Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([C:36](OCC)=[O:37])=[C:14]([CH2:33][CH2:34][CH3:35])[N:15]2[C:20]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:17]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[N:16]2)=O)C.CCOCC>C1COCC1>[OH:9][CH2:10][C:12]1[C:13]([CH2:36][OH:37])=[C:14]([CH2:33][CH2:34][CH3:35])[N:15]2[C:20]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:18][C:17]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[N:16]2
Reactant: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1c(CO)c(CO)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Temperature: 0 °C

Procedure:
To a suspension of lithium aluminum hydride (118 mg, 3.11 mmol) in THF (10 mL) was added 2-morpholino-4-yl-4-phenyl-7-propyl-pyrrolo [1,2-b]pyridazine-5,6-dicarboxylic acid diethyl ester (15) (242 mg, 0.52 mmol). The reaction mixture was heated at reflux for 1 h. After cooling to 0° C., Et2O (10 mL) was added and an excess reagent in the reaction mixture was quenched by brine. The resulting precipitate was removed by filtration. The filtrate was dried over Na2SO4 and concentrated in vacuo to provide the title compound. 1H NMR (DMSO-d6) δ 0.92 (t, J=7.2 Hz, 3H), 1.63-1.71 (m, 2H), 2.91 (t, J=7.2 Hz, 2H), 3.40 (br t, J=5.0 Hz, 4H), 3.72 (br t, J=5.0 Hz, 4H), 4.05 (d, J=5.0 Hz, 2H), 4.22 (t, J=5.0 Hz, 1H), 4.55 (d, J=5.1 Hz, 2H), 4.61 (t, J=5.1 Hz, 1H), 6.34 (s, 1H), 7.46-7.48 (m, 3H), 7.53-7.56 (m, 2H). Mass Spectrum (ESI+) m/e=364 (M−OH).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>C(O)(=O)C.Cl.O.C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][N:9]=[C:21]([C:22](=[O:24])[CH3:23])[C:18](=[O:20])[CH3:19]
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)C(=NNc1ccccc1Cl)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of 2-chloroaniline (1000 mg, 7.87 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (652 mg, 9.45 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (1940 mg, 23.62 mmol) and acetylacetone (1024 mg, 10.24 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(2-chlorophenyl)hydrazono]pentane-2,4-dione (860 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)=[O:6]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(C(F)(F)F)ccc1Br)N1CCOCC1
Reaction time: 0.17 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzoic acid (200 mg, 0.74 mmol) was dissolved in DMF (4.65 mL) and HATU (424 mg, 1.12 mmol) added to the resultant mixture at rt. The solution was stirred for 10 min then treated with N,N-diisopropylethylamine (0.51 mL, 3.0 mmol) and morpholine (0.096 mL, 1.1 mmol). The reaction was stirred for 15 hours then quenched by the addition of saturated NH4Cl (5 mL) and EtOAc (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL) and the combined organic extracts washed with brine, dried over Na2SO4 and concentrated to dryness. The crude product was purified by FCC to give the title compound. 1H NMR (500 MHz, CDCl3) δ 7.76-7.71 (m, 1H), 7.55-7.49 (m, 2H), 3.92-3.86 (m, 1H), 3.83-3.69 (m, 4H), 3.66-3.58 (m, 1H), 3.32-3.24 (m, 1H), 3.25-3.17 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH:45]([C:47](=[O:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[NH2:46]>O.CN(C)C=O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH:46][NH:45][C:47](=[O:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[O:13])=[CH:8]2
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.50 g), 1H-1,2,3-benzotriazol-1-ol (0.24 g) and N,N-dimethylformamide (10 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.30 g) at room temperature, and the mixture was stirred for 10 min. Ethyl hydrazino(oxo)acetate (0.33 g) was added, and the reaction mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (0.43 g, yield 63%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 133-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[H][H]>N.CO.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:30][NH2:31])=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CN)c1
Yield: 14.6 %

Procedure:
To tert-Butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (1.09 g, 2.22 mmol) in 6 ml of 7 N ammonia in methanol at ambient temperature was added Raney-Ni (0.019 g) and the reaction was stirred under a balloon of hydrogen gas at ambient temperature. The reaction was filtered and concentrated to give tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(aminomethyl)phenyl)acetate (0.160 g, 15%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1C(O)=O.B.[O:14]1CCC[CH2:15]1.CO>O1CCCC1>[O:1]1[C:5]2[C:6]([CH2:15][OH:14])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: O=C(O)C1Cc2ccccc2O1
Agent: B
Solvent: CO
Product: OCc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-Dihydrobenzofuran carboxylic acid (5.047 g) in tetrahydrofuran at −10° C. was treated dropwise with a solution of 1.0 M borane-tetrahydrofuran (20 mL). The temperature was allowed to warm to room temperature overnight, treated with additional 1.0 M borane-tetrahydrofuran (10 mL), and stirred at room temperature for 2 hours. The mixture was cooled to 5° C., slowly treated with methanol (20 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate (2×), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:ethyl acetate, 3:2) to provide the title compound. MS (DCI/NH3) m/z 168 (M+NH4)+; 1H NMR (CDCl3) δ 3.21 (t, 2H), 4.60 (t, 2H), 4.68 (s, 2H), 6.83 (t, 1H), 7.08 (dd, 1H), 7.14 (dd, 1H).
Reaction SMILES: [OH:1][CH:2]([C@H:6]1[O:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])CCO.I([O-])(=O)(=O)=O>CC(C)=O.O>[CH:2]([C@H:6]1[O:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:1]
Reactant: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1C(O)CCO
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1C=O
Reaction time: 4 h
Yield: 92.2 %

Procedure:
A solution of 1,1-dimethylethyl [[(2S,3R) 3-(1,3-dihydroxypropyl)-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate (50 g, 138 mmol) in acetone (350 mL) was treated with a solution of periodate (50 g, 235 mmol, 1.7 eq) in water (1.2 L). The reaction mixture was stirred vigorously under nitrogen and monitored by TLC. After about 4 hours, the reaction was complete by TLC analysis. Acetone was removed under reduced pressure without heating. The reaction mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were dried and concentrated under reduced pressure without heating to give 40 g of 1,1-dimethylethyl [[(2S,3S) 3-formyl-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate as a clear oil: [α]D=-1.142 (10.147 mg/cc in MeOH); 1H NMR (CDCl3) δ 1.38 (m, 2H), 1.42 (s, 9H), 1.61 (m, 8H), 1.73 (m, 2H), 3.52 (dd, 1H), 3.72 (dd,1H), 3.88 (s, 2H), 4.38 (dd, 1H), 4.52 (m, 1H), 9.62 (s, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]([CH3:44])[CH2:37][CH:38]1[O:43][CH2:42][CH2:41][NH:40][CH2:39]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:40]4[CH2:41][CH2:42][O:43][CH:38]([CH2:37][N:36]([CH3:44])[CH3:35])[CH2:39]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN(C)CC1CNCCO1
Product: CN(C)CC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-dimethylaminomethyl-morpholin-4-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Dimethyl-morpholin-2-ylmethyl-amine following General Procedure B.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@@H:15]1[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:17][C:16]1=[O:24])[CH2:12][CH2:13][CH3:14].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:11]([C@@:15]1([C:33]([O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:17][C:16]1=[O:24])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCC[C@H]1OC(=O)[C@@H]1CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC[C@@H]1OC(=O)[C@]1(CCCC)C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
To a −78° C. solution of NaHMDS (1.2 equiv, 0.91 mmol, 45 μL, 2M in THF) in 5 mL THF was added 150 mg (0.73 mmol) of β-lactone 3a dissolved in 2.5 mL THF. After 1.5 h, benzylchloroformate (1.1 equiv, 0.833 mmol, 120 μL) was added at one time and stirred for an additional 3 h. This solution was warmed to 23° C. over 1 h and worked up as described above for β-lactone 8b. Flash chromatography on SiO2 (5% Et2O:hexanes) gave β-lactone 8c (185 mg, 74% yield) as a colorless oil: Rf 0.48 (15% Et2O:Hexanes); IR (thin film) 1824, 1757, 1716 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H), 5.27, 5.22 (AB q, J=12.0, 2H), 4.52 (dd, J=4.8, 8.4 Hz, 1H), 2.50-2.56 (m, 1H), 2.22-2.30 (m, 2H), 1.71-1.85 (m, 1H), 1.44-1.60 (m, 4H), 1.15-1.39 (m, 8H), 0.81-0.92 (m, 6H); 13C NMR (500 MHz, CDCl3) 14, 14.6, 14.7, 23.1, 23.3, 23.6, 24.9, 25.8, 26.9, 29.4, 30.4, 31.1, 31.9, 32.3, 40.4, 71.6, 79.8, 121.7, 129.2, 129.4, 129.5, 129.8, 133.1, 152.7, 163.7, 167.3; ESI LRMS Calcd. for C20H28LiO4+[M+Li]: 339. Found: 338.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][CH:14]([F:27])[CH:15]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>O1CCCC1.C(OCC)(=O)C.C1CCCCC1>[F:13][CH:14]([F:27])[CH:15]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][CH2:17][N:51]1[C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]2[C:47]1=[O:57]
Reactant: OCCC(NCc1ccccc1)C(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C1c2ccccc2C(=O)N1CCC(NCc1ccccc1)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of diethyl azodicarboxylate (0.639 g, 3.65 mM), in anhydrous tetrahydrofuran (5 ml) is added, dropwise, over a period of 0.5 hours, at room temperature to a mixture of 4,4-difluoro-3-benzylamino-butanol (0.790 g, 3.65 mM) prepared as in Step C, triphenylphosphine (0.962 g, 3.65 mM), and phthalimide (0.540 g, 3.65 mM) in tetrahydrofuran (20 ml). After stirring for 2.5 hours at room temperature, the solvent is evaporated in vacuo. The residue is taken off in benzene and the solution filtered. The solid is washed three time with benzene. The filtrate is evaporated to dryness; the residue is taken off in diethyl ether. Filtration and evaporation of the solvent in vacuo yields a yellow oil. The expected phthalimide is isolated by column chromatography (medium pressure silica gel chromatography technique, ethyl acetate/cyclohexane 2:8): 0.800 g (yield 65%).
Reaction SMILES: [CH2:1]([S:3]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)=[O:4])[CH3:2].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:3]([CH2:1][CH3:2])=[O:4])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCS(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)CC)n1

Procedure:
A mixture of 4.35 g. 3-ethylsulphinyl-1,2,4-triazole, 6.0 ml. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was filtered and the filtrate distilled under reduced pressure to remove solvent, giving a residual oil which solidified on cooling. This solid product was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-diallylcarbamoyl-3-ethylsulphinyl-1,2,4-triazole, m.p. 41° - 43° C. Elemental analysis satisfactory.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Na].C(N(CC)CC)C.[SH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CS
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
Into a 100 ml round-bottomed flask were placed 14.8 g (10 ml, 79.6 mmol) 2,4-dinitrofluorobenzene, THF (20 ml, freshly distilled from sodium benzophenone) and triethylamine (11.1 ml, 79.6 mmol). The reaction was cooled in an ice bath while 9.55 g (8.73 ml, 79.6 mmol) ethyl 2-mercaptoacetate dissolved in THF (10 ml) was added dropwise. The resulting nearly black solution was allowed to warm slowly to room temperature and stirred 18 hours. The reaction mixture was poured onto 150 ml ice and the resulting layers were separated. The aqueous phase was extracted with EtOAc (2×125 ml). The organic layers were combined and washed with water (100 ml), dried over MgSO4 and concentrated to dryness in vacuo to yield 16.9 g of red-brown solid (74.1% yield).
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.[C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])(O)=[O:13]>C(Cl)Cl>[NH2:3][C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])=[O:13]
Reactant: On1nnc2ccccc21
Reactant: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(N)=O
Reaction time: 1 h
Yield: 35.7 %

Procedure:
1-Hydroxybenzotriazole hydrate (0.00318 mole) was added to a solution of compound 105 (0.00159 mole) in DCM (160 mL) at room temperature. N,N′-methane-tetrayl-biscyclohexanamine (0.00206 mole) was added neat at room temperature. After 60 minutes, NH3 gas was bubbled in for 5 minutes, and a solid precipitated out. The mixture was allowed to sit over the weekend. The mixture was filtered, and the filtrate was extracted with saturated NaHCO3. The organic phases were dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography, yielding 0.21 g of 1,1-dimethylethyl 2-[4-(aminocarbonyl)-5-propyl-1H-imidazol-2-yl]-2,3-dihydro-1H-indole-1-carboxylate (compound 106).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[CH:22]([N:25]1[C:29](B(O)O)=[CH:28][CH:27]=[N:26]1)([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([C:29]3[N:25]([CH:22]([CH3:24])[CH3:23])[N:26]=[CH:27][CH:28]=3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: CC(C)n1nccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccnn2C(C)C)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 100 °C
Yield: 44.4 %

Procedure:
To a solution of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.12 mmol), (1-isopropyl-1H-pyrazol-5-yl)boronic acid (23 mg, 0.12 mmol) and Na2CO3 (22 mg, 0.25 mmol) in 1,4-dioxane (0.5 mL) and water (0.05 mL) was added Pd (dppf)Cl2 (10 mg) under nitrogen. The mixture was heated at 100° C. for 4 hour and filtered through the Celite pad. The filtrate was extracted with EtOAc, and then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by the prep-TLC (PE:EA=1:1) to give 5-bromo-2-(1-isopropyl-1H-pyrazol-5-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (25 mg, yield: 50%). 1H-NMR (CDCl3, 400 MHz) δ 8.50 (s, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 6.58 (d, J=2.0 Hz, 1H), 5.74 (d, J=3.6 Hz, 1H), 4.45˜4.52 (m, 1H), 3.28 (s, 3H), 3.04 (s, 3H), 2.82 (d, J=4.8 Hz, 3H), 1.51 (s, 6H). MS (M+H)+: 469/471.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]3[S:19]C(=S)N[C:16]3=[O:21])[S:12][CH:13]=2)=[CH:6][CH:5]=1.Cl>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([SH:19])[C:16]([OH:21])=[O:1])[S:12][CH:13]=2)=[CH:22][CH:23]=1
Reactant: O=C1NC(=S)SC1=Cc1cc(Cc2ccc(Cl)cc2)cs1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C(S)=Cc1cc(Cc2ccc(Cl)cc2)cs1
Temperature: 45 °C
Yield: 95 %

Procedure:
To a 20-mL scintillation vial fitted with a magnetic stir bar under a N2 atmosphere was added 3.5 mL of NaOH (2.0 M), and heated to 45° C. 5-((4-(4-chlorobenzyl)thiophen-2-yl)methylene)-2-thioxothiazolidin-4-one was added to the 2 M NaOH solution. After complete dissolution, the temperature of the reaction vial was increased to 60° C. over a 30 min period. The vial was subsequently cooled to 5° C. and cold 10% (v/v) aq. HCl solution was added until a precipitate formed (approx. pH 2-3). The resulting precipitate was collected by filtration, washed several times with water, and dried thoroughly under vacuum at 40° C. to give 3-(4-(4-chlorobenzyl)thiophen-2-yl)-2-mercaptoacrylic acid (379 mg, 95% yield). Note: 1H NMR showed a number of peaks in the aromatic region. The presence of the signal for the vinyl proton and the loss of the rhodanine moiety (i.e.; absence of the proton attached to the nitrogen in the rhodanine moiety) was used as an indicator of the desired compound. The material was used in the next step without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]([CH3:15])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH3:14][O:13][C:10]1[C:9]([CH3:15])=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[C:11]=1[CH3:12]
Reactant: COc1c(C)cnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cnc(CO)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
94.9 g of (4-methoxy-3,5-dimethyl-2-pyridyl)methyl acetate were dissolved in 570 ml of ethanol. 285 ml of 3N sodium hydroxide solution were then added dropwise thereto at 0° and the mixture was stirred at room temperature for 3 hours. The ethanol was subsequently removed in vacuo, whereupon the residual aqueous solution was extracted three times with 300 ml of methylene chloride. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from petroleum ether and there was obtained 4-methoxy-3,5-dimethyl-2-pyridylmethanol of melting point 49°-51°.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24]N5CCCCC5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.IC.C(=O)([O-])[O-].[K+].[K+].C(O[CH2:44][CH3:45])(=O)C>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:45]5[CH2:44][CH2:14][N:13]([CH3:22])[CH2:8][CH2:7]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(ON3CCCCC3)cc2c1=O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C)CC3)cc2c1=O
Reaction time: 19 h

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-(piperidin-yloxy)quinazolin-3(4H)-yl]benzamide (0.3 g), iodomethane (0.044 ml) and potassium carbonate (0.397 g) were stirred in DMF (2 ml) for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. The residue was dissolved in methylene chloride (2 ml) and stirred with PS-isocyanate resin (1.25 mmol/g) (0.28 g) and MP-carbonate (2.89 mmol/g) (0.488 g) for 19 hours and then filtered and concentrated to yield the title compound (0.129 g) as a cream solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 1.70 (m, 2H), 1.97 (m, 2H), 2.13 (s, 3H), 2.19 (s, 3H), 2.22 (m, 2H), 2.60 (m, 2H), 2.85 (m, 1H), 4.55 (m, 1H), 7.51 (d, 1H), 7.52 (d, 1H), 7.59 (s, 1H), 7.72 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.17 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 433.