Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:5]([NH2:12])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO.[C:22]([O:25][CH2:26]C)(=[O:24])C.[C]=O>C(N(CC)CC)C>[CH3:26][O:25][C:22]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[N:6][C:5]([NH2:12])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1)=[O:24]
Reactant: CCOC(C)=O
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1-c1ccc(Cl)cc1
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(N)nc1C(F)(F)F

Procedure:
A mixture of 12.57 g 5-bromo-3-(4-chloro-phenyl)-6-trifluoromethyl-pyrazin-2-ylamine, 0.60 g palladium(II)chloride-dppf-dichloromethane complex, 75 ml methanol, 75 ml ethyl acetate and 10.0 ml triethylamine was heated to 110° C. in an autoclav under 70 bar of carbon monoxide for 20 h. The solvents were evaporated and the residue was purified by chromatography on silica gel with dichloromethane to yield 6.48 g of the title compound as off white solid. MS (M−H) at 330.1.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:31].[NH2:32][N:33](C)[C:34](=O)OC(C)(C)C>>[ClH:31].[ClH:31].[CH3:34][N:33]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:32]1
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: Cl
Product: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (72 g, 160 mmol) was added hydrochloric acid (610 mL of 4.0 M, 2.5 mol). The reaction mixture was allowed to stir at 25° C. for 2 hours. Solvent was removed under vacuum, and the obtained solid was azeotroped with EtOH (3×700 mL). The resulting beige-white solid was dissolved in EtOH (685 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-methyl-carbamate (29 mL, 200 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid (200 mL of 4.0 M, 800 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a thick white slurry developed. The slurry was allowed to slowly cool to 25° C., and solids were collected by vacuum filtration. The filter cake was rinsed with a 10% solution of EtOH in hexane (2×500 mL). The solid was placed in a vacuum oven overnight (20 mm Hg/45° C.). 1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (42 g, 78%) was obtained as an off-white solid. ESI-MS m/z calc. 255.3. found 256.3 (M+1)+; Retention time: 1.30 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 7.82-7.76 (m, 1H), 7.61 (s, 1H), 7.40-7.34 (s, 1H), 7.22-7.14 (m, 2H), 4.19 (s, 3H), 3.52-3.42 (m, 2H), 3.41-3.33 (m, 2H), 2.39-2.07 (m, 4H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[F:15][C:16]1[C:23]([F:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]([F:29])=[C:20]([F:30])[C:17]=1[CH2:18]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH:14][CH2:18][C:17]2[C:20]([F:30])=[C:21]([F:29])[C:22]([C:25]([F:26])([F:28])[F:27])=[C:23]([F:24])[C:16]=2[F:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(N)cc1C(=O)O
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 53 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 2-ethanoyloxy-5-aminobenzoic acid (0.81 g, 4.10 mmole) which was prepared from Synthesis Example (14-3), DMF (15 ml), TEA (0.1 ml), tetrabutyl ammonium iodide (5 mg), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.02 ml, 6.15 mmole), 0.92 g (53.0% yield) of was obtained 2-ethanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid as a white solid.:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH2:16][CH3:17])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH2:23][CH3:24])=[C:19](/[F:22])\[CH2:20][OH:21])[C:3]=1[O:25][CH2:26][CH3:27].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH2:16][CH3:17])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH2:23][CH3:24])=[C:19](/[F:22])\[CH:20]=[O:21])[C:3]=1[O:25][CH2:26][CH3:27]
Reactant: CCOc1c(/C(CC)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)CC
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1c(/C(CC)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)CC

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-8-sec-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-pent-2-en-1-ol (Compound A-143, 411 mg, 0.94 mmol), tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4-methylmorpholine N-oxide (274 mg, 2.34 mmol) were reacted in acetonitrile and dichloromethane to give the title compound as a yellow oil after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH3:21])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH:9]=[C:10]1[C:15](=[O:16])OC(C)(C)OC1=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Br:1][C:2]1[C:3]([O:20][CH3:21])=[N:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:9]=[CH:10][C:15]2=[O:16]
Reactant: COc1nccc(NC=C2C(=O)OC(C)(C)OC2=O)c1Br
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1ncc2c(=O)cc[nH]c2c1Br
Temperature: 250 °C

Procedure:
A two neck round bottomed flask equipped with an air condenser was charged with 5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (23 g, 64 mmol) and diphenyl ether (230 mL). The reaction mixture was heated at 250° C. for 30 min under nitrogen atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtained 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one as a brown solid.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>C(O)(C)C>[O:12]1[C:9]2=[CH:10][C:11]3[C:2]([NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:17]([C:15]#[CH:16])[CH:18]=4)=[N:3][CH:4]=[N:5][C:6]=3[CH:7]=[C:8]2[O:14][CH2:13]1
Reactant: C#Cc1cccc(N)c1
Reactant: Clc1ncnc2cc3c(cc12)OCO3
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc4c(cc23)OCO4)c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A mixture of 8-chloro-[1,3]dioxolo[4,5-g]quinazoline (0.200 g, 1.04 mmol) and 3-ethynylaniline (0.127 g, 1.09 mmol) in 5 mL isopropanol was heated to reflux overnight, then cooled to ambient temperature. Precipitate was collected and washed to give [1,3]dioxolo[4,5-g]quinazolin-8-yl-(3-ethynyl-phenyl)-amine (0.266 g, 78%): mp greater than 350° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.C(O)C>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1ccncc1
Yield: 43 %

Procedure:
To a solution of 3-(4-pyridyl)-acrylic acid (25.0 g, 168 mmol) in 1:1 ethanol:THF (250 mL) was added 10% Pd(0)/C (2.50 g). The reaction vessel was placed under 110 psi of H2 until 1.0 equivalent of H2 had been consumed as indicated by a pressure drop in the reaction vessel. The mixture was then diluted with 1 L of hot methanol and filtered through celite, rinsing with hot methanol. The liquid obtained was concentrated in vacuo, affording 11.0 g (43% of 3-(4-pyridyl)-propionic acid. This material was dissolved in DMF (300 mL), and to this solution was added the aminochromanol intermediate from Example 1, Step L (12.0 g, 72.5 mmol), HOBT (11.7 g, 87.0 mmol), di-iso-propylethylamine (27.8 mL, 159 mmol) and HBTU (27.5 g, 72.5 mmol). After 2 hours at ambient temperature, the reaction was quenched with 0.5 N aqueous NaHCO3 (500 mL) and diluted with ethyl acetate (1 L). The organic layer was washed with 0.5 N NaHCO3 (300 mL×3), brine (300 mL), dried (MgSO4), and concentrated in vacuo, affording 13.2 g (61%) of the amide as a white solid. A portion of this material (2.27 g, 7.61 mmol) was dissolved in dichloromethane (100 mL), and 2-methoxypropene (3.64 mL, 38 mmol) was added, followed by camphorsulfonic acid (1.20 g, 5.17 mmol). After 3 hours at ambient temperature the reaction was quenched by the addition of 1.4 mL of triethylamine, and concentrated in vacuo. Purification by flash chromatography (3% methanol in ethyl acetate) afforded the title compound as a clear oil. 1H NMR (CDCl3, 400 MHz) 8.55 (d, 2H), 7.58 (s, 1H), 7.26 (m, 3H), 7.00 (d, 1H), 6.84 (t, 1H), 5.81 (s, 1h), 4.88 (s, 1H), 4.40 (d, 2H), 4.18 (m, 3H), 3.02 (m, 3H), 2.70 (m, 1H), 1.62 (s, 3H), 1.30 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Li][C:15]#[N:16].C(P(=O)(OCC)OCC)#N.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[C:15]#[N:16]
Reactant: [Li]C#N
Reactant: COc1cccc2c1CCCC2=O
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CCC=C2C#N
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 339.9 %

Procedure:
5-Methoxy-1-tetralone (8.80 g) was dissolved in 50 ml of anhydrous THF and cooled to 5° C. under N2 atmosphere. LiCN (0.50 g.) was added to the stirred solution, followed by dropwise addition of diethyl cyanophosphonate (9.1 ml) over 10 min. After 45 min at 5° C., the reaction was poured into 200 ml H2O and extracted with EtOAc (3×100 ml). The combined organic extracts were washed with water (3×150 ml), saturated NaCl (150 ml), dried (MgSO4), and evaporated under reduced pressure. The resulting colorless oil was dissolved in benzene (100 ml) and p-toluenesulfonic acid (0.50 g) was added. The reaction was stirred at reflux for 2 hr, cooled to room temperature, and poured into 5% NaHCO3 solution (150 ml). The reaction was extracted with Et2O (2×100 ml) and the combined organic extracts were washed with saturated NaCl solution (150 ml), dried (MgSO 4), and evaporated under reduced pressure to yield 9.55 g of a white solid. The product was recrystallized from MeOH to yield 7.81 g of the product as white needles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([O:10][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH3:9])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(O)c1cccc(F)c1
Product: CC(Oc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Yield: 77 %

Procedure:
Prepared in analogy to example 16a) from 1-(3-fluoro-phenyl)-ethanol (Balasubramanian et al., Synth. Commun., 1994, 24 (8), 1049) and 4-nitrophenol. Yellow oil. Yield=77%. MS: m/e=261.2 (M+).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:28]([Cu])#[N:29]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O

Procedure:
This compound was synthesized from 1-bromo-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (prepared as shown in Scheme 2, according to US 2004/0254215 A1, 1H NMR (CDCl3) δ=11.89 (s, 1H), 8.36 (d, 1H), 7.57 (d, 1H), 7.44 to 7.50 (m, 1H), 7.08 to 7.16 (m, 4H), 4.47 (t, 2H), 1.78 to 1.93 (m, 2H), 1.38 to 1.58 (m, 2H), 0.99 (t, 3H)) and CuCN in analogy to Example 3(a)); MS-(−)-ion: M−1=379.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[C:4]=1[CH3:15].[CH3:16][NH:17][CH2:18][CH2:19][OH:20].CCN(CC)CC>C1COCC1>[OH:20][CH2:19][CH2:18][N:17]([CH3:16])[S:10]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:15])[C:5]=1[CH3:14])(=[O:12])=[O:11]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CNCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N(C)CCO)c(C)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A soln. of 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (2.29 g, 9.19 mmol) in THF (30 ml) was added dropwise to a soln. of 2-methylaminoethanol (0.89 g, 0.95 ml, 11.8 mmol) and Et3N (5 ml) in THF (15 ml) at 0° C. The mixture was subsequently stirred at RT for 5 h and then concentrated i. vac., the residue was taken up in NaHCO3 soln. and the mixture was extracted with EtOAc (3×30 ml). The combined organic phases were dried with Na2SO4 and concentrated i. vac.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[C:24]([F:26])[CH:25]=1.O>CN(C=O)C>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([F:26])[CH:25]=1)[O:27][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Oc1cc(F)cc(F)c1
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
5-Fluoro-2-nitro-benzonitrile (5 g, 30.1 mmol) in dry DMF (60 mL) was treated first with cesium carbonate (11.7 g, 36.12 mmol) followed by 3,5-difluoro-phenol. The reaction was stirred at room temperature for 1 hour and then poured into iced water (600 mL). After stirring for 2 hours, a pale yellow solid was filtered with suction, washed with water furnishing, after drying at 50° C. under vacuum, 7.73 g of title compound in 93% yield.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CN(C)C=O>[O:7]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(C)=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccccc1
Reaction time: 4 h
Yield: 7.4 %

Procedure:
A mixture of phenol (18.8 g) and sodium hydroxide (8 g) was stirred at 60°-70° in dimethylformamide (162 ml) and water (18 ml) while 1-bromo-3-methylbut-2-ene (VII, R1 =R2 =CH3, Hal=Br) (29.8 g) was added dropwise over 11/2 h. The mixture was stirred at 60° for 4 h after the addition was complete. It was then poured into water (800 ml) and extracted with ether (3×300 ml). The ether extract was washed with 10% sodium hydroxide (200 ml) and then with water (3×200 ml) before drying over anhydrous sodium sulphate. The solvent was removed in vacuo, and the residue distilled to give 1-phenoxy-3-methylbut-2-ene (2.4 g, yield 75%) as a clear liquid b.p. 116°-118°/18 mm. Hg.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:40]1[CH2:39][CH2:38][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:42][CH2:41]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
700 mg (1.78 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 341 mg (1.78 mmol) of 1-(3-methoxyphenyl)piperazine and a spatula tip of silica gel are stirred in 20 ml of dichloromethane at room temperature for one hour and then under reflux for 35 hours. The target compound is obtained after purification on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15]O)[C:4]=2[CH:3]=[CH:2]1.S(Cl)([Cl:19])=O.CN(C)C=O>C(Cl)Cl>[Cl:19][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: OCCCOCCc1cccc2sccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCCCOCCc1cccc2sccc12

Procedure:
In 7.0 mL of methylene chloride was dissolved 1.40 g of 3-[2-(1-benzothiophen-4-yl)ethoxy]-1-propanol, followed by adding thereto 1.10 mL of thionyl chloride and 0.05 mL of N,N-dimethylformamide, and the resulting mixture was heated under reflux for 5 hours. Then, the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography (eluent; hexane:ethyl acetate=20:1) to obtain 1.43 g of 4-[2-(3-chloropropoxy)ethyl]-1-benzothiophene as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[H][H]>C(O)C.C(O)=O.[OH-].[Pd+2].[OH-]>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: [H][H]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 4, 0.210 g) in ethanol (6 mL) was added to a flask containing palladium hydroxide (0.020 g) and formic acid (3 drops) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with 10% aqueous potassium carbonate solution, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10% to give methyl 7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (0.137 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:16][CH2:17][C:18]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)CCl)CC1

Procedure:
The title compound 604 mg (89%) was obtained in a manner similar to the Manufacturing Example 3 by use of tert-butyl trans-4-aminocyclohexylcarbamate and chloroacetyl chloride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1.[CH3:17][C:18]1[C:26]2[CH2:25][O:24][C:23](=[O:27])[C:22]=2[CH:21]=[CH:20][C:19]=1[C@H:28]1[CH2:30][O:29]1.CCN(C(C)C)C(C)C>C(O)C>[OH:29][C@H:28]([C:19]1[C:18]([CH3:17])=[C:26]2[C:22](=[CH:21][CH:20]=1)[C:23](=[O:27])[O:24][CH2:25]2)[CH2:30][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@@H](O)CN2CCC3(CC2)C(=O)Nc2ccccc23)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
Commercially available spiro[indoline-3,4′-piperidin]-2-one hydrochloride (500 mg, 2.10 mmol) was combined with 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4A) (398 mg, 2.10 mmol) and DIEA (439 μL, 2.51 mmol) in ethanol (7 mL) and heated at 80° C. for 3 h. The reaction mixture was concentrated and purified by MPLC eluting first with 30% ethyl acetatehexanes and then with 10% methanol/DCM to afford the title compound which was a mixture of regioisomers. MS-ESI (m/z): 393 (M+1)+;
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1)[CH2:7][CH2:8]C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[C:17]([N:15]1[CH:11]([O:10][CH2:6][CH2:7][CH3:8])[CH2:12][CH2:13][C:14]1=[O:16])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCOC1CCC(=O)N1C(=O)c1ccccc1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
17 cm3 of a 1.5M solution of n-butyllithium in n-hexane is added at -60° C. to a solution of 4 g of 5-(1-butyloxy) pyrrolidin-2-one in 90 cm3 of tetrahydrofuran. The whole is agitated for 15 minutes at -60° C. then, at this temperature, a solution of 3.58 g of benzoyl chloride in 25 cm3 of tetrahydrofuran is added. After allowing the temperature to return to the ambient, the solvent is evaporated under reduced pressure and the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of expected product is obtained. b.p. =200°-210° C. under 0.07 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[CH2:15][N:16]([CH2:30][C:31]([OH:33])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46].C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[CH2:15][N:16]([CH2:30][C:31]([O:33][C:41]2[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=2[F:35])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:18]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2cccc(Oc3ccccc3)c2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2cccc(Oc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [[2-((S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxyphenyl)amino]acetic acid 27 (4.36 g, 9.39 mmol) in DMF (30 mL) were added pentafluorophenol (1.88 g, 10.21 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (1.96 g, 10.22 mmol). The reaction mixture was stirred overnight at room temperature. It was then diluted with ethyl acetate, washed with 10% hydrochloric acid (×2), brine (×2), dried (Na2SO4) and concentrated in vacuo. The resultant solid was evaporated twice from diethyl ether to give the title compound as a colourless, glassy solid (3.4 g, 57%) which was used directly in the next step.