Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1.FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[CH3:1][C@@H:2]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: C[C@H](Cn1cccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: NCCN
Solvent: O
Product: C[C@H](Cn1cccn1)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-pyrazol-1-yl-ethyl)-amide (86 mg, 0.16 mmol) was dissolved in dichloromethane (2.2 ml) and cooled in ice bath. Trifluoroacetic acid (1 ml) was slowly added and the reaction was stirred at room temperature for 2 h. The reaction was evaporated and the residue was dissolved in dichloromethane (1 ml). Ethylenediamine (0.63 ml, 9.4 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The resulting precipitate was filtered off, rinsed with water and diethyl ether and dried under high vacuum to give 37 mg (57%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-pyrazol-1-yl-ethyl)-amide. MS: (M+Na)+=441; mp=252-253° C. 1H NMR (300 MHz, DMSO-d6) δ: 9.08 (s, 1H), 8.46 (s, 1H), 8.21-8.33 (m, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.63-7.75 (m, 2H), 7.31-7.40 (m, 1H), 6.97-7.10 (m, 1H), 6.12-6.23 (m, 1H), 4.46-4.63 (m, 1H), 4.32-4.44 (m, 2H), 4.14 (s, 3H), 1.23 (d, J=6.4 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:19].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH3:17][N:15]([CH3:16])[C:13]([CH2:12][C:6]1([CH2:5][CH2:4][CH2:3][C:2]([OH:19])=[O:1])[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)=[O:14]
Reactant: CN(C)C(=O)CC1(CCCCO)C=CCCC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CC1(CCCC(=O)O)C=CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the relevant 2-[1-(4-hydroxybutyl)-cyclohex-2-enyl]-N,N-dimethyl-acetamide isomer (6) or (6′) (13.7 g, 57.1 mmol) in DMF (200 mL) was added pyridinium dichromate (65.3 g, 241.0 mmol) and the mixture stirred at room temperature for 24 hours. The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (5×). The combined organic layers were washed with a saturated NaCl solution and dried over anhydrous MgSO4. The solvent was removed in vacuo, the residual DMF was removed by vacuum distillation (Kugelrohr-type) to afford 13.3 g of the desired product which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9]C)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH3:19])[N:13]=[N:12]1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH3:19])[N:13]=[N:12]1
Reactant: CCCn1nnn(-c2cc(OC)c(F)cc2F)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCn1nnn(-c2cc(O)c(F)cc2F)c1=O
Temperature: 25 °C
Reaction time: 70 h
Yield: 81.6 %

Procedure:
Under a dry nitrogen atmosphere a stirred solution of 0.18 G (0.00067 mole) of 1-(2,4-difluoro-5-methoxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (compound 10) in 5 mL of methylene chloride was cooled to -40° C. To this cold solution was added dropwise a solution of 0.5 g (0.002 mole) of boron tribromide in 5 mL of methylene chloride. After complete addition, the mixture was allowed to warm to room temperature and was stirred for approximately 70 hours. The mixture was poured into ice water and the two phases separated. The aqueous phase was extracted with methylene chloride. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to leave 0.14 g of 1-(2,4-difluoro-5-hydroxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one as a solid, mp 65°-67° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[C:31]1([NH:30][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNc4ccccc4)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15g) and aniline (0.1ml) in dimethylformamide (10ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give crude crystals, which were recrystallized from ethanol-hexane to give N-(4-((phenylamino)methyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 115) (0.1g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A mixture of 82 (0.5 g, 1.9 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 hr, the reaction was cooled and then diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4 and concentrated to give a solid. The solid was triturated with CH2Cl2 and filtered to give a solid (0.20 g, 47%); Mp=216-218° C.; 1H NMR (DMSO-d6) δ 9.95 (br s, 1 H), 7.74 (d, 2 H, J=8.8 Hz), 7.66 (d, 1 H, J=1.9 Hz), 7.59 (d, 1 H, J=8.8 Hz), 7.27 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 7.17 (s,1 H), 6.88 (d, 2 H, J=8.7 Hz); MS 243/245 [M−H]−
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([O:33][CH3:34])[CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH2:16][C:17]2[CH:21]=[C:20]([CH3:22])[O:19][N:18]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:26]([O:33][CH3:34])[CH:25]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Cc1cc(CN(C(=O)OC(C)(C)C)c2cnccc2I)no1
Product: COc1cc(F)ccc1-c1ccncc1N(Cc1cc(C)on1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from tert-butyl 4-iodopyridin-3-yl((5-methylisoxazol-3-yl)methyl)carbamate and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 18 hours at 90° C. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (88%). MS (ESI): m/z=414.182 [M+H]+.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10][C:11]1[N:16]=[C:15](/[C:17](=[N:22]/[S@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])/[CH2:18][CH2:19][O:20][CH3:21])[C:14]([F:29])=[C:13]([Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:12]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.C[Si](C)(C)Cl.[Zn].[Cu]Cl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[C@@:17]([C:15]1[C:14]([F:29])=[C:13]([Si:30]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:35][CH3:36])[CH:12]=[C:11]([Br:10])[N:16]=1)([NH:22][S@:23]([C:25]([CH3:26])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][O:20][CH3:21])[CH3:7]
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(/C(CCOC)=N/[S@@](=O)C(C)(C)C)c1F
Reactant: CCOC(=O)C(F)(F)Br
Agent: Cl[Cu]
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@](CCOC)(N[S@@](=O)C(C)(C)C)c1nc(Br)cc([Si](CC)(CC)CC)c1F
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a suspension of zinc (3.07 g, 47 mmol) and copper(I) chloride (233 mg, 2.349 mmol) in dry THF (90 ml) were added 4 drops of trimethylchlorosilane under nitrogen to activate the zinc. After 10 minutes ethyl 2-bromo-2,2-difluoroacetate (9.54 g, 47 mmol) was added slowly by syringe over a period of 20 minutes between 25° and 30° C. adjusted with an external cooling bath (exothermic). The reaction mixture was kept in an ultrasound bath for 30 minutes. This black fine suspension was added drop wise to a solution of (S)-2-methyl-propane-2-sulfinic acid [1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-3-methoxy-prop-(E)-ylidene]-amide (7.51 g, 15.66 mmol) in dry THF (75 ml) at 0° C. under inert atmosphere. After 15 min the reaction mixture was kept at 50° C. for 2 h and was then added to a cold aq. ammonium chloride solution (5%). Ethyl acetate was added and the organic phase was washed with aq. citric acid (5% solution), water, sat. sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The crude yellowish oil (9.77 g, roughly a 4:1 mixture of diastereoisomers) was chromatographed over silica gel (Redisep column 120 g, cyclohexane/ethyl acetate 85:15) to give the title compound as a yellow oil. 6.11 g yellow oil. (64.6% yield).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[CH3:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].I[C:44]1[CH:48]=[CH:47][N:46]([CH3:49])[N:45]=1.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.O.CN(C)C=O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[CH3:18])[CH:9]=[C:10]([C:44]3[CH:48]=[CH:47][N:46]([CH3:49])[N:45]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Cn1ccc(I)n1
Reactant: CC1CCCCC1n1cc(Br)c2[nH]nc(N)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCCC1n1cc(-c2ccn(C)n2)c2[nH]nc(N)c2c1=O
Temperature: 110 °C
Yield: 25.4 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-methylcyclohexyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step G (200 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (861 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (22.0 mg), potassium acetate (121 mg) and N,N-dimethylformamide (3.0 mL) was heated with microwave irradiation at 110° C. for 5 hr. The reaction mixture was cooled to room temperature, and 3-iodo-1-methyl-1H-pyrazole (384 mg), aqueous sodium carbonate solution (2 M, 0.610 mL) and tetrakis(triphenylphosphine)palladium(0) (71.0 mg) were added thereto at room temperature. The reaction mixture was heated with microwave irradiation at 140° C. for 1 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/dichloromethane) to give the title compound (51.0 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:16][C@@:17]([C:22]([NH2:24])=[O:23])([CH:19]([CH3:21])[CH3:20])[NH2:18].C(=O)(O)[O-].[Na+]>CS(C)=O>[C:22]([C:17]([NH:18][CH2:2][C:3]1[N:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:16])[CH:19]([CH3:21])[CH3:20])(=[O:23])[NH2:24]
Reactant: CC(C)[C@](C)(N)C(N)=O
Reactant: CCOC(=O)c1cc(CC)cnc1CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(CC)cnc1CNC(C)(C(N)=O)C(C)C

Procedure:
A mixture of 77 g of ethyl 2-chloromethyl-5-ethylnicotinate (0.338 mol), 44 g of α-methylvalinamide (0.338 mol) and 33.5 g of sodium bicarbonate (0.4 mol) in 60 mL dimethylsulfoxide is stirred and heated at 80° for 16 hours. The reaction is partitioned between 1:1 ethylacetate-hexane and water. The organic layer is washed thoroughly with water, dried, and concentrated in vacuo to a gum. Chromatography of this gum on silica gel using hexane-ethyl acetate mixtures as eluant affords the title product, mp 68°-72°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][CH:7]1[C:11](=O)[CH2:10][CH2:9][O:8]1.[OH-].[Na+]>O>[CH3:6][CH:7]1[O:8][CH2:9][CH2:10][C:11]21[S:5][CH2:4][CH2:3][NH:2]2
Reactant: CC1OCCC1=O
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1OCCC12NCCS2
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To 15.4 g of 2-aminoethanethiol-HCl (0.13 mole) dissolved into 50 ml of water were added slowly 20 g of 2-methyl-3-tetrahydrofuranone (0.2 mole) (solution pH=2.7). The pH was kept to neutrality by adding 10% aqueous NaOH. After 1 hour, extraction of the water solution with Et2O, drying of the organic phase with MgSO4 and distillation of the crude product (Bp 1.7 mbar, 93°-96° C.) gave 18 g of the desired product (yield=90%). The product was obtained as a mixture of two diastereoisomers (isomers a and b).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH:6]([CH2:7][CH2:8][CH3:9])[C:5]2[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[N+:16]([O-])([O-:18])=[O:17].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[O:15]=[S:2]1(=[O:1])[CH:6]([CH2:7][CH2:8][CH3:9])[C:5]2[C:10]([Cl:14])=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:4]=2[NH:3]1
Reactant: CCCC1c2c(Cl)cccc2NS1(=O)=O
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCC1c2c(Cl)ccc([N+](=O)[O-])c2NS1(=O)=O
Reaction time: 24 h
Yield: 17.8 %

Procedure:
1,3-dihydro-2,2-dioxo-4-chloro-3-propyl-2,1 -benzisothiazole (131 mg, 0.54 mmol) was dissolved in chloroform (30 ml) followed by the addition of ammonium nitrate (44 mg, 0.54 mmol) and trifluoroacetic anhydride (397 mg, 214.4 mmol). The mixture is allowed to stir. After 24 hours, the reaction mixture is diluted with chloroform and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (50% Ethyl acetate/Hexane) gave the desired product (28 mg, 20%). EI-MS m/z 289.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]=C2CCCCI2C2C=CC=CC=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(#N)C.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][N:22]2[S:19]([C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N=C2CCCCI2c2ccccc2)cc1
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2c2ccc(Cl)cc2)cc1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a suspension of 1-chloro-4-vinylbenzene (0.1195 ml, 0.9957 mmol), tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.01856 g, 0.04979 mmol), and 4 angstrom molecular sieves (300 mg) in dry acetonitrile (2.5 ml) degassed with argon was added [N-[(p-nitrophenyl)sulfonyl]imino]phenyliodinane (0.6037 g, 1.494 mmol) portion-wise over 2 hours as a solid. It was stirred overnight under argon, then was loaded directly onto a Biotage SP1 system eluting with a 2-30% linear gradient of EtOAc in hexanes to yield 276 mg of the title compound (81.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[O:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.O.O[N:50]1[C:54]2[CH:55]=CC=C[C:53]=2N=N1.C(N)(C)C>ClCCl.O>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[O:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:11])([CH3:12])[C:8]([NH:50][CH:54]([CH3:55])[CH3:53])=[O:9]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)C(=O)O)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)C(=O)NC(C)C)c1OC
Reaction time: 0.17 h
Yield: 25.3 %

Procedure:
To a stirring solution of 3-(2,3-dimethoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)-2,2-dimethylpropanoic acid (100 mg, 0.25 mmol) in dichloromethane (10 mL) was added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl) (71.6 mg, 0.375 mmol), triethylamine (1 mL, 0.75 mmol) and 1-hydroxybenzotriazole hydrate (HOBT) (76.5 mg, 0.50 mmol) and stirred for 10 min. To this isopropyl amine (59 mg, 1.00 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid (27 mg, 27%).
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][NH:14][C:15]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])=[N:16][N:17]=1>O.C(O)(=O)C>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[N:16][C:15]([C:18]2[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=2[F:24])=[N:14][N:13]=1
Reactant: Fc1cccc(F)c1C1=NN=C(c2ccccc2Br)NN1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cccc(F)c1-c1nnc(-c2ccccc2Br)nn1
Yield: 95.7 %

Procedure:
A solution of 0.26 g of sodium nitrite in 1 ml of water is dropped to a solution containing 0.62 g of 3-(2-bromophenyl)-6-(2,6-difluorophenyl)-1,2-dihydro-1,2,4,5-tetrazine [prepared in the preceeding step c.)] in 2 ml of glacial acetic acid at room temperature under stirring. The progress of the reaction is followed by thin layer chromatography (TLC). The reddish-violet crystals are filtered, washed with water until neutral and dried to give 0.59 g of crystalline desired product, i.e. the title compound of Example 1. This crude product is recrystallized from a mixture of gasoline and acetone, m.p.: 168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1cncc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)c1cc(Cl)ccc1COc1cncc(F)c1)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-{[(5-fluoropyridin-3-yl)oxy]methyl}benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [CH3:1][N:2]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[N:22][CH:23]=1)[CH:3]1[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[NH:11][C:10]3=[O:17].FC(F)(F)C(O[C:32]1[C:37]([F:38])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42])=O.FC1C(O)=C(F)C(F)=C(F)C=1F.FC(F)(F)C(O)=O>CC(N(C)C)=O.N1C=CC=CC=1>[CH3:1][N:2]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([O:26][C:32]2[C:33]([F:42])=[C:34]([F:41])[C:35]([F:40])=[C:36]([F:39])[C:37]=2[F:38])=[O:25])=[N:22][CH:23]=1)[CH:3]1[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[NH:11][C:10]3=[O:17]
Reactant: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)O)nc1)CC3
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)nc1)CC3
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylic acid (0.01 g), pentafluorophenyl trifluoroacetate (0.16 g; prepared by the reaction of pentafluorophenol and trifluoroacetic acid), pyridine (0.045 g) and DMA (5 ml) was stirred at ambient temperature for 5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of ethyl acetate and methanol as eluant. There was thus obtained pentafluorophenyl 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-pyridine-2-carboxylate as a foam (0.1 g);
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:5][CH:4]([C:6]2([C:9]3[N:14]=[C:13]4[S:15][C:16]([C:18]5[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=5[F:26])=[N:17][C:12]4=[CH:11][CH:10]=3)[CH2:8][CH2:7]2)[CH2:3]1.Cl.[NH:29]1[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1>>[F:27][C:2]1([F:1])[CH2:3][CH:4]([C:6]2([C:9]3[N:14]=[C:13]4[S:15][C:16]([C:18]5[CH:25]=[CH:24][C:21]([CH2:22][N:29]6[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]6)=[CH:20][C:19]=5[F:26])=[N:17][C:12]4=[CH:11][CH:10]=3)[CH2:7][CH2:8]2)[CH2:5]1
Reactant: COC(=O)C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(C5CC(F)(F)C5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(C6CC(F)(F)C6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 4-(5-(1-(3,3-difluorocyclobutyl)cyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzaldehyde (112.0 mg, 0.288 mmol) and methyl azetidine-3-carboxylate hydrochloride (65.6 mg, 0.433 mmol) according to Reference R and the general procedure for reductive amination gave methyl 1-(4-(5-(1-(3,3-difluorocyclobutyl)cyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate as a white solid. MS (ESI) m/z: Calculated: 487.2; Observed: 487.8 (M++1).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([C:14]#[N:15])[C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([C:14]#[N:15])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CC(C(=O)O)=C(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To 200 ml. of methanol:water (1:4) solution containing 55 g. (0.2 mole) of ethyl β,β-diphenyl-α-cyanoacrylate (CYASORB N-35, American Cyanamid), 18 g. of 50% NaOH (0.22 mole) is added and the soluton is stirred at about 20° C. overnight. After it is washed with ether, the aqueous solution is neutralized with dilute HCl to precipitate the product. The yield is 48 g., 97%, m.p., 207°-209° C.