Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:31][C:12]3[N:13]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[F:30])[CH:14]=[C:15]([C:18]4[O:22][CH:21]=[N:20][CH:19]=4)[C:16](=[O:17])[C:11]=3[C:10]=2[CH2:32]Br)=[CH:5][CH:4]=1.C([N:36]([CH:40]([CH3:42])C)[CH:37](C)C)C.[CH2:43]([CH2:50]N)[C:44]1C=CC=[CH:46][CH:45]=1>CN(C)C=O>[CH2:40]([N:36]([CH2:32][C:10]1[C:11]2[C:16](=[O:17])[C:15]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:14][N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:12]=2[S:31][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:37])[C:42]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:50]=1
Reactant: COc1ccc(-c2sc3c(c2CBr)c(=O)c(-c2cnco2)cn3Cc2ccccc2F)cc1
Reactant: NCCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)c(-c2cnco2)cn3Cc2ccccc2F)cc1

Procedure:
To a solution of the compound (0.07 g, 0.16 mmol) obtained in Example 2 in dimethylformamide (20 ml) are added under ice-cooling ethyldiisopropylamine (0.0243 g, 0.19 mmol) and N-benzylmethylamine (24.2 μl, 0.19 mmol).
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[N:26]=4)[N:23]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:35]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[N:26]=4)[N:23]=3)[CH2:12][CH2:13]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 84.5 %

Procedure:
482 mg of ethyl 2-[6-[4-[4-(diphenylmethyl)piperazino] butyl]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was dissolved in 2 ml of ethanol; 1.8 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 1 hour. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water and ajusted to pH 5 by the addition of 1 N hydrochloric acid. Ethyl acetate was added to cause crystallization; the crystal precipitated was washed with water-acetone (2:1) and dried to yield 386 mg of the title compound.
Reaction SMILES: [C:1]([C:3](=[C:9]([OH:15])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].O(C)[Na].[Na].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C(O)C.C(#N)C>[C:1]([C:3](=[C:9]([O:15][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(O)C(CC)CC
Reactant: CC(C)(C)C(=O)Cl
Agent: CO[Na]
Agent: [Na]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)C(C#N)=C(OC(=O)C(C)(C)C)C(CC)CC
Temperature: 20 °C

Procedure:
36 g (0.17 mol) of ethyl 2-cyano-3-hydroxy-4-ethyl-2-hexenoate were dissolved in ethanol, and 31 g (0.17 mol) of 30% strength NaOCH3 solution were added. The mixture was then concentrated to dryness, and the sodium enolate was released by adding toluene and reconcentration of alcohol residues. 39.7 g (0.17 mol) of the resulting sodium salt were initially charged in acetonitrile and, at 0° C. with warming to 20° C., mixed dropwise with 27.4 g (0.23 mol) of pivaloyl chloride. After 16 g of stirring at 25° C., the reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with 2% strength NaOH. The organic phase was dried and concentrated. Customary purification gave 41.5 g (83% of theory) of the title compound (b.p. 102° C./1 mbar).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[CH:16][CH:17]=[C:7]2[C:6]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]4[CH:15]=[CH:16][CH:17]=[C:7]4[C:6]3=[O:18])[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: O=c1c2cccn2c2ccccc2n1CCCCl
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c2cccn2c2ccccc2n1CCCN1CCC(c2ccc(Cl)cc2)CC1
Temperature: 140 °C
Yield: 68.4 %

Procedure:
5-(3-chloropropyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (100 mg; 0.38 mmol) was added to a 5 mL microwave vessel containing a magnetic stir bar. 4-(4-chlorophenyl)piperidine (82.8 mg; 0.42 mmol), potassium carbonate (78.77 mg; 0.57 mmol), and 2 mL of acetonitrile were added to the vessel. The vessel was sealed and heated to 140° C. for 1 hour, after which the solvent was evaporated and the reaction mixture was purified by flash chromatography to yield 5-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (110 mg; 0.26 mmol; 70%) [M+1]+=420.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[I-].C(N(CC)CC)C.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:22]1([C:28]#[C:29][NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:8][CH:2]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc(NC#Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2-bromo-4-trifluoromethoxyaniline (0.500 g), cupper iodide (I) (18.6 mg), bis(triphenylphosphine)palladium (II) dichloride (68.5 mg), triethylamine (0.817 mL) and tetrahydrofuran (7.8 mL) was added phenylacetylene (0.279 mL) at room temperature under stirring, and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether (30 mL) and then filtered through celite (registered trademark). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (206 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.C(N(CC)CC)C.[NH2:32][CH2:33][CH:34]([OH:37])[CH2:35][OH:36].O>CN(C)C=O>[OH:37][CH:34]([CH2:35][OH:36])[CH2:33][NH:32][C:22]([C:9]1[C:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:14][C:15]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=2[CH:8]=1)=[O:24]
Reactant: NCC(O)CO
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc2c3c(c(C(=O)NCC(O)CO)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To a solution of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid and 0.3 g (0.93 mmol) O(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoro-borate (TBTU) in dimethylformamide (5 ml) were added 240 μl (1.9 mmol) triethylamine and 71 μl (0.93 mmol) 3-amino-propane-1,2-diol and the suspension was stirred overnight at room temperature. The reaction was poured into water, the precipitate filtered off and purified by column chromatography on silica gel (dichloromethane/methanol=8:1) to afford 100 mg (270%) of the title compound as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:20]1([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl.C(Cl)(Cl)[Cl:31].CO>O1CCOCC1.C(O)(=O)C>[NH:1]([Cl:31])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:20]1([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)NCl
Yield: 100 %

Procedure:
Boc-Phe-morpholinamide (12.8 g, 38 mmol) was placed in a 250 ml flask, then 4N HCl in dioxane (30 ml) was added. The mixture was stirred for six hours at which time TLC (silica gel; CHCl3 :MeOH:acetic acid, 90:8:2) indicated that the reaction was completed. Dioxane and excess HCl were removed. A white solid, identified by 1HNMR as HCl-Phe-morpholinamide, was obtained in 100 percent yield (10.3 g, 38 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:23])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(=O)[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.C1C[O:34][CH2:33]C1>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[N:11]([S:8]([C:4]3[CH:3]=[C:2]([NH:1][C:33]([CH:26]([CH3:25])[C:27]([OH:29])=[O:28])=[O:34])[CH:7]=[CH:6][CH:5]=3)(=[O:10])=[O:9])[C:12](=[O:23])[NH:13]2)=[CH:18][CH:17]=1
Reactant: C1CCOC1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Product: CC(C(=O)O)C(=O)Nc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Yield: 96 %

Procedure:
100 mg (0.28 mmol) of Compound 12 was dissolved in 5 ml of THF, 100 mg (1.0 mmol) of succinic anhydride was added, and the resultant mixture was heated and refluxed for 3 hours. The reaction solution was concentrated in vacuo and the crude product thus obtained was crystallized with ethyl acetate-diethyl ether to obtain 120 mg (yield 96%) of the above-identified compound. Properties: colorless crystal, Melting point: 187-188° C., PMR (δ ppm, DMSO-d6): 2.54 (2H, d), 2.59 (2H, d), 7.12 (1H, s), 7.24 (1H, d), 7.59 (1H, t), 7.80 (1H, d), 7.86 (1H, d), 7.96 (1H, d), 8.41 (1H, s), 10.40 (1H, s), 11.63 (1H, br), 12.10 (1H, br).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16](I)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Br:1][C:2]1[S:3][C:4]([C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:31]#[C:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccccc3)c([N+](=O)[O-])c2)sc1Br

Procedure:
A solution of 2 (150 mg, 0.29 mmol), phenylacetylene (32 μL, 0.29 mmol), Pd(PPh3)2Cl2 (21 mg, 0.03 mmol), K2CO3 (42 mg, 0.29 mmol), and Et3N (40 μL, 0.29 mmol) in DMF (3 mL) was stirred for 24 hours at room temperature. Water (5 mL) was added to the mixture and then extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 3 as a solid foam (101 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=1.6 Hz, 1H), 8.06 (dd, J=1.6, 8.0 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.64 (m, 2H), 7.52 (s, 1H), 7.42 (m, 3H), 3.75 (s, 3H), and 3.70 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 183.9, 170.1, 149.5, 142.2, 137.0, 136.3, 135.7, 135.3, 132.9, 132.5, 130.1, 128.8, 125.6, 124.3, 122.8, 122.1, 101.1, 84.7, 52.7, and 35.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH3:14]
Reactant: COCC(C)O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC(C)COC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of 1-methoxy-2-propanol (900 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 30 min. The reaction mixture is diluted with heptane, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 133° C. to give 1.03 g of the product 473. 1H NMR (CDCl3) δ 4.20 (q, 2H), 3.72 (m, 1H), 3.45 (dd, 1H), 3.37 (dd, 1H), 3.35 (s, 3H), 1.27 (t, 3H), 1.19 (d, 3H).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:34]=[CH:33][C:25]4[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=4[CH:23]=3)[CH:15]=2)=[C:9]([CH3:35])[CH:8]=1)[CH3:2].S(O[O-])([O-])(=O)=[O:37].[K+].[K+].[OH2:44]>CO>[CH2:1]([S:3]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:35])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:34]=[CH:33][C:25]4[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=4[CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)(=[O:37])=[O:44])[CH3:2]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCSCCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)O)c2)c(C)c1
Reactant: O
Agent: [K+]
Solvent: CO
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a solution of [(3S)-6-({4′-[2-(ethylthio)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid (0.304 g, 0.617 mmol) in methanol (10 mL) was added dropwise a solution of potassium peroxysulfate (trade name: OXONE, 0.569 g, 0.926 mmol) in water (5 mL) under ice-cooling, and the mixture was stirred for 12 hr, during which the mixture was allowed to gradually warm to room temperature. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC, and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.237 g, yield 73%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[C:24]([O:46][CH3:47])[N:23]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pt]=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([N:30]2[CH2:31][CH2:32][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:34][CH2:35]2)[N:25]=[C:24]([O:46][CH3:47])[N:23]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(OC)c(N2CCC(c3ccc4cccnc4n3)CC2)n1
Agent: O=[Pt]
Solvent: CCO
Product: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(OC)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1
Reaction time: 2 h
Yield: 35.1 %

Procedure:
A mixture of 85 mg (1.32 mmoles) of tert-butyl 2-benzyloxycarbonylamino-3-[2,5-dimethoxy-6-(4-[1,8]naphthyridin-2-yl-piperidin-1-yl)-pyrimidin-4-ylamino]-propionate and 30 mg of platinum oxide in 50 ml of ethanol is stirred for 2 hours under hydrogen at atmospheric pressure. The reaction mixture is filtered on Clarcel then evaporated to dryness under reduced pressure (2 kPa). The residue is chromatographed on silica with a gradient of heptane-ethyl acetate-methanol of 100-O-0 to 0-100-0 then 0-95-5. 300 mg of expected product is obtained in the form of a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:8]=[CH:9][C:10]=1[F:11])(=O)C.S(Cl)(Cl)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C1COCC1.C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:14](=[O:16])/[CH:13]=[CH:12]/[C:7]2[CH:8]=[CH:9][C:10]([F:11])=[C:5]([OH:4])[CH:6]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(=O)Oc1cc(/C=C/C(=O)O)ccc1F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(/C=C/c1ccc(F)c(O)c1)Nc1cccc(Cl)c1
Temperature: 35 °C
Yield: 33.8 %

Procedure:
A solution (E)-3-(3-acetoxy-4-fluoro-phenyl)-acrylic acid (0.17 g, 0.76 mmol) and thionyl chloride (0.069 mL, 0.95 mmol) in dry THF (2 mL) was stirred at 55° C. for 3 hrs. Then a further aliquot of thionyl chloride (0.008 mL, 0.11 mmol) was added and the mixture was stirred at reflux temperature for additional 1.5 hrs. After cooling to about 35° C., a solution of 3-chloro-aniline (0.204 mL, 1.90 mmol) dry THF (0.5 mL) was added dropwise. After stirring at RT for 16 hrs, the reaction mixture was diluted with DCM and washed with water, aqueous hydrochloric acid, and brine. The organic layer was then dried over sodium sulphate and evaporated. The resulting raw material was taken up without further purification with THF (2 mL), and a 3N methanolic solution of hydrochloric acid (4 mL-12 mmols) was added to the so obtained solution. The resulting mixture was stirred at RT for 16 hrs, concentrated under reduced pressure, taken up with solvent an re-evaporated (3 times with MeOH and once with acetone) to give a light yellow residue that was sequentially triturated with toluene, ethyl ether and dichloromethane. After the last filtration and drying, 75 mg of the title (E)-N-(3-chloro-phenyl)-3-(4-fluoro-3-hydroxy-phenyl)-acrylamide were obtained, as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:24](=O)[CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[C:3]([C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH3:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC=O
Reactant: Cc1cccc(N2CCNCC2)c1C1=CC(C)(C)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN1CCN(c2cccc(C)c2C2=CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of 1-[3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (115 mg, 0.368 mmol) produced in Example (71c), propionaldehyde (0.079 mL, 1.1 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (246 mg, 1.1 mmol), followed by stirring for 1 hour and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 124 mg of 1-[3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazine as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[C:73]([O:74][CH3:75])=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[C:66]([F:76])[CH:65]=1>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[C:73]([O:74][CH3:75])[C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][C:66]=1[F:76]
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(OC)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1F
Yield: 23.9 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (150 mg, 0.259 mmol), was reacted with diisopropylethylamine (171 mg, 1.32 mmol), diphenylphosphinic chloride (155 mg, 0.656 mmol), then reacted with methyl 4-amino-2-fluoro-5-methoxybenzoate (Aldrich, 55 mg, 0.274 mmol,) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-2-fluoro-5-methoxy-benzoic acid methyl ester (40 mg, 24%). MS (ES+) m/z [(M+H)+]: 646
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[SH:12][C:13]1[NH:14][C:15]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1>>[N:11]1[CH:10]=[CH:9][N:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][S:12][C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:15]=4[N:14]=3)[C:4]=12
Reactant: Cc1cccc2nc(S)[nH]c12
Reactant: OCc1cccn2ccnc12
Product: Cc1cccc2[nH]c(SCc3cccn4ccnc34)nc12

Procedure:
A solution of 20 g (0.13 mole) of 2-methyl-6-nitroaniline in 22.9 ml of concentrated aqueous hydrochloric acid, 200 ml of tetrahydrofuran, and 350 ml of methanol was hydrogenated at room temperature using 25 p.s.i. of hydrogen gas over 2.0 g of 5% palladium on carbon. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 150 ml of ethanol and neutralized with 17.2 g (0.26 mole) of potassium hydroxide dissolved in 30 ml of water. Potassium ethylxanthate (23 g, 0.155 mole) was added and the mixture was heated at reflux for 18 hours. Upon cooling, a solid was collected, washed with water, and air dried to yield 6.2 g of 2-mercapto-4-methylbenzimidazole, as confirmed by the nmr and infrared spectra. The title compound (987 mg) was prepared by the method of Example 6 using 8-hydroxymethylimidazo[1,2-a]pyridine as the hydrochloride salt (700 mg, 3.8 mmole) and using 655 mg (4.0 mmole) of 2-mercapto-4-methylbenzimidazole instead of 2-mercapto-5-methoxybenzimidazole. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:37](=[O:39])[CH3:38])[CH2:12]1)[CH2:10][C:9]2=[O:26]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(C)=O)C1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A suspension of Intermediate 4 (280 mg, 0.90 mmol) in DCM (7.5 ml) was treated with DIPEA (0.32 ml, 1.8 mmol) and acetyl chloride (0.09 ml, 1.35 mmol). The reaction mixture was stirred at RT for 1 h and the solution was then evaporated under vacuum to give (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester as a light brown solid (280 mg).