Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42](=[O:53])[NH:43][C:44]4([C:47]5[N:52]=[CH:51][CH:50]=[CH:49][N:48]=5)[CH2:46][CH2:45]4)[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60].CC#N>ClCCl>[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60].[OH2:4].[CH:37]([C:33]1[C:34](=[O:36])[CH2:35][C@:23]2(/[CH:40]=[CH:41]/[C:42](=[O:53])[NH:43][C:44]3([C:47]4[N:52]=[CH:51][CH:50]=[CH:49][N:48]=4)[CH2:46][CH2:45]3)[CH2:22][CH2:21][C@:20]3([CH3:54])[C@H:25]([CH2:26][CH2:27][C@H:28]4[C@@:19]3([CH3:55])[CH2:18][CH2:17][C@@H:16]3[C@:29]4([CH3:32])[CH2:30][CH2:31][C@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[C:15]3([CH3:56])[CH3:57])[C:24]=12)([CH3:39])[CH3:38].[F:62][C:61]([F:64])([F:63])[C:59]([OH:65])=[O:60]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ncccn3)CC2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ncccn3)CC2)CC1=O
Product: O

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((E)-3-oxo-3-((1-(pyrimidin-2-yl)cyclopropyl)amino)prop-1-en-1-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (460 mg, 0.576 mmol) in dichloromethane (6 mL) was added TFA (3 mL, 0.576 mmol). The reaction mixture was stirred at r.t for 2 hs and evaporated in vacuo to afford crude product, which was purified by preparative-HPLC (Mobile Phase: A=0.05% TFA/H2O, B=MeCN) to give the title compound, trifluoroacetic acid salt (100 mg, 0.116 mmol, 20.19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.18 (br. s., 1H), 8.78-8.57 (m, 3H), 7.39-7.15 (m, 1H), 6.68 (d, J=16.1 Hz, 1H), 5.94 (d, J=16.1 Hz, 1H), 4.40 (dd, J=4.6, 11.2 Hz, 1H), 3.30-3.11 (m, 1H), 2.90-2.67 (m, 1H), 2.59-2.52 (m, 1H), 2.28-2.01 (m, 3H), 2.01-0.75 (m, 49H); LC/MS: m/z calculated 741.5. Found 742.4 (M+1)+.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.C(O[CH:13]=[CH:14][C:15](=O)[C:16]([O:18][CH3:19])=[O:17])C.O>C(O)(=O)C>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[N:8]2)=[CH:3][CH:2]=1.[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:8]2)=[CH:3][CH:2]=1
Reactant: CCOC=CC(=O)C(=O)OC
Reactant: Cc1ccc(NN)cc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccn(-c2ccc(C)cc2)n1
Product: COC(=O)c1ccnn1-c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
12.5 g of p-tolylhydrazine in 150 ml of glacial acetic acid were added to a solution of 16 g of methyl 4-ethoxy-2-oxobut-3-enoat in 100 ml of glacial acetic acid at 50° C. The mixture was stirred at 100° C. for 5 hours, poured into 1 liter of water, and extracted twice with 100 ml of ethyl acetate. The organic phase was washed with saturated NaHCO3 solution and subsequently with water, and dried. After evaporating in a water-pump vacuum, the mixture was separated by distillation in a high vacuum. 4.1 g of methyl 1-(4-methylphenyl)-pyrazole-5-carboxylate of boiling point 116°-120° C./0.01 torr (example 8) and 5.3 g of methyl 1-(4-methylphenyl)-pyrazole-3-carboxylate of boiling point 138°-142° C./0.01 torr were obtained. The compounds were characterized by 1H NMR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1.[C:13]([CH2:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][C:18](=[O:19])[CH2:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: Cc1cc(Br)cc([N+](=O)[O-])c1NC(=O)CC(C)(C)C
Temperature: 140 °C
Yield: 88.5 %

Procedure:
4-Bromo-2-methyl-6-nitro-phenylamine (2.22 g) and tert-butylacetyl chloride (1.30 g) were mixed in acetonitrile (3 mL) and heated to 140° C. for 40 minutes in a sealed microwave process vial. Water (5 mL) was added and the product was collected by filtration and washed with water and heptane to furnish 2.80 g (86% yield) of the title compound as a yellow solid. LC-MS (m/z) 329 (MH+); tR=3.07, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.01 (s, 9H), 2.21 (s, 2H), 2.29 (s, 3H), 7.87 (d, 1H), 7.95 (d, 1H), 9.77 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=3)[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:36][CH:35]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5cccc(CN(C)S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
175 c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.007 g, 6%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.7 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.55-7.46 (m, 3H), 7.42 (d, J=7.4 Hz, 1H), 7.00-6.91 (m, 3H), 6.65 (s, 3H), 4.42 (s, 2H), 3.19-3.14 (m, 4H), 2.87 (s, 3H), 2.83 (s, 3H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS=506 (MH)+.
Reaction SMILES: Cl[CH2:2][CH2:3]Cl.[CH2:5]([OH:7])[CH3:6].S(=O)(=O)(O)O.O.[C:14]([O:17][CH2:18][CH3:19])(=[O:16])C>>[OH:7][CH:5]([CH2:2][CH3:3])[CH2:6][C:14]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCO
Reactant: CCOC(C)=O
Reactant: ClCCCl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CC(O)CC

Procedure:
The mixture of 1.9 g of ethyl R-(+)-3-butyryloxypentanate, 16 ml of 1,2-dichloroethane, 16 ml of ethanol and 0.3 ml of sulfuric acid was refluxed for 40 hours, water and ethyl acetate was added and the mixture was stirred. The separated organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then with water, and dried on anhydrous magnesium sulfate. The solvent was distilled away, and 1.0 g crude product was obtained. The crude product was chromatographically purified, and 0.63 g of ethyl R-(-)-3-hydroxypentanate. [α]D24 =-29.7° (C=0.90, CHCl3). As described above, the optical purity of the obtained compound was tested by using Eu(hfc)3 as a shift agent. It was 88% ee. Moreover, the formulation of the above compounds was supported well by their NMR charts.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[NH:17][C:18](=[O:32])[CH2:19][N:20]1[CH2:25][CH2:24][N:23]2C(C)(C)[NH:27][C:28](=[O:29])[CH:22]2[CH2:21]1.Cl.[OH-].[Na+]>>[NH2:27][C:28]([CH:22]1[NH:23][CH2:24][CH2:25][N:20]([CH2:19][C:18]([NH:17][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][C:4]=2[CH3:16])=[O:32])[CH2:21]1)=[O:29]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCN2C(C1)C(=O)NC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCNC(C(N)=O)C1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A mixture of 11.10 parts of N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]hexahydro-3,3-dimethyl-1-oxoimidazo[1,5-a]pyrazine-7(8H)acetamide and 100 parts of a hydrochloric acid solution 0.5N was stirred for 2 hours at reflux temperature. After cooling, the reaction mixture was treated with a sodium hydroxide solution 50%. The product was extracted twice with dichloromethane. The combined extracts were dried. filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 8.19 parts (82.6%) of 3-(aminocarbonyl)-N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]-1-piperazineacetamide (int. 2).
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH4+].[Cl-]>CCOCC.C1COCC1>[Cl:1][C:2]([F:8])([F:9])[C:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)C(F)(F)Cl
Reaction time: 2 h

Procedure:
A solution of 20 g of ethyl chlorodifluoroacetate in 150 ml ether was treated with one equivalent of benzyl magnesium chloride in 63 ml THF at -40° C. under nitrogen. After 2 hours, the reaction was poured into aqueous NH4Cl and extracted with ether. Evaporation and distillation (0.1 mm Hg) of the residue gave 24.8 g of an oil which was used directly.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([C:18](=[O:21])[CH2:19]Br)[CH:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[C:11]=1[OH:12])([CH3:5])[CH2:3][CH3:4].[I-:22].[Na+].CCCCCC>COCCOC>[CH3:1][C:2]([C:6]1[CH:7]=[C:8]([C:18](=[O:21])[CH2:19][I:22])[CH:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[C:11]=1[OH:12])([CH3:5])[CH2:3][CH3:4]
Reactant: [I-]
Reactant: CCC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)CC)c1O
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CCC(C)(C)c1cc(C(=O)CI)cc(C(C)(C)CC)c1O
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a solution of 3.56 g (10 mmol) of 1-(3,5-bis(1,1-dimethylpropyl)-4-hydroxyphenyl)-2-bromo-ethanone in 15 ml of 1,2-dimethoxyethane, a solution of 1.65 g (11 mmol) of sodium iodide in 10 ml of 1,2-dimethoxyethane is added dropwise at room temperature. After the addition, stirring is continued for 16 hours at room temperature. Then 5 ml of hexane is added and, after stirring for additional 15 minutes, the precipitated salts are removed by filtration. The obtained solution is evaporated and the resulting residue is purified by recrystallization from hexane to give 2.15 g (53%) of compound 204, m.p. 76-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[CH:12](=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[N:16]1[CH:17]=[CH:18][C:13](/[CH:12]=[N:1]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][O:5][C:6]3=[O:11])=[CH:14][CH:15]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1ccncc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OCc2c(/N=C/c3ccncc3)cccc21
Temperature: 25 °C
Yield: 77 %

Procedure:
A mixture of 4-aminoisobenzofuran-1(3H)-one (894 mg, 6 mmol), isonicotinaldehyde (2.568 g, 24 mmol) and anhydrous sodium sulfate (3.6 g) in anhydrous ethanol (70 mL) was heated to reflux for two days. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to give the crude product. The crude product was washed with petroleum ether to give (E)-4-(pyridin-4-ylmethyleneamino)isobenzofuran-1(3H)-one (1.1 g, yield 77%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.44 (s, 1H), 7.40-7.42 (d, J=7.6 Hz, 1H), 7.59-7.63 (t, J=7.6 Hz, 1H), 7.77-7.79 (d, J=5.6 Hz, 2H), 7.84-7.86 (d, J=7.6 Hz, 1H), 8.54 (s, 1H), 8.81-8.82 (d, J=4.8 Hz, 1H); LC-MS (ESI) m/z: 239 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][CH2:20]4)[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:28]([O-:33])(=[O:32])[C:29]([O-:31])=[O:30].[CH3:34][N:35]=[C:36]=[O:37]>ClCCl>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]([C:36]([NH:35][CH3:34])=[O:37])[CH2:20]4)[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: O=C([O-])C(=O)[O-]
Reactant: Clc1ccc2c(C3=CCN(CCC4CNc5ccccc54)CC3)c[nH]c2c1
Solvent: ClCCl
Product: CNC(=O)N1CC(CCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-3-[1-[2-(2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole, oxalate 30a, as the free base, (3.6 g) in dichloromethane (100 ml) was added methylisocyanate (1.4 g) in dichloromethane (20 ml). The mixture was stirred at room temperature for 16 h, and the solvent was removed in vacuo. The residue was purified on silica gel eluted with ethyl acetate-ethanol-triethylamine (90:10:5) to give the crude product, which was recrystallized (methanol-ethyl acetate-ether) to give the title compound (1.8 g). 1H NMR (DMSO-d6) δ 1.60-1.70 (m, 1H), 1.95-2.05 (m, 1H), 2.40-2.60 (m, 4H), 2.60-2.75 (m, 5H), 3.15 (q, 2H), 3.35-3.50 (m, 1H), 3.55-3.65 (m, 1H), 4.00 (t, 1H), 6.10 (broad s, 1H), 6.55 (d, 1H), 6.85 (t, 1H), 7.05 (d, 1H), 7.10 (t, 1H), 7.20 (d, 1H), 7.45 (s, 2H), 7.80 (d, 1H), 7.85 (d, 1H), 11.25 (broad s, 1H). MS m/z (%): 437, 435 (MH+, 2%, 6%), 201 (54%), 189 (100%), 144 (64%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[C:20]([NH:26][C@H:27]([C:30]([OH:32])=O)[CH2:28][OH:29])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].[CH:33]1[C:43]2[CH:42]=[CH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[C:38](=[C:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)[C:37]=2[CH:36]=[CH:35][CH:34]=1.Cl>ClCCl>[CH:33]1[C:43]2[CH:42]=[CH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[C:38](=[C:48]3[CH2:49][CH2:50][N:51]([C:30](=[O:32])[C@@H:27]([NH:26][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:28][OH:29])[CH2:52][CH2:53]3)[C:37]=2[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)N[C@@H](CO)C(=O)O
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N[C@@H](CO)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
880 mg (4.59 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 0.63 ml (4.52 mmol) of triethylamine and 860 mg (4.55 mmol) of pivaloyl-L-serine were added to 1.231 g (4.50 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine in 20 ml of dichloromethane in ice bath, and they were stirred at room temperature overnight. 1 N hydrochloric acid was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3 to 1:2) to obtain the title compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[C:12]([O:16][C:17]([O:19][N:20]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:43]2[C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[N:36]=[CH:35][C:34]=2[N:33]=[C:32]1[CH2:44][CH2:45][CH3:46])[C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+:48].C1(S(Cl)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:48][C:35]1[C:34]2[N:33]=[C:32]([CH2:44][CH2:45][CH3:46])[N:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:20]([O:19][C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])[C:21](=[O:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[C:43]=2[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N:36]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)C(C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (75% purity, 4.03 g, 17.5 mmol) was added to a solution of N-[(tert-butoxycarbonyl)oxy]-2,2-dimethyl-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]propanamide (5.00 g, 10.0 mmol) in chloroform (975 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was cooled to 0° C. and concentrated ammonium hydroxide (20 mL) was added, followed by benzene sulfonyl chloride (2.49 mL, 19.5 mmol). The reaction mixture was stirred for 2 hours at room temperature, then was transferred to a separatory funnel. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to afford 3.35 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-[(tert-butoxycarbonyl)oxy]-2,2-dimethylpropanamide.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:27][C:20]=1[C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CCCOC(=O)c1cc(N)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)c1cc(NC(=O)C2=C(C)OCCS2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (4.4 g, 0.037 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (5.25 g, 0.033 mole) and methylene chloride (50 ml). The mixture was warmed to a gentle reflux for 3 hours, stirred overnight at room temperature, and evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2- methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml), chilled, and treated dropwise over about 2 hours with a solution of propyl 5-amino-2-chlorobenzoate (7.0 g, 0.033 mole) and triethylamine (3.5 g, 0.035 mole) in methylene chloride (50 ml).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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>[F:33][C:9]1[CH:8]=[C:7]([C:40]2[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=2)[CH:12]=[CH:11][C:10]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:25]=[CH:24][CH:23]=2)=[N:14]1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: COCCOC
Solvent: O
Product: COc1cn(-c2ccc(-c3cnn(C)c3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (104 mg, 0.50 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3 (106 mg, 1.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with THF and recrystallized from MeOH/H2O to give the title compound (162 mg, 81% yield) as a white solid: mp 195-197° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.91 (3H, s), 3.96 (3H, s), 6.38 (1H, t, J=8.3 Hz), 7.06 (1H, ddd, J=0.8, 1.9, 8.3 Hz), 7.23 (1H, dd, J=1.9, 12.8 Hz), 7.30 (1H, d, J=1.9 Hz), 7.36-7.47 (5H, m), 7.64 (1H, s), 7.74 (1H, d, J=0.8 Hz), 7.79 (1H, d, J=1.9 Hz), 7.81 (1H, d, J=2.6 Hz). LC-MS (ESI) m/z 443 [M+H]+. Anal. Calcd for C24H19FN6O2: C, 65.15; H, 4.33; N, 18.99. Found: C, 65.15; H, 4.30; N, 19.02.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:27][CH2:26][CH2:25][C:5]2=[C:6]2[C:10]=1[NH:9][C:8]([C:11](=[O:14])[NH:12][CH3:13])=[C:7]2[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.O1CCCC1>[Pd].C(O)C>[CH3:13][NH:12][C:11]([C:8]1[NH:9][C:10]2[C:6]([C:7]=1[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]1[CH2:25][CH2:26][O:27][C:4]1=[CH:3][CH:2]=2)=[O:14]
Reactant: CNC(=O)c1[nH]c2c(Br)cc3c(c2c1CCNC(=O)OC(C)(C)C)CCO3
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1[nH]c2ccc3c(c2c1CCNC(=O)OC(C)(C)C)CCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a mixture of tert-butyl {2-[5-bromo-7-(methylcarbamoyl)-1,6-dihydro-2H-furo[3,2-e]indol-8-yl]ethyl}carbamate (569 mg), triethylamine (0.724 mL), tetrahydrofuran (10.0 mL), and ethanol (30.0 mL) was added 10% palladium on carbon (50% water included, 284 mg) under an argon gas flow, followed by stirring at room temperature overnight under a hydrogen atmosphere (3.2 kgf/cm2). The catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to obtain tert-butyl {2-[7-(methylcarbamoyl)-1,6-dihydro-2H-furo[3,2-e]indol-8-yl]ethyl}carbamate (434 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[CH2:35]([OH:37])[CH3:36]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:36][CH2:35][OH:37])[C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CCO
Product: Cc1ccccc1N1CN(CCO)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=530.2 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and (3-bromoethoxy)-tert.-butyldimethylsilane. HCl in ethanol (3% conc.) cleaved the intermediate TBDMS-ether.