Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[CH:24][CH:23]=3)[C:18](=[O:19])[N:17]([CH3:20])[C:16]([NH2:21])=[N:15]2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:21][C:16]1[N:17]([CH3:20])[C:18](=[O:19])[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH2:7])[CH:9]=2)([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[CH:24][CH:23]=2)[N:15]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(NC(=O)OC(C)(C)C)c2)N=C1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(N)c2)N=C1N
Reaction time: 4.5 h
Yield: 99.3 %

Procedure:
{3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-phenyl}-carbamic acid tert-butyl ester (15.3 g, 34.3 mmol) was dissolved in trifluoroacetic acid/methylene chloride (1:1) (20 mL) and allowed to stir for 4.5 h. Additional trifluoroacetic acid (3.0 mL) was added and the reaction was allowed to stir for an additional hour and concentrated. To the residue was added Na2CO3 followed by extraction with methylene chloride. The organic layer was dried over Na2SO4 and concentrated in vacuo to provide the title compound (11.8 g, 99%), characterized by NMR and mass spectral analyses. MS (ES+) m/e 347 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][OH:38])[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)(Cl)[Cl:47]>>[ClH:47].[ClH:47].[OH:38][CH2:37][CH2:36][N:33]1[CH2:34][CH2:35][CH:30]([CH2:29][O:28][C:22]2[CH:21]=[C:20]3[C:25]([CH2:26][CH2:27][N:18]([C:9]([NH2:10])=[NH:8])[CH2:19]3)=[CH:24][CH:23]=2)[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(CCO)CC3)cc2C1
Reactant: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N=C(N)N1CCc2ccc(OCC3CCN(CCO)CC3)cc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-[1-(2-hydroxyethyl)-piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (60 mg) in chloroform (0.6 ml)solution was added trifluoroacetic acid (0.3 ml), and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was evaporated and to the obtained residue was added a hydrogen chloride—ethanol solution and insoluble material was removed. The resultant mixture was concentrated and dried under reduced pressure to give the title compound (40 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][N:13]([Si](C(C)(C)C)(C)C)[C:12](=[O:22])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[C:28]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.O>O1CCCC1.CCCCCC>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH:10]2[CH2:14][NH:13][C:12](=[O:22])[CH2:11]2)=[CH:3][C:2]=1[C:28]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1ccc(C2CC(=O)N([Si](C)(C)C(C)(C)C)C2)cc1Br
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2CNC(=O)C2)cc1C1(O)CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
2.2 g (0.7 mmol) of 4-(3-bromo-4-methoxy-phenyl)-1-tert-butyldimethylsilylpyrrolidin-2-one in 30 ml of absolute tetrahydrofuran is combined at -70° C. with 8.2 ml (0.7 ml) of a butyllithium solution in hexane. The mixture is allowed to warm up to 0° C., agitated at this temperature for 10 minutes, and again cooled to -70° C. Then a solution of 0.48 g of cyclopentanone in 10 ml of tetrahydrofuran is added dropwise thereto, the mixture is allowed to warm gradually to 0° C., and stirred at this temperature for one hour. After addition of 0.1 ml of water, the mixture is evaporated and chromatographed over silica gel with methylene chloride:acetone=1:1 as the eluent. After repeating chromatography of the corresponding fractions over silica gel with methylene chloride:ethanol=10:1 as the eluent, 110 mg of 4-[4-methoxy-3-(1-hydroxycyclopent-1-yl)phenyl]pyrrolidin-2-one is obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[C:19](OC(=O)C)(=[O:21])C>C(O)=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([CH:19]=[O:21])[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CNC1CCCc2ccc(OC)cc21
Solvent: O=CO
Product: COC(=O)CN(C=O)C1CCCc2ccc(OC)cc21
Reaction time: 70 h
Yield: 101.1 %

Procedure:
2.40 g of N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)glycine methyl ester are added dropwise with cooling to 5° C. to 5.52 g of formic acid. Additionally 1.79 g of acetic anhydride are added, and the mixture is kept at room temperature for 70 hours. Destillation under vacuum affords 2.7 g (97% of theory) of N-formyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)glycine methyl ester as a colourless resin.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].CCN(CC)CC.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:21])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(C=O)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 4-hydroxy-3-(methoxy)benzaldehyde (0.760 g; 5.00 mmol) and Et3N (1.39 mL; 10.0 mmol) in anhyd CH2Cl2 (10 mL) at 0° C. was added Tf2O (0.92 mL; 5.5 mmol), dropwise over 2 min. The mixture was allowed to warm slowly to room temperature (overnight), diluted with CH2Cl2, washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.01 (s, 3H), 7.42 (d, J=8.2 Hz, 1H), 7.52 (dd, J=8.2, 1.8 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 9.99 (s, 1H).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.C(P(CCCC)CCCC)CCC.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][S:60](=[O:64])(=[O:63])[CH2:59][CH2:58]1>C(Cl)Cl.CCOCC>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][S:60](=[O:64])(=[O:63])[CH2:59][CH2:58]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=S1(=O)CCN(CCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCS(=O)(=O)CC1
Reaction time: 18 h
Yield: 3.6 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (525 mg, 2.1 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0 mmol), (prepared as described for the starting material in Example 2), tributylphosphine (420 mg, 2.1 mmol) and 4-(2-hydroxyethyl)-1,1-dioxothiomorpholine (140 mg, 7.8 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (14 ml of a 1M solution, 14 mmol) and the precipitate was collected by filtration. The residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was triturated with ether/methylene chloride collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2-(1,1-dioxothiomorpholino)ethoxy)-6-methoxyquinazoline (120 mg, 36%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[C:25]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[O:37][CH:38]([CH3:40])[CH3:39])[C:30](OC)=O)#[N:26]>C1COCC1>[C:25]([C:27]1[CH:28]=[C:29]([C:30]2[O:1][N:2]=[C:3]([C:4]3[C:14]4[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10][CH2:9][C:8]=4[CH:7]=[CH:6][CH:5]=3)[N:22]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH:38]([CH3:39])[CH3:40])#[N:26]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=N)NO)c2CC1
Reactant: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C#N
Yield: 85.8 %

Procedure:
1,1-Dimethylethyl 6-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 15) (360 mg, 1.179 mmol) was dissolved in THF (50 ml) and stirred with sodium hydride (60% dispersion in mineral oil, 51.9 mg, 1.297 mmol) under argon at room temperature for 30 minutes. Then methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate (may be prepared as described in WO2005058848) (388 mg, 1.768 mmol) was added as a THF solution (5 ml) and the reaction heated at reflux temperature for 1.5 hours. The cooled reaction was evaporated and partitioned between DCM (100 ml) and water (100 ml). The water layer was washed with DCM (50 ml) and the combined DCM layers dried (hydrophobic frit) and evaporated. The product was isolated by silica chromatography (eluting with DCM) to give 1,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (505 mg, 1.011 mmol, 86% yield) as a white foam. δH (400 MHz, CDCl3) 8.41 (1H, s), 8.33 (1H, dd), 7.7 (1H, dd), 7.31-7.25 (2H, m), 7.13 (1H, d), 4.80 (1H, sept), 3.63-3.62 (4H, m), 3.3-3.2 (2H, m), 2.95-3.05 (2H, m), 1.47 (6H, d), 1.43 (9H, br.s); MS (ES) C27H30N4O4 requires 474; found 475 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[N:16]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])[CH2:20][CH2:19][CH2:18][CH2:17]1.C[O:29][C:30](=[O:39])[CH:31](Br)[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([CH2:32][CH:31]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:6]=[N:5]2)[C:30]([OH:29])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Oc1ccccc1N1CCCC1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2N2CCCC2)cc1=O
Yield: 57 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-pyrrolidin-1-yl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(2-pyrrolidin-1-yl-phenoxy)-6H-pyridazin-1-yl]propionic acid (9 g, 57%) as a yellow solid; LC-MS 398 [M+H+]; HPLC [acetonitrile (0.1% trifluoroacetic acid) in water (0.1% trifluoroacetic acid)=100%˜50%, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm], 254 nm, 97%, 214 nm, 96%. 1H-NMR (300 MHz, CDCl3): δ 7.82 (s, 1H), 7.15 (t, J=7.2 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.75-6.82 (m, 2H), 5.92 (s, 1H), 5.49 (s, 1H), 3.25 (s, 4H), 2.31 (s, 1H), 2.15 (s, 1H), 1.25-1.87 (m, 11H), 1.08-1.16 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]2[N:14]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]5[N:33]=[C:34]([CH:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=5)=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:69](=[O:79])[CH:70]([NH:74][C:75]([O:77][CH3:78])=[O:76])[CH:71]([CH3:73])[CH3:72])[CH2:9]1)=O)(C)(C)C.C(OC(=O)NC1CCCN(CC2NC(C3C=CC(C4C=CC(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)=CC=4)=CC=3)=CN=2)C1=O)(C)(C)C>>[CH3:78][O:77][C:75]([NH:74][CH:70]([CH:71]([CH3:73])[CH3:72])[C:69]([N:10]1[CH:11]([C:13]2[N:14]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]5[N:33]=[C:34]([CH:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])[CH:36]=5)=[CH:30][CH:31]=4)=[CH:20][CH:19]=3)[N:17]=2)[CH2:12][NH:8][CH2:9]1)=[O:79])=[O:76]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4cn(COCC[Si](C)(C)C)c(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)cn1COCC[Si](C)(C)C)C(C)C
Agent: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4cn(COCC[Si](C)(C)C)c(C5CNCN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)cn1COCC[Si](C)(C)C)C(C)C

Procedure:
3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazole was prepared using method 804 substituting 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester for {1-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C53H77N9O8Si2 calculated 1023.5 observed [M+1]+ 1024.7; rt=2.81 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>C1COCC1.C(OCC)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reaction time: 18 h
Yield: 42.4 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (263 mg, 1.39 mmol) in THF (3 mL) was added sodium hydride (55% dispersion in mineral oil, 66.7 mg, 1.53 mmol). After stirring for 15 min at room temperature methyl 6-chloronicotinate (286 mg, 1.67 mmol) was added and the reaction mixture was stirred for 18 h. The mixture was then diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic extracts dried over sodium sulfate. Filtration and concentration followed by purification by chromatography (silica, heptane:ethyl acetate 1:0 to 7:3) afforded the title compound (191 mg, 42%) as a colorless oil MS: m/e=325.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.C=C[C:13](=[O:17])[CH2:14][CH2:15][CH3:16].[CH:18]1C=CC=C[CH:19]=1>>[NH2:1][C:2]1[CH:18]=[CH:19][C:5]([OH:6])([C:7]([O:9][CH3:10])=[O:8])[CH2:4][C:3]=1[C:13](=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: C=CC(=O)CCC
Reactant: COC(=O)c1ccc(N)o1
Reactant: c1ccccc1
Product: CCCC(=O)C1=C(N)C=CC(O)(C(=O)OC)C1

Procedure:
A stirred solution of methyl 5-amino-2-furoate (1.4 g, 10 mmol) and 1-hexen-3-one (7 mL, 60 mmol) in benzene (50 mL) was heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 2:1 hexanes/ethyl acetate) provided methyl 4-amino-5-butyryl-1-hydroxycyclohexa-2,4-diene-1-carboxylate (1.25 g): 1H NMR (300 MHz, CDCl3): δ 6.26-6.23 (m, 1H), 6.09-6.05 (m, 1H), 3.80 (s, 3H), 3.02-2.96 (m, 1H), 2.89-2.84 (m, 1H), 2.42-2.37 (m, 2H), 1.64-1.57 (m, 2H), 0.96-0.88 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=[C:16]([C:27]#[N:28])[CH:15]=2)=[O:12])[N:7]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:47]>>[ClH:47].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=[C:16]([C:27]#[N:28])[CH:15]=2)=[O:12])[N:7]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH2:35][NH:34][CH2:33][CH2:32]3)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cc(C#N)cc(Oc4cccnc4)c3)ccc2C1
Product: CC(C)(C)c1cc(NC(=O)Nc2cc(C#N)cc(Oc3cccnc3)c2)n(-c2ccc3c(c2)CCNC3)n1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
In CH2Cl2 (8 mL) was placed tert-butyl 6-(3-tert-butyl-5-(3-(3-cyano-5-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (83 mg, 0.14 mmol). HCl (g) was bubbled into reaction mixture until the solution was saturated and the solution was then stirred at RT for 4 hrs. Concentration in vacuo gave a solid which was triturated with ether (10 mL). The solid was collected by filtration, washed with ether (2 mL) and dried to afford 1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-cyano-5-(pyridin-3-yloxy)phenyl)urea hydrochloric acid salt (69 mg, 93% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.26 (s, 9H), 3.06-3.09 (m, 2H), 3.35-3.40 (m, 2H), 4.28-4.30 (m, 2H), 6.33 (s, 1H), 7.23-7.24 (m, 1H), 7.31-7.34 (m, 1H), 7.39-7.47 (m, 4H), 7.63-7.67 (m, 2H), 7.77-7.78 (m, 1H), 8.52-8.54 (m, 1H), 8.59 (m, 1H), 8.93 (s, 1H), 9.42-9.43 (m, 2H), 10.16 (s, 1H); MS (ESI) m/z: 527.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[C@@H:18](O)[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:31])CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[C@H:18]([F:31])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCN(CC)S(F)(F)F
Reactant: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Solvent: O
Solvent: ClCCl
Product: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](F)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a stirred solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile obtained in example 21 (400 mg, 1.14 mmol) in DCM (10 mL) at 0° C. was added DAST (0.18 mL, 1.34 mmol) and stirred at room temperature for 1 h. Once the starting material had disappeared (monitored by TLC), the reaction mixture was diluted with DCM, water and extracted, organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 30% EtOAc in Hexane) provided the title compound (215 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH2:15][CH2:14]1)=[O:12].[CH:28]([CH:30]1[CH2:32][CH:31]1[C:33]([O:35][CH2:36][CH3:37])=[O:34])=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>>[CH2:36]([O:35][C:33]([CH:31]1[CH2:32][CH:30]1[CH2:28][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=2[Cl:1])=[O:12])[CH2:14][CH2:15]1)=[O:34])[CH3:37]
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CCOC(=O)C1CC1C=O
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Product: CCOC(=O)C1CC1CN1CCN(C(=O)c2cnccc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 150 °C
Yield: 45.6 %

Procedure:
To a solution of 0.10 g (0.25 mmol) [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 3) were added 0.036 g (0.25 mmol) ethyl 2-formyl-1-cyclopropane-carboxylate (commercially available, CAS RN 20417-61-2), 0.008 g (0.026 mmol) dibutyltin dichloride and 0.06 mL (0.50 mmol) phenylsilane. The resulting solution was heated for 10 min. in a microwave oven at 150° C. The light yellow solution was evaporated and dissolved in acetonitrile containing a few drops of N,N-dimethylformamide. The suspension was filtered using a syringe micro filter and purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 60 mg (46%) of the desired compound as a light brown foam. MS (ESI): m/z=526.13 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:25]1([C:24]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:37])=[CH:39][CH:40]=2)=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.807 g, 4.38 mmol) in dry dichloromethane (20 mL) cooled in an ice bath was added N,N-diisopropylethyl amine (1.14 mL). The solution was treated dropwise with a suspension of 4-benzoylbenzoyl chloride (prepared from 3 mmol of 4-benzoylbenzoic acid and oxalyl chloride) in 8 mL of dichloromethane. The solution was stirred overnight at room temperature, diluted with dichloromethane, washed with water, 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was flash chromatographed over silica gel Merck-60 with a solvent gradient of 5 to 20% of ethyl acetate in hexane to provide the title compound (1.2 g) as a crystalline solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16](=[O:17])[N:15]([CH2:18][C:19](O)=[O:20])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[S:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([N:28](CC)CC)C.O.N>C(Cl)Cl.C(OC(Cl)=O)C(C)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16](=[O:17])[N:15]([CH2:18][C:19]([NH2:28])=[O:20])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[S:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)Oc1ccc(C2Sc3ccccc3N(CC(=O)O)C2=O)cc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccc(C2Sc3ccccc3N(CC(N)=O)C2=O)cc1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a stirred solution of [2-(4-acetoxyphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-4-yl]acetic acid (compound No. 26, 4.6 g) and triethylamine (1.8 ml) in CH2Cl2 (45 ml), isobutylchloroformate (1.7 ml) is added dropwise at -12° C. After the addition, the reaction mixture is stirred for 10 minutes at the same temperature. Conc. ammonia water (7.2 ml) is added to the mixture. The mixture is stirred for 30 minutes at room temperature, and washed with saturated sodium hydrogen carbonate solution and N HCl. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3.5 g (76%) of the titled compound.