Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:11](Br)[N:10]=[C:9]1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([S:33]([N:36]1[C:40]2[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH2:48])(=[O:35])=[O:34])([CH3:32])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C>[CH:30]([S:33]([N:36]1[C:40]2[CH:41]=[C:42]([C:11]3[N:10]=[C:9]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[F:29])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]=3[C:13]3[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=3)[CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH2:48])(=[O:34])=[O:35])([CH3:32])[CH3:31]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Reactant: Fc1cc(F)cc(-c2c(Br)nc(-c3ccc(F)cc3F)n2Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(-c4ccc(F)cc4F)n(Cc4ccccc4)c3-c3cc(F)cc(F)c3)cc21
Temperature: 25 °C
Yield: 104.3 %

Procedure:
Reflux a mixture of 1-benzyl-4-bromo-5-(3,5-difluoro-phenyl)-2-(2,4-difluoro-phenyl)-imidazole (0.061 g, 0.13 mmol), 1-isopropylsulfonyl-2-amino-benzimidazole-6-boronic acid (0.113 g, 0.40 mmol) (described in preparation 56), trans-dichlorobis(triphenylphosphine) palladium (II) (0.009 g, 0.013 mmol), 2 M sodium carbonate (0.20 mL) and 1,2-dimethoxyethane (5 mL) for 18 hours. Cool to ambient temperature, dilute with ethyl acetate and wash with saturated sodium bicarbonate, saturated sodium chloride, dry with magnesium sulfate, filter and remove solvents under reduced pressure. Purify on silica gel with dichloromethane/methanol mixtures to provide the title compound (0.084 g). MS(ES+): m/z=620.1 (M+H)+
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]=[C:12]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15][CH2:14][O:13]1.O>ClCCl>[OH:13][CH2:14][CH2:15][C:16]1([CH2:12][OH:11])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCOC2=O)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)(CCO)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
Diisobutylaluminium hydride (1.0M in dichloromethane, 3.60 mL, 3.60 mmol) was added over 10 minutes to a stirred, cooled (−78° C.) solution of 1,1-dimethylethyl 1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 23, 400 mg, 1.57 mmol) in dichloromethane (4 mL) and the mixture stirred at −78° C. for 3 hours, then at 0° C. for 2 hours. Water (1.6 mL) was added very slowly at 0° C. and the mixture was warmed to room temperature and stirred overnight. The mixture was filtered through Hyflo™, washing with dichloromethane, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to give the title compound (255 mg, 63%). m/z (ES+) 260 (M+1).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([OH:19])=O)[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH2:27][S:28][CH3:29])[NH2:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>ClCCl.O>[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH2:27][S:28][CH3:29])[NH:25][C:17](=[O:19])[C@@H:12]([C@@H:13]([CH2:15][CH3:16])[CH3:14])[NH:11][S:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])=[O:10]
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
To a solution of N-(benzylsulfonyl)-D-isoleucine (6.3 g, 22.2 mmol) and L-methionine methyl ester hydrochloride (6.7 g, 33.3 mmol) in dichloromethane (100 ml), HOBt (4.1 g, 26.6 mmol), EDC HCl (5.1 g, 1.2 mmol) and N-methylmorpholine (3.4 g, 33.3 mmol) were added and stirred at room temperature under a nitrogen stream. After 12 hours, water was added to the reaction mixture, which was then extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated under reduced pressure and the residue was applied to flash column chromatography (Merck Silicagel 60; mobile phase: dichloromethane) to give N-(benzylsulfonyl)-D-isoleucyl-L-methionine methyl ester (6.4 g, 14.9 mmol; yield 67%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Nc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
4-Hydroxybenzoic acid (1.01 g, 7.31 mmol) and 4-aminophenol (1.19 g, 10.9 mmol) were dissolved in 15 mL of dry DMF. To the above solution EDCl (1.40 g, 7.31 mmoL) was added in one portion and the resulting mixture was stirred at rt overnight under nitrogen. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated, washed consecutively with 1 N HCl, water, saturated sodium bicarbonate solution, water, and brine, and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography using EtOAc in hexane as an eluent (10% to 20%) to give 580 mg (34% yield) of 4-hydroxy-N-(4-hydroxyphenyl)-benzamide. MS (ES) m/z: 230.04 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([C:11](=[O:13])[N:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:14][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:13])[N:12]=[C:3]1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cn1c(CCl)nc(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(COc2ccc(C=O)cc2)nc(=O)c2ccccc21
Yield: 0.6 %

Procedure:
The title compound (3.64 mg, 65%) was prepared from 2-chloromethyl-1-methyl-4-oxo-1,4-dihydroquinazoline (416 mg, 2.0 mmol) and 4hydroxybenzaldehyde (244 mg, 2.0 mmol) in the presence of K2CO3 (276 mg, 2.0 mmol) as base by a similar procedure to that described in preparation 13.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[C:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nccc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1ccc(-c2nccc3ccccc23)cc1
Yield: 81.2 %

Procedure:
1-Chloroisoquinoline (5.0 g, 30 mmol) and phenylboronic acid (4.5 g, 37 mmol) was dissolved into 100 mL of ethylene glycol dimethyl ether, followed by the addition of triphenylphosphine (0.7 g, 3 mmol) and Pd(II) acetate (0.17 g, 0.75 mmol). The reaction mixture was refluxed for 16 hours. The reaction mixture was cooled and the aqueous layer discarded. Additional ethyl acetate was added and the solvent was washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to give 1-phenylisoquinoline (5.0 g, 79% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([C:35]#[N:36])=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:15]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]2[C:10]([C:35]#[N:36])=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:15]=2)=[O:45])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(Sc3ccc(Cl)cc3)c2C#N)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(S(=O)c3ccc(Cl)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
N-(4-{4-[(4-chlorophenyl)sulfanyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)acetamide (0.0575 g, 0.107 mmol) was dissolved in methylene chloride (5.00 mL), followed by addition of m-chloroperbenzoic acid (0.0194 g, 0.112 mmol). The reaction mixture was stirred at room temperature for 1 hr. The solution was concentrated, and purified by column chromatography. The eluent was 50-100% ethyl acetate in hexane to yield a solid product (0.0324 g, 54.7%) LCMS: (AA) ES+ 553, 555. 1H NMR (300 MHz, CDCl3) δ: 8.47 (m, 2H), 8.41 (s, 1H), 8.36 (d, 1H), 8.06 (dd, 2H), 7.46 (dd, 2H), 7.45 (d, 1H), 5.53-5.59 (dd, 1H), 4.08-4.16 (m, 1H), 3.73-3.81 (m, 1H), 2.25 (s, 3H), 2.10-2.18 (m, 1H), 2.00-2.07 (m, 2H), 1.69-1.80 (m, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.C(N(CC)CC)C.[CH2:20]([O:22][C:23](=[O:37])[CH:24]([CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25](=O)[CH3:26])[CH3:21].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:28]=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N:4]([CH3:12])[CH3:3])[CH:6]=2)[C:25]=1[CH3:26])=[O:37])[CH3:21]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: CN(C)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(N(C)C)c2)c1C

Procedure:
N,N-dimethyl-1,3-phenylenediamine dihydrochloride (5 mmol, 1.09), triethylamine (10 mmol, 1.4 mL), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol (25 mL), then heated under reflux (12 hrs). The solvents were removed under vacuum, the resulting oil was redissolved in methylene chloride, then applied to a silica column. The purified product was collected as a translucent oil. The named compound was identified by 1H-NMR (CDCl3, ppm) 1.28 t (3H) , 2.35 s (3H) , 2.77 s (6H) , 4.2 q (2H) , 6.3-6.7 m (4H), and 7.0-7.3 m (5H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[C:5]2[C:6]([N:10]3[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]3)=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.ClC1C2N(N=C(N)N=2)C=CN=1.N1CC[C@@H](O)C1.Cl[C:35]1[CH:43]=[C:42]2[C:38]([C:39]([CH3:46])([CH3:45])[C:40](=[O:44])[NH:41]2)=[CH:37][CH:36]=1>>[OH:15][C@@H:12]1[CH2:13][CH2:14][N:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:35]4[CH:43]=[C:42]5[C:38]([C:39]([CH3:46])([CH3:45])[C:40](=[O:44])[NH:41]5)=[CH:37][CH:36]=4)[N:16]=3)[CH:9]=[CH:8][N:7]=2)[CH2:11]1
Reactant: Nc1nc2c(N3CC[C@@H](O)C3)nccn2n1
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Agent: Nc1nc2c(Cl)nccn2n1
Agent: O[C@@H]1CCNC1
Product: CC1(C)C(=O)Nc2cc(Nc3nc4c(N5CC[C@@H](O)C5)nccn4n3)ccc21

Procedure:
(R)-1-(2-Amino-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-pyrrolidin-3-ol, synthesized by reaction of 8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and (R)-pyrrolidin-3-ol following general procedure 3, is coupled with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one under Buchwald Hartwig conditions using general procedure 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:35])[C:16](=[O:34])[C:17]2[CH:22]=[C:21]([S:23]CC[Si](C)(C)C)[CH:20]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:18]=2)=[C:4]([O:36][CH3:37])[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:35])[C:16](=[O:34])[C:17]2[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([SH:23])[CH:22]=2)=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(SCC[Si](C)(C)C)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of N-(4-(4-fluoro-2-methoxyphenyl)-6-methylpyridin-3-yl)-N-methyl-3-(trifluoromethyl)-5-(2-(trimethylsilyl)ethylthio)benzamide (0.477 g, 866 μmol) in THF (10 mL) was added tetrabutylammonium fluoride (1M solution in THF, 4.55 mL, 4.55 mmol) and the clear, light yellow solution was stirred at room temperature for 75 minutes. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of CH2Cl2:MeOH (100:0 to 90:10). Light brown solid (93%). MS (ESI): m/z=449.10 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:13]=2[CH3:33])=[CH:8][CH:7]=1)=[O:5])C>C1COCC1.[OH-].[Na+]>[CH3:33][C:13]1[CH:14]=[CH:15][C:16]([NH:18][C:19](=[O:32])[C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)c3ccc(N4CCOCC4)cc3)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)cc2)cc1-c1ccc(C(=O)O)cc1

Procedure:
2′-Methyl-5′-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carboxylic acid ethyl ester (2.4 g) was stirred in a mixture of THF (25 ml) and 1M sodium hydroxide (50 ml) at 10° C. for 4 h. The mixture was allowed to cool and the THF was evaporated. The residue was acidified and the resultant colourless precipitate collected by filtration and dried (1.98 g).
Reaction SMILES: BrBr.[F:3][C:4]([F:17])([F:16])[C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:15]=1.[S-:18][C:19]#[N:20].[K+].[CH3:22][S:23]([OH:26])(=[O:25])=[O:24]>C(O)(=O)C.C(OC(C)C)(C)C.C(O)(C)C>[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[NH:20]=[C:19]1[N:14]2[C:8]3[C:7](=[CH:6][C:5]([C:4]([F:3])([F:16])[F:17])=[CH:15][C:9]=3[CH2:10][CH2:11][CH2:12][CH2:13]2)[S:18]1
Reactant: FC(F)(F)c1ccc2c(c1)CCCCN2
Reactant: N#C[S-]
Agent: BrBr
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: N=c1sc2cc(C(F)(F)F)cc3c2n1CCCC3

Procedure:
The procedure is carried out as in Example 1, but starting with 2.38 g of bromine in 5 ml of acetic acid, 3.2 g of 7-trifluoromethyl-2,3,4,5-tetrahydro-1H-[1]benzazepine and 5 g of potassium thiocyanate in 35 ml of acetic acid. The brown-yellow oil isolated is chromatographed on a silica gel, eluting with ethyl acetate. A yellow oil is obtained which is dissolved in 15 ml of isopropyl ether to which there is added 1 ml of a 1.94 N solution of methanesulphonic acid in isopropanol. The white precipitate formed is filtered off and then dried under vacuum (70 Pa) at 50° C. 0.7 g of 2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazolo[5,4,3-jk][1]benzazepine methanesulphonate is thus obtained in the form of a white solid melting at 226° C. [analysis C13H15F3N2O3S, % calculated C 42.38, H: 4.1, F: 15.2, N: 7.5, O: 13.3, S: 17.41, % found C: 42.4, H: 3.9, F: 15.2, N: 7.5, S: 17.4].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1.CS(O)(=O)=O.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][N:10]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Clc1cc2[nH]nc(I)c2cn1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
At r.t. to a suspension of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.55 g, 2.0 mmol) in methylene chloride (6 mL) and tetrahydrofuran (3 mL) was added methanesulfonic acid (20 μL, 0.4 mmol), followed by dihydropyran (0.54 mL, 5.9 mmol) (Aldrich, Cat. #: D106208). The mixture was stirred at r.t. overnight. Then, it was stirred at 60° C. for 4 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.72 g).
Reaction SMILES: [Na].C(O)C.[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][C:18]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl>[N+:31]([C:18]1[CH:19]=[C:20]([C:21](=[O:22])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:29]=[CH:30][C:17]=1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])([O-:33])=[O:32]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium ethoxide, formed by reacting 4.6 g. (0.2 mole) of sodium metal with 200 ml. of ethanol, at 0° C. was added 32 g. (0.2 mole) of diethyl malonate followed by 26.1 g. (0.1 mole) of 4-chloro-3-nitrobenzophenone. The mixture was allowed to stir at room temperature for 2 hours and was then poured into 400 ml. of ice cold 2N hydrochloric acid and 300 ml. of methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to an oil. The residual oil was induced to crystallize by trituration with hexane containing trace amounts of diisopropyl ether, 34.75 g., m.p. 68°-70° C. The sample was further purified by trituration with hot hexane-diisopropyl ether, 30.84 g. (80% yield). Anal. Calcd. for C20H19NO7 : C, 62.3; H, 5.0; N, 3.6. Found: C, 62.3; H, 4.9; N, 3.6.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[O:12]1[C:8]([C:6]2[CH:7]=[C:2]([N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[O:13])[CH:3]=[N:4][CH:5]=2)=[CH:9][N:10]=[CH:11]1
Reactant: Brc1cncc(-c2cnco2)c1
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1ccccn1-c1cncc(-c2cnco2)c1
Temperature: 120 °C

Procedure:
To an oven-dried sealed tube containing a solution of 3-bromo-5-oxazol-5-yl-pyridine VIII-a (1.00 g, 4.44 mol) in degassed 1,4-dioxane (20 mL) was added 2-hydroxypyridine (507 mg, 5.33 mmol), K2CO3 (1.23 g, 1.78 mmol), Cut (169 mg, 0.899 mmol) and rac-trans-N,N′-dimethylcyclohexane diamine (280 μL, 1.78 mmol). The tube was flushed with argon and sealed then heated in an oil bath at 120° C. overnight. After cooling to RT, the mixture was filtered and the filter cake washed with 1,4-dioxane. The mixture was evaporated and the residue purified by column chromatography (2% to 5% EtOH in DCM) to give the desired product VIII-b as a beige solid (752 mg, 71%). 1H NMR (300 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.80 (dd, J=6.8, 1.6 Hz, 1H), 7.57 (ddd, J=8.8, 6.6, 1.9 Hz, 1H), 6.54 (d, J=9.2 Hz, 1H), 6.39 (t, J=6.7 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:13]1([C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[C:19]([NH:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=2[CH3:29])=[O:20])[CH2:15][CH2:14]1)#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]1([C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[C:19]([NH:21][C:22]2[CH:27]=[C:26]([O:28][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[CH:25]=[CH:24][C:23]=2[CH3:29])=[O:20])[CH2:15][CH2:14]1)#[N:12]
Reactant: Cc1ccc(O)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (3.19 g, 22.5 mmol) and 3-(1-cyanocyclopropyl)-N-(5-hydroxy-2-methylphenyl)benzamide (6.00 g, 20.5 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.25 g, 30.8 mmol) and the mixture was stirred at 80° C. for 6 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with water (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→40/60), and the obtained solution was concentrated under reduced pressure to give the title compound (9.08 g, quantitatively) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=2[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1cccc(F)c1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(F)c1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 2,3-difluorophenol: 1H-NMR (CDCl3) δ 7.94 (1H, d, J=2.6 Hz), 7.47 (1H, dd, J=8.7, 2.6 Hz), 7.05–6.86 (3H, m), 6.72–6.60 (1H, m), 3.85 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CN(C=O)C.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
To a solution of 4-hydroxy-3-nitrobenzaldehyde (10.0 g, 59.8 mmol) in tetrahydrofuran (600 mL)) and DMF (240 mL) was added dry sodium hydride (1.58 g, 65.82 mmol) and ethyl bromoacetate (7.30 mL, 65.82 mmol). The reaction was refluxed for 24 hours. The reaction was then concentrated and diluted with ethyl acetate (500 mL) and acidified to pH 2 with 1N HCl. The organic layer was then washed with saturated sodium bicarbonate (2×200 mL), sodium chloride (2×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a dark red oil. The oil was used in the next step without purification. 1H NMR (d6-DMSO) δ 1.18 (t, 3H), 4.15 (q, 2H), 5.14 (s, 2H), 7.49 (d, 1H), 8.11 (dd, 1H), 8.41 (s, 1H), 9.93 (s, 1H). MS: M+−1=252.1 Da.