Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])(O)O.Cl[C:16]1[C:17](=[O:35])[N:18]([CH2:33][CH3:34])[C:19]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:23]=[CH:22][C:20]=2[N:21]=1.CCOC(C)=O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[C:19]2[N:18]([CH2:33][CH3:34])[C:17](=[O:35])[C:16]([C:4]3[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=3[CH3:13])[C:7]([OH:9])=[O:8])=[N:21][C:20]=2[CH:22]=[N:23]1
Reactant: CCn1c(=O)c(Cl)nc2cnn(-c3ccc(F)cc3F)c21
Reactant: Cc1c(F)cc(C(=O)O)cc1B(O)O
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(C(=O)O)cc(F)c2C)nc2cnn(-c3ccc(F)cc3F)c21
Temperature: 130 °C

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 μmol), 3-borono-5-fluoro-4-methylbenzoic acid (175 mg, 0.88 mmol) and 5-chloro-1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (250 mg, 0.80 mmol) in 4.0 mL dioxane and 2.0 mL of 1 N sodium carbonate was heated in a microwave at 130° C. for 30 min. The reaction mixture was treated with EtOAc (15 mL) and extracted with 1N NaOH (3×10 mL). The aqueous extracts were treated with 5 N HCl to pH 2 and extracted with DCM (3×15 mL). The combined DCM layers were dried over MgSO4, filtered and concentrated affording 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoic acid as a light orange-brown viscous oil. This material was used without purification. MS (ES+): 429.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[C:14]([C:15](O)=[O:16])=[CH:13][N:12]([CH3:18])[C:9]=32)=[CH:4][N:3]=1.C1C=CC2N(O)N=[N:25]C=2C=1.N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[C:14]([C:15]([NH2:25])=[O:16])=[CH:13][N:12]([CH3:18])[C:9]=32)=[CH:4][N:3]=1
Reactant: Cn1cc(C(=O)O)c2c1-c1nc(N)ncc1CC2
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(N)=O)c2c1-c1nc(N)ncc1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 8-amino-1-methyl-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid M2 (0.08 mmol) in dry DMF (4 mL), HOBT.NH3 (0.164 mmol), TBTU (0.164 mmol) and DIEA (0.328 mmol) were added. The mixture was stirred at rt for 24 h then the solvent was evaporated. The residue was suspended in 10 mL of water, filtered, washed with water and dried in vacuo, providing the title compound (55% yield). ESI (+) MS: m/z 244 (MH+). 1H NMR: 2.73 (t, J=7.44, 2H), 3.00 (t, J=7.44, 2H), 4.04 (s, 3H), 6.94 (bs, 1H), 7.35 (bs, 1H), 7.73 (s, 1H), 7.96 (s, 1H), 7.76 (bs, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][C:10]=2[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:28]=1[NH2:29]>COCCO>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([N:34]4[CH2:39][CH2:38][CH:37]([N:40]5[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]5)[CH2:36][CH2:35]4)=[CH:33][C:27]=3[O:26][CH3:25])[N:7]=[CH:6][N:5]=2)=[C:10]([S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:11]=1)([CH3:18])=[O:16]
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1cc(Cl)ncn1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1cc(Nc2ccc(P(C)(C)=O)cc2S(=O)(=O)C(C)C)ncn1

Procedure:
To the compound 6-chloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.16 mmol) in 1 mL of 2-methoxyethanol is added 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (prepared in Example 75: 0.71 g, 0.16 mmol). The mixture is stirred at 110° C. until formation of the desired compound. The mixture is basified with saturated sodium bicarbonate solution and extracted with limited amount of ethyl acetate. The compound can be purified by chromatography.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: BrCCCCCCCCC1CCCC1
Reactant: CCCCCCCc1ccc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCc1ccc(-c2ccc(OCCCCCCCCC3CCCC3)cc2)nc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A mixture of 0.157 g of 4-(5-heptyl-2-pyridyl)-phenol, 0.153 g of (8-bromooctyl)-cyclopentane, 6 ml of dimethylformamide and 0.24 g of finely powdered potassium carbonate was stirred at 55° C. for 3 hours. The reaction mixture was partitioned between water and diethyl ether. The organic phase was washed with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and the filtrate was concentrated. Chromatography of the crude product (0.28 g) on 10 g of silica gel with hexane/ethyl acetate 37:3 (v/v) and two-fold recrystallization of the product-containing fractions from 3 ml of hexane each time gave 0.16 g of pure 5-heptyl-2-[4-(8-cyclopentyl-octyloxy)-phenyl]-pyridine; m.p. (C-SI) 38.3° C., SI -SC 56.9° C., cl.p. (SC -I) 72.6° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([O:15][CH3:16])[CH3:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[N+:24]([C:27]1[CH:34]=[CH:33][C:30](CBr)=[CH:29][CH:28]=1)([O-:26])=[O:25].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:16][O:15][CH:13]([CH:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH2:6][C:30]1[CH:33]=[CH:34][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(C)C1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(C)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-methoxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.4 mmol) in CH2Cl2 (25 mL) is cooled to 0° C. and TFA (2.5 mL) is added dropwise. The mixture is allowed to stir at room temperature overnight. The volatiles were removed and CH3CN (20 mL) is added. After addition of 4-nitrobenzyl bromide (1.25 g, 5.78 mmol) and K2CO3 (2.0 g, 14.4 mmol) the mixture is stirred at room temperature for 5 hours. Aqueous workup followed by chromatography. (260 mg, 25%). 1H NMR (300 MHz, CDCl3) ∂8.17 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.4 Hz), 4.29 (1H, d, J=14.4 Hz), 3.48 (1H, d, J=14.4 Hz), 3.30-3.33 (1H, m), 3.32 (3H, s), 2.88-2.91 (1H, m), 2.73-2.78 (1H, m), 2.14-2.19 (1H, m), 1.61-1.85 (4H, m), 1.15 (3H, d, J=6.6 Hz).
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)[CH:13]=2)=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:24]1[C:25]2[C:32]([CH3:33])=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:2][C:3]1([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)[CH:13]=2)=[O:10])[CH2:4][CH2:5][N:6]([C:24]2[C:25]3[C:32]([CH3:33])=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:7][CH2:8]1
Reactant: CC1(C(=O)Nc2cccc(-c3cnco3)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(-c5cnco5)c4)CC3)c12
Temperature: 105 °C

Procedure:
A pressure vessel was charged with a solution of 4-methyl-N-(3-(oxazol-5-yl)phenyl)piperidine-4-carboxamide hydrochloride from step B (51.9 mg, 0.17 mmol) and isopropanol (3 mL), and to this solution was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (55.0 mg, 0.329 mmol) and N,N-diisopropylethylamine (297.9 mg, 0.40 mL, 2.31 mmol). The vessel was sealed, and the reaction was heated to 105° C. for 15 hours. The reaction was worked up by normal means, and the residue was purified by prep HPLC to afford the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH3:15])([C:11]([F:14])([F:13])[F:12])[CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].[F:18][C:19]([S:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)([F:21])[F:20]>>[F:18][C:19]([S:22][CH2:23][CH2:24][CH:8]([S:5]([CH2:4][C:3]([CH3:15])([C:2]([F:1])([F:16])[F:17])[C:11]([F:13])([F:12])[F:14])(=[O:6])=[O:7])[C:9]#[N:10])([F:21])[F:20]
Reactant: CC(CS(=O)(=O)CC#N)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Product: CC(CS(=O)(=O)C(C#N)CCSC(F)(F)F)(C(F)(F)F)C(F)(F)F

Procedure:
Compound II-28 was prepared from (3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propane-1-sulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[N:16][OH:17])([O-:3])=[O:2]
Reactant: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(C=NO)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 71 %

Procedure:
9.7 parts of 2-nitro-4-dimethylaminobenzaldehyde is dissolved in 50 parts of ethyl alcohol and a solution of 4.1 parts of hydroxylamine hydrochloride and 5 parts of sodium acetate in water is added. After the mixture has been boiled for one hour it is suction filtered. 7.5 parts (71% of theory) of 2-nitro-4-dimethylaminobenzaldoxime is obtained having a melting point of 140° to 143°C: ##SPC18##
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH:10]([CH2:16][O:17][C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)[CH2:9]1)=O)(C)(C)C.[ClH:41]>O1CCOCC1.C(Cl)Cl>[ClH:41].[ClH:41].[CH2:37]([C:21]1[N:20]=[N:19][C:18]([O:17][CH2:16][CH:10]2[C:11]([F:15])([F:14])[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]2)=[CH:23][C:22]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:26][CH:25]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nnc(OCC2CN(C(=O)OC(C)(C)C)CCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OCC2CN(C)CCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 50 °C

Procedure:
A mixture of 3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4,4-difluoro-piperidine-1-carboxylic acid tert-butyl ester (0.36 mmol, 0.2 g) and 4M HCl in dioxane solution (3 mL) in 10 mL of DCM was heated at 50° C. for 1 h. Removed the solvent afforded the crude 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4,4-difluoro-piperidin-3-ylmethoxy)-pyridazine dihydrochloride as a yellowish solid.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CCO>[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:18])=[O:2])=[CH:9][CH:8]=1)=[CH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C=Cc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C=Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
73A (80 mg, 0.34 mmol) was suspended in EtOH (0.5 mL) and aqueous NaOH (1 M, 2 mL) and was heated to 80° C. for one hour. Upon cooling to room temperature, the solution was acidified with HCl (concentrated), was cooled to 0° C., and was filtered. The white crystalline precipitate was dried under vacuum (75 mg, quant.). NMR 1H (ppm, CDCl3): 7.93 (d, J3=8.3 Hz, 2H), 7.56-7.53 (m, 4H), 7.33 (t, J3=7.4 Hz, 2H), 7.27-7.11 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[I:12]I.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:10]([I:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: II
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(Cl)c(I)cc1C(=O)O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask was added a solution of 4-chloro-2-methylbenzoic acid (30.0 g, 176 mmol, 1.00 equiv) in acetic acid (300 mL). NaIO4 (19.0 g, 88.8 mmol, 0.50 equiv), I2 (49.0 g, 193 mmol, 1.10 equiv), and sulfuric acid (3 mL) were added to the reaction. The resulting mixture was stirred overnight at 110° C. After cooling to ambient temperature, the reaction was carefully quenched with 500 mL of Na2S2O3 (aq., sat.). The resulting solids were collected by filtration and then dissolved in 500 mL of ethyl acetate. The organic phase was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This resulted in 20.0 g (38%) of 4-chloro-5-iodo-2-methylbenzoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]3[CH2:18][CH2:17][CH2:16][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:20]I>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]3[CH2:18][CH2:17][CH2:16][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[I:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cncc2[C@@H]2CCCN12
Reactant: II
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(I)c2[C@@H]2CCCN12

Procedure:
27.3 g (100 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was stirred at 100° for 3 hours with 88 g (350 mmol) of iodine in 200 ml of N,N-dimethylformamide. The reaction mixture was cooled, the separated product was filtered off, rinsed with ethyl acetate and, after drying, there was obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-iodo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 298°-300°.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[CH3:8][C:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH3:8][C:9]1([NH:15][C:16]([NH:18][C:4]2[CH2:5][O:1][C:2](=[O:7])[CH:3]=2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(NC(N)=O)CCCCC1
Reactant: O=C1COC(=O)C1
Product: CC1(NC(=O)NC2=CC(=O)OC2)CCCCC1
Yield: 38.2 %

Procedure:
Using the procedure described in Example 2 using 5 g of 2,4-furandione and 6 g of 1-methylcyclohexylurea there is obtained 3.5 g 1-(1-methylcyclohexyl)-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 183°C. (decomposition).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:26])[C:16]=2[N:15]=[C:14]1[CH2:27][CH3:28].[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[NH2:26][C:17]1[C:16]2[N:15]=[C:14]([CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
Triethylamine (0.59 mL, 4.3 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) in chloroform (100 mL). The solution was stirred in an ice bath for 5 min. Phenyl isocyanate (0.38 mL, 3.5 mmol) was slowly added. The resulting precipitate was isolated by filtration, washed with chloroform (4×30 mL), and then dried in an Abderhalden drying apparatus overnight to provide 1.11 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as a white solid, m.p. 179.7-181.4° C. Analysis: Calculated for C23H26N6O.0.6H2O: % C, 66.84; % H, 6.63; % N, 20.33. Found: % C, 67.20; % H, 6.61; % N, 20.46.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)=[O:32])[CH:25]=1)[C:15]([CH3:40])([CH3:39])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)=[O:32])[CH:27]=[CH:28][CH:29]=1)[C:15]([CH3:40])([CH3:39])[CH2:14]2
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(NC(=O)c2cnccn2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(Cl)cc(C(=O)NS(=O)(=O)C3CC3)c2NC1c1cccc(NC(=O)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (182 mg, 1.5 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (57 mg, 1.43 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-3,3-dimethyl-2-{3-[(pyrazine-2-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (65 mg, 0.15 mmol) and 1,1′-carbonyldiimidazole (49 mg, 0.3 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h, the above suspension of cyclopropanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded pyrazine-2-carboxylic acid [3-(6-chloro-8-cyclopropanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (40 mg, 49%) as a white solid: LC/MS m/e calcd for C26H26ClN5O4S (M+H)+: 541.05, observed: 540.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[S:9][C:10]([CH:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:17]=2)O)=[C:11]([Cl:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[S:9][C:10]([CH2:14][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:17]=2)=[C:11]([Cl:13])[N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)c(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To 5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-chloro-thiazol-2-yl-carbamic acid tert-butyl ester (590, 0.200 g, 0.32 mmol) in dichloromethane (15.0 mL) were added triethylsilane (0.600 mL, 376 mmol) and trifluoroacetic acid (0.300 mL, 3.89 mmol). The reaction was stirred at room temperature for 3 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give the desired compound (591, 0.155 g, 88.7%). MS (ESI) [M+H+]+=538.9.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].I[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:6][CH:3]([CH2:4][CH3:5])[C:2]#[C:1][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (40 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-pentynyl)-3-[(3methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 78 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CN1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.100 g, 0.381 mmol) obtained in Example A31, Step 1 in methanol (1.5 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0557 g, 0.381 mmol) and piperidine (0.00324 g, 0.0381 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain (Z)-2-((1H-pyrrolo[2,3-b]pyridin-3-yl)methylene)-6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.109 g, 73%).