Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([NH:35][CH2:36][C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=5)=[O:34])[C:30]([O:44]C)=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([NH:35][CH2:36][C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=5)=[O:34])[C:30]([OH:44])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)NCc4ccc(F)cn4)n3)cc12
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)NCc4ccc(F)cn4)n3)cc12
Temperature: 100 °C
Reaction time: 10 h
Yield: 64.3 %

Procedure:
To a stirring solution of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-((5-fluoropyridin-2-yl)methyl)-3-methoxypicolinamide (40 mg, 0.05 mmol) in DMF (5 mL) was added Py.HCl (400 mg, 2.22 mmol) under N2 protection. The mixture was stirred in a pre-heated oil-bath at 100° C. for 10 h. The mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. After being washed with brine, dried over Na2SO4, filtered and evaporated, the crude product was purified by prep-TLC (PE:EtOAc=2:1) to give the product of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-((5-fluoropyridin-2-yl)methyl)-3-hydroxypicolinamide (20 mg, yield: 58%). 1H-NMR (CDCl3, 400 MHz) δ 12.14 (s, 1H), 8.91 (d, J=5.6 Hz, 1H), 8.33 (s, 1H), 7.94 (s, 1H), 7.86˜7.89 (m, 2H), 7.60 (d, J=8.8 Hz, 1H), 7.52 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.31˜7.33 (m, 2H), 7.15 (d, J=8.8 Hz, 2H), 5.78 (d, J=4.0 Hz, 1H), 4.68 (d, J=5.6 Hz, 2H), 3.12 (s, 3H), 2.92 (d, J=4.8 Hz, 3H), 2.76 (s, 3H). MS (M+H)+: 622.
Reaction SMILES: [CH:1]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:2]2[C:3](=[O:13])[CH:4]=[CH:5][C:6]1=[O:12].C([O-])(O)=[O:15].[Na+].OO.O>CC(C)=O>[O:15]1[CH:4]2[CH:5]1[C:6](=[O:12])[CH:7]1[CH:2]([C:3]2=[O:13])[CH:1]2[CH2:11][CH:8]1[CH:9]=[CH:10]2
Reactant: O=C([O-])O
Reactant: O=C1C=CC(=O)C2C3C=CC(C3)C12
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1C2OC2C(=O)C2C3C=CC(C3)C12
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.35 %

Procedure:
A solution of tricyclo[6.2.1.02,7]undeca-4,9-diene-3,6-dione (14) (26.13 g, 150 mmol) in acetone (100 ml) was cooled to 0° C. on an ice-bath. To the solution was added saturated aqueous NaHCO3 (33 ml). To the mixture was added dropwise 34.5% aqueous hydrogen peroxide (142 ml) while keeping at 0° C. After the addition, the reaction mixture was stirred at 0° C. for 1 hr and then water (100 ml) was added. From the mixture solution, the product was extracted with diethyl ether (total 700 ml). The extract was washed with saturated aqueous NaCl and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to afford as the residue 4,5-epoxy-tricyclo[6.2.1.02,7]undec-9-ene-3,6-dione (15) (28.06 g, 148 mmol, 98.35% yield) in light yellowish white crystals.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:13][C:11]1[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:22]=2)[CH:12]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(Br)cc2nnc(N)nc12
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+]
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc2nnc(N)nc12
Temperature: 25 °C
Yield: 71.3 %

Procedure:
An oven dried 25 mL round bottom flask was charged with 7-bromo-5-methyl-benzo[1,2,4]triazin-3-ylamine (1.05 g, 4.49 mmol, 1 equiv), 3-Nitro phenyl boronic acid (1.05 g, 6.29 mmol, 1.4 equiv), sodium carbonate (1.9 g, 18 mmol, 4 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.519 g, 0.449 mmol, 0.1 equiv). The reactants were flushed with argon and diluted with ethylene glycol dimethyl ether (6 mL), ethanol (1 mL) and DI water (1 mL). The reaction vessel was outfitted with condenser and refluxed for 2.5 hours. The reaction was cooled to ambient temperature and diluted with water. The resulting precipitate was filtered off, washed thoroughly with water and dried. Brown solids (0.9 g, 73% yield). MS (ESI+): m/z=282.4, LC retention time: 2.77 min.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11]O>CCOCC.C(Cl)Cl>[Br:2][CH2:11][C:10]1[O:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:6]=1[CH3:5]
Reactant: BrP(Br)Br
Reactant: Cc1nc(-c2ccccc2)oc1CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nc(-c2ccccc2)oc1CBr
Reaction time: 4 h

Procedure:
80 mL (0.67 mmol) of PBr3 is added slowly to a solution of 104 mg (0.57 mmol) of (4-methyl-2-phenyl-oxazol-5-yl)-methanol in 0.5 mL of Et2O and 1.5 mL of CH2Cl2 at 0° C. The coolin bath is removed, and the reaction mixture is stirred for 4 h. The reaction mixture is then partitioned between saturated aqueous NaHCO3 solution and Et2O. The organic phase is separated and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to produce 5-bromomethyl-4-methyl-2-phenyl-oxazole as a solid; 1H NMR (250 MHz, CDCl3) δ7.90-7.99 (m, 2H), 7.32-7.40 (m, 3H), 4.50 (s, 2H), 2.16 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:10]2)[N:3]=1.[CH3:24][Al](C)C>O1CCCC1.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>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][C@H:11]1[CH2:12][CH2:13][N:9]([C:4]2[N:3]=[C:2]([CH3:24])[C:7]([F:8])=[CH:6][N:5]=2)[CH2:10]1
Reactant: Fc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1Cl
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)ncc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
Dissolve (S)-[1-(4-chloro-5-fluoropyrimidin-2-yl)-pyrrolidin-3-yl]-(2,4-dichlorobenzyl)-amine (318 mg, 0.84 mmol) in dry tetrahydrofuran (7.5 mL) and add trimethylaluminium (510 μL, 1.01 mmol, 2 M in hexanes) and tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol). Stir at 70° C. overnight. Quench by addition of water and extract with chloroform. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter and chromatograph on silica gel. Dissolve the residue in methanol (2 mL) and deposit onto SCX cartridge, eluting with methanol, then 2 M ammonia in methanol. Concentrate the ammonia washing to give the title compound (180 mg, 60%). 1H NMR (400 MHz, MeOH-d4) δ 7.88 (1H, d, J=6.4 Hz), 7.43-7.54 (2H, m), 7.27-7.37 (1H, m), 3.84-3.96 (4H, m), 3.67-3.78 (1H, m), 3.55-3.64 (1H, m), 3.43-3.53 (1H, m), 2.41 (3H, s), 2.14-2.26 (1H, m), 1.89-2.00 (1H, m); MS (ES): m/z=355 [M+].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([O:25][CH3:26])=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[CH:16]=1)[CH3:10]>ClCCCl>[C:5]([C:21]1[CH:22]=[C:17]([C:15]2[CH:16]=[C:11]([CH2:9][CH3:10])[CH:12]=[CH:13][C:14]=2[O:25][CH3:26])[CH:18]=[CH:19][C:20]=1[OH:23])(=[O:7])[CH3:6]
Reactant: CCc1ccc(OC)c(-c2ccc(OC)cc2)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1ccc(OC)c(-c2ccc(O)c(C(C)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture was prepared by suspending 5.0 g of aluminium chloride into 25 ml of 1,2-dichloroethane. The mixture was added 1.0 ml of acetylchloride, stirred for 1 hour at room temperature. The reaction mixture, wherein 2.4 g of 5-ethyl-2,4'-dimethoxybiphenyl was added, was stirred for 2 hours with cooling by the ice bath and stirred from further 2 hours at room temperature. Ice water was added into the reaction mixture, and extracted with chloroform. The extract was washed with 10% water solution of sodium hydrogencarbonate and an aqueous solution saturated with NaCl, dried with sodium sulfate and concentrated. The concentrate was purified by a silica gel column-chromatography (n-hexane:ethyl acetate=50:1) to yield 1.6 g of 3'-acetyl-5-ethyl-4'-hydroxy-2-methoxybiphenyl.
Reaction SMILES: [C:1]([C:3](=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1)#[N:2]>C(O)C.[Pt].[H][H]>[C:1]([C:3](=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH3:18])[C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1)#[N:2]
Reactant: CN1CCCC1=C(C#N)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CN1CCCC1=C(C#N)c1ccc(N)cc1
Yield: 62.7 %

Procedure:
Dissolve 10 g of 2-(α-cyano-4-nitrobenzylidene)-1-methylpyrrolidine in ethanol and then reduce it with platinum/hydrogen. After completion of hydrogen uptake, filter the catalyst from the hydrogenated product, distil off the solvent and recrystallize the residue from 50 ml of ethanol to obtain 5.5 g of the title compound as light-brown crystals of m.p. 116° to 118°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[C:8]([C:18]2[C:19](O)=[CH:20][C:21]3[O:25][CH2:24][CH2:23][C:22]=3[CH:26]=2)([CH2:16][OH:17])[C:7]1=[O:28])[CH3:2].ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[C:8]2([CH2:16][O:17][C:19]3[CH:20]=[C:21]4[C:22](=[CH:26][C:18]2=3)[CH2:23][CH2:24][O:25]4)[C:7]1=[O:28])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2cc(Cl)ccc21
Yield: 90 %

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using ethyl[5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 90% yield as a colorless solid: MS (ES+) m/z 400.8 (M+1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl.[CH3:36][CH:37](O)[CH3:38]>ClCCl.[K].[Fe]>[F:1][C:2]([F:34])([F:33])[C:3]([C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:23]=[C:24]([NH:28][C:20]([NH:17][C:37]4[CH:38]=[CH:15][N:14]=[CH:13][CH:36]=4)=[O:21])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: CC(C)O
Agent: [Fe]
Agent: Cl
Agent: [K]
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1cccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)(3-nitrophenyl)methanone (1.730 mmol, 850 mg) and iron powder (17.30 mmol, 966 mg) in 2-propanol was added a small volume of hydrochloric acid (37%). The reaction was refluxed for 1 hour then was allowed to cool to room temperature. The reaction was diluted with dichloromethane and solid potassium carbonated was added. The reaction was stirred for 1 hour then was filtered through celite washing with dichloromethane. The filtrate was concentrated under reduced pressure. The crude material was chromatographed on silica eluting with ethyl acetate to give the title compound (440 mg). MS (ESI) m/z 462.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=3)[C:9]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[C:8]2[C:22]([O:24]CC)=[O:23])=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=3)[C:9]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[C:8]2[C:22]([OH:24])=[O:23])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1c(-c2cccs2)c2cc(Cl)ccc2n1Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2cccs2)c2cc(Cl)ccc2n1Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Preparation 6, but using ethyl 1-(p-chlorobenzyl)-5-chloro-3-thiophenylindole-2-carboxylate from Example 1 as the starting material and tetrahydrofuran as the solvent, the title compound was prepared, mp 185°-188° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](Cl)=[O:10])[CH:5]=[CH:6][CH:7]=1>CCCCCCC.C(OCC)(=O)C>[CH2:9]([O:10][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH:8]=[CH2:4]
Reactant: O=C(Cl)Cc1cccc(Br)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Cc1cccc(Br)c1

Procedure:
The title compound was prepared in an analogous manner as described for intermediate B3A from (3-bromo-phenyl)-acetyl chloride (intermediate B2B) (12.1 g, ca. 50 mmol). The compound was obtained after silica gel column chromatography with n-heptane/ethyl acetate as a light yellow liquid (7.934 g, 62%). MS (ISP): m/z=272.1 [(M+NH4)+] and 274.1 [(M+2+NH4)+]
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2F)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccccc1F

Procedure:
From 2-amino-4-(2-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1([C:27]2[N:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:30]3[CH:31]=[N:32][C:27]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[N:28][CH:29]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCOCC2)nc1

Procedure:
2-Morpholin-4-yl-pyrimidine-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 2-morpholin-4-yl-pyrimidine-5-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 2H) 8.55 (t, J=5.50 Hz, 1H) 8.21 (d, J=8.78 Hz, 1H) 7.90 (s, 1H) 7.56-7.67 (m, 3H) 7.49-7.55 (m, 2H) 7.39 (dd, J=8.66, 1.88 Hz, 1H) 6.84 (d, J=2.01 Hz, 1H) 4.29 (d, J=5.52 Hz, 2H) 3.67-3.76 (m, 3H) 1.52-1.61 (m, 2H) 1.39-1.48 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15]4([C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.CN(C)C=O.C[NH:38][C@H:39]1[CH2:44][CH2:43][CH2:42][CH2:41][C@@H:40]1[NH:45][CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[N:38]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:25]6[CH:24]=[CH:23][N:22]=[CH:21][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[N:45]=[CH:46]1
Reactant: CN[C@H]1CCCC[C@@H]1NC
Reactant: O=C1OC2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccncc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-n5cnc6ccccc65)cc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (30 mg, 0.00007 mol), 1H-Imidazole, 2-methyl-(7.15 mg, 0.0000871 mol) in N,N-dimethylformamide (1 mL, 0.01 mol) were added (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.1 mg, 0.000014 mol), copper(I) iodide (1 mg, 0.000007 mol), and cesium carbonate (49.7 mg, 0.000152 mol). The mixture was microwaved at 200 Celsius for 60 minutes. Then the mixture was cooled down to r.t. and filtered. The filtrate was adjusted to be acidic using TFA and stirred for 30 minutes, then diluted with methanol and purified by revised phase prep-HPLC followed by chiral HPLC to afford the desired compound. MS (ESI): 451.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:7][C:8]([C@H:10]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[CH:24][CH:23]=1)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])[C:4]([OH:6])=O.[CH3:39][O:40][CH2:41][C@@H:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:7][C:8]([C@H:10]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[CH:24][CH:23]=1)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:9])[C:4]([NH:49][C@@H:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:41][O:40][CH3:39])=[O:6]
Reactant: COc1cccc(-c2ccc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)(C)C)cc2C)c1
Reactant: COC[C@@H](N)c1ccccc1
Product: COC[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(-c2cccc(OC)c2)c(C)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 80.9 %

Procedure:
According to the procedure of Preparation 19 d), tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-(carboxy)propyl]amino}carbonyl)-6-(3′-methoxy-2-methylbiphen-4-yl)hexanoate (660 mg, 1.26 mmol) was reacted with (1S)-2-methoxy-1-phenylethylamine (190 mg, 1.260 mmol). Work-up as above, followed by flash chromatography (eluting with hexane:ethyl acetate=3:1) to give tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1s)-2-methoxy-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3′-methoxy-2-methylbiphen-4-yl)hexanoate (672 mg, 81%) as a colourless foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]([C:19]3[N:20]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([C:28]([O:30]C)=[O:29])[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:40])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:7]=[C:6]([C:19]3[N:20]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([C:28]([OH:30])=[O:29])[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCc2c(-c3cc4ccc(C(=O)O)cc4n3COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c2C1
Temperature: 60 °C
Yield: 95.4 %

Procedure:
To a solution of methyl 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylate (33 g, 57 mmol) in a mixed solvent of tetrahydrofuran (165 ml) and methanol (165 ml) was added 4 N aqueous sodium hydroxide solution (71 ml, 284 mmol), and the mixture was heated at 60° C. for 2 hr. After cooling, the reaction mixture was concentrated, 10% aqueous citric acid solution was added to the residue to adjust the pH to 5, and the mixture was extracted with ethyl acetate. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (31 g, yield 97%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:14]([CH3:15])=[CH:13][C@H:12]2[C@@:7]([OH:20])([C@@H:8]([CH3:19])[CH2:9][CH2:10][C@H:11]2[C:16]([CH3:18])=[CH2:17])[C@H:6]1[OH:21])(=[O:3])[CH3:2].[C:22]1(C)[CH:27]=CC(S(O)(=O)=O)=C[CH:23]=1>COC(OC)(C)C>[C:1]([O:4][C@H:5]1[C@@H:6]2[O:21][C:22]([CH3:27])([CH3:23])[O:20][C@:7]32[C@@H:12]([C@H:11]([C:16]([CH3:18])=[CH2:17])[CH2:10][CH2:9][C@@H:8]3[CH3:19])[CH:13]=[C:14]1[CH3:15])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@H](C)[C@]2(O)[C@@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Product: C=C(C)[C@@H]1CC[C@H](C)[C@@]23OC(C)(C)O[C@H]2[C@H](OC(C)=O)C(C)=C[C@H]13
Reaction time: 72 h
Yield: 776 %

Procedure:
A stirred solution of (1S,2R,4aR,5R,8S,8aS)-1,8a-dihydroxy-5-isopropenyl-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydro-2-naphthalenyl acetate (Preparation 126, 10 g) in 2,2-dimethoxypropane (200 ml) was treated with para-toluenesulfonic acid (700 mg). After 3 days, the solution was concentrated in vacuo and the residue purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (5:95) to give the product (10.55 g).
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(O)(=O)C>CN(C)C=O>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)N([C@H](C)c3ccccc3)[C@H]3COC(=O)[C@H]32)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
9.75 g (0.22 mol) of sodium hydride (55 percent in oil) was added in 10 portions in 2 hours at -10° C. under argon to a solution of 50.0 g (0.2 mol) of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d]-imidazol-2,4(3H,3aH)-dione and 39.8 g (0.25 mol) of 4-methoxybenzyl chloride in 500 ml of dried N,N-dimethylformamide. The reaction mixture was stirred at 5° C. for 2 hours and then at room temperature for another 2 hours. Then 8 ml of acetic acid was added. Then the mixture was evaporated to dryness. Then the residue was taken up in 100 ml of water and 200 ml of dichloromethane, the phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. After suspension in ethanol with refluxing, cooling and filtering, 53.5 g (72 percent) of the title product was obtained in the form of white needles. Concerning the product: