Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)=O.CO>O1CCCC1>[CH3:1][NH:3][CH:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=CNC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Solvent: C1CCOC1
Solvent: CO
Product: CNC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 8.9 %

Procedure:
To a suspension of 7 g of 10-formamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 225 ml of anhydrous tetrahydrofuran maintained at 0° C. are added, dropwise over 10 minutes, 62.5 ml of a 2M solution of borane/methyl sulphide complex in tetrahydrofuran. The mixture is stirred for 10 minutes at the same temperature and then for 18 hours at a temperature in the region of 20° C. After addition of 100 ml of methanol and stirring for 1 hour, the insoluble material is separated out by filtration and washed with 25 ml of methanol. The filtrate and the washings are combined and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 35° C. The product obtained (3.9 g) is chromatographed on 390 g of neutral silica gel (0.020-0.045 mm) contained in a column of diameter 5.3 cm, eluting with a chloroform/methanol/28% aqueous ammonia mixture (82/15/3 by volume) and collecting 35 ml fractions. Fractions 25 to 31 are combined and concentrated to dryness under reduced pressure (1 mmHg; 0.13 kPa) at 90° C. 0.59 g of 10-methylamino-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one is thus obtained, melting at 184° C. [N.M.R. spectrum: [200 MHz; (CD3) 2SO d6 ; δ in ppm): 1.85 (s, 3H: --CH3); 5.13 (8, 1H: --CH-- 10); 7.36 and 7.43 (2t broad, J=8 Hz, 1H each: --H7 and --H8); 7.61 and 8.17 (2s broad, 1H each: --H of the imidazole); 7.62 and 7.85 (2d broad, J=8 Hz, 1H each: --H6 and --H9); 12.35 (broad s, 1H: --CONH-- of the ring)].
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CCO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33](=[O:1])[NH2:34])[CH:28]=2)[C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(C#N)c2)c2ccc3[nH]ccc3c2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(C(N)=O)c2)c2ccc3[nH]ccc3c2)CC1

Procedure:
A solution of NaOH (54 mg, 1.35 mmol) in water (0.2 mL) was added to a solution of 4-[(3-cyano-benzyl)-(1H-indol-5-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (115 mg, 0.27 mmol) (prepared as described in Example 2 Step 1) in EtOH (10 mL). The reaction mixture was heated at reflux for 16 hours, the solvent was evaporated and the residue was purified by flash chromatography (0% to 25% of MeOH in DCM) to give 4-[(3-carbamoyl-benzyl)-(1H-indol-5-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester. This material was dissolved in DCM (5 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred for 16 hours, it was then evaporated under reduced pressure and the residue was basified by addition of an aqueous solution of NH4OH. The crude material was purified first by flash chromatography and then by preparative HPLC (Agilent Technologies Zorbax SB-Phenyl column (21.2 mm inner diameter by 100 mm length, 7 micron particle size), water (0.1% TFA added)/acetonitrile 75/25 gradient to 5/95 over 10 minutes at 20 ml/min flow rate) to give the desired 3-{[(1H-indol-5-yl)-piperidin-4-yl-amino]-methyl}-benzamide trifluoroacetate, MS=349 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C([O:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][N:29]=1)(C)(C)C.[OH-].[K+]>CCO>[C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([C:1](=[O:3])/[CH:2]=[CH:34]/[C:31]3[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:25]([OH:36])=[O:24])=[N:29][CH:30]=3)=[CH:5][CH:6]=2)[CH2:10][CH2:11]1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1ccc(CN2CCN(C(C)=O)CC2)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCN(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-[4-(4-acetyl-benzyl)piperazin-1-yl]-ethanone (prepared following the procedure described in Preparation 12, 500 mg, 1.92 mmol), (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 448 mg, 1.92 mmol) and 1.7 M KOH (1.2 ml) in EtOH (19 ml) was stirred at room temperature for 6 h and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.1) and the resulting product was dissolved in DCM (1.5 ml) and TFA (0.560 ml). The solution was stirred at room temperature for 3 h and then the solvent was evaporated to give 300 mg (E)-3-(5-{(E)-3-[4-(4-acetyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its bis-trifluoroacetate salt (the compound was used without further purification in the next step).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[O:2].I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:11]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCOc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
4-formyl-phenol (5 g, 41 mmol), iodohexane (10.5 g, 49 mmol) and K2CO3 (8.5 g, 61 mmol) in acetonitrile (150 ml) were refluxed overnight under N2. After being cooled to room temperature, water (10 ml) was added and acetonitrile was evaporated. Water (150 ml) and Et2O (150 ml) were then added. The ethereal layer was extracted and washed with water (2×100 ml), brine (100 ml), dried over MgSO4, filtered and evaporated to dryness to afford 8.3 g (98%) of compound 1 as a slightly yellow oil after during at 80° C. under vacuum.
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]=O)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.[NH2:16][NH:17][C:18]([NH2:20])=[O:19].C(N(CC)CC)C>CO>[CH:1]([C:4]1[C:12](/[CH:13]=[N:16]/[NH:17][C:18]([NH2:20])=[O:19])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nn2ccccc2c1C=O
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)c1nn2ccccc2c1/C=N/NC(N)=O
Yield: 70.6 %

Procedure:
A mixture of 2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g, 1 equivalent), semicarbazide hydrochloride (0.35 g, 1.2 equivalents), and triethylamine (0.4 mL, 1.1 equivalent) in 5 mL of methanol was reflux for 30 minutes. The solution was concentrated and the crude solids produced were extracted with THF, and the mixture was filtered through a 1 inch thick layer of sodium sulfate on top of a thin pad of silica gel to remove the ammonium salt. The filtrate was concentrated and the solid deposited was recrystallized from THF and hexanes to give (E)-2-((2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methylene)hydrazinecarboxamide (0.46 g, 70% yield) as a yellow solid. Compound 1074.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:14][C:15]1[N:24]=[C:23](Cl)[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1.O>O1CCOCC1>[Cl:14][C:15]1[N:24]=[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1nc(Cl)nc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl malonate (0.76 mL) was dissolved in dioxane (25 mL), sodium hydride (200 mg) was added, and the mixture was stirred at room temperature for 30 min. Then, 2,4-dichloro-6,7-dimethoxyquinazoline (1.3 g) was added, and the mixture was heated under reflux for 3.5 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound (840 mg) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH3:10][C:11]1(C)[O:18]C(=O)[CH2:15][C:13](=O)[O:12]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:9]=[C:7]([CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:10][C:11]([O:12][CH2:13][CH3:15])=[O:18]
Reactant: O=C(O)Cc1ccsc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Cc1ccsc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
A stirred solution of 711 mg (5.0 mmol) of 3-thienylacetic acid, 720 mg (5.0 mmol) of Meldrum's acid, and 610 mg (5.0 mmol) of 4-dimethylaminopyridine in 10 mL of DCM was treated with a solution of 1.03 g (5.0 mmol) of DCC in 10 mL of DCM. The resulting solution was stirred at room temperature for 16 h, during which time a white precipitate appeared in the reaction mixture. The reaction mixture was filtered through a pad of Celite to remove the precipitated dicyclohexylurea and the filtrate was washed successively with 1 N HCl (1×15 mL), H2O (1×15 mL), brine (1×15 mL). The filtrate was dried (MgSO4) and solvents were removed in vacuo. The resulting crude oil was dissolved in 8 mL of absolute ethanol and heated to 80° C. for 4 h. The reaction mixture was cooled to room temperature and ethanol was removed in vacuo. Purification of the resulting oil by silica gel flash column chromatography eluting with hexanes/EtOAc 2:1 afforded 1.02 g (97%) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.27 (m, 1H), 7.06 (s, 1H), 6.92 (m, 1H), 4.09 (q, 2H, J=6.8), 3.83 (s, 2H), 3.41 (s, 2H), 1.22 (t, 3H, J=6.8).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])([OH:3])=O.FC(F)(F)C(O)=O.[N+:27]([C:30]1[CH:46]=[CH:45][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:44][CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(#N)C.C(N(CC)C(C)C)(C)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][S:9][C@@H:7]2[CH2:6][N:5]([CH3:19])[C@H:4]([C:1]([N:41]3[CH2:42][CH2:43][CH2:44][N:38]([C:36]([O:35][CH2:34][C:33]4[CH:45]=[CH:46][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)=[O:37])[CH2:39][CH2:40]3)=[O:3])[CH2:8]2)=[CH:12][CH:13]=1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C)C2)cc1
Temperature: 35 °C
Reaction time: 0.42 h
Yield: 72 %

Procedure:
A suspension of 1.8 g of (2S,4S)-2-carboxy-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (ii) above] and 1.26 g of N,N'-carbonyldiimidazole in 18 ml of dry acetonitrile was stirred at 35° C. for 25 minutes. A solution of 3.7 g of 1-(4-nitrobenzyloxycarbonyl)homopiperazine trifluoroacetate in 20 ml of dry acetonitrile and 2.0 ml of N,N-diisopropylethylamine were then simultaneously added dropwise, whilst ice-cooling, to the reaction mixture, and the resulting mixture was stirred at room temperature for 8 hours, after which it was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogencarbonate, with a phosphate buffer solution (pH 6.86), with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel (Merck Art 9385), using a 95:5 by volume mixture of acetonitrile and water, to give 2.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](C(O)=O)[CH2:7][CH2:6]2.C(N(CC)CC)C.[Br:39]N1C(=O)CCC1=O>ClCCl>[Br:39][C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC(C(=O)O)=C2Oc1ccc(OCCN2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(Br)=C2Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a flask, add 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)-3,4-dihydronaphthalene-2-carboxylic acid (0.4 g, 0.68 mmol), dichloromethane (10 mL), and triethylamine (0.2 mL, 1.43 mmol). Stir the mixture at 25° C. for 10 min. Add N-Bromosuccinimide (0.5 g; 4.13 equiv; 2.81 mmol) in portions. Cool the reaction mixture to room temperature and quench with ice-water. Extract the mixture with ethyl acetate three times and discard the aqueous phase. Dry the combined organic layers over MgSO4, filter, and concentrate to dryness to give 1-(2-(4-(2-Bromo-6-methoxy-3,4-dihydronaphthalen-1-yloxy)phenoxy)ethyl)piperidine as a yellow oil (300 mg).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26]3[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=3)=[N:18][N:17]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.Cl.C(OCC)C>ClCCl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26]3[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=3)=[N:18][N:17]=2)[CH2:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CNC1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Dissolve tert-butyl methyl(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)carbamate (7.77 g, 18.39 mmol) in dichloromethane (100 mL). Add an excess of 1 M hydrogen chloride in diethyl ether (20 mL, 80 mmol) to the solution and stir at ambient temperature for 2 h. Concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (dichloromethane:2 M NH3 in MeOH=10:1) to provide the title compound as a yellow foam (5.83 g, 98%). ES/MS m/z 323.2 (M+1).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5](=[O:18])/[C:6](/[C:16]#[N:17])=[C:7](\[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)/[CH3:8]>C(OCC)C.[Cu]I>[CH3:3][O:4][C:5](=[O:18])[CH:6]([C:16]#[N:17])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)([CH3:1])[CH3:8]
Reactant: COC(=O)/C(C#N)=C(/C)c1cccc(Br)c1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C(C#N)C(C)(C)c1cccc(Br)c1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
To a chilled (0° C.) suspension of Soxhlet-extraction-purified CuI (14.28 g, 0.075 mol, 1.5 equiv.) in 150 mL of anhydrous diethyl ether, was added a 1.6M solution of methyl lithium (84.4 mL, 0.135 mol, 2.7 equiv.) in diethyl ether. The mixture was stirred for 10 minutes, cooled to −25° C. and a solution of (Z)-3-(3-bromophenyl)-2-cyanobut-2-enoic acid methyl ester (14.13 g, 0.05 mol) in 150 mL of anhydrous diethyl ether was added dropwise. The mixture was stirred at −25° C. for 30 minutes, warmed to room temperature, and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organics were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to afford a brown oil. The oil was purified via flash chromatography using a hexanes-ethyl acetate gradient to afford 3-(3-bromophenyl)-2-cyano-3-methylbutyric acid methyl ester. Yield: 8.88 g (60%).
Reaction SMILES: C(OC([C:7]1[N:8]=[CH:9][C:10]2[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:13]=3)=O)(C)C.[C:44]1([Li])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[O:51]1CCC[CH2:52]1>CCOCC.CCCCCC>[CH2:52]([O:51][C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:26])[CH3:27])=[CH:14][CH:13]=3)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C1CCOC1
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: [Li]c1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: COCc1c(OCc2ccccc2)ncc2[nH]c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3c12
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of 230 mg of 4-methoxymethyl-9-tosyl-6-triisopropylsilyloxy-beta-carboline-3-carboxylic acid isopropyl ester in 3.5 ml of absolute tetrahydrofuran was mixed at -60° C. under argon with 0.38 ml of a 1.08 molar phenyllithium solution in ether/hexane, stirred for 1 hour at -60° C. and heated slowly to room temperature. After 16 hours of standing at room temperature, the reaction mixture was mixed with N-acetic acid/ethyl acetate, the ethyl acetate phase was washed with water and saturated sodium chloride solution, dried and concentrated by evaporation. After column chromatography on silica gel with cyclohexane/ethyl acetate 1:1 as eluant, 69 mg of title compound was obtained.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].Cl>C(O)(C)C>[C:1]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)OC(=O)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)O
Product: CC(C)OC(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 94.4 %

Procedure:
In 10 ml of isopropanol was dissolved 1.0 g of isopropyl (3S)-3-(N-Boc)amino-4-phenyl-2-oxobutyrate, followed by addition of 0.7 g of aluminium isopropoxide, and heating under reflux for 4 hours. After the termination of the reaction was confirmed, an aqueous 1N hydrochloric acid solution was added to the resulting mixture, to adjust the mixture to pH 3.0, and the resulting mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate and water, followed by layer separation, and the resulting aqueous layer was extracted in ethyl acetate. The extract solution was washed in water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, followed by filtration and concentration, to obtain 0.95 g of isopropyl (2S, 3S)-3-(N-Boc)amino-4-phenyl-2-hydroxybutyrate in a yield of 94.5%. The results of the HPLC analysis thereof are shown below. HPLC analysis conditions
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13]CC)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>C(OCC)(=O)C>[CH2:16]([O:23][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:9][CH2:10]2)=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(Cl)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C1(c2ccc(OCc3ccccc3)nc2)CC1

Procedure:
A mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (45.1 mg, 0.000200 mol), benzyl alcohol (0.50 mL, 0.0048 mol) and sodium hydride (9.50 mg, 0.000238 mol) was irradiated by microwave at 150° C. for 15 minutes. After cooling, additional sodium hydride (9.5 mg) was added to the mixture. The mixture then was irradiated by microwave at 150° C. for 15 minutes. Ethyl acetate (5 mL) was added and the resulting mixture was washed with water and brine successively. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combiflash with ethyl acetate/hexane to give the desired product.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17](=[O:18])[C:16]4([CH2:23][CH2:22][N:21](C(O)=O)[CH2:20][CH2:19]4)[N:15]([CH3:27])[C:14]3=[O:28])[N:9]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:7]=2[N:8]=1)#[N:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:29][N:9]1[C:7]2[N:8]=[C:3]([C:1]#[N:2])[N:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2([CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[N:15]([CH3:27])[C:14]1=[O:28]
Reactant: CN1C(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)C12CCN(C(=O)O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)C12CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.62 g (0.015 moles) of 3-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid .tert.-butyl ester in 30 ml of CH2Cl2, 30 ml (389 mmoles) of TFA is added at 0° C. After bing stirred for 1 hour at ambient temperature, sat. NaHCO3 is added at 0° C. to the reaction mixture and the mixture is extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give desired 7-(2,2-dimethyl-propyl)-6-(1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in quantitative yield. The crude product is used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:16][O:15][CH2:14]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:14][O:15][CH2:16]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2COC2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(=O)O)ccc1OC1COC1
Reaction time: 1 h

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (498 mg, 3 mmol) was added DMF (3 mL) and sodium hydride (240 mg, 6.0 mmol) followed by oxetan-3-ol (445 mg, 6 mmol) and the reaction mixture was heated at 80° C. for 4 hours. The reaction was cooled and quenched with brine solution and extracted with EtOAc (3×10 mL). The organic layer was separated and dried over sodium sulfate and evaporated to give methyl 3-methyl-4-(oxetan-3-yloxy)benzoate. To methyl 3-methyl-4-(oxetan-3-yloxy)benzoate was added sodium hydroxide (3 mL of 1 M NaOH, 3 mmol) solution and the reaction mixture was stirred for 1 hour. The reaction was acidified with 1 M HCl solution to pH 3 and extracted with EtOAc. The organics were separated and dried and concentrated in vacuo to give 3-methyl-4-(oxetan-3-yloxy)benzoic acid. ESI-MS m/z calc. 208.1. found 209.3 (M+1)+; Retention time: 1.04 minutes (3 min run).