Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][CH2:13][CH2:14][OH:15].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO.O>[NH2:9][C:4]1[C:3]([NH:12][CH2:13][CH2:14][OH:15])=[C:2]([Cl:1])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1NCCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(F)c(Cl)c1NCCO
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
2-[(2-Chloro-3-fluoro-6-nitrophenyl)amino]ethanol (5.52 g, 22.7 mmol) is dissolved in MeOH (40.0 mL). A premixed solution of Na2S2O4 (13.8 g, 79.5 mmol) in water (40.0 mL) is added to the first solution. The resulting solution is stirred for 5 minutes at 60° C. followed by 2 hours at room temperature. The solvents are evaporated, and the resulting residue is suspended in a saturated solution of NaHCO3 (40.0 mL). The aqueous phase is extracted 4 times with EtOAc (4×40.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated. The product is sufficiently pure by 1H NMR (2.07 g, 45%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.99 (m, 2H) 3.32 (s, 1H) 3.48 (t, J=5.57 Hz, 2H) 4.09 (s, 1H) 4.73-4.95 (m, 2H) 6.55 (dd, J=8.79, 5.66 Hz, 1H) 6.71 (t, J=8.89 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[NH2:34].Cl>C(O)C.C(OCC)C>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([NH:34][C:33]3[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:31]([O:30][CH3:29])[CH:32]=3)[N:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2Nc2nc(S(C)(=O)=O)ncc2C#N)cc1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1cc(Nc2ncc(C#N)c(Nc3ccccc3C(=O)c3ccc(C)cc3)n2)cc(OC)c1OC
Temperature: 180 °C
Yield: 36.6 %

Procedure:
To a mixture of 4-{[2-(4-methylbenzoyl)phenyl]amino}-2-(methylsulfonyl) pyrimidine-5-carbonitrile (54 mg, 0.138 mmol) and 3,4,5-trimethoxyaniline (26 mg, 0.142 mmol) in absolute ethanol (3 ml) was added 1N HCl in diethyl ether (3 drops). The reaction was facilitated using microwave irradiation. The reaction was heated at 180° C. for 600 sec. using Personal Chemistry SmithSynthesizer. On cooling a crude yellow solid was collected by filtration. Pure sample was obtained after chromatography to give 4-{[2-(4-methylbenzoyl)phenyl]amino}-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-5-carbonitrile (25 mg, %) as a canary yellow solid. 1H NMR (DMSO-d6): δ 10.0 (s, 1H), 9.39 (br s, 1H), 8.39 (s, 1H), 8.04 (d, 1H, J=8.4 Hz), 7.58-7.48 (m, 4H), 7.28 (t, 1H, J=7.6 Hz), 7.22 (d, 2H, J=7.9 Hz), 6.91 (s, 1H), 3.65 (s, 3H), 3.61 (s, 6H), 2.35 (s, 3H); ES-MS m/z 496 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[N:14]=[C:15]=[O:16]>CN(C=O)C.C1(C)C=CC=CC=1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[NH:14][C:15]([N:8]=[C:7]1[NH:6][C:4](=[O:5])[CH2:3][N:2]1[CH3:1])=[O:16]
Reactant: O=C=Nc1ccco1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1CC(=O)NC1=NC(=O)Nc1ccco1
Reaction time: 1 h
Yield: 8.3 %

Procedure:
To a stirred mixture of 6.9 g (60 mM) of creatinine in 100 ml of anhydrous DMF was added a solution of 6.5 g (60 mM) of 2-furanyl isocyanate in 75 ml of toluene. After stirring the mixture 1 hr. at 25° C. and then 1 hr. at 55° C., the solvents were removed in vacuo and the residue taken up in ethyl acetate and washed with water. The solvent was removed and the residue chromatographed over silica gel using ether-ethyl acetate (4:1) as the eluant. The fractions containing the product were combined and concentrated to leave 1.1 g of the above urea as an off-white solid, m.p. 173°-175° C. (dec.)
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[C:17]([C:27]([O:29][CH3:30])=[O:28])=[C:16]([CH2:31][O:32][CH3:33])[NH:15][C:14]2=[O:34])=[O:12])=CC=1)([O-])=O.[C:35]1([C:41]2([C:51]3[S:52][CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][NH2:50])[CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:30][O:29][C:27]([C:17]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[N:13]([C:11](=[O:12])[NH:50][CH2:49][CH2:48][CH2:47][N:44]2[CH2:43][CH2:42][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:51]3[S:52][CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:45]2)[C:14](=[O:34])[NH:15][C:16]=1[CH2:31][O:32][CH3:33])=[O:28]
Reactant: NCCCN1CCC(c2ccccc2)(c2cccs2)CC1
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3ccccc3)(c3cccs3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of 6-(3,4-difluorophenyl)-4-methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-dicarboxylic acid 5-methyl ester 1-(4-nitrophenyl)ester (29 mg, 0.06 mmol) in 2 ml of CH2Cl2 was added 3-(4-phenyl-4-thiophen-2-yl-piperidin-1-yl)propylamine (20 mg, 0.07 mmol) and the resulting solution was stirred for 2 h at 25° C. The reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel (5% MeOH/CHCl3) to yield 25 mg (64%) of the desired product which was converted to a HCl salt and recrystallized from EtOAC-Et2O to afford 22 mg of the product as a white solid: mp 157-159° C.; Anal. Calc. For C33H36F2N4O5S requires C, 58.6; H, 5.33; N, 8.29. Found: C, 57.3; H, 5.45; 7.90.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([O:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:35]2)=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([O:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[CH:35]2)=[CH:30][C:29]=1[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc2cc(B3OC(C)(C)C(C)(C)O3)c(OCc3ccccc3)cc2c1
Product: CN(c1ccc(-c2cc3ccc(OCCCNC(=O)OC(C)(C)C)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1

Procedure:
Intermediate 1-1 (242.5 mg, 0.86 mmol) and tert-butyl (3-((7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)propyl)carbamate (662 mg, 1.18 mmol) were reacted following GENERAL METHOD 1-1 for Suzuki coupling with the following modifications: Instead of SCX purification, the crude material was purified by flash chromatography (eluting with 1-15% 7N NH3 in MeOH/DCM) to afford a yellow oil. The oil was triturated with Et2O then concentrated in vacuo to dryness affording tert-butyl (3-((7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)propyl)carbamate a pale-yellow solid (492 mg, 83% yield). MS (M+1)=654.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=3)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:45]1[NH:49][C:48]([C@@H:50]2[CH2:54][C@H:53]([CH2:55][O:56][CH3:57])[CH2:52][N:51]2[C:58](=[O:68])[C@@H:59]([NH:63][C:64](=[O:67])[O:65][CH3:66])[CH:60]([CH3:62])[CH3:61])=[N:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CS(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30]([C:45]2[NH:49][C:48]([C@@H:50]4[CH2:54][CH:53]([CH2:55][O:56][CH3:57])[CH2:52][N:51]4[C:58](=[O:68])[C@@H:59]([NH:63][C:64]([O:65][CH3:66])=[O:67])[CH:60]([CH3:62])[CH3:61])=[N:47][CH:46]=2)=[CH:29][CH:28]=3)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-4
Reactant: COC[C@H]1C[C@@H](c2ncc(Br)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COCC1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7C[C@H]8C[C@H]8N7C(=O)OC(C)(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 95 °C

Procedure:
To a solution of (1R,3S,5R)-tert-butyl-3-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (213 mg, 0.37 mmol), methyl (S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (142 mg, 0.31 mmol), tetrakis(triphenylphosphine) palladium(0) (35 mg, 0.03 mmol) and dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) (22 mg, 0.03 mmol) in a mixture of 1,4-dioxane (3.0 mL) and dimethylsulfoxide (3.0 mL) was added a solution of potassium carbonate (2M in water, 0.46 mL, 0.9 mmol). The resulting mixture was degassed and then heated to 95° C. under argon for 7 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to (1R,3S,5R)-tert-butyl 3-(9-(2-((S)-1-((S)-2-(methoxycarbonyl amino)-3-methylbutanoyl)-4-methoxymethylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (101 mg, 42%).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)#[N:2].[OH-:20].[K+].O>CC(O)(C)C>[N:17]1[CH:18]=[CH:19][C:14]([C:4]2[S:5][C:6]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)=[CH:7][C:3]=2[C:1]([NH2:2])=[O:20])=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: N#Cc1cc(-c2ccncc2)sc1-c1ccncc1
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: NC(=O)c1cc(-c2ccncc2)sc1-c1ccncc1
Yield: 70.2 %

Procedure:
A mixture of 3-cyano-2,5-di(4-pyridyl)thiophene (40 mg, 0.152 mmol), potassium hydroxide (25 mg, 0.446 mmol) in 2-methyl-2-propanol (2 mL) was heated at reflux temperature for 2 hours. After cooling, the mixture was poured into water. The precipitates were collected by filtration, and dried under reduced pressure to give the title compound (30 mg, 70% yield).
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]=[C:17]=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N:19]([Si](C)(C)C)=[N+:20]=[N-:21]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:15]([N:16]2[C:17](=[O:18])[NH:21][N:20]=[N:19]2)=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCCN1C(=O)COc2cc(F)c(N=C=O)cc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCN1C(=O)COc2cc(F)c(-n3nn[nH]c3=O)cc21
Temperature: 25 °C
Yield: 43.7 %

Procedure:
Under a dry nitrogen atmosphere, 4.3 grams of 7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one-6yl isocyanate and 4.3 g (0.037 mole) of azidotrimethylsilane were heated at reflux for approximately 18 hours. The mixture was allowed to cool to room temperature and was diluted with toluene. This mixture was poured into ice-water forming a precipitate. The precipitate was collected by vaccum filtration, and the filter cake was rinsed first with water followed by diethyl ether. The filter cake was dissolved in acetone, and the organic solution was dried over anhydrous magnesium sulfate. This mixture was filtered, and the filtrate was evaporated under reduced pressure to yield 2.2 grams of 1-(7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one-6-yl)-1,4-dihydro-5H-tetrazol-5 one as a solid m.p. 145°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[C:5]([NH:12][CH3:13])[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH:27]1[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1>>[N:29]12[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30]1)[CH:27]([NH:26][C:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([NH:12][CH3:13])=[N:6][CH:7]=1)=[O:11])[CH2:28]2
Reactant: NC1CN2CCC1CC2
Reactant: CNc1ncc(C(=O)O)c(OC)n1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CNc1ncc(C(=O)NC2CN3CCC2CC3)c(OC)n1

Procedure:
Following the procedure of Example 22, 4-methoxy-2-(methylamino)-5-pyrimidinecarboxylic acid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.C[Si]([N:27]=[C:28]=[S:29])(C)C>C1C=CC=CC=1.O>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([C:28](=[S:29])[NH2:27])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: Cc1ccnc2c1CCCC2
Agent: [Li]CCCC
Solvent: O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: Cc1ccnc2c1CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-5,6,7,8-tetrahydroquinoline (5.83 g., 0.04 mole) in dry benzene (40 ml.) was cooled to 0° and to the stirred solution was added dropwise a 15% w/w solution of butyl lithium in hexane (17.5 ml., 0.04 mole) under an atmosphere of nitrogen. The red reaction mixture was stirred at 0° for a further 30 minutes. Trimethylsilylisothiocyanate (5.6 ml., 0.04 mole) was then added dropwise, maintaining the temperature at 0°. After an additional 30 minutes, the solution of 4-methyl-5,6,7,8-tetrahydroquinoline-8-(N-lithio-N-trimethylsilyl)thiocarboxamide was allowed to warm to room temperature and diluted with water (40 ml.) causing hydrolysis to 4-methyl-5,6,7,8-tetrahydroquinoline-8-(N-trimethylsilyl) thiocarboxamide and subsequent hydrolysis to the title compound. The pH was adjusted to 2.0 by addition of conc. HCl and the benzene layer separated and discarded. The aqueous phase was adjusted to pH 10.0 by adding anhydrous Na2CO3 and extracted with CHCl3 (3 × 40 ml.). The CHCl3 solution was then dried (MgSO4), filtered and evaporated (reduced pressure) to afford an oil (5.77 g.). Addition of ether caused crystallisation of the title compound as colourless needles. Filtration afforded 0.69 g. of base which was converted to the hydrochloride by dissolving in a minimum of EtOH, adding EtOH/HCl until just acid followed by ether to induce crystallisation. Filtration provided the title compound hydrochloride as colourless needles, (0.64 g.), m.p. 213° C. Analysis: Found: C, 54.95; H, 6.40; N, 11.52. C11H14N2S.HCl requires C, 54.42; H, 6.23; N, 11.54%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CCOC(/N=N/C(OCC)=O)=O.[CH2:41]([C:43]1[CH:65]=[CH:64][CH:63]=[CH:62][C:44]=1[NH:45][C:46]1[C:55]2[C:50](=[CH:51][C:52](O)=[C:53]([O:56][CH3:57])[CH:54]=2)[N:49]=[CH:48][C:47]=1[C:59]([NH2:61])=[O:60])[CH3:42]>C(Cl)Cl.C1COCC1>[CH2:41]([C:43]1[CH:65]=[CH:64][CH:63]=[CH:62][C:44]=1[NH:45][C:46]1[C:55]2[C:50](=[CH:51][C:52]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:53]([O:56][CH3:57])[CH:54]=2)[N:49]=[CH:48][C:47]=1[C:59]([NH2:61])=[O:60])[CH3:42]
Reactant: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(O)c(OC)cc12
Reactant: OCCN1CCNCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OCCN3CCNCC3)c(OC)cc12
Yield: 50.4 %

Procedure:
Triphenylphosphine (0.12 g, 0.44 mmol) and 1-(2-hydroxyethyl)piperazine (25 μl, 0.22 mmol) was dissloved in CH2Cl2 and THF at −15° C. and stirred for 30 min. DEAD (70 μl, 0.44 mmol) was added dropwise at −15° C. 4-(2-ethylanilino)-7-hydroxy-6-methoxy-3-quinolinecarboxamide (0.50 g, 0.15 mmol) was suspended in THF and then added to the reaction. The reaction was stirred over night, allowing the temperature rise to ˜10° C. The solvent was removed under reduced pressure and the product was purified using preparative HPLC affording 34 mg (24%) of a clear oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][C:25]([O:27]CC)=[O:26])=[N:16]3)=[CH:12][CH:11]=2)=[O:8])[CH:4]=[N:3]1.O.[OH-].[Li+].O.Cl>O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][C:25]([OH:27])=[O:26])=[N:16]3)=[CH:30][CH:31]=2)=[O:8])[CH:4]=[N:3]1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3cnn(C)c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C(=O)Nc2ccc(Cn3nc(CC(=O)O)c4ccccc43)cc2)cn1
Yield: 94.3 %

Procedure:
Ethyl 2-[1-[4-(1-methyl-1H-pyrazol-4-carboxamido)benzyl]-1H-indazol-3-yl]acetate (279 mg, 0.67 mmol) was dissolved in tetrahydrofuran (20 mL), and in an ice bath, 10 mL aqueous solution dissolving lithium hydroxide monohydrate (84 mg, 2.0 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 246 mg, at a yield of 94.5%.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OCC1C=CC=CC=1)CC.[BrH:35].[C:36](O)(=O)[CH3:37]>>[BrH:35].[CH2:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:36][CH3:37]
Reactant: CCCCCCCCCC(CC)SCCCCCCCCCCNC(=O)OCc1ccccc1
Reactant: CC(=O)O
Agent: Br
Product: CCCCCCCCCCCCSCCCCCCCCCCN

Procedure:
In a 1000 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 27.0 g of the carboxylic acid synthesized in Synthetic example 21, 10.0 g of thionyl chloride, one drop of DMF and 100 ml of chloroform, and the mixture was refluxed for 2 hours on an oil bath. After completion of the reaction, chloroform and excessive thionyl chloride were removed by distillation under reduced pressure to obtain acid chloride. Whole content of the resulting acid chloride was diluted with 100 ml of acetone, and added dropwise under ice-cooling to 5.9 g of sodium azide dissolved in 60 ml of distilled water which had been previously charged in a 300 ml flask. After completion of the dropwise addition, the mixture was stirred at the same temperature for one hour and the mixture was extracted twice with 300 ml of toluene. The organic layers were combined and washed three times with distilled water and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and the filtrate was refluxed for one hour. To the mixture were added 11.3 g of benzyl alcohol and 3 drops of triethylamine, and the resulting mixture was further refluxed for 2 hours. After completion of the reaction, toluene was removed under reduced pressure and the residual crystals were recrystallized from ethanol to obtain 26.5 g of benzyl N-(10-dodecylthio)decylcarbamate. In a 300 ml flask were charged 24.5 g of the resulting benzyl N-(10-dodecylthio)decylcarbamate, 20 ml of 48% hydrobromic acid and 180 ml of glacial acetic acid and the mixture was refluxed for 2 hours. After completion of the reaction, glacial acetic acid was removed under reduced pressure and the residual crystals were recrystallized from ethanol to obtain 17.0 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[Br:11]Br.C(OCC)(=O)C>CO.C(O)(=O)C>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: BrBr
Reactant: COc1cccc(C)c1N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(Br)cc(C)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
In a 100 mL round bottom flask, 2-methoxy-6-methyl-phenylamine (4.54 g, 33.16 mmol) was dissolved in 15 mL MeOH and 5 mL acetic acid. The flask was cooled to 0° C. Bromine (1.7 mL, 33.16 mmol) in 5 mL acetic acid was added to the reaction dropwise (over 30 minutes). The reaction mixture was stirred at 0° C. for 2 hours, then was warmed up to room temperature for 1 hour. The reaction mixture was concentrated down. 1N NaOH was added to neutralize the reaction at 0° C. Ethyl acetate was added to extract the reaction mixture. The organic layer was concentrated after drying over anhydrous sodium sulfate to give a dark brown solid (5.8 g, 81%). LC-MS shows 218.0 (M+1). 1H NMR (300 MHz, CDCl3): δ 6.88 (s, 1H), 6.81 (s, 1H), 3.84 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[C:12]1([C:10]2[N:11]=[C:7]([C:3]3[CH:2]=[N+:1]([O-:26])[CH:6]=[CH:5][CH:4]=3)[S:8][CH:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(-c2csc(-c3cccnc3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc(-c2nc(-c3ccccc3)cs2)c1
Reaction time: 2 h
Yield: 28.7 %

Procedure:
In 50 ml of dichloromethane was dissolved 1 g of 2-(pyridin-3-yl)-4-phenylthiazole. Thereto was added 900 mg of m-chloroperbenzoic acid at room temperature. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with an aqueous sodium hydrogencarbonate solution and dried The solvent was removed by distillation. The residue was recrystallized from ethyl acetate to obtain 306 mg of 3-(4-phenylthiazol-2-yl) pyridine-N-oxide as a brown powder.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH:6]1[C:16]2[CH:15]=[CH:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>C1COCC1.O>[CH:1]1([C:11]2([OH:21])[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH:14]=[CH:15][C:16]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]2=3)[CH2:3][CH2:2]1
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C2CC2)c2ccccc2C=Cc2ccccc21

Procedure:
A solution of cyclopropylmagnesium bromide in dry THF (prepared from cyclopropylbromide (8.0 g, 0.067 mol), magnesium turnings (1.3 g, 0.053 mol) and dry THF (35 ml)) was placed under an atmosphere of nitrogen. A solution of 5H-dibenzo[a,d]cyclohepten-5-one (6.0 g, 0.028 mol) in dry THF (15 ml) was added dropwise and when addition was complete the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled on an ice-bath and saturated ammonium chloride (35 ml) was carefully added. The mixture was diluted with water (50 ml) and extracted with diethyl ether (2×50 ml). The combined organic extracts were washed with water, dried (Na2SO4) and the solvent was evaporated in vacuo to give 8.6 g of crude 5-cyclopropyl-5H-dibenzo[a,d]cyclohepten-5-ol.