Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([O:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=[O:16]>O1CCCC1.O>[CH:3]1([N:2]([CH3:1])[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][O:26][C:19]2[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([CH:15]=[O:16])[CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: O=Cc1cc(OCCCC(=O)Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a well-stirred solution of N-methyl-N-cyclohexylamine (29.5 ml) and sodium carbonate (28.8 g) in tetrahydrofuran (250 ml) and water (500 ml) cooled to 0° C. in an ice bath was added the tetrahydrofuran solution of the 4-(3-formyl-4-nitrophenyl)oxybutanoic acid chloride from Preparation 3 dropwise. When addition of the acid chloride was completed, the cooling bath was removed and the mixture allowed to stir at room temperature for 1 hour. Most of the tetrahydrofuran was removed by evaporation and the aqueous residue partitioned between ethyl acetate and saturated sodium carbonate (500 ml each). The combined organic layers were washed with additional saturated sodium carbonate (2×20 ml), water (1×100 ml), 1M HCl (2×200 ml) and with brine (2×200 ml) and dried with sodium sulfate. The ethyl acetate was evaporated to give a residue which was crystallized from ethyl acetate to give N-cyclohexyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutanamide, (m.p. 98°-100° C.). Alternatively, the extraction residue was chromatographed on silica gel (10% ethyl acetate in dichloromethane as eluant.)
Reaction SMILES: ClC1C=CC(C2C3C=C(C4C=C[N:21]=CC=4)SC=3C(=O)CCC2)=CC=1.COC(OC)N(C)C.O1CCCC1.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[C:51]3[CH:52]=[C:53]([C:55]4[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=4)[S:54][C:50]=3[C:49](=O)/[C:48](=[CH:62]/[N:63](C)C)/[CH2:47][CH2:46]2)=[CH:41][CH:40]=1.C(O)(=O)C.O.NN>>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[C:51]3[CH:52]=[C:53]([C:55]4[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=4)[S:54][C:50]=3[C:49]3[NH:21][N:63]=[CH:62][C:48]=3[CH2:47][CH2:46]2)=[CH:41][CH:40]=1
Reactant: CN(C)/C=C1\CCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc2C1=O
Reactant: O=C1CCCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Agent: COC(OC)N(C)C
Agent: NN
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Clc1ccc(C2CCc3cn[nH]c3-c3sc(-c4ccncc4)cc32)cc1
Temperature: 25 °C
Yield: 9 %

Procedure:
A solution of 4-(4-chlorophenyl)-2-pyridin-4-yl-4,5,6,7-tetrahydro-8H-cyclohepta[b]thiophen-8-one (81.5 mg, 0.230 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.514 mL, 3.87 mmol) in tetrahydrofuran (9.27 mL, 114 mmol) was refluxed under argon for 6 hr. The reaction was cooled to room temperature and concentrated under reduced pressure. The obtained residue (81.0 mg, 0.212 mmol), (7E)-4-(4-chlorophenyl)-7-[(dimethylamino)methylene]-2-pyridin-4-yl-4,5,6,7-tetrahydro-8H-cyclohepta thiophen-8-one, was dissolved in acetic acid (6.55 mL, 115 mmol) then hydrazine hydrate (0.112 mL, 2.30 mmol) was added and the reaction mixture was heated at 50° C. for 16 h. The mixture was allowed to cool to rt and concentrated under reduced pressure. The residue was diluted with ethyl acetate (5 mL) then washed with a saturated aqueous solution of NaHCO3 (5 mL), then brine (5 mL), then dried over anhydrous MgSO4, filtered, and concentrated. The obtained residue was purified by preparative HPLC to yield 7.4 mg product as a white solid (9.0% yield). LCMS: (AA) ES+ , 378. 1H NMR (400 MHz, DMSO-d6) δ: 12.8 (br s, 1H), 8.49-8.52 (dd, J=1.7 Hz, J=4.7 Hz, 2H), 7.53-7.55 (dd, J=1.7 Hz, J=4.7 Hz, 2H), 7.34-7.39 (m, 3H), 7.04-7.08 (m, 2H), 4.65-4.70 (m, 1H), 2.63-2.75 (m, 1H), 2.20-2.32 (m, 2H), 2.0-2.10 (m, 1H).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:14]([NH:16][CH2:17][CH2:18][CH:19]([O:26][Si](C(C)(C)C)(C)C)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>Cl.CO>[C:1]12([CH2:11][CH2:12][N:13]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:14]([NH:16][CH2:17][CH2:18][CH:19]([OH:26])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCC(O[Si](C)(C)C(C)(C)C)c1ccncc1
Agent: Cl
Solvent: CO
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCC(O)c1ccncc1
Yield: 55.3 %

Procedure:
A solution of 1-[2-(1-adamantyl)ethyl]-3-[3-(t-butyldimethylsilyloxy)-3-(4-pyridyl)propyl]-1-pentylurea (Compound No. 1-138) (136 mg, 0.250 mmol) in 10% hydrogen chloride-methanol (2.3 ml) was stirred at room temperature for three days. The solvent was evaporated under reduced pressure, the residue was distributed with ethyl acetate (50 ml), water (30 ml) and a 1 N aqueous sodium hydroxide solution (20 ml), and the organic layer was washed with a saturated aqueous sodium chloride solution (40 ml). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the titled compound (59.2 mg, colorless noncrystalline powder, 55.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:30]([CH3:35])[C:31](=[O:34])[CH:32]=[CH2:33])=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:30]([CH3:35])[C:31](=[O:34])/[CH:32]=[CH:33]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1cn(Cc2ccccc2)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 33.8 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1.05 g, 4.60 mmole), N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-acrylamide (1.40 g, 4.60 mmole), Pd(OAc)2 (0.10 g, 0.46 mmole), tri-ortho-tolylphosphine (0.28 g, 0.92 mmole) and diisopropylethylamine (1.20 mL 6.90 mmole) in propionitrile (75 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (300 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (5% MeOH/CHCl3). The title compound (0.70 g. 35%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.B.O1CCCC1.Cl.C(OCC)C>O>[ClH:1].[Cl:1][C:2]1[C:10]([C:11]([F:13])([F:14])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[CH2:4][NH2:6]
Reactant: NC(=O)c1ccc(F)c(C(F)(F)F)c1Cl
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: NCc1ccc(F)c(C(F)(F)F)c1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
2-Chloro-4-fluoro-3-(trifluoromethyl)benzamide (0.490 g, 2.03 mmol) was treated with 1M borane in tetrahydrofuran (20.33 ml, 20.33 mmol) and stirred at 60° C. overnight. The mixture was then treated with 2N aqueous hydrogen chloride until gas evolution ceased and then stirred at 100° C. for 2 hrs. The mixture was reduced in vacuo and the residue was taken up in a minimum of water and washed with dichloromethane (30 ml). The pH of the aqueous layer was adjusted to pH11 by the addition of 2N aqueous sodium hydroxide solution and then extracted with dichloromethane (2×25 ml). The dichloromethane layers were separated using a hydrophobic frit, combined and evaporated in vacuo to leave a pale yellow oil. A 1M solution of hydrogen chloride in diethyl ether (3 ml, 3 mmol) was added and the resulting white solid was filtered off to give pure {[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]methyl}amine hydrochloride (0.210 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH2:37]([S:39](Cl)(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])[N:15]=[C:14]([C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCOc1nc(-c2ccncc2)nc(NS(=O)(=O)c2ccc(C)cn2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 107 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with ethanesulfonylchloride to give 100 mg 5-methyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=3.89 min, [M+1]+=601.50, [M−1]−=599.53.
Reaction SMILES: [Cl:1][C:2]1[C:7](CO)=[CH:6][C:5]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C[OH:39]>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:30][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:39])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(CO)c(Cl)cc1F
Reactant: CO
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g (0.0016 mole) of N-(4-chloro-2-fluoro-5-hydroxymethylphenyl]-3,4,5,6-tetrahydrophthalimide, 0.66 g (0.0055 mole) of phenyl isocyanate, 0.73 g (0.0072 mole) of triethylamine, and 25 ml of methylene was stirred at room temperature overnight. Sufficient methanol was added to react with the excess phenyl isocyanate, and the reaction mixture was stirred for an additional 24 hours. The reaction mixture was diluted with ethyl acetate and was washed successively with water and 5% hydrochloric acid. The organic phase was dried, filtered, and the solvent was evaporated under reduced pressure. The residue was passed through a column of silica gel. The appropriate fractions were combined, and the solvent was evaporated under reduced pressure, leaving a white solid as a residue. This solid was recrystallized from ethyl acetate/heptane, yielding 0.29 g of N-[4-chloro-2-fluoro-5-(phenylaminocarbonyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide as a white solid, m.p. 149°-151° C. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: N1CCC(C(OC([C:12]2[CH:13]=[N:14][C:15]([N:18]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[F:30])=[N:16][CH:17]=2)C)=O)CC1.[OH-].[Na+].Cl.[C:49]([O:52]CC)(=[O:51])[CH3:50]>C(O)C>[F:45][C:42]([F:43])([F:44])[C:34]1[CH:33]=[C:32]([CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=1)[CH2:31][N:18]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=1[F:30])[C:15]1[N:16]=[CH:17][C:12]([N:18]2[CH2:31][CH2:32][CH:50]([C:49]([OH:52])=[O:51])[CH2:20][CH2:19]2)=[CH:13][N:14]=1
Reactant: CC(OC(=O)C1CCNCC1)c1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2F)nc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)Cc3cc(C(F)(F)F)ccc3F)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-{2-[(3,5-Bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-ethyl piperidine-4-carboxylate (105 mg) is dissolved in ethanol (4 ml) and thereto is added a 1N-aqueous sodium hydroxide solution (2 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 1-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carboxylic acid (81 mg). MS (m/z): 625 [M+H]+
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)[CH2:2]2.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>O1CCCC1>[ClH:19].[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([N:9]1[CH2:10][CH2:11][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:25]1=[O:26])[CH2:2]2
Reactant: Clc1cccc(NCCNC2CN3CCC2CC3)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cl
Product: O=C1N(c2cccc(Cl)c2)CCN1C1CN2CCC1CC2

Procedure:
To a stirred solution of N-(1-azabicyclo[2.2.2]oct-3 yl)-N'-(3-chlorphenyl)-1,2-diaminoethane (2.7 g; 0.0097 moles) in anhydrous tetrahydrofuran (10 ml), N,N-carbonyldiimidazole (2.04 g; 0.0125 moles) is added.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:18]3[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccccc1CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1CN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 237.2 %

Procedure:
The same operation as in Example (90a) was performed using 7-nitro-2,3-dihydro-4H-1,4-benzoxazine (described in Higuchi, Robert I.; Arienti, Kristen L.; Lopez, Francisco J.; Mani, Neelakhanda S.; Mais, Dale E.; Caferro, Thomas R.; Long, Yun Oliver; Jones, Todd K.; Edwards, James P.; Zhi, Lin; Schrader, William T.; et al.; J. Med. Chem.; 50; 10; 2007; 2486-2496, 0.6 g, 3.3 mmol), sodium hydride (55% content, 145 mg, 3.3 mmol), ethyl 2-chloromethyl-benzoate (1.95 g, 10.8 mmol) and DMF (30 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/3, 2/3, 3/2, 3/1) to obtain 2.68 g of the title compound as a yellow solid (72%).
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:36])/[CH:25]=[CH:26]/[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2].O>CN(C)C=O>[CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:36])/[CH:25]=[CH:26]\[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(=O)/C=C/C(=O)N2CCN(C)CC2)ccc1OCC(=O)Nc1nc2ccccc2s1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)/C=C\C(=O)N2CCN(C)CC2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 6.5 h
Yield: 45 %

Procedure:
A solution of 2-{2-isopropyl-4-[trans-3-(4-methyl-1-piperazinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (100 mg) in dimethylformamide (10 ml) is allowed to stand for 6.5 hours by a window in order to be exposed to direct sunlight. To the mixture is added water, the precipitated crystals are collected by filtration, and recrystallized from ethanol to give 2-{2-isopropyl-4-[cis-3-(4-methyl-1-piperazinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (45 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N+:11]([O-:14])([OH:13])=[O:12].OS(O)(=O)=O.O>OS(O)(=O)=O>[CH3:1][C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:1][C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5]([N+:11]([O-:14])=[O:12])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2nsnc12
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2nsnc12
Product: Cc1ccc([N+](=O)[O-])c2nsnc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-methyl-benzo[1,2,5]thiadiazole (5.57 g, 37.1 mmol) in conc. H2SO4 (14.5 mL) at 0° C. was slowly added HNO3/H2SO4 (3.25 mL/4.25 mL). The reaction mixture was stirred at 0° C. for 20 min and then at rt for 30 min and then was poured into iced water (200 mL). The resulting precipitate was isolated by filtration, rinsed with water and purified by silica gel flash chromatography, eluting with CHCl3 to give compound 839B (1.5 g) as a yellow solid and 4-methyl-7-nitrobenzo[1,2,5]thiadiazole (2.0 g) as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[CH:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=1)#[N:8].S([CH2:31][N+:32]#[C-:33])(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[C:7]([C:9]1[CH:10]=[C:11]([C:15]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:31][NH:32][CH:33]=2)[CH:12]=[CH:13][CH:14]=1)#[N:8]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)/C=C/c1cccc(C#N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]cc1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a suspension of 12.0 g (107 mmol) of potassium tert-butoxide at 60% in oil, in 100 ml of anhydrous tetrahydrofuran, is added dropwise a mixture of 13.3 g (71.1 mmol) of methyl(E)-3-(3-cyanophenyl)acrylate (CAS 193151-10-9) and 13.9 g (71.1 mmol) of tosylmethyl isocyanide (CAS 36635-61-7) dissolved in 100 ml of tetrahydrofuran, while maintaining the temperature of the reaction medium at about 25° C. The mixture is then stirred for 2 hours at room temperature, and is then partially concentrated under reduced pressure. This solution is then poured into ice-water and the reaction product is then extracted with dichloromethane. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is triturated in chloroform to give 10.8 g of methyl 4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in the form of a beige-coloured solid after cooling, filtering off and drying.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[CH:4][N:3]=1.ClC1C=CC=[C:25]([C:29]([O:31]O)=[O:30])C=1>O1CCCC1>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][O:31][C:29](=[O:30])[CH3:25])=[N:3][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of 2-methyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (18.04 g), 3-chloroperbenzoic acid (18.85 g) and tetrahydrofuran (100 ml) was stirred at room temperature overnight, and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with tetrahydrofuran. A solution of the obtained colorless oily substance in acetic anhydride (100 ml) was added slowly to acetic anhydride (200 ml) heated at 130° C., which was stirred for 2 hours, and concentrated. The residue was dissolved in ethyl acetate, which was washed with an aqueous saturated sodium bicarbonate solution, then with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain [5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]acetate (18.09 g, yield 83%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(#N)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.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CSc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (550 mg, 2.22 mmol), 2-(methylthio)phenylboronic acid (484 mg, 2.88 mmol), sodium carbonate (705 mg, 6.65 mmol), Pd(PPh3)4 (128 mg, 0.11 mmol), acetonitrile (5.2 mL), and water (1.3 mL) at 100° C. in a microwave reactor for 1 h. Purification by column chromatography (silica gel, 0-20% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline as a white amorphous solid. Mass Spectrum (ESI) m/e=336.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].[OH:29][C:30]1([CH3:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:20]([N:33]3[CH2:34][CH2:35][C:30]([OH:29])([CH3:36])[CH2:31][CH2:32]3)=[O:21])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC1(O)CCNCC1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)N3CCC(C)(O)CC3)nc12

Procedure:
Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine, phenyl chloroformate and 4-hydroxy-4-methyl-piperidine, the title compound was prepared as off-white solid (56% yield). MS: m/e=406(M+H+), mp 90-95° C.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:4].[Br:15]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:12][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(NC(=O)C(C)(C)C)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 4.3 %

Procedure:
2,2 ethyl-N-(6-methyl-2-pyridinyl)propaneamide (21-1) (32 g) and N-bromosuccinimide (29.6 g) were added to carbon tetrachloride (300 ml) and to the mixture was added AIBN (15 mg), followed by reluxing for 20 hours under light emitted by 500 W lamp. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column-chromatography (hexane/ethyl acetate=10/1) to yield the compound 21-2 (1.94 g, 5%) as a pure white solid.