Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1.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>[CH3:18][O:17][CH:14]1[CH2:15][CH2:16][C:7]2([CH2:6][C:5]3[C:9](=[CH:10][C:2]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH2:12][CH2:13]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Cc1ccc(-c3cccc(C#N)c3)cc1C2=O
Temperature: 100 °C
Reaction time: 0.1 h
Yield: 46.4 %

Procedure:
To a solution of 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (40 mg, 0.130 mmol) and 3-cyanophenylboronic acid (30.5 mg, 0.208 mmol) in Cs2CO3 (2 M, 0.247 mL) and 1,4-dioxane (1.2 mL) under N2 was added Pd(PPh3)2Cl2 (7.5 mg). The mixture was stirred at 100° C. for 6 minutes. After cooled to room temperature, the organic layer was dried and concentrated to give the residue, which was purified by TLC to give 3-(4-methoxy-1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-6′-yl)benzonitrile (20 mg, 46%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N+:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>C1COCC1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.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>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([N+:28]([O-:30])=[O:29])[CH:36]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4cccc([N+](=O)[O-])c4)n3)cnc2n1
Temperature: 25 °C

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (prepared according to Example 34) (250 mg, 0.62 mmol), 3-nitrobenzeneboronic acid (207 mg, 1.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (71 mg, 10 mol %) in THF (3 ml) and 2N Na2CO3 solution (1.24 ml, 2.48 mnmol) was heated at reflux for 2.5 h. The mixture was cooled to room temperature, diluted with CH2Cl2 (30 ml), separated and concentrated to approximately 2 ml under reduced pressure. Purification by column chromatography on silica using 3% MeOH/CH2Cl2 afforded 7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(3-nitrophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine: m/z (ES+) 491 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)=[O:6].CNCCCCCC.Cl.O>CS(C)=O>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:4]([C:5]([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[O:6])=[C:3]([OH:2])[CH:21]=1
Reactant: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2OC)n1
Agent: CCCCCCNC
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2O)n1
Temperature: 0 °C
Yield: 72.8 %

Procedure:
A suspension (6 ml) of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole (3.0 g) in dimethyl sulfoxide was dissolved with heat, and N-methyl-N-hexylamine (2.3 g) was added dropwise to the solution, refluxed for 2 hours. The reaction mixture was allowed to cool, poured into a mixture of 1 N hydrochloric acid (30 ml) and ice water (30 ml), and further, water was added thereto. Crystals so precipitated were collected by filtration, washed with water, and air-dried to thereby obtain crude crystals. The crystals were followed by recrystallization from 1,4-dioxane, 2.1 g of 2-[N-(4,5-dimethoxy-2-hydroxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole was obtained (yield: 64.6%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH3:32])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][C:13]1=[O:23]>N1C=CC=CC=1>[C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:23])[C:12]2([NH:11][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH3:32])#[N:22]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1ccccc1C1(N)C(=O)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(NC(=O)Oc2ccccc2)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 111 %

Procedure:
1.2 ml (9.38 mMol) of phenyl chloroformate were added dropwise to 2.5 g (8.5 mMol) of product 2a dissolved in 50 ml of pyridine at 0° C. The reaction solution was then stirred at room temperature for 16 h. The solution was subsequently poured into ice-water, and the aqueous phase was extracted with ethyl acetate (AcOEt). The organic phase was washed several times with water, dried and concentrated in vacuo. 3.9 g of the product were obtained.
Reaction SMILES: C([C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)(=O)C.O=C(Cl)OC(Cl)(Cl)Cl.O.[O:23]1CCO[CH2:25][CH2:24]1>>[OH:13][C:7]1[CH:6]=[C:5]([C:24](=[O:23])[CH3:25])[CH:4]=[CH:12][C:8]=1[C:9]#[N:11]
Reactant: CC(=O)c1ccc(O)c(C(N)=O)c1
Reactant: C1COCCO1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)c1ccc(C#N)c(O)c1
Reaction time: 18 h

Procedure:
5-acetylsalicylamide (10.04 g, 56 mmol) and diphosgene (18.4 g, 93 mmol) were heated in dioxane (65 ml) to70° C. under nitrogen for 18 hours. The mixture was cooled, cautiously poured into cold water (700 ml) and stirred for 1 hour to destroy excess diphosgene reagent. The mixture was extracted with ethyl acetate, and the organic solution washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was recrystallized from toluene/acetonitrile to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:12]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([O:8][C:12]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
Into a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of phenylmethanol (10.7 g, 98.95 mmol, 1.05 equiv) in N,N-dimethylformamide (100 mL). This was followed by the addition of sodium hydride (3.9 g, 162.50 mmol, 1.20 equiv, 70%) in several batches at 0° C. The mixture was stirred for 25 min at 0° C. To this was added a solution of methyl 2-fluoro-3-nitrobenzoate (18.8 g, 94.41 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The mixture was diluted with 700 mL of ethyl acetate. The resulting mixture was washed with 3×800 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40). This resulted in 20 g (74%) of methyl 2-(benzyloxy)-3-nitrobenzoate as yellow oil. MS (ESI) m/z 288 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>C1(C)C=CC=CC=1.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]2)=[CH:9][CH:8]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 101 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
4-(3-Fluoro-benzyloxy)-phenylamine (31.2 g, 144 mmol) was dissolved in toluene (208 mL) and acetic acid (52 mL). Itaconic acid (18.96 g, 144 mmol) was added to the stirred mixture. The mixture was heated to reflux (101° C.) and kept at this temperature for 3 h. On cooling, the product started to crystallize. At 10° C., heptane (125 mL) was added to the suspension which was stirred 1 h at 0° C. and filtered. The crystals were washed with toluene/heptane 1:1 and with heptane and dried in vacuo to afford the crude product (43.2 g). The crude product was purified by treatment with hot isopropyl acetate to give rac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (40.5 g, 86%; HPLC: 99.2% area), m.p. 148-149° C. (uncorr.).
Reaction SMILES: C([O-])(O)=O.[Na+].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][C:12](Cl)=[O:13].[C:15]1([S:21][CH2:22][CH2:23][S:24][C:25]2[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCC>O1CCOCC1>[C:15]1([S:21][CH2:22][CH2:23][S:24][C:25]2[C:30]([NH:31][C:12](=[O:13])[CH2:11][C:7]3[S:6][CH:10]=[CH:9][CH:8]=3)=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cccnc1SCCSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=C(Cc1cccs1)Nc1cccnc1SCCSc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
420 mg (5.0 mmol) NaHCO3 and 402 mg (2.5 mmol) 2-(thiophen-2-yl)acetic acid chloride were added to a solution of 262 mg (1.0 mmol) [2-(2-phenylsulfanyl-ethylsulfanyl)-pyridin-3-yl]amine (VPF-006) in dioxane (25 ml) at 0° C. and then the mixture was stirred for 16 h at RT. Then it was diluted with EE and washed with water and brine. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 9:1) of the residue yielded 186 mg (0.5 mmol, 48%) N-[2-(2-phenylsulfanyl-ethylsulfanyl)-pyridin-3-yl]-2-thiophen-2-yl acetamide. MS: m/z 387.1 [M+H]+.
Reaction SMILES: [C:1]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:24])=O>CCCCC>[C:1]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([Cl:24])=[O:21])[CH2:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Solvent: CCCCC
Product: O=C(NC[C@H]1CC[C@H](C(=O)Cl)CC1)OCc1ccccc1
Temperature: 40 °C

Procedure:
A mixture of trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carboxylic acid (5.02 g, 17.3 mmol), prepared as in step 1, and thionyl chloride was heated at 40° C. for 30 minutes. The reaction mixture was cooled to ambient temperature and diluted with pentane (50 mL). Trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carbonyl chloride (4.37 g) was isolated by filtration and drying in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.OO.C(=O)(O)[O-].[Na+]>C(O)=O.O>[CH2:15]1[N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18][N:13]2[C:3]3[CH:4]=[CH:5][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:7][C:2]=3[N:1]=[C:14]12
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)OCC)CC2)c(N)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc1n2CCN(C(=O)OCC)C1
Temperature: 50 °C
Yield: 11.1 %

Procedure:
Formic acid (0.29 g, 6.22 mmol) and purified water (5 ml) were added to ethyl 4-(2-amino-4-ethoxycarbonylphenyl)piperazine-1-carboxylate (2.0 g, 6.22 mmol) prepared in the Step 38-1-2. A 30% hydrogen peroxide solution (0.63 g, 18.67 mmol) was further added thereto, and the mixture was heated and stirred at 50° C. Formic acid (2 ml) and 2 ml of a 30% hydrogen peroxide solution were further added to the mixture. The resulting mixture was stirred for another one hour, then allowed to cool, and stirred. After being cooled to a room temperature, the mixture was neutralized with a saturated sodium bicarbonate solution and subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 to 1:2) to give the title compound (0.22 g, 11%) as a white powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[CH:21](C1OC(C)=CC(=O)C=1OCC1C=CC=CC=1)[CH2:22]C>>[CH3:1][O:2][CH:3]([C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:21][CH3:22]
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Reactant: CCC(O)c1oc(C)cc(=O)c1OCc1ccccc1
Product: CCC(OC)c1oc(C)cc(=O)c1OCc1ccccc1
Yield: 90.3 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1 H)-one using 2-(1-hydroxypropyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one (5.48 g, 20 mmol, 1 eq.) yielded the title compound (5.2 g, 90.3%) as an orange oil which solidified on cooling. Recrystallisation from CH2Cl2/Pet. ether 40/60 afforded the pure product as a white crystalline solid. m.p. 63-65 ° C.
Reaction SMILES: Br[C:2]1[C:15]2[NH:14][C:13]3[CH2:12][CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][C:8]=3[C:7](=[O:18])[C:6]=2[C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.C(OCC)(=O)C>[Pd].CO>[CH3:16][C:10]1([CH3:17])[CH2:9][C:8]2[C:7](=[O:18])[C:6]3[C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=[CH:2][C:15]=3[NH:14][C:13]=2[CH2:12][CH2:11]1
Reactant: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CC(C)(C)CC3
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CC(C)(C)CC3
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.1 %

Procedure:
A mixture of methyl 4-bromo-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydro-acridine-1-carboxylate (4.0 g, 11 mmol), ethyl acetate (300 mL), Pd/C (5% Pd on carbon, 50% water, 4.0 g) was stirred at room temperature under an atmosphere of hydrogen for 6 hours. Methanol (100 mL) and Pd/C (5% Pd on carbon, 50% water, 8.0 g) was added to the mixture and stirred for another 1 hour. The mixture was filtered through celite and the filtrate was concentrated to give the desired product (3.3 g, crude) which was used to next step without further purification. 1H NMR (DMSO-d6) δ 11.70-11.72 (m, 1H), 7.60-7.63 (m, 2H), 7.13-7.14 (m, 1H), 3.79 (s, 3H), 2.76-2.77 (m, 2H), 2.23 (s, 2H), 1.55-1.57 (m, 2H), and 0.97 (s, 6H). MS (ESI) m/e [M+1]+286.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35])[CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=2)[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1cccc(F)c1)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(F)c1
Yield: 97 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.25 g, 0.69 mmol) prepared in example 4b was reacted with 1-(3-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 11a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.35 g, 97%).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH:21]=1>>[N:20]1([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Product: O=c1[nH]c2cc([N+](=O)[O-])c(-n3cnc4ccccc43)cc2n2c(=O)[nH]nc12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and benzimidazole by a method analogous to the method described in example 11. M.p.>300° C. decomp.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][N:31]([CH:38]1[CH2:41][O:40][CH2:39]1)[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:30])[CH:38]5[CH2:39][O:40][CH2:41]5)[CH2:33][CH2:34]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CN(C1CCNCC1)C1COC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N(C)C4COC4)CC3)n(C)c2n1
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (179 mg, 0.46 mmol), methyloxetan-3-ylpiperidin-4-ylamine (94 mg, 0.55 mmol) and 4 Å powdered molecular sieves (400 mg) in DCE (10 mL) was stirred at room temperature for 5 h before the addition of sodium triacetoxyborohydride (233 mg, 0.92 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%) affording 418 as a cream solid (93 mg, 37%). LCMS (Method I): RT 2.31 min [M+H]+546.4. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.78-7.72 (m, 1 H); 7.29-7.22 (m, 2 H); 4.67 (t, J=6.5 Hz, 2 H); 4.60 (t, J=6.6 Hz, 2 H); 4.34 (m, 4 H); 3.98-3.88 (m, 1 H); 3.89-3.82 (m, 7 H); 3.72 (s, 2 H); 3.35 (q, J=7.5 Hz, 2 H); 2.94 (d, J=11.2 Hz, 2 H); 2.35-2.24 (m, 1 H); 2.21 (s, 3 H); 2.13 (t, J=11.2 Hz, 2 H); 1.64 (d, J=12.2 Hz, 2 H); 1.54 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH2:39][C:40]#[N:41])[CH:36]=[CH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:34]=[C:35]([CH2:39][C:40]#[N:41])[CH:36]=[CH:37][CH:38]=3)=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: CC1(C)OB(c2cccc(CC#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1cccc(CC#N)c1)nn2C1CCCC1
Yield: 87.2 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (160 mg) obtained in Step C of Example 12, (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (160 mg), tetrakis(triphenylphosphine)palladium(0) (50.6 mg) and 2M aqueous sodium carbonate solution (1.10 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (127 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](C(O)=O)=[C:6]2[CH3:19].Cl>N1C2C(=CC=CC=2)C=CC=1.CCOC(C)=O.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[NH:8][CH:7]=[C:6]2[CH3:19]
Reactant: COc1cc2c(C)c(C(=O)O)[nH]c2cc1C(F)(F)F
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: COc1cc2c(C)c[nH]c2cc1C(F)(F)F
Yield: 53 %

Procedure:
To a solution of 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid (2.0 g, 7 mmol) in 5 ml quinoline was added copper powder (50 mg), and the reaction mixture was heated to reflux for 1.5 hours. Copper powder (50 mg) was added, and the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled, diluted with EtOAc, poured into 50 ml 6 N HCl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed (10% EtOAc/Hexanes) to give 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole (850 mg, 51% ) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:16](=O)[CH2:17][CH3:18])[CH:6]([C:12](=O)[CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[BrH:21].[NH:22]([C:24]1[NH:25][CH2:26][CH2:27][N:28]=1)[NH2:23].C(O)(C)C.C(OCC)C>C(OCC)C>[BrH:21].[C:4]([C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH2:13][CH3:14])[N:23]([NH:22][C:24]2[NH:28][CH2:27][CH2:26][N:25]=2)[C:16]=1[CH2:17][CH3:18])([O:3][CH2:1][CH3:2])=[O:20]
Reactant: NNC1=NCCN1
Reactant: CCOC(=O)C(C(=O)CC)C(C(=O)CC)C(=O)OCC
Agent: Br
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)c1c(C(=O)OCC)c(CC)n(NC2=NCCN2)c1CC

Procedure:
The compound is obtained following substantially the method described in Example 3, by reacting 13 g. (0.0455 mole) of diethyl-2,3-dipropionyl-succinate with 8.14 g. (0.0449 mole) of 2-hydrazino-4,5-dihydro-1H-imidazole hydrobromide. Yield 55 g. M.p. 181°-2°C (from isopropanol/diethyl ether). The free base melts at 155°C (from diethyl ether).