Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH:35]1([CH2:38][N:39]([CH2:60][CH:61]2[CH2:63][CH2:62]2)[C:40]2[C:41]([S:58][CH3:59])=[N:42][N:43]3[C:48]([C:49]4[C:54]([CH3:55])=[CH:53][C:52]([CH3:56])=[CH:51][C:50]=4[OH:57])=[CH:47][CH:46]=[CH:45][C:44]=23)[CH2:37][CH2:36]1>O1CCCC1.C(OCC)(=O)C.O>[CH:35]1([CH2:38][N:39]([CH2:60][CH:61]2[CH2:63][CH2:62]2)[C:40]2[C:41]([S:58][CH3:59])=[N:42][N:43]3[C:48]([C:49]4[C:54]([CH3:55])=[CH:53][C:52]([CH3:56])=[CH:51][C:50]=4[O:57][CH2:1][CH3:2])=[CH:47][CH:46]=[CH:45][C:44]=23)[CH2:36][CH2:37]1
Reactant: CCO
Reactant: CSc1nn2c(-c3c(C)cc(C)cc3O)cccc2c1N(CC1CC1)CC1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding ethanol (2 μL), triphenylphosphine (15 mg) and diethyl azodicarboxylate (9 μL) to a solution of 2-[3-[di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3,5-dimethylphenol (15 mg) in tetrahydrofuran (0.45 mL) under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The reaction mixture was added to water, extraction was performed with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (3.7 mg) was obtained from the n-hexane:ethyl acetate (9:1) fraction as a yellow oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[NH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:25][CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:25][CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
Phosphorus oxychloride (515 ml) was added to 7-(benzyloxy)-6-methoxy-3,4-dihydro-4-quinazolinone (400 mg) and diisopropylethylamine (0.3 ml), and the mixture was refluxed for 20 min. The reaction solution was cooled to room temperature. A 10% aqueous sodium hydroxide solution was then added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over sodium sulfate. The organic layer was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was dried through a vacuum pump to give 420 mg (yield 99%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:7]([F:16])=[CH:6][C:5]=1[O:17][CH3:18].[OH-].[Na+]>C(O)C>[F:16][C:7]1[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:9][C:4]([C:3]([OH:19])=[O:2])=[C:5]([O:17][CH3:18])[CH:6]=1
Reactant: COC(=O)c1cc(N2CCOCC2)c(F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(F)c(N2CCOCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A suspension of 4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (1.2.0 g, 4.46 mmol) in ethanol (22.0 mL) was treated with aq 2 N NaOH (13 mL, 26.7 mmol). The mixture was stirred at room temperature for 2 h, concentrated until most of the ethanol was removed and acidified with aq 2 N HCl to pH 1. After extracting with ethyl acetate, the organic layer was washed with saturated aq NaCl, dried over MgSO4 and concentrated to give 4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid (0.90 g, 79%): 1H NMR (DMSO-d6 300 MHz) δ 12.62 (s, 1H), 7.34 (d, J=10.5 Hz, 1H), 7.04 (d, J=14.7 Hz, 1H), 3.76 (s, 3H), 3.70 (t, J=4.7 Hz, 4H), 2.90 (t, J=4.7 Hz, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Cl)=[CH:4][C:3]=1[Cl:12].[BH4-].[Na+].C[O-].[Na+].CC(OC)(C)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][O:11]2)=[CH:4][C:3]=1[Cl:12]
Reactant: O=C(CCl)c1ccc(Br)c(Cl)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: COC(C)(C)C
Product: Clc1cc(C2CO2)ccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
To a stirred solution of 1-(4-bromo-3-chlorophenyl)-2-chloroethanone (18.4 g) in ethanol (200 ml) at 5° C. was added portionwise over 5 min NaBH4 (2.23 g). The reaction mixture was then stirred at room temperature for 90 min to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (1.59 g) was then added and the reaction mixture was stirred at 50° C. for 4 h. TLC analysis showed the reaction was complete. The reaction mixture was then poured into TBME and extracted with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-(4-bromo-3-chlorophenyl)oxirane (15.2 g) as a brown oil which was used in the next step without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])O1.[Br:29][C:30]1[CH:35]=[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH:33]=[C:32](I)[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>C(O)C.C1(C)C=CC=CC=1.O.[Cl-].[Na+].O>[Br:29][C:30]1[CH:31]=[C:32]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[Si:18]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[CH:19]([CH3:21])[CH3:20])[CH:33]=[C:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH:35]=1
Reactant: COc1ccc(COc2cc(Br)cc(I)c2)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(COc2cc(Br)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Temperature: 90 °C
Reaction time: 14 h
Yield: 91.3 %

Procedure:
A 1 L flask was charged with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (17.44 g, 43.67 mmol) and 1-Bromo-3-iodo-5-(4-methoxy-benzyloxy)-benzene (18.30 g, 43.67 mmol) in ethanol (180 mL) and toluene (180 mL) under argon. Tetrakis-triphenylphosphin-palladium (1.51 g, 1.31 mmol) was added. Then a solution of sodium carbonate (9.26 g, 87.34 mmol) in water (92.6 mL) was added and the mixture heated to 90° C. and stirred for 14 h. After cooling down to room temperature AcOEt (300 mL) and brine (200 mL) were added under stirring. The mixture was filtered through a pad of Hyflo. After separation of the layers the aqueous one was extracted with AcOEt (2×300 mL). The combined organic layers were washed with water and brine (150 mL), dried over Na2SO4, filtered and evaporated to dryness. After flash chromatography on silica gel (1 kg, AcOEt/heptane 1:19) 4-[3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-1-triisopropylsilanyl-1H-indole (22.5 g, 91%) was obtained as a colorless oil.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([CH:58]5[CH2:60][CH2:59]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.C(O)(C(F)(F)F)=O.CN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1.C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=CC(C5NN=CC=5)=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[ClH:166]>CO.O>[ClH:166].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([CH:58]5[CH2:60][CH2:59]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C5CC5)cccc4c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C5CC5)cccc4c3=O)cc2)CCC1

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, a mixture containing 70% {1-[4-(8-cyclopropyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester and 30% {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was reacted with 1-methylpyrazole-4-boronic acid pinacol ester following the procedure of (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester. The combined products were dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 5 g C18 cartridge {gradient 10 to 90% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (11 mg). 1H NMR (300 MHz, DMSO-d6): δ 8.60 (s, 3H), 7.91 (dd, J=7.1 and 2.4 Hz, 1H), 7.52-7.27 (m, 11H), 2.65-2.47 (m, 4H), 2.45-2.34 (m, 1H), 2.26-2.09 (m, 1H), 1.88-1.73 (m, 1H), 1.14-1.04 (m, 2H), 0.90-0.82 (m, 2H). LCMS (Method E): RT=4.01 min, [M+H]+=408. 3-[4-(1-amino-cyclobutyl)-phenyl]-8-(1-methyl-1H-pyrazol-4-yl)-2-phenyl-chromen-4-one hydrochloride was also isolated.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[C:4]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])[CH:3]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][C:4]=2[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[C:23]1[CH3:32]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1sc(Cl)cc1S(=O)(=O)c1ccccn1
Product: COC(=O)Cn1c(C)c(Cc2sc(Cl)cc2S(=O)(=O)c2ccccn2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 42b using 5-chloro-3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O.O>[CH2:3]([O:10][N:11]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=1)=[O:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCBr
Reactant: CCCCc1ccc(NC(=O)NOCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN(OCc1ccccc1)C(=O)Nc1ccc(CCCC)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Sodium hydride (0.14 g of 80% in mineral oil, 4.7 mmol) was added to a solution of 1-benzyloxy-3-(4-butylphenyl)urea (1.25 g, 4.2 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was heated briefly on a steam bath under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature then 1-bromopentane (0.63 g, 4.2 mmol) was added. The reaction mixture was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with water and then extracted with diethyl ether. The organic layer was washed with water, dried with magnesium sulfate and then concentrated to provide 1.47 g of crude product as a brown oil. This material was purified by flash chromatography (silica gel; 1:19 ethyl acetate:hexanes) to provide 0.96 g of 1-benzyloxy-3-(4-butylphenyl)-1-pentylurea as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:21])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](OCC)=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=1[OH:21]
Reactant: CCOC(=O)CCCCCC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1c(C)c(O)c(CCCCCCO)c(C)c1O

Procedure:
A solution of 2,3,5-trimethyl-6-(5'-ethoxycarbonylpentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4,in the form of ethylester) (0.1 part) in diethyl ether (10 volume parts) was treated with lithium aluminum hydride in the same manner as Example 53 to give 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-hydroquinone (formula III-2 wherein R=H3C, n=4, in the free form). The product was treated with ferric chloride in the same manner as Example 53 and then crystallized from diethyl ether. The procedure provided 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-1,4-benzoquinone (formula IV-2, wherein R=H3C, n=4 in the free form) as yellow needles melting at 43°-45° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:6][CH2:7][CH3:8])=[O:3].[S:15]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[N:17]=[CH:16]1>N1C=CC=CC=1>[CH:9]1([CH:5]([O:4][C:2]([N:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=[C:20]2[C:18]2[N:17]=[CH:16][S:15][CH:19]=2)=[O:3])[CH2:6][CH2:7][CH3:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: CCCC(OC(=O)Cl)C1CCCCC1
Solvent: c1ccncc1
Product: CCCC(OC(=O)n1c(-c2cscn2)nc2ccccc21)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
28.3 G. (0.129 moles) of 1-cyclohexyl-1-butyl chloroformate is added over a period of 20 minutes at a temperature of 20° C to a stirred suspension of 25.1 g. (0.125 moles) of 2-(4-thiazolyl)-benzimidazole and 200 ml. of pyridine. A clear solution initially results which is followed by the precipitation of pyridine hydrochloride. The reaction mixture is then stirred for 16 hours at room temperature filtered and the filtrate evaporated to dryness in vacuo. The product is extracted from the residue with 250 ml. of methylene chloride which is filtered and the filtrate washed twice with 250 ml. of 0.25 N-hydrochloric acid and 200 ml. of saturated sodium bicarbonate solution. The methylene chloride is dried, treated with charcoal, filtered and evaporated to dryness in vacuo. The residual oil is chromatographed on a column of silica gel eluting with benzene affording 21.6 g. (45%) of a pale yellow viscous oil. Thin layer chromatography demonstrates that the oil is pure material which analyzes as 1-(1-cyclohexylbutoxycarbonyl)-2-(4-thiazolyl)-benzimidazole.
Reaction SMILES: [CH3:1][NH2:2].C([Li])CCC.[C:8](/[C:16](=[C:19](/OC)\[CH3:20])/[C:17]#[N:18])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8](/[C:16](=[C:19](/[NH:2][CH3:1])\[CH3:20])/[C:17]#[N:18])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccccc1
Agent: [Li]CCCC
Product: CN/C(C)=C(\C#N)C(=O)c1ccccc1

Procedure:
In the glass liner of a stainless steel bomb cooled to -78° is condensed 10 ml. of methylamine. To this is added 0.5 ml. of 2 M n-butyllithium (in hexane), followed by 5.0 g. of 2-benzoyl-3-methoxycrotononitrile. The bomb is sealed and heated on a steam bath overnight. The bomb is then cooled, opened and the contents evaporated. The residue is dissolved in chloroform, passed through a Magnesol® pad and the filtrate is evaporated. The residue is recrystallized from chloroform-hexane yielding the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:36])(=[O:35])[NH2:34])=[CH:23][CH:22]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:35])(=[O:36])[NH:34][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[Cl:37])=[CH:23][CH:22]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-2-(3-nitrophenyl)-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step C) and 2-chlorobenzoic acid (2.5 equivalents), CDI (2.5 equiv), and DBU (2.5 equiv) according to the procedure of Example 51 to give a 95% yield of the desired material as a cream-colored solid after flash chromatography, mp 92°-95° C., homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 645 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:44]2[CH2:46][CH2:45]2)[C:16](=[O:43])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:36][C:35]4[CH:34]=[N:33][N:32]([CH3:37])[C:31]=4[NH:30][C:29]4[CH:38]=[CH:39][CH:40]=[CH:41][C:28]3=4)=[O:26])=[CH:21][C:20]=2[CH3:42])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:47]>O1CCOCC1>[ClH:47].[CH:44]1([N:15]([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16](=[O:43])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:36][C:35]4[CH:34]=[N:33][N:32]([CH3:37])[C:31]=4[NH:30][C:29]4[CH:38]=[CH:39][CH:40]=[CH:41][C:28]3=4)=[O:26])=[CH:21][C:20]=2[CH3:42])[CH2:45][CH2:46]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N(CC1CCNCC1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
4-[(Cyclopropyl-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester from Example E87.1 (235 mg, 0.37 mmol) was dissolved in 4M HCl solution in dioxan (5 ml). The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in 1M HCl, washed twice with dichloromethane and freeze-dried to give an off-white solid identified as the title compound (82 mg, 39%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:32])=O>>[C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH:25][CH2:26][C:27]([Cl:32])=[O:29])=[O:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CNC(=O)c1ccc2c(c1)C(CCNC(=O)Cc1ccccc1)CCO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CNC(=O)c1ccc2c(c1)C(CCNC(=O)Cc1ccccc1)CCO2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product obtained in Step A (3 mmol), dissolved in thionyl chloride, is stirred at 60° C. under a current of nitrogen for one hour. The thionyl chloride is evaporated off under reduced pressure and the residue is dried with the aid of a vane pump to yield the title product.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:18]([F:20])[F:19])[O:7][C@H:6]1[N:30]1[CH:35]=[C:34]([Cl:36])[C:33]([NH2:37])=[N:32][C:31]1=[O:38])(=O)C.CO>N>[NH2:37][C:33]1[C:34]([Cl:36])=[CH:35][N:30]([C@H:6]2[C@H:5]([OH:4])[C@H:9]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@:8]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH:18]([F:19])[F:20])[O:7]2)[C:31](=[O:38])[N:32]=1
Reactant: CC(=O)O[C@H]1[C@H](n2cc(Cl)c(N)nc2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Agent: N
Solvent: CO
Product: Nc1nc(=O)n([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2O)cc1Cl
Yield: 61.8 %

Procedure:
A mixture of compound 29 (0.235 g, 0.43 mmol) in NH3.MeOH (10 mL) was stirred at r.t for 3 h and then evaporated to dryness under reduced pressure. Purification by silica gel chromatography column [dichloromethane:methanol (40:1)] gave 30 as a white solid (0.135 g, 62%). LC-MS: (M+H)+=508.1
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23](/[CH:26]=[C:27]2\[C:28](=[O:38])[NH:29][C:30]3[C:35]\2=[C:34](I)[C:33]([F:37])=[CH:32][CH:31]=3)[NH:22][CH:21]=1)=[O:19])[CH3:16]>CN(C=O)C.CCN(CC)CC.CCOC(C)=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>[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23](/[CH:26]=[C:27]2\[C:28](=[O:38])[NH:29][C:30]3[C:35]\2=[C:34]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:33]([F:37])=[CH:32][CH:31]=3)[NH:22][CH:21]=1)=[O:19])[CH3:16]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#C[C@@H]4CCCN4)c32)c1C
Reaction time: 2 h

Procedure:
Using Method C above, (S)-N-Boc-2-Ethynyl-pyrrolidine (106 mg, 0.55 mmol) (Example 87B) was coupled with (Z)-5-(5-fluoro-4-iodo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (80 mg, 0.18 mmol) (Example 116B) using (Ph3P)4Pd (21 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-40% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-5-[[5-Fluoro-2-oxo-4-[(pyrrolidin-2-yl)ethynyl]-1,2-dihydro-indol-3-ylidene]methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester was obtained after silica gel column chromatography with a 0-100% EtOAc in hexanes-30% THF in EtOAc gradient and precipitation out of THF with excess of hexanes. (Yield 21 mg, 28%).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].[O:8]1[CH2:12][CH2:11][N:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]([CH:17]=[C:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1>O1CCCC1>[O:8]1[CH2:12][CH2:11][N:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]([CH:17]=[C:18]2[CH2:19][CH2:20][N:21]([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:22][CH2:23]2)=[CH:24][CH:25]=1
Reactant: C#CCCC(=O)O
Reactant: C(=C1CCNCC1)c1ccc(C2=NCCO2)cc1
Solvent: C1CCOC1
Product: C#CCCC(=O)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
356 mg (2.2 mmol) of N,N'-carbonyldiimidazole in 3 ml of tetrahydrofuran are added to 200 mg (2 mmol) of 4-pentynoic acid in 2 ml of tetrahydrofuran at ambient temperature. The mixture is stirred at 40° C. for 1 hour. 363 mg (1.5 mmol) of 4-[4-(2-oxazolin-2-yl)benzylidene]piperidine are then added and the mixture is stirred at 40° C. for a further 2 hours. The reaction solution is then evaporated down and the residue is purified by column chromatography (Silica gel; ethyl acetate). 320 mg (66% of theory) of the title compound of melting point 118° C. are obtained.