]([CH3:17])[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([N:26]4[CH:27]=[C:22]([CH3:21])[CH:23]=[CH:24][C:25]4=[O:28])[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1)([CH3:18])[CH3:15]
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(=O)[nH]c1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N(C)C(C)C)C4)sc3c2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 22, except for substituting the product of Example 52A for the product of Example 1E and substituting 5-methyl-2-pyridone for 3(2H)-pyridazinone. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J=8.59 Hz, 1H) 7.88 (d, J=2.15 Hz, 1H) 7.42 (dd, J=8.59, 1.84 Hz, 1H) 7.26-7.30 (m, 1H) 7.15 (s, 1H) 6.62 (d, J=9.21 Hz, 1H) 3.51-3.64 (m, 1H) 3.13-3.27 (m, 1H) 2.90-3.02 (m, 1H) 2.62-2.72 (m, 2H) 2.28-2.40 (m, 2H) 2.13 (s, 3H) 2.12 (s, 3H) 1.02 (d, J=6.44 Hz, 6H). MS: (M+H)+=368.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O)[C:6](=O)[CH3:7])[CH3:2].Cl.[NH2:19][NH2:20].Cl.C([O-])(O)=O.[Na+]>C(O)C.O.O1CCOCC1>[CH2:1]([O:3][C:4]([C:5]1[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:19][NH:20][C:6]=1[CH3:7])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(=O)c1ccncc1
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 3-oxo-2-(pyridine-4-carbonyl)-butyric acid ethyl ester (1 g, 4.25 mmol) in 10 ml ethanol, were added a solution of hydrazine hydrochloride (291 mg, 4.25 mmol) in 4 ml water and, then 0.1 ml of 4M HCl in dioxane. The yellow solution was stirred 1 h at room temperature, poured on a saturated solution of NaHCO3 and extracted twice with EtOAc. The organic phases were washed with brine, dried over magnesium sulfate, and evaporated to afford the title compound as light yellow solid (815 mg, 83%). MS: 232.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:40]([O:41][CH3:42])=[O:43])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: COC(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 31.7 mg, 0.0705 mmol) was dissolved in anhydrous methylene dichloride (1 mL), triethylamine (30 μL, 0.22 mmol) and methyl chlorocarbonate (10 μL, 0.13 mmol) were added thereto, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (26.8 mg) as a pale yellow amorphous product. (Yield 79%)
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:12](=[CH:13][CH:14]=1)[C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][NH:6]2.O.[C:16](O)(=O)C=O.[OH-].[K+].Cl.[OH-].[Na+]>O>[F:2][C:3]1[CH:4]=[C:5]2[C:12]([C:8]3[CH2:9][CH2:10][NH:11][CH2:16][C:7]=3[NH:6]2)=[CH:13][CH:14]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: O=CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Fc1ccc2c3c([nH]c2c1)CNCC3
Temperature: 25 °C

Procedure:
6-Fluorotryptamine hydrochloride (0.511 g, 2.38 mmol) was dissolved in water (9 ml). Glyoxylic acid monohydrate (0.241 g, 2.618 mmol) was added, followed by KOH (0.129 g, 2.31 mmol). The resultant solid was stirred at ambient temperature for one hour before concentrated HCl (0.6 ml) was added in one portion. The mixture was refluxed for 30 minutes, more concentrated hydrogen chloride (0.6 ml) was added and the mixture was again refluxed for 15 minutes. The mixture was cooled to room temperature and basified to pH12 using 5N sodium hydroxide. It was extracted with chloroform (4×75 ml), separated, dried over magnesium sulphate, filtered and concentrated in vacuo to yield an off-white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[C:10]([F:16])[CH:9]=1>CN(C=O)C.CCOC(C)=O>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:1]=[N+:2]=[N-:3])=[C:10]([F:16])[CH:9]=1
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])c(F)c1
Reaction time: 18 h
Yield: 100 %

Procedure:
Sodium azide (609 mg) was added to a solution of 4-bromomethyl-3-fluorobenzoic acid methyl ester from Example E3.2 (2.1 g, 8.5 mmol) in DMF (30 ml). The mixture was stirred for 18 h, diluted with EtOAc, washed with water and brine and concentrated in vacuo to give a colourless oil identified as the title compound (1.8 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=1)([O-])=O.Cl.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([NH2:14])[CH:7]=2)[CH:12]=[CH:13][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2ccc([N+](=O)[O-])cc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc2ccc(N)cc2c1

Procedure:
To 1.39 g (6.37 mmol) of 2,7-dinitronaphthalene (124) was added 25 mL of concentrated HCl and 15 mL of ethanol. Then, 9.6 g (50.9 mmol) of tin (II) chloride was added and the reaction was heated at 78 C for 24 hours. The reaction was made basic with NaOH and extracted with ethyl acetate. The ethyl acetate layer was dried (MgSO4), filtered, and the volatiles removed by rotary evaporation. The product was purified by silica gel column chromatography eluting with 1% methanol in dichloromethane. This provided 0.965 g of compound 125.