Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1(N=C=NC2CCCCC2)CCCCC1>C(OC)(C)(C)C.CN(C)C1C=CN=CC=1>[CH3:19][O:20][C:21]([C@H:22]([O:6][C:5](=[O:7])[CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC(=O)O
Reactant: COC(=O)[C@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@H](OC(=O)C/C=C(\C)CC/C=C(\C)CCC=C(C)C)c1ccccc1
Temperature: 28 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
To a solution of 12.5 g (50 mmol) (E,E)-4,8,12-trimethyl-trideca-3,7,11-trienoic acid (isomeric purity of 95%) [K. Ishihara et al., J. Am. Chem. Soc. 2002, 124, 3647-3655] in 100 ml methyl tert-butyl ether (MTBE) were added at r.t. 8.35 g (50 mmol) (R)-(−)-mandelic acid methyl ester, [α]D=−147.3 (c=1.0, MeOH), and 1.5 g 4-dimethylaminopyridine (DMAP). After stirring for 15 min at 28° C., 10.5 g (51 mmol) N,N′-dicyclohexylcarbodiimide (DCC) were added, during which the temperature raised to 35° C. The reaction mixture was stirred for 1.5 h at 38-40° C., cooled to r.t. and filtered. The resulting solution was concentrated in vacuo. The residue (23.1 g) was purified over 100 g silicagel, elution of the product with hexane/MTBE 1:1. Concentration of the combined fractions in vacuo and drying of the product in high vacuo (50° C./0.08 Torr) afforded 19.5 g (97%) of (E,E)-4,8,12-trimethyl-trideca-3,7,11-trienoic acid (R)-methoxycarbonyl-phenyl-methyl ester (1) in form of a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]([F:11])=[CH:9][C:8](Br)=[C:7]2[C:3]=1[C:4]([C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[N:5][NH:6]2.BrC1C=C2C(C(C3C=NC(OC)=CC=3)=NN2)=CC=1F.[CH2:40]([NH:42][C:43](=[O:60])[C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:45]=1)[CH3:41].C(=O)(O)[O-].[Na+]>C(O)(C)C.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>[CH2:40]([NH:42][C:43](=[O:60])[C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[C:46]([C:9]2[CH:8]=[C:7]3[C:3]([C:4]([C:13]4[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=4)=[N:5][NH:6]3)=[CH:2][C:10]=2[F:11])[CH:45]=1)[CH3:41]
Reactant: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1ccc(-c2n[nH]c3c(Br)cc(F)c(Br)c23)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(-c2n[nH]c3cc(Br)c(F)cc23)cn1
Agent: O=C([O-])O
Solvent: CC(C)O
Product: CCNC(=O)c1ccc(C)c(-c2cc3[nH]nc(-c4ccc(OC)nc4)c3cc2F)c1
Temperature: 150 °C

Procedure:
A mixture of 4,7-dibromo-5-fluoro-3-[6-(methyloxy)-3-pyridinyl]-1H-indazole and 6-bromo-5-fluoro-3-[6-(methyloxy)-3-pyridinyl]-1H-indazole (2:1) (Intermediate 9, 20 mg), N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 10, 32 mg), 1M aqueous sodium bicarbonate (1 ml) and tetrakis(triphenylphosphine)palladium (6 mg) in isopropanol was heated in a sealed vessel by microwave at 150° C. for 15 min. The reaction mixture was partitioned between chloroform and water and the organic layer was separated using a hydrophobic filter tube. The organic layer was concentrated under vacuum and the residue was purified by reverse phase preparative HPLC to give the title compound (3 mg).
Reaction SMILES: O1CCCC1.[O:6]([C:13]([C:15]1[C:23]2[N:22]=[N:21][NH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(OC(Cl)(Cl)Cl)[O:25][C:26]([Cl:29])(Cl)Cl>C(OCC)(=O)C>[C:26]([Cl:29])(=[O:25])[NH2:20].[O:6]([C:13]([C:15]1[C:23]2[N:22]=[N:21][NH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C(Oc1ccccc1)c1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)Cl
Reaction time: 1 h

Procedure:
A tetrahydrofuran (75 mL) solution of phenoxycarbonylbenzotriazole (19.1 g) was dropped into an ethyl acetate solution (100 mL) of bis(trichloromethyl) carbonate (9.5 g) at 10° C. The resultant solution was stirred at 40° C. for 3 hrs. After the solvent was distilled away at reduced pressure, 200 mL of hexane were added to the concentrated residue, and the material was stirred for 1 hr. The crystals were filtered out and dried to obtain carbamoyl chloride of phenoxycarbonylbenzotriazole (to be abbreviated as PBT-COCl hereinafter) (22.4 g).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[C:20]([Cl:28])[CH:19]=1>C(O)(=O)C>[C:23]([C:22]1[CH:26]=[C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=[C:20]([Cl:28])[C:21]=1[OH:27])([OH:25])=[O:24]
Reactant: Nc1cc(Cl)c(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)cc(Cl)c1O

Procedure:
a mixture of 10.3 g. (0.047 mole) of 2-phenacylcyclohexanone, 8.8 g. (0.047 mole) of 5-amino-3-chlorosalicylic acid, and 45 ml. of glacial acetic acid was heated under reflux for 1 hour, cooled and filtered. The collected solid was recrystallized from acetonitrile to provide 13.3 g. (77%) of crystals, m.p. 223°-225°.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]2[S:15]([O-:18])(=[O:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:19]>O.[C].[Pd]>[C:1]1([NH:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([O-:18])(=[O:17])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:19]
Reactant: O=S(=O)([O-])C1C=CC=CC1=NNc1ccccc1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])c1ccccc1NNc1ccccc1
Yield: 86 %

Procedure:
104 g of phenylhydrazine was dissolved in 800 ml of methanol, and a solution obtained by dissolving 56 g of sodium o-formylbenzenesulfonate in 200 ml of methanol was dropwise added thereto at room temperature. The resulting mixture was heated for 2 hours under reflux with stirring. After cooling, the crystal formed was separated by filtration and then washed with methanol to obtain 69 g of sodium 2-phenylhydrazonobenzenesulfonate (Intermediate A). 50 g of Intermediate A thus obtained was dissolved in 250 ml of water and then hydrogenated in an autoclave by adding palladium-carbon catalyst thereto. After the catalyst was removed by filtration, 250 ml of isopropanol was added to the hydrogenated product whereupon a colorless product precipitated out. This product was separated out by filtration and washed with isopropanol and then dried to obtain 43 g of sodium 2-phenylhydrazinobenzenesulfonate (Intermediate B). Next, 40 g of Intermediate B, 19 g of diethyl malonate, 25 g of sodium methylate (28% methanol solution) and 100 ml of n-butanol were blended and heated for 10 hours under reflux. N-butanol was concentrated and 200 ml of water was added to the residue. Next, the aqueous layer was made acidic with concentrated hydrochloric acid, whereby a crystal precipitated out. This was separated out by filtration and washed with a small amount of methanol to give 39 g of Intermediate C (1-phenyl-2-(2-sulfobenzyl)- 3,5-pyrazolidinedione sodium salt).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[C:5]([CH3:19])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[Cl:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:4]([F:20])[C:5]([CH3:19])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: Cc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A suspension of 0.38 g (1.21 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.42 g (4.88 mmol) of piperazine and 20 mL of acetonitrile was refluxed for 4 hours, and then stirred at room temperature overnight. The precipitate was collected by filtration, washed with water and acetonitrile, and dried in vacuo to give 0.32 g of the title compound, mp 234°-235° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC2CCOCC2)=O)CC1)#N>>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:26])([F:25])[F:27])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCCC2)CC1
Agent: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCOCC2)CC1
Product: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2OC2CCCC2)CC1

Procedure:
The title compound was prepared in analogy to example 175 using (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-cyclopentyloxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 195) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-(tetrahydro-pyran-4-yloxy)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 469.2 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)=[CH:15][CH:14]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCc2cc(OCc3ccc(F)cc3)ccc21
Reaction time: 12 h

Procedure:
The 5-hydroxy-1-indanone (20 g, 134.9 mmol) was solved in dry in N,N′-dimethylformamide (120 mL) and the 4-fluorobenzyl bromide (18.2 mL, 148.4 mmol) was added followed by potassium carbonate anhydrous (24.2 g, 175.4 mmol) and the mixture was stirred for 12 h to 110 IC. Water was added and the resulting precipitate was filtrated and dried (34.6 g, 100%). MS: m/e=256.1 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 12 h
Yield: 80.5 %

Procedure:
To a stirred solution of 5-Bromo-pyridin-2-ylamine (100 mg, 0.578 mmol) in dry THF was added acetic anhydride (70.25 mg, 0.693 mmol). The reaction mixture was stirred at 20° C. for 12 hrs. THF was distilled out and to it was added ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and dried over anhy sodium sulphate. Removal of the solvent afforded N-(5-Bromo-pyridin-2-yl)-acetamide (100 mg, 80%). This was carried to next step without further purification.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>N.CO>[C:29]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:37])=[O:36])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cccc(-c2ccccc2)c1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Biphenyl-3-sulfonyl chloride (25 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (2.0 mg). MS m/z 405 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[O:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30](O)=[O:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C@H:26]4[CH2:27][CH2:28][CH2:29][O:25]4)=[O:31])[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)[C@H]2CCCO2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a mixture of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (62.4 mg, 0.167 mmol), (R)-(+)-tetrahydro-2-furoic acid (21.0 uL, 0.217 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (118.4 mg, 0.2284 mmol), and 4-dimethylaminopyridine (4.083 mg, 0.03342 mmol) was added N,N-dimethylformamide (2.0 mL, 26 mmol) and N,N-diisopropylethylamine (88 uL, 0.50 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate and washed twice with water and once with brine. The organic layer was dried over MgSO4, and filtered through a plug of silica gel, rinsing with ethyl acetate. The filtrate was concentrated and then purified via reverse phase HPLC and lyophilized to yield 45.0 mg (65%) of (R)-N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)tetrahydrofuran-2-carboxamide. LCMS (ESI): RT (min)=4.594, M+H=416.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.64 (s, 1H), 9.18 (s, 1H), 8.49 (s, 1H), 7.99 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.68 (dd, J=11.6, 1.9 Hz, 2H), 7.64 (dd, J=8.3, 2.1 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 4.38 (dd, J=8.1, 5.6 Hz, 1H), 3.98 (dd, J=14.5, 6.8 Hz, 1H), 3.82 (dd, J=14.5, 6.9 Hz, 1H), 2.23 (s, 3H), 2.22-2.14 (m, 1H), 2.13-2.03 (m, 1H), 1.98 (td, J=12.6, 6.6 Hz, 1H), 1.86 (p, J=6.9 Hz, 2H), 0.95-0.77 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[N:18][NH:19]2)=[CH:15][CH:14]=1)=O>>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]\[C:13]1[CH:21]=[C:20]3[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[N:18][NH:19]3)=[CH:15][CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2c(/C=C/c3ccc(C(=O)O)cc3)n[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccc(C(=O)O)cc3)n[nH]c2c1
Yield: 20.9 %

Procedure:
The title compound (17 mg, 21%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using indolin-2-one (26.6 mg, 0.2 mmol) and (E)-4-(2-(6-formyl-1H-indazol-3-yl)vinyl)benzoic acid (58.4 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H), 12.90 (s, br, 1H), 10.64 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.91 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.80 (s, 1H), 7.74 (d, J=16.8 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H partially overlapping with the singlet at 7.62), 7.62 (s, 1H partially overlapping with the doublet at 7.63), 7.24 (t, J=7.4 Hz, 1H), 6.91-6.82 (m, 2H); MS ESI 408.2 [M+H]+, calcd for [C25H17N3O3+H]+ 408.1.
Reaction SMILES: [Si](OC[C:20]1([C:36]#[N:37])[CH2:24][CH:23]=[CH:22][N:21]1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:56]1CCC[CH2:57]1>>[CH2:34]([O:33][C:31]([C:28]1[CH:27]=[CH:26][C:25]([N:21]2[C:22]([CH2:57][OH:56])=[CH:23][CH:24]=[C:20]2[C:36]#[N:37])=[CH:30][CH:29]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)c1ccc(N2C=CCC2(C#N)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(=O)c1ccc(-n2c(C#N)ccc2CO)cc1

Procedure:
To a solution of 2-tert-butyldiphenylsilyloxymethyl-1-(4-ethoxycarbonylphenyl)pyrrole-2-carbonitrile (1.9 g) in tetrahydrofuran (19 ml) was added tetrabutylammonium fluoride (5.6 ml, 1M tetrahydrofuran solution) through syringe at ambient temperature. The mixture was stirred for half an hour at the same temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with aqueous hydrochloric acid, water and brine, and then dried, and concentrated in vacuo. The oily residue was chromatographed on silica gel (elution by ethyl acetate/n-hexane=1/1) to give 1-(4-ethoxycarbonylphenyl)-5-hydroxymethylpyrrole-2-carbonitrile (702.5 mg) as an oil.
Reaction SMILES: Br.[CH:2]1([C:5]([CH:7]2[CH2:9][CH2:8]2)=[NH:6])[CH2:4][CH2:3]1.[Cl:10]([O-:14])(=[O:13])(=[O:12])=[O:11].[NH4+]>CS(C)=O>[Cl:10]([O-:14])(=[O:13])(=[O:12])=[O:11].[N+:6]12[CH2:9][CH2:8][CH2:7][C:5]=1[CH2:2][CH2:3][CH2:4]2
Reactant: N=C(C1CC1)C1CC1
Agent: Br
Agent: [NH4+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CS(C)=O
Product: C1CC2=[N+](C1)CCC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of dicyclopropylmethanimine hydrobromide (1.00 g, 5.26 mmol) in 6.0 ml of dimethyl sulfoxide was added 1.29 g (10.5 mmol) of ammonium perchlorate. The mixture was heated with stirring at 100° C. for 1 hour. The solvent was distilled out in vacuo and isobutyl alcohol was added to the residue. Precipitated crystals was obtained and recrystallized from ethanol to afford 0.90 g (Yield: 82%) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F)C1CC1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F)C1CC1

Procedure:
The title compound was prepared from [2-amino-5-(cyclopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example J19) (259 mg, 0.75 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (192 mg, 0.78 mmol) according to the general procedure M. Obtained as a yellow solid (228 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6]([F:27])([F:26])[CH2:7]2.[O:28]1[C:32]2=[CH:33][CH:34]=[CH:35][C:36]([C:37](O)=[O:38])=[C:31]2[CH2:30][CH2:29]1>>[F:26][C:6]1([F:27])[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:37]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[O:28][CH2:29][CH2:30][C:31]=23)=[O:38])[CH2:7]1
Reactant: O=C(O)c1cccc2c1CCO2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCO3)c1

Procedure:
prepared by reaction of (1S,2S,5R)-(2-aminomethyl-7,7-difluoro-3-aza-bicyclo[3.3.0]-oct-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-dihydro-benzofuran-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:12][S:13]([O:10][CH2:9][C:5]1[C:4]([F:11])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[F:8])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1c(F)cc(Br)cc1F
Solvent: ClCCl
Product: CS(=O)(=O)OCc1c(F)cc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4-bromo-2,6-difluorophenyl)methanol (24.8 g, 112.1 mmol) in CH2Cl2 (400 mL) was added TEA (22.68 g, 224.28 mmol) and methylsulfonyl chloride (12.84 mL, 156.9 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h, quenched with aqueous NH4Cl, and diluted with EtOAc. The organic layer was washed with 1N HCl (2×), H2O, brine, dried over MgSO4, and condensed to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1OC
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1OC
Reaction time: 7 h
Yield: 88.5 %

Procedure:
To a solution of 1000 g (6.024 mol) of 3,4-dimethoxybenzaldehyde in 3 L pyridine, 1378.3 g (13.25 mol) of malonic acid and 100 mL of piperidine were added. The resulting mixture was stirred at 105° C. to 110° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and slowly quenched the reaction mixture into 10 L of 5% sodium hydroxide solution at 25° C. to 30° C. (pH: 9-10). The reaction mixture was washed with ethyl acetate (2×5 L) and the organic layer separated was washed with 2 L of 5% sodium hydroxide solution. The aqueous layers were combined and cooled to 15° C. to 20° C. The aqueous layer was acidified slowly with 2.5 L of 50% sulphuric acid below 20° C. (pH: 1-2). After an additional 30-45 min stirring at 15° C. to 20° C., the solid obtained was collected by filtration, washed with 10 L of water followed by 4 L of n-hexane. The partially dried compound was unloaded into trays and dried at 55° C. to 60° C. for 8-10 h to give 1110 g of the title compound.