Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]1([CH2:16][O:15][C:14]3[CH:17]=[C:18]4[C:22](=[CH:23][C:13]1=3)[CH2:21][CH2:20][O:19]4)[C:5](=[O:12])[NH:6]2.N1C2C(=CC=CC=2)[C:26]2([C:36]3=CC4OCOC=4[CH:43]=[C:35]3[O:34][CH2:33]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]1([CH2:16][O:15][C:14]3[CH:17]=[C:18]4[C:22](=[CH:23][C:13]1=3)[CH2:21][CH2:20][O:19]4)[C:5](=[O:12])[N:6]2[CH2:43][C@H:35]1[CH2:36][CH2:26][CH2:33][O:34]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Cc1ccc(F)c2c1NC(=O)C21COc2cc3c(cc21)CCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: Cc1ccc(F)c2c1N(C[C@H]1CCCO1)C(=O)C21COc2cc3c(cc21)CCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 4′-fluoro-7′-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (76%) as a colorless solid: mp 175-176° C. (diethyl ether); 1H NMR (300 MHz, CD3OD) δ7.14-7.06 (m, 1H), 6.71-6.52 (m, 2H), 6.25 (d, J=2.3 Hz, 1H), 4.80-4.78 (m, 2H), 4.51 (t, J=8.6 Hz, 2H), 4.26-3.69 (m, 5H), 3.00 (t, J=8.6 Hz, 2H), 2.56 (s, 3H), 2.16-1.87 (m, 3H), 1.78-1.69 (m, 1H); MS (ES+) m/z 396.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(#N)C.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:43])=[C:30]([C@:32]23[CH2:40][O:39][CH2:38][C@@:37]2([F:41])[CH2:36][O:35][C:34]([NH2:42])=[N:33]3)[CH:31]=1>C(OCC)(=O)C.O.C(O)C>[NH2:42][C:34]1[O:35][CH2:36][C@:37]2([F:41])[CH2:38][O:39][CH2:40][C@:32]2([C:30]2[CH:31]=[C:26]([NH:25][C:8]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:27]=[CH:28][C:29]=2[F:43])[N:33]=1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)COC[C@@]2(F)CO1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCO
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(Cl)cn4)ccc3F)COC[C@@]2(F)CO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
Scheme 3, steps M, substep 2 or step N, substep 3 (amidation): A mixture of 5-chloropyrazine-2-carboxylic acid (1.53 g, 9.66 mmol) in acetonitrile (15 mL, 283 mmol) is treated with DMF (115 μL, 1.49 mmol) and oxalyl chloride (970 μL, 11.1 mmol). The mixture is stirred at ambient temperature under nitrogen for 20 minutes. In a separate flask is added (4aR,7aS)-7a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-2-amine (2.00 g, 7.43 mmol), ethanol (7.4 mL), water (7.4 mL) and the mixture is heated at 50° C. The acid chloride is added to the solution prepared above and the reaction mixture is stirred at 50° C. for 20 minutes. The reaction is cooled to room temperature, diluted with ethyl acetate (200 mL), and washed with water (40 mL) and saturated aqueous NaHCO3 (40 mL). The aqueous washes are combined and extracted with ethyl acetate (100 mL). The combined organic layers are dried (Na2SO4) and the solvent removed in vacuo to give the crude product. The crude product is purified by silica gel flash chromatography, eluting with ethyl acetate to give the title product (2.85 g, 94%). ES/MS (m/e): 410 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21]S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[C:34]=1O>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21][C:34]2[C:33]([F:32])=[CH:38][C:37]([F:39])=[CH:36][C:35]=2[F:40])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2COc2c(F)cc(F)cc2F)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 86.1 %

Procedure:
4-(2-Methanesulfonyloxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (27.0 g, 60.6 mmol, 1.0 eq.) was dissolved in MeCN (540 mL) and added to K2CO3 (25 g, 180 mmol, 3.0 eq.) and 2,4,6-trifluorophenol (13.5 g, 90.9 mmol, 1.5 eq.). The mixture was vigorously stirred at 50° C. for 6 hours, removed from the heat, and stirred overnight. The mixture was cooled at room temperature, and diluted with EtOAc (700 mL) and water (700 mL). The phases were separated, and the organic layer was washed twice with 1.0 M NaOH in water (2×400 mL) and saturated aqueous NaCl (1×400 mL), then dried over Na2SO4 and the solvent removed to yield crude 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine-1-carboxylic acid t-butyl ester (25.0 g). The crude product was combined with smaller scale runs for a total of 30 g, and purified by chromatography (0-10% EtOAc in hexanes) to yield 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine-1-carboxylic acid t-butyl ester (22.0 g).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.N1C=CC=CC=1.[C:52](Cl)(=[O:56])[O:53][CH2:54][CH3:55]>C(Cl)Cl>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:52]([O:53][CH2:54][CH3:55])=[O:56])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)Cl
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N(CC)C(=O)OCC)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) and pyridine (371 μl) are dissolved in methylene chloride (5 ml), and thereto is added ethyl chlorocarbonate (293 μl) under ice-cooling. The reaction solution is stirred at room temperature overnight and the organic solvent is concentrated under reduced pressure. To the residue are added ethyl acetate and an aqueous citric acid solution, and the mixture is separated. 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 (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (176 mg). MS (m/z): 725 [M+H]+
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:18]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CNCCC#Cc1ccccn1
Product: COc1ccccc1C(=O)N(C)CCC#Cc1ccccn1
Yield: 77.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-methoxybenzoyl chloride (69 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 71 mg of 2-methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a green-brown oil (Yield: 77%).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4]1.[CH2:11]([NH:13][C:14]1[C:19]([CH:20]=O)=[CH:18][N:17]=[C:16]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:15]=1)[CH3:12].O>C(OCCO)C>[CH2:11]([N:13]1[C:14]2[N:15]=[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:17]=[CH:18][C:19]=2[CH:20]=[C:8]([C:5]2[CH:6]=[CH:7][S:3][CH:4]=2)[C:9]1=[NH:10])[CH3:12]
Reactant: N#CCc1ccsc1
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Product: CCn1c(=N)c(-c2ccsc2)cc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of 2-ethoxyethanol was added 3-thiopheneacetonitrile (168 mg, 1.36 mmol). After stirring for 5 minutes at room temperature, 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.24 mmol) was added, and the reaction heated at 120° C. for 2 hours, resulting in a dark brown solution. Upon cooling, the solution was poured into water which caused precipitation. The resulting precipitate was removed by filtration and washed with water. The crude product was purified by flash chromatography, eluting with 5% methanol/methylene chloride, followed by 10% methanol/methylene chloride. Concentration of product fractions yielded 340 mg (78%) of (8-ethyl-7-imino-6-thiophen-3-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine; mp 220°-222° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:13][C:12]2[CH:11]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[S:9][C:8]=2[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:2]([C:6]1[S:13][C:12]2[CH:11]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[S:9][C:8]=2[CH:7]=1)=[O:1]
Reactant: NS(=O)(=O)c1cc2sc(C3OCCO3)cc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)c1cc2sc(C=O)cc2s1

Procedure:
2,3-Dibromothiophene (1) is converted to 3-Bromothiophene-2-carboxaldehyde (2) through a series of reactions with n-butyl lithium yielding 2-litho-3-bromothiophene, followed by N-formylpiperidine and 3N HCl. This 3-bromothiophene-2-carboxaldehyde (2) is then placed in toluene solution containing ethylene glycol to which is added pyridinium tosylate yielding 3-bromo-2-(2-dioxolanyl)thiophene (3). This 3-bromo-2-(2-dioxolanyl)thiophene (3) is then reacted with n-butyllithium followed by sulfur, then by methyl bromoacetate, to yield methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4). This methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4) is next dissolved in acetone and p-toluenesulfonic acid monohydrate is added in catalytic amount yielding methyl 3-(2-formylthiophene-3-yl)-3-thiapropionate (5). This methyl 3-(2-formylthiophene-3-yl)3-thiapropionate (5) is then treated in solution with piperidinium acetate yielding methyl thieno[3,2-b]thiophene-2-carboxylate (6). This methyl thieno[3,2-b]thiophene-2-carboxylate (6) is then placed in solution with lithium aluminum hydride yielding 2-hydroxymethylthieno[3,2-b]-thiophene (7). This 2-hydroxymethylthieno[3,2-b]-thiophene (7) is then added to a suspension of pyridinium chlorochromate in methylene chloride and yields thieno[3,2-b]thiophene-2-carboxaldehyde (8). This thieno[3,2-b]thiophene-2-carboxaldehyde (8) is then mixed with ethylene glycol, pyridinium tosylate and benzene yielding 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9). This 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9) is then reacted with n-butyllithium after which SO2 is bubbled onto the surface and N-chlorosuccinimide and NH4OH are added separately at the appropriate time. This series of steps yields 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10). This 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10) may then be reacted with p-toluenesulfonic acid monohydrate in acetone to yield 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11). The 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11) is then reacted with an appropriate amine yielding the intermediate iminium salt (12) which may then be reduced with NaBH4 or NaCNBH3 to give the desired 5-substituted thieno[3,2-b]thiophene-2-sulfonamide.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[NH:23][C:22]2=[O:36])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[CH:38]=[O:39].O>C1C=CC=CC=1>[OH:39][CH:38]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:22]1=[O:36])[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: CC(C)(C)OC(=O)C=O
Reactant: O=C1NC(SCC#Cc2ccc(F)cc2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1
Yield: 75.1 %

Procedure:
3-(Triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one (1.02g) and t-butyl glyoxalate (2.76g) were refluxed in dry benzene (50ml) with provision for the removal of water. After 1 hour the benzene solution was washed 5 times with water, dried and evaporated. The residue was chromatographed on silica to give 1-(1-Hydroxy-1-t-butyoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one as an amorphous solid (0.969g). νmax (CHCl3) 1770, 1735 cm-1.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:26])[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[O:27]1CCCC1.O.[OH-].[Li+].OO>[OH-].[Na+].O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:26])=[O:27])=[CH:24][CH:23]=1
Reactant: C1CCOC1
Reactant: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Product: C=CC[C@H](C(=O)O)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
Combine (S)-4-benzyl-3-(2-(4-fluorophenyl)pent-4-enoyl)-2-oxazolidinone (9.66 g, 27.34 mol), tetrahydrofuran (160 mL), and water (40 mL). Cool in an ice bath. Add lithium hydroxide hydrate (2.52 g, 60 mmol) and an aqueous solution of hydrogen peroxide (10 mL, 30% 116 mmol). After 3 hours, dilute the reaction mixture with an aqueous 1 M sodium hydroxide solution and extract twice with diethyl ether. Cool the aqueous layer in an ice bath, acidify with an aqueous concentrated hydrochloric acid solution (about 15 mL), and extract twice with dichloromethane. Extract the combined organic layers with a saturated aqueous sodium thiosulfate solution, dry over MgSO4, filter, and evaporate in vacuo to give (S)-2-(4-fluorophenyl)pent-4-enoic acid.
Reaction SMILES: [C:1]([C:9](=[CH:28]N(C)C)[CH2:10][C:11]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([NH:38][NH2:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([N:38]2[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:12])[CH:28]=[N:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=C(CC(=O)OCCN1CCN(c2ccccc2)CC1)C(=O)c1ccccc1
Product: O=C(Cc1cnn(-c2ccccc2)c1-c1ccccc1)OCCN1CCN(c2ccccc2)CC1

Procedure:
2-(4-phenylpiperazino)-ethyl 3-benzoyl-4-dimethylamino-3-butenoate respectively, with phenylhydrazine.
Reaction SMILES: [CH3:1][C@@:2]1([CH:8]=[CH:9][C:10]2[N:11]([CH2:15][CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1>C(O)C.[Pd]>[CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH2:15][CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: CCn1cccc1C=C[C@]1(C)COC(=O)N1
Agent: [Pd]
Solvent: CCO
Product: CCn1cccc1CC[C@]1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a suspension of 10% palladium-charcoal (50% wet with water) (500 mg) in ethanol (10 ml) was added a solution of (4R)-4-methyl-4-[2-(1-ethylpyrrol-2-yl)ethenyl]-1,3-oxazolidin-2-one (5.7 g, 25.9 mmol) obtained in Reference example 22 in ethanol (50 ml), and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After stirring, the palladium-charcoal in the reaction mixture was filtered off using celite, and the filtrate was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:7) as the eluent to afford the title compound (5.0 g, yield: 87%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[N:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:24]C(=O)OCC2C=CC=CC=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[NH2:24][CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:35]
Reactant: O=C(NC1Cc2nc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC1Cc2nc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 2A (96 mg, 0.207 mmol) in THF (6 mL) and MeOH (6 mL) at RT was added palladium 5% wt on activated carbon (64 mg). The reaction mixture was stirred under a hydrogen balloon for 1 h. The reaction was filtered and the filtrate concentrated to give the title compound as a foam (68 mg, 100%). LC/MS (method A): retention time=2.65 min, (M+H)+=330.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][NH:11][C:12]([CH:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15]2)=O)=[CH:5][CH:4]=1.FC(F)(F)C([O-])=O.[NH4+:35]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:35]=[C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15]3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(C(=O)CNC(=O)C2CN(Cc3ccccc3)CCO2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)cc1
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 96.9 %

Procedure:
A mixture of N-{2-[4-(methyloxy)phenyl]-2-oxoethyl}-4-(phenylmethyl)-2-morpholinecarboxamide (2.5 g, 6.79 mmol) and ammonium trifluoroacetate (4.45 g, 33.9 mmol) was stirred for 2.5 hours at 150° C. Water (150 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×80 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated to afford the title compound (2.3 g) as a brown solid. LC-MS (ES) m/z=350 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc1
Reaction time: 0.67 h
Yield: 86.3 %

Procedure:
A stirred solution of 4-bromoanisole (639 mg) in THF (15 ml) under argon was cooled to −78° C. A solution of n-butyllithium (2.07 ml, 1.6 M in hexane) was added slowly while keeping the temperature below −70° C. After stirring for 40 min, a solution of 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (400 mg, example 74, step 4) in THF (15 ml) was added while keeping the temperature below −70° C. The mixture was stirred at this temperature for 1 hour. The reaction was stopped by addition of saturated aqueous ammonium chloride solution (15 ml). Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phase was washed with water and brine, dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 3:2) to give the title compound (390 mg) as a light yellow oil, MS (ESI+): m/z=409.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)=[O:13].F[B-](F)(F)F.[CH2:26]([O+](CC)CC)[CH3:27].O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:15][C:16]([O:20][CH2:26][CH3:27])=[N:17][CH2:18][CH2:19]1)=[O:13]
Reactant: CC[O+](CC)CC
Reactant: O=C1CN(C(=O)c2cccc(C(F)(F)F)c2Cl)CCN1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC1=NCCN(C(=O)c2cccc(C(F)(F)F)c2Cl)C1
Reaction time: 18 h

Procedure:
To a solution of 4-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-piperazinone (0.613 g, 2 mmol, e.g. as prepared in Intermediate 1) in Dichloromethane (5 ml) at room temperature was added triethyloxonium tetrafluoroborate (950 mg, 5.00 mmol). The reaction mixture was stirred for 18 hours. Dichloromethane (20 ml) and iced water (10 ml) were added and the pH was adjusted to pH 7 with solid sodium hydrogen carbonate. The organic phase was separated, washed with brine, dried and evaporated to give crude 1-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[C:17]([NH:24][OH:25])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(#N)C.N12CCCN=C1CCCCC2>O.Cl>[C:20]([O:19][C:17]([NH:24][O:25][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:16])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NO
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NOCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a mixture of commercially available N-(4-bromobutyl)phthalimide (2.82 g, 10 mmol) and N-Boc-hydroxylamine (2.08 g, 15.6 mmol) was added acetonitrile (2 ml) and successively 1,8-diazabicyclo[5.4.0]undec-7-ene (2.25 ml, 15 mmol). The reaction mixture was stirred at room temperature for 30 min and then at 50° C. for 2 days. It was diluted with a mixture of water (30 ml) and 1 N hydrochloric acid (20 ml). It was extracted with ethyl acetate (2×100 ml). The organic phase was washed with brine (50 ml) and was dried over magnesium sulphate. The crude product was purified by chromatography on silica (60 g), using a gradient of heptane/ethyl acetate 1:0 to 0:1 as eluent to give 2.08 g of 2-(4-(tert-butoxycarbonylaminoxy)butyl)isoindole-1,3-dione.