Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(O[C:10]([CH3:12])=[CH2:11])(C)=C.C(O)(=O)C(O)=[O:15]>C(Cl)Cl>[C:1]([O:5][C:12](=[O:15])[CH:10]=[CH2:11])(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(O)C(=O)O
Reactant: C=C(C)OC(=C)C
Reactant: C=CC(=O)O
Solvent: ClCCl
Product: C=CC(=O)OC(=O)C=C
Reaction time: 24.5 h

Procedure:
Acrylic acid (1.47 g, 0.02 mole), diisopropenyl ether (0.99 g, 0.01 mole) and oxalic acid (0.008 g, 8.9×10-5 moles) were mixed in a nitrogen-filled 10-ml volumetric flask. A 30-μl aliquot of this mixture was transferred to a nuclear magnetic resonance tube, mixed with CDCl3 (0.5 ml), methylene chloride (10 μ) and tetramethylsilane. After 24.5 hours, the sample in the nuclear magnetic resonance tube showed that the reaction was almost complete as the acid was nearly consumed. The amount of acrylic anhydride produced was 1.5:1 to that of the 2,2-propane diacrylate. Conversely the mixture in the original volumetric flask had a much lower conversion of reactants to products and almost no anhydride. After 14 days, the amount of acrylic anhydride in the nuclear magnetic resonance tube increased while that in the volumetric flask did not. The ratio of acrylic anhydride to 2,2-propane diacrylate was 3.3:1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7]=1[C:18]([F:21])([F:20])[F:19])=[O:5])C.[OH-].[K+].Cl>C1COCC1.CO.O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:18]([F:20])([F:21])[F:19])[N:8]2[CH3:17])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)n(C)c2cc(OC)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)O)c(C(F)(F)F)n(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of 6-methoxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid ethyl ester 76e (1.5 g, 4.98 mmole) in 10 ml THF and 5 ml MeOH was added a solution of KOH (2.8 g, 50 mmole) in 5 ml water with ice bath cooling. The mixture was warmed to room temperature and stirred overnight. Concentrated aqueous HCl solution was added to adjust the pH to 1. The mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was further purified by column chromatography (eluting with 1-5% MeOH in CH2Cl2) to give 880 mg product (65% yield). 1H NMR (300 MHz, CD3OD) δ7.90 (1H, d, J=9.0 Hz), 7.01 (1H, d, J=2.1 Hz), 6.91 (1H, dd, J=2.1, 9.0 Hz), 3.90 (3H, s), 3.88 (3H, s).
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:45])[NH:11][CH:12]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:13]([OH:37])[CH2:14][N:15]([S:20]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[C:26]3=[CH:33][N:34]([CH3:36])C)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[CH2:46](N)[C:47](C)([CH3:49])[CH3:48]>C(O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:45])[NH:11][CH:12]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:13]([OH:37])[CH2:14][N:15]([S:20]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[C:26]3=[CH:33][NH:34][CH2:36][C:47]([CH3:49])([CH3:48])[CH3:46])(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:2]1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)C(=CN(C)C)C(=O)N2
Reactant: CC(C)(C)CN
Solvent: CCO
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)C(=CNCC(C)(C)C)C(=O)N2
Reaction time: 22 h
Yield: 70.1 %

Procedure:
To a solution of {1-benzyl-3-[(3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 21 (32mg, 0.05 mmol) in absolute ethanol (1 ml) was added neopentylamine (29 μl, 0.25 mmol). The resulting solution was stirred 22 h and then concentrated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μm) using 8:2 ethyl acetate:hexane as eluant to provide [1-benzyl-3-({3-[(2,2-dimethyl-propylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 22 (24 mg, 70%). TLC: Rf 0.63 (ethyl acetate:hexanes). MS m/z 685 (MH)+. 1H NMR (CDCl3) is consistent with structure.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[C:20]1([N:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:15]3[C:10]([C:11]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:13]=[CH:14]3)=[N:9]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)c1cccc2c(-c3ccccc3)n[nH]c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc2c(-c3ccccc3)n(-c3ccccc3)nc12
Yield: 15.6 %

Procedure:
3-Phenyl-7-trifluoromethylindazole (0.2 g, 0.76 mmol), phenyl boronic acid (186 mg, 1.53 mmol), copper II acetate (208 mg, 1.14 mmol), and pyridine (93 uL, 1.14 mmol) in 6 mL methylene chloride were stirred at room temperature for 72 hours. The reaction mixture was filtered through Celite®, poured into NH4Cl (sat. soln.) and extracted with EtOAc. The combined organic layers were dried with Na2SO4, concentrated and the resulting residue was purified by HPLC (10-100% CH3CN—H2O) to provide the desired compound as a white solid (40 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:35]([N:34]([CH2:37][CH3:38])[C:32]([CH:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:33])[CH3:36]
Reactant: CCC(CC)C(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Reactant: CCN(CC)C(=O)C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(CC)C(=O)Nc1ccc(C2=CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.8 %

Procedure:
To a solution of 4-[4-(2-ethyl-butyrylamino)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (96 mg, 0.25 mmol) in MeOH (5 mL) was added HCl (2 mL, 1 M in Et2O). After 16 h at 25° C., the mixture was concentrated and the residue re-dissolved in DMF (2 mL). The solution was treated with 2-chloro-N,N-diethyl-2-phenyl-acetamide (225 mg, 0.32 mmol) and K2CO3 (138 mg, 1.0 mmol), and was stirred at 25° C. for 16 h. The resulting mixture was purified by PTLC to provide the title compound (25 mg, 21%). MS: 480.4. 1H NMR (CDCl3): 7.57-7.45 (m, 3H), 7.40-7.27 (m, 4H), 7.20-7.06 (m, 2H), 5.90 (s, 1H), 4.43 (s, 1H), 3.55-3.15 (m, 6H), 2.92-2.83 (m, 1H), 2.74-2.64 (m, 1H), 2.53-2.44 (m, 2H), 2.07-1.98 (m, 1H), 1.76-1.47 (m, 4H), 1.17-0.90 (m, 12H).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([CH:23]=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([CH:23]=[CH2:1])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C=O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
A slurry of methyltriphenylphosphonium bromide (450 g, 1.3 mmol, 3.0 eq.) in THF (200 mL) was cooled to −78° C. 2M Sodium bis(trimethylsilyl)amide (580 mL, 2.8 eq.) was added and the mixture was stirred for 3 hours. A solution of (R)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (84 g, 421.6 mmol, 1.0 eq.) in THF (100 mL) was added dropwise at −65°. Upon completion of the reaction, the product was purified by column chromatography (200-300 mesh, hexanes:EtOAc=1:3, 3 L) to yield (S)-3-vinyl-pyrrolidine-1-carboxylic acid t-butyl ester (40 g).
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22](Br)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH2:35][CH3:36])(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH2:35][CH3:36])(=[O:15])[CH3:14]
Reactant: CCC[C@H]1C[C@@H](Nc2ccccc2)c2cc(Br)ccc2N1C(C)=O
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCC[C@H]1C[C@@H](Nc2ccccc2)c2cc(-c3ccc(C(=O)O)cc3)ccc2N1C(C)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A mixture of 4-(dihydroxyboranyl)benzoic acid (25.7 mg, 0.155 mmol), (cis)-1-acetyl-6-bromo-N-phenyl-2-propyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 86) (40 mg, 0.103 mmol), tetrakis(triphenylphosphine)palladium(0) (11.93 mg, 10.33 μmol) and potassium carbonate (42.8 mg, 0.310 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was stirred at 130° C. for 15 min under microwave irradiation then cooled to room temperature and concentrated in vacuo. Purification of the residue by MDAP (modifier:formic acid) gave 4-[(cis)-1-acetyl-4-(phenylamino)-2-propyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid (19 mg, 0.044 mmol, 43%).
Reaction SMILES: [CH2:1]([C:3]1[C:19]([F:20])=[CH:18][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[F:17])=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].C(N(C(C)C)CC)(C)C.Cl>ClCCl.CN(C)C=O>[CH2:1]([C:3]1[C:19]([F:20])=[CH:18][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:32]3[CH2:33][CH2:34][NH:29][C:30](=[O:35])[CH2:31]3)=[O:14])=[CH:10][C:9]=2[F:17])=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: O=C1CNCCN1
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)O)cc2F)cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (55 mg, 0.18 mmol; which may be prepared as described in D2) in dichloromethane (1.8 mL) under Argon cooled at 0° C. were added oxalyl chloride (2M in dichloromethane, 135 μL, 0.27 mmol) and a drop of N,N-dimethylformamide. The mixture was allowed to come to room temperature over 2 hours, and then piperazin-2-one (20 mg, 0.20 mmol) followed by diisopropylethylamine (93 μL, 0.53 mmol) were added. The reaction mixture was cooled to 0° C. and a solution of 1N HCl was added. After stirring a few minutes, dichloromethane was added and the aqueous layer (pH 7) was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel, using dichloromethane/methanol (95:5) as eluent. The title product was obtained as a yellow oil (38 mg, 55%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:22])[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:6]2=[O:31])[CH2:3][CH2:2]1.[CH3:32][C:33]([CH3:35])=O.C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1.ClCCl>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([NH:21][CH:33]([CH3:35])[CH3:32])=[CH:19][CH:20]=4)[NH:10][C:9]=3[C:8](=[O:22])[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:6]2=[O:31])[CH2:3][CH2:2]1
Reactant: CC(C)=O
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Yield: 23.8 %

Procedure:
To a solution of 3-cyclopropylmethyl-8-[4-aminobenzyl]-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (0.21 g, 0.50 mmol) in tetrahydrofuran (tetrahydrofuran) (5 mL) was added acetone (36.7 μL, 5.0 mmol) and sodium cyanoborohydride (Aldrich, catalog number 15,615-9) (94.3 mg, 1.5 mmol). Stirred vigorously at ambient temperature and glacial acetic acid (J. T. Baker, catalog number 9508-5) (50 μL, 0.87 mmol) added. After 3 h additional glacial acetic acid (50 μL, 0.87 mmol) was added and the mixture stirred at ambient temperature for an additional 1 h. The reaction mixture was diluted with dichloromethane and washed with 1M aqueous sodium hydroxide (2×), brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by chromatography using silica eluted with 1:2 hexanes/ethyl acetate. Concentration of the appropriate fractions gave the product as a colorless solid (0.055 g, 23%). 1H NMR, δH(DMSO-d6, 300 MHz) 13.29 (br s, 1H), 7.30–6.85 (m, 6H), 6.40 (d, J=8.8 Hz, 2H), 5.16 (d, J=8.4 Hz, 1H), 5.04 (s, 2H), 3.78 (s, 2H), 3.42 (sept, J=6.4 Hz, 1H), 1.25–1.10 (m, 1H), 1.01 (d, J=6.2 Hz, 6H) and 0.45–0.30 (m, 4H)
Reaction SMILES: COCCOCCOC.O.[C-:11]#[N:12].[Na+].[O:14]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:29][C:30]([Cl:40])=[CH:31][CH:32]1[CH:34]([C:35](Cl)=[O:36])[C:33]1([CH3:39])[CH3:38]>COCCOCCOC>[Cl:29][C:30]([Cl:40])=[CH:31][CH:32]1[CH:34]([C:35]([O:25][CH:24]([C:11]#[N:12])[C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:22]=2)=[O:36])[C:33]1([CH3:39])[CH3:38]
Reactant: [C-]#N
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 2 h
Yield: 104.5 %

Procedure:
A reaction flask was cooled to 0° and charged with 20 ml of diethylene glycol dimethyl ether/water solution (1/1 by volume) and sodium cyanide (0.78 g, 0.016 mole). The resultant solution was stirred, and 3-phenoxybenzaldehyde (1.98 g, 0.01 mole) was added in 5 ml of diethylene glycol dimethyl ether. 3-(2,2-Dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (2.73 g, 0.012 mole) was added dropwise to the stirred reaction mixture at 20° over a 10 minute period. Stirring was continued for 2 hours. The reaction mixture was then extracted three times with 15 ml portions of diethyl ether, once with 15 ml of water, once with a 2 N solution of aqueous sodium hydroxide, three times with water (15 ml), dried over magnesium sulfate, and concentrated under reduced pressure to afford α-cyano-3-phenoxybenzyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (4.35 g, 90% pure glpc).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH3:14])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:16](I)[CH2:17][CH2:18][CH3:19].N1C(C)=CC=CC=1C>>[CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH3:14])[N:6]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCOC(=O)[C@H](C)Nc1ccc(Cl)cc1
Reactant: CCCCI
Solvent: Cc1cccc(C)n1
Product: CCCCN(c1ccc(Cl)cc1)[C@@H](C)C(=O)OCC
Temperature: 135 °C

Procedure:
N-(4-Chlorophenyl)alanine ethyl ester (4.5 g, 0.02 mol), n-butyl iodide (3.6 g, 0.02 mol) and 2,6-lutidine (2.5 g, 0.025 mol) were sealed in a glass tube and the contents were heated at 135° C. for 48 h. The tube was then cooled, and the contents were partitioned between 250 mL ethyl acetate and 200 mL brine. The organic layer was separated, dried over anhyd. sodium sulfate, and concentrated at reduced pressure. The resulting oil was chromatographed on silica gel using heptane:THF (4:1) as the eluant. The ester was isolated as a colorless oil (2.5 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][N:8]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][N:8]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of tert-butyl (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate, 1b, (2.1 g, 3.5 mmol) in CH2Cl2 (30 mL) was added trifluoroacetic acid (20 mL). After stirring the reaction mixture at room temperature for 75 min, the mixture was concentrated under vacuo. The crude residue was diluted with EtOAc and neutralized with 1N sodium hydroxide solution. The aqueous phase was separated and extracted again with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated under vacuo to afford the desired product (1c) as a light yellow solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cccnc21
Temperature: 60 °C
Yield: 8.6 %

Procedure:
To a stirred solution of N-tert-butyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (306 mg, 638 μmol) in DMF (15 mL) was added ethylenediamine (1.92 g, 2.15 mL, 31.9 mmol) followed by TBAF (1.91 mL, 1.91 mmol) and the mixture heated at 60° C. under nitrogen for 15 h. The mixture was cooled, diluted with dichloromethane, washed with water and brine, then dried (MgSO4), filtered and concentrated to obtain an oil. This was triturated with water to remove tetrabutylammonium hydroxide, filtered, and the residue purified by chromatography (silica, 5-10% methanol in dichloromethane) to obtain N-tert-butyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (19.2 mg, 55.0 μmol, 9%) as a light yellow powder. MS (M+H)+=350; 1H NMR (DMSO-d6) δ: 9.12 (s, 1H), 8.84 (dd, J=8.2, 1.6 Hz, 1H), 8.70 (dd, J=4.5, 1.5 Hz, 1H), 8.42 (s, 1H), 7.93 (s, 1H), 7.39 (dd, J=8.0, 4.5 Hz, 1H), 4.22 (s, 3H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>>[CH2:26]([O:25][C:21]([CH:22]=[CH:23][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1)=[O:24])[CH3:27].[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: C=CC(=O)OCC
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Agent: CCC(=O)[O-]
Product: CCOC(=O)C=Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 21.6 %

Procedure:
This compound is prepared according to synthesis 68, from 114 mg (0.3 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate and 36 μL (0.33 mmol) of ethyl acrylate. After purification by chromatography on silica (eluent dichloromethane/methanol 98/2) then trituration in ethanol, 23 mg (22%) of 8-(2-ethoxycarbonyl-vinyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[F:12][C:13]([F:43])([F:42])[C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][N:26]([CH3:41])[C:27](=[O:40])[CH:28](OS(C)(=O)=O)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(N(CC)CC)C>CC(C)=O>[F:12][C:13]([F:42])([F:43])[C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][N:26]([CH3:41])[C:27](=[O:40])[CH:28]([N:8]2[CH2:7][CH2:6][CH:5]([NH:4][C:3]([NH:2][CH3:1])=[O:11])[CH2:10][CH2:9]2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(OS(C)(=O)=O)c1ccccc1
Reactant: CNC(=O)NC1CCNCC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)NC1CCN(C(C(=O)N(C)CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Yield: 32.8 %

Procedure:
6.8 g of 4-(3-methylureido)-piperidine are refluxed together with 19.2 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide (prepared analogously to the method described in WO 99/62893) and 6.8 ml of triethylamine in 400 ml of acetone for 8 hours. Then the solution is evaporated down, combined with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract is dried, the solvent is eliminated in vacuo and the residue is chromatographed with methylene chloride/methanol 9:1 over silica gel. The fractions found to be uniform by TLC are combined and the solvent is eliminated in vacuo. N-[2-(3,5-bis-tifluormethyl-phenyl)-ethyl]-N-methyl-2-[4-(3-methyl-ureido)-piperidin-1-yl]-2-phenyl-acetamide is crystallised from the residue with ethanolic hydrochloric acid and ether in the form of the hydrochloride, yielding 7.1 g of colourless crystals. 1H-NMR (250 MHz, CD3OD) δppm=7.93-7.33 (8H, m); 5.58; 5.38 (1H, 2s); 4.03-2.59 (5H, m); 3.05 (4H, m); 2.98; 2.90 (3H, 2s); 2.74; 2.70 (3H, 2s); NH in the solvent blind peak 4.89; 2.27-1.52 (4H, m). Most signals are split by amide rotation.
Reaction SMILES: Cl.O=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([O:30][CH2:31][CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH2:17]3)(=[O:15])=[O:14])[CH:11]=2)[N:6]=[CH:5][NH:4]1.S(Cl)([Cl:35])=O.CN(C)C=O.C(Cl)(Cl)Cl>O>[Cl:35][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([O:30][CH2:31][CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH2:17]3)(=[O:15])=[O:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(CN1CCN(S(=O)(=O)c2ccc3nc[nH]c(=O)c3c2)CC1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(CN1CCN(S(=O)(=O)c2ccc3ncnc(Cl)c3c2)CC1)c1ccccc1
Yield: 80 %

Procedure:
To 9.57 g of 1-(3,4-dihydro-4-oxo-6-quinazolinesulfonyl)-4-(2-ethoxy-2-phenylethyl)piperazine hydrochloride were added 40 ml of thionyl chloride and 4.8 ml of N,N-dimethylformamide, and the mixture was refluxed under heating. To the residue thus obtained were added 60 ml of chloroform and 30 ml of a mixture of ice and water, and the mixture was stirred under cooling with ice. Then the chloroform layer was separated therefrom and the aqueous layer was extracted with chloroform and the chloroform layer obtained was combined with the one previously separated. The chloroform layer was washed with, in order, water, a saturated sodium bicarbonate solution and water, and then dried with Glauber's salt. The chloroform layer thus obtained was condensed under reduced pressure to give 7.33 g of 1-(4-chloro-6-quinazolinesulfonyl)-4-(2-ethoxy-2-phenylethyl)piperazine as an oily substance in a yield of 80%.