Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:11]([C:4]5[CH:3]=[C:2]([CH3:1])[O:6][C:5]=5[C:7]([F:8])([F:9])[F:10])=[O:13])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1cc(C(=O)O)c(C(F)(F)F)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)o1
Yield: 65.6 %

Procedure:
In the same manner as in Example 18-4 and using 5-methyl-2-(trifluoromethyl)-3-furoic acid (175 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (72.0 mg, 66%) was obtained as a white solid.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Br:21])=[CH:23][CH:24]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Brc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 79.4 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.04 g, 0.15 mmol) was reacted with 4-bromobenzaldehyde (0.028 g, 0.15 mmol) in the presence of glacial acetic acid (0.009 g, 0.15 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.012 g, 0.18 mmol) in methanol (5 ml) (Procedure D) to give compound 16l (0.052 g, 80%) as an oil.
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+](=[CH2:20])=[N-].CO.CCOCC>C(O)(=O)C.[Zn]>[CH2:10]([CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:20][C:8](=[O:9])[CH2:2]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=[N+]=[N-]
Reactant: CCCCCCCC1CCC2C1C(=O)C2(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCC1CCC2CC(=O)CC12
Temperature: 70 °C

Procedure:
The procedure followed is the same as that described in Example 29 substituting the starting material from Example 34, 6,6-dichloro-2-(hept-1-yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-heptylbicyclo[3.2.0]heptan-6-one} and isomers (14.2 g, 0.051 moles), an etheral diazomethane solution (175 ml), methanol (5 ml), and acetic acid (15 ml). After the acetic acid is added the solvent is removed under vacuum leaving a clear yellow oil. The crude product is then dissolved in acetic acid (100 ml) and stirred while zinc powder (29 g) is slowly added. The reaction is heated in a 70° C. water bath for 1 hour, after which time ether (500 ml) is added and the solution filtered. The filtrate is washed with brine (100 ml) and then with a solution of saturated bicarbonate. The ether layer is separated and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (4.3 g, 0.015 moles).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:3].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:3][C:2]([CH3:12])([C:4](=[O:11])[CH:5]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:1]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: BrCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)C(CCCCOc1ccccc1)n1cncn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 14.3 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one (cf. German Laid-Open Application DOS No. 2,638,470) in 20 ml of dimethylformamide was added dropwise, under a dry nitrogen atmosphere, to a stirred suspension of 2.3 g of sodium hydride in 20 ml of dimethylformamide, the reaction temperature being kept at 20°-30° C. by cooling; the mixture was subsequently stirred for 20 hours at room temperature. A solution of 19.5 g of 1-bromo-4-phenoxybutane in 20 ml of dimethylformamide was then added dropwise at 5°-10° C., with continued stirring, and while cooling with ice. After completion of the addition, stirring was continued for 10 hours at 5°-10° C., after which 200 ml of water were added and the mixture was extracted with twice 100 ml of methylene chloride. The combined organic phases were extracted by shaking with water and dried over magnesium sulfate; removal of the solvent under reduced pressure gave an oil from which, on trituration with 20 ml of diisopropyl ether, 17 g of colorless crystals were precipitated; melting point 59°-62° C.
Reaction SMILES: N.[N+:2]([C:5]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([O-])=O.CO.Cl>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].O>[NH2:2][C:5]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Nc1cc(Br)ccc1C=O
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
16.1 ml of an aqueous 29% ammonia solution was added to a mixture of 5.0 g of 2-nitro-4-bromobenzaldehyde, 60.4 g of iron (II) sulfate heptahydrate, 200 ml of methanol, 100 ml of water and 335 μl of concentrated hydrochloric acid in an oil bath kept at 90° C., followed by heating under stirring for 10 minutes. After cooling as it was, insoluble matters were filtered through Celite and the filtrate was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed, to give 3.9 g of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2B2OC(C)(C)C(C)(C)O2)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:36]1[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][N:37]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>COCCOC.O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([C:36]3[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:18][CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=2)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccnc1Cl
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ncccc2Cl)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Temperature: 85 °C
Yield: 28.8 %

Procedure:
Stir a solution of 850 mg (1.77 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate and 524 mg (3.54 mmol) of 2,3-dichloropyridine in a mixture of 4 mL of DME and 2 mL of water for 15 minutes under argon, then add successively 734 mg (5.32 mmol) of K2CO3 and 61 mg (0.05 mmol) of Pd(PPh3)4 and heat the reaction mixture for 4 h at 85° C. Then distribute the reaction mixture between 10 mL of EtOAc and 10 mL of brine. Dry the organic phase over Na2SO4, filter, and then concentrate under reduced pressure. Purify the residue obtained on a silica column, eluting with a cyclohexane/EtOAc gradient from 0 to 20% of EtOAc. After concentration under reduced pressure, we obtain 237 mg of methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-3-chloro-2,3′-bipyridine-6′-carboxylate in the form of oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:24]>CO.[Pd]>[NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:24]
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)C[C@H](O)[C@@H](N)CC(C)C

Procedure:
818 mg of Z-Sta-OMe dissolved in 40 ml of methanol are hydrogenated at room temperature and normal pressure in the presence of 190 mg of palladium-on-carbon catalyst (10% Pd) until saturation. During hydrogenation, the pH value is maintained constantly at 5 by the continuous addition of 0.5N HCl. After hydrogenation the catalyst is filtered off and the filtrate is concentrated by evaporation. H-Sta-OMe×HCl is obtained in the form of a colourless foam; Rf (G)=0.21. This crude product is used directly in stage 13.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[C:10]=3[NH:11][C:12](=[O:39])[CH:13]([NH:15][C:16]([C@H:18]([CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C@H:19]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[C:10]=3[NH:11][C:12](=[O:39])[CH:13]([NH:15][C:16]([C@H:18]([CH2:33][CH2:34][C:35]([F:37])([F:38])[F:36])[C@H:19]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:20]([OH:22])=[O:21])=[O:17])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cccc2c1NC(=O)C(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)OC(C)(C)C)N=C2c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc2c1NC(=O)C(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)O)N=C2c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A solution of Intermediate 2A (115 mg, 0.174 mmol) in DCM (3 mL) was treated with TFA (0.668 mL, 1.737 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The crude mixture was diluted with toluene and again concentrated to dryness to afford Intermediate 2B (87 mg, 0.144 mmol, 83% yield). HPLC RT=3.695 (H2O/CH3CN with TFA, Waters Sunfire C18 2.1×30 mm 3.5 um, 4 min gradient, detection at 220 nm). MS(ES): m/z=606.1 [M+H+].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:16][CH3:17].[N:18]([O-:20])=[O:19].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(OCCCCl)c(OC)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 14.0 of the above-obtained solution mainly containing methyl 4-(3-chloropropoxy)-3-methoxybenzoate, 0.20 g (2.60 mmol) of sodium nitrite, and 17.5 mL of acetic acid. The resulting mixture was heated to 40-50° C. under stirring. To the reaction mixture was dropwise added slowly 22.4 g (215.2 mmol) of nitric acid (60 wt. %), and the mixture was kept at the same temperature for 2 hours. After the reaction was complete, 42 mL of water was added to the reaction mixture. Then, the organic portion was separated and washed with warm water. Analysis of the organic portion by high performance liquid chromatography (absolute quantitative analysis) indicated that 15.7 g (reaction yield: 96.2%) of methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate was produced.
Reaction SMILES: CNC[C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.BrC1C=CC=CC=1CBr>C(#N)C>[CH:6]1[C:5]2[C:10](=[CH:11][C:12]3[C:17]([CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1
Reactant: CNCc1c2ccccc2cc2ccccc12
Agent: BrCc1ccccc1Br
Solvent: CC#N
Product: c1ccc2cc3ccccc3cc2c1
Yield: 95 %

Procedure:
A solution of 9-((methylamino)methyl)anthracene (1.00 g, 4.5 mmol), 2-bromobenzyl bromide (1.13 g, 4.5 mmol) and K2CO, (0.691 g, 5.0 mmol) in 50 mL of acetonitrile was refluxed under nitrogen for 18 hr. The solution was filtered on a sintered-glass filter and solvent was removed from the filtrate under reduced pressure to yield 9-(N-Methyl-N-(o-bromobenzyl)amino)methyl)anthracene (95% by NMR). The resulting solid was taken up in diethyl ether (50 mL), and treated at 0° C. with 1 equiv of butyllithium. The mixture was stirred at 0° C. for 2 h at which time 5 equiv of trimethyborate was added via a cannula. After warming the mixture to room temperature, 50 mL of water was added to quench the reaction. The ether layer was separated, washed with 3×10 mL water, and dried over sodium sulfate. Removal of the solvent under reduced pressure provided a solid identical to that obtained in (A) in 52% yield.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])/[C:3](/[C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:4]/OS(C1C=CC(C)=CC=1)(=O)=O.[NH3:29]>C(OCC)C>[F:27][C:2]([F:1])([F:28])[C:3]1([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:4][NH:29]1
Reactant: CCOC(=O)c1cccc(/C(=N\OS(=O)(=O)c2ccc(C)cc2)C(F)(F)F)c1
Reactant: N
Solvent: CCOCC
Product: CCOC(=O)c1cccc(C2(C(F)(F)F)NN2)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of ethyl 3-(2,2,2-trifluoroacetyl)benzoate (500 mg, 2.15 mmol) in ethanol was added pyridine (5 mL) and hydroxylamine hydrochloride (500 mg, 7.2 mmol) and the resulting mixture stirred at 57° C. for 3 hours. The reaction mixture was cooled and passed through an ion exchange column eluting with methanol (30 mL). The methanol solution was evaporated in vacuo to give (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate as an oil in 71% yield, 401 mg which was used in the next step without further purification. To a stirred solution of (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate (401 mg, 1.54 mmol) in dichloromethane (10 mL) was added DMAP (17 mg, 0.14 mmol) and the mixture cooled to 0° C. 4-methylbenzene-1-sulfonyl chloride (331 mg, 1.74 mmol) was added portion-wise as a solution in dichloromethane (5 mL). The reaction mixture was then left to stand at room temperature for 18 hours. The mixture was diluted with water (10 mL) and the organic layer separated, dried over magnesium sulfate and evaporated in vacuo to afford (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate as an oil in 78% yield, 500 mg. This material was used in the next step without further purification. A mixture of (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate (500 mg, 1.2 mmol) in diethylether (5 mL) in a 3-necked flask equipped with an internal thermometer and condenser was cooled to −78° C. Ammonia gas was introduced for 5 min and then stirring continued for 45 min. The reaction mixture was warmed to −33° C. and stirred for 2 hours after which it was allowed to warm to room temperature overnight with stirring.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14](C(C3C=CC=CC=3)=O)[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[NH:14][CH2:13][CH2:12][C:11]=2[N:10]=[C:9]1[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccccc1)CC2
Agent: Cl
Solvent: CO
Product: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1NCC2
Yield: 78 %

Procedure:
(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-phenyl-methanone from Example E5a.1 (5.73 g, 14.6 mmol) was placed in methanol (50 ml) and a 6M HCl aqueous solution (200 ml) was added. The reaction mixture was heated at reflux for 18 h then concentrated in vacuo. The residue was dissolved in dichloromethane, basified with saturated NaHCO3 then washed with brine, dried and concentrated in vacuo to yield the title compound (3.30 g, 78%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][C:11](B(O)O)=[CH:12][C:7]=3[NH:6][C:5]2=[O:16])[CH2:3][CH2:2]1.Br[CH:18]=[C:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:20]1=2.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.O1CCOCC1>[CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][C:11]([CH:18]=[C:19]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[CH2:23][O:22][C:21]5[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:20]4=5)=[CH:12][C:7]=3[NH:6][C:5]2=[O:16])[CH2:3][CH2:2]1
Reactant: Fc1ccc2c(c1)OCc1ccccc1C2=CBr
Reactant: O=c1[nH]c2cc(B(O)O)ccc2n1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(C=C3c4ccccc4COc4cc(F)ccc43)ccc2n1C1CC1
Yield: 29.7 %

Procedure:
Following procedures essentially as described in Example 219, mix 1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-boronic acid (120 mg, 0.55 mmol) (prepared essentially as described in Preparation 36), 11-bromomethylene-3-fluoro-6,11-dihydro-dibenzo[b,e]oxepine (E and Z mixture, 177 mg, 0.58 mmol), 2N Na2CO3 (0.7 mL), dioxane (8 mL) and (Ph3P)4Pd (38 mg, 0.033 mmol). Purify the crude product by column chromatography using THF/hexane to give 65 mg title compound as a gray powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[F:19][C:20]([F:28])([F:27])[C:21]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][C:21]([C:20]([F:28])([F:27])[F:19])([OH:26])[CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: OC1(C(F)(F)F)CCNC1
Product: OC1(C(F)(F)F)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)C1
Yield: 62 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (286 mg, 1.010 mmol) and 3-(trifluoromethyl)pyrrolidin-3-ol (157 mg, 1.010 mmol) were combined and purified as per Preparation Hb to give 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol (62% yield). LC-MS (M+H)+=402.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:9]=[N-:10].[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([N:8]=[N+:9]=[N-:10])=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cccs1)N=[N+]=[N-]
Temperature: 10 °C
Yield: 55.5 %

Procedure:
A solution of thiophene-2-carbaldehyde (650 mg, 5.8 mmol) and ethyl azidoacetate (6.89 grams, 53.4 mmol) in dry toluene (40 ml) was added to a cold (−5° C.) solution of sodium ethoxide (about 53 mmol) in ethanol (60 ml) during a time period of one hour, under nitrogen atmosphere. Stirring was continued for another hour while maintaining the temperature under 10° C. The reaction mixture was then cooled to 0° C. and acidified with HCl 0.1 M. After separation of the phases, the aqueous phase was extracted with ether (3×30 ml), the combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 718 mg of pure 2-azido-3-thiophen-2-yl-acrylic acid ethyl ester (55% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[N:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:25]([C:33]1[S:34][CH2:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][C@:37]2([C:42]2[CH:47]=[C:46](Br)[CH:45]=[CH:44][C:43]=2[F:49])[N:38]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.O>CN(C=O)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>[NH2:25][C:33]1[S:34][CH2:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][C@:37]2([C:42]2[CH:47]=[C:46]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=3)[C:1]#[N:2])[CH:45]=[CH:44][C:43]=2[F:49])[N:38]=1
Reactant: N#Cc1cncc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CCC[C@H]2CS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cncc(-c2ccc(F)c([C@]34CCC[C@H]3CSC(N)=N4)c2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-Cyano-3-pyridinylboronic acid (37.9 mg), tetrakis(triphenylphosphine)palladium and a 1 N sodium carbonate solution (256 μL) were added to a solution of (±)-N,N-bis(tert-butoxycarbonyl) [(4aR*,7aS*)-7a-(5-bromo-2-fluorophenyl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]amine (70.0 mg) in DMF (5 mL). After replacement with nitrogen, the mixture was stirred at 80° C. for two hours. After cooling to room temperature, water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for two hours. The reaction mixture was diluted with water, followed by neutralization with a saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23].C1COCC1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:22]([CH3:23])[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCCNC(=O)OCc1ccccc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCCNC(=O)OCc1ccccc1
Yield: 76 %

Procedure:
To a solution of N-(benzyloxycarbonyl)-4-(mesyloxy)butylamine (2.51 g) in anhydrous dimethylformamide (28 ml) are added 2.0 M dimethylamine THF solution 12.5 ml. anhydrous potassium carbonate (1.72 g) and sodium iodide (3.74 g), and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the whole is extracted with ether. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 1.59 g (76%) of N-(benzyloxycarbonyl)-4-(dimethylamino)butylamine.