Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@@:10]21[C:51]1[S:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[CH2:52][C:53]3[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=3)[C:43]=1[CH2:42][CH2:41][O:40]2)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:59]([C:56]1[CH:55]=[CH:54][C:53]([CH2:52][C:48]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:49]=2[S:50][C:51]2[C@@:10]4([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]4)[O:40][CH2:41][CH2:42][C:43]3=2)=[CH:58][CH:57]=1)[CH3:60]
Reactant: CCc1ccc(Cc2cccc3c4c(sc23)[C@@]2(OCC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1ccc(Cc2cccc3c4c(sc23)[C@@]2(OCC4)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 81.4 %

Procedure:
To a solution of (1S,3′R,4′S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-8-[(4-ethylphenyl)methyl]-3,3′,4,4′,5′,6′-hexahydro-spiro[2-oxa-9-thia-fluorene-1,2′-[2H]pyran] (23 mg, 0.028 mmol) in methanol (1 mL) and ethyl acetate (1 mL) was added 10% palladium on carbon (10 mg). The resultant mixture was stirred under a hydrogen atmosphere for 1 hour at room temperature, and the catalyst was then filtered off. Solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution=dichloromethane:methanol (10:1)), to thereby obtain the titled compound (10.4 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[Cl:11]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH2:6])=[C:7]([Cl:11])[C:8]=1[Cl:9]
Reactant: Cc1cc(Br)c(Cl)cc1N
Reactant: O=C1CCC(=O)N1Cl
Product: Cc1cc(Br)c(Cl)c(Cl)c1N

Procedure:
This material was prepared from 4-bromo-5-chloro-2-methylaniline by chlorination with N-chlorosuccinimide. The product was isolated as a solid, m.p. 66°-68° C. The product was characterized by IR and 1H NMR spectroscopy and combustion analysis.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]>O>[CH2:3]([C:2](=[CH:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:1]=[O:6])[CH2:4][CH3:5]
Reactant: CCCCC=O
Solvent: O
Product: CCCCC=C(C=O)CCC

Procedure:
The nitrogen present in the crude product leaves the gas separator 8 via line 9 together with an azeotrope containing water, n-pentanal and the products. The stream was cooled (cooler and separator are not shown in FIG. 1). At the separator an organic phase and an aqueous phase were formed. The organic phase was passed to the product separator 11. The aqueous phase was discarded.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:2].CO.O.[BH4-].[Na+]>O1CCCC1.[Co](Cl)Cl>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1cc(F)cc(C#N)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(F)cc(CN)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
To a mixed solution of tert-butyl 3-cyano-5-fluorobenzoate (3.00 g) in tetrahydrofuran (60.0 mL)-methanol (30.0 mL) was added a mixture of cobalt (II) chloride (4.40 g) and water (60.0 mL) under ice-cooling, and then sodium borohydride (1.54 g) was added under an argon flow, followed by stirring at room temperature for 30 minutes. The insoluble material was filtered through Celite and then washed with a mixed solvent of tetrahydrofuran-methanol-water (2:1:2, and then the filtrate was concentrated under reduced pressure. To the residue was added a saturated aqueous sodium chloride solution, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform-methanol) to obtain tert-butyl 3-(aminomethyl)-5-fluorobenzoate (1.46 g).
Reaction SMILES: [C:1]12([C:9]3[C:18]4[NH:17][CH2:16][CH2:15][CH2:14][C:13]=4[NH:12][C:11](=O)[CH:10]=3)[CH2:8][CH2:7][C:4]([CH:5]=[CH:6]1)=[CH:3][CH2:2]2.CN(C=O)C.S(Cl)([Cl:27])=O>>[Cl:27][C:11]1[N:12]=[C:13]2[C:18](=[C:9]([C:1]34[CH2:8][CH2:7][C:4]([CH:5]=[CH:6]3)=[CH:3][CH2:2]4)[CH:10]=1)[NH:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=S(Cl)Cl
Reactant: O=c1cc(C23C=CC(=CC2)CC3)c2c([nH]1)CCCN2
Solvent: CN(C)C=O
Product: Clc1cc(C23C=CC(=CC2)CC3)c2c(n1)CCCN2
Temperature: 70 °C
Yield: 66 %

Procedure:
To a solution of 1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-one (435 mg, 1.72 mmol) in 2.5 ml of thionyl chloride was added 100 μL of DMF, and the reaction mixture was heated at 70° C. for 10 h, and concentrated in vacuo. The residue was poured on ice-water and saturated aq. NaHCO3 solution was added to adjust pH to 10-11. The mixture was extracted with EtOAc (2×50 mL), dried over Na2SO4, concentrated and purified by flash chromatography (EtOAc:hexane, 1:4) to give 6-chloro-1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridine (310 mg, 66%) as a white solid; 1H NMR (CDCl3, 300 MHz) 7.58 (m, 2H), 7.43 (m, 3H), 7.29 (s, 1H), 3.35 (s, 1H), 3.18 (m, 2H), 2.63 (m, 2H), 1.99 (m, 2H), 1.73 (m, 2H) ppm; MS (ES) 271.39 (M+H).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (30 mg; 0.03 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (62 mg; 0.1 mmol), sodium tert-butoxide (240 mg; 2.5 mmol), 1-bromo-4-trifluoromethoxy-benzene (410 mg; 1.7 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (421 mg; 2.1 mmol) are suspended in dry toluene (5 mL) and the mixture is irradiated in a mono-mode microwave oven for 30 minutes at 120° C. The mixture is then cooled down to room temperature, is diluted with ethyl acetate (15 mL), filtered over Celite and concentrated under reduced pressure. The crude residue is then diluted in dichloromethane (15 mL) and filtered over a short silica gel pad. The desired product is eluted from the silica gel pad (dichloromethane (150 mL) followed by dichloromethane:methanol 98:2 (100 mL)). The fractions of interest are collected, pooled and concentrated under reduced pressure to afford the desired product (396 mg; 1.1 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2.N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[Si:23]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc2cccc(O)c2n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
8-Hydroxyquinoline-2-carbaldehyde (5.00 g, 28.9 mmol) and imidazole (4.32 g, 63.5 mmol) was dissolved in dichloromethane (50 mL) under an atmosphere of dry N2. The reaction mixture was then cooled to 0° C. and tert-butylchlorodimethylsilane (4.94 g, 31.8 mmol) was added. The reaction was stirred overnight at ambient temperature, and then partitioned between dichloromethane and water. The organic layer was washed with water and aqueous saturated NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification via flash chromatography (2:1 Hexanes/dichloromethane followed by 1:1 hexanes/dichloromethane) provided 6.50 g, 78% of the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:17]([OH:19])=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)C)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
370 mg (0.75 mmol) of tert-butyl 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 319 mg (purity 91%, 93% of theory)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>C1COCC1.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)O)c(F)c1

Procedure:
A solution of 2-fluoro-4-nitro-benzoic acid (2.8 g, 15.1 mmol) in 100 mL THF was combined with palladium/charcoal 10% (250 mg) and hydrogenated for 6.5 h in a Parr apparatus at ambient temperature at 3 bar hydrogen pressure. Then the mixture is filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].[CH3:23][O:24][C:25]1[N:30]=[C:29](S(C)(=O)=O)[N:28]=[C:27]([O:35][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH3:37])[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][C:29]1[N:28]=[C:27]([O:35][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH3:37])[CH:26]=[C:25]([O:24][CH3:23])[N:30]=1
Reactant: COC(=O)C(C)Oc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1cc(OC)nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 377 mg of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylsulfonylpyrimidine and 3 ml of N,N-dimethylformamide, 196 mg of potassium carbonate was added, and the mixture was stirred for 1 hour at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 630 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine [present compound 1-42].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:12])[N:2]=1.S(O)(O)(=O)=O.[NH2:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:33]1[CH:34]=[CH:35][N:36]=[C:32]1[NH:31][C:23]([C:22]1[C:16]2[O:15][C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])=[N:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)=[O:24]
Reactant: O=C(Nc1nc2cccc(C(=O)O)c2o1)c1cc2ccccc2cn1
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2o1)c1cc2ccccc2cn1

Procedure:
Isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-benzooxazol-2-yl]-amide was synthesized according to General Procedure A using 137 mg (0.411 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-benzooxazole-7-carboxylic acid, 111 mg (0.822 mmol) 2-aminoimidazole sulfate, 171 mg (0.45 mmol) HBTU, 0.29 mL (1.65 mmol,) of DIEA and 2 mL of DMF stirring at 90° C. for 2 h. 98.9 mg (0.248 mmol, 60%) of the product was obtained. LCMS: 399 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:18])[C:7]=1[CH2:8][C@H:9]1[CH2:13][C:12]2([CH2:17][CH:16]=[CH:15][CH2:14]2)[CH2:11][NH:10]1.CO>CCOC(C)=O.C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:18])[C:7]=1[CH2:8][C@H:9]1[CH2:13][C:12]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][NH:10]1
Reactant: Clc1cncc(Cl)c1C[C@H]1CC2(CC=CC2)CN1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1cncc(Cl)c1C[C@H]1CC2(CCCC2)CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A mixture of (R)-3-((3,5-dichloropyridin-4-yl)methyl)-2-azaspiro[4.4]non-7-ene (0.090 g, 0.318 mmol) and palladium 10 wt. % on activated carbon (0.034 g, 0.032 mmol) in EtOAc (4 ml) was stirred under hydrogen balloon at room temperature for 3 h. Starting material was converted to the desired project with mono-chloro product (˜4:1). The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (12 g), eluting with a gradient of 5% to 50% 1 M NH3.MeOH in DCM, to provide (R)-3-((3,5-dichloropyridin-4-yl)methyl)-2-azaspiro[4.4]nonane (0.053 g, 0.186 mmol, 58.5% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 8.42-8.50 (m, 2H), 3.63-3.83 (m, 1H), 3.28 (br. s., 2H), 3.02 (d, J=10.37 Hz, 1H), 2.87 (br. s., 1H), 1.73-1.83 (m, 1H), 1.54-1.72 (m, 9H), 1.42-1.53 (m, 1H); LCMS (ESI) m/z 285.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:11]=1)([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cnccc1C1CCCC(N2C(=O)c3ccccc3C2=O)C1
Reaction time: 72 h
Yield: 73 %

Procedure:
To a solution of 2-(3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (1.0 equiv.) in acetic acid (0.1 M) was added 10% Pd/C (0.2 equiv.) and the reaction was stirred under a H2 balloon. After 3 days, the reaction was filtered through Celite, washed with ethyl acetate and methanol, the filtrate was diluted with ethyl acetate and washed twice with sat. 2M Na2CO3. The organic phase was dried with magnesium sulfate, filtered and concentrated. The crude material was triturated with hexanes and ethyl acetate to afford 2-(3-(3-aminopyridin-4-yl)cyclohexyl)isoindoline-1,3-dione in 73% yield. LC/MS=322.2 (M+H), Rt=0.64 min.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[O:4][C:5]2[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=1
Reactant: Cc1ccnc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Cc1ccnc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)-4-methylpyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H16FN5O, 373.13; m/z found, 374.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.44 (s, 2H), 8.39 (d, J=5.1, 1H), 7.57-7.44 (m, 3H), 7.41-7.31 (m, 3H), 7.25 (d, J=7.2, 1H), 7.07 (d, J=4.9, 1H), 6.89 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CS(O[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:26][N:25]=3)=[CH:20][C:18]=2[CH:19]=1)(=O)=O>>[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[CH:26][C:27]([C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:28][CH:29]=3)=[CH:20][C:18]=2[CH:19]=1
Reactant: C[C@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Agent: Br
Product: C[C@H]1CCCN1CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
(2S)-2-Methylpyrrolidine hydrobromide and the product from Example 44E (2-{5-[4-(4-morpholinylcarbonyl)phenyl]-1-benzofuran-2-yl}ethyl methanesulfonate) are processed as described in Example 1D to provide the titled compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[CH:6]1([Mg]Cl)[CH:10]=[CH:9][CH:8]=[CH:7]1>>[CH2:2]([C:10]1[CH2:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: Cl[Mg]C1C=CC=C1
Reactant: C=CCCBr
Product: C=CCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 4-bromo-1-butene (100 g of 97 wt %, 0.719 mol) was added cyclopentadienyl magnesium chloride (800 mL of 1 M solution in THF, 0.8 mol) at 0° C. in 50 minutes. After stirring for an additional 15 minutes at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a brown liquid (94.2 g, crude but-3-enylcyclopentadiene). To the crude but-3-enylcyclopentadiene (94.2 g) dissolved in THF (500 mL) was added n-BuLi (70 mL of 10 M in hexanes, 0.7 mol at −78° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (133.8 g, 0.735 mol) dissolved in THF (400 mL) at 0° C. in 35 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (152 g, 74.4% yield based on 4-bromo-1-butene) as a dark red viscous oil. 1H NMR (300 MHz, CDCl3) δ 7.29-7.41 (m, 10H), 6.50-6.53 (dd, J=5.2 Hz, 1.4 Hz, 1H), 6.29-6.31 (dd, J=5.2 Hz, 1.4 Hz, 1H), 6.02-6.05 (m, 1H), 5.82-5.98 (m, 1H), 4.94-5.16 (m, 2H), 2.53-2.60 (m, 2H), 2.33-2.43 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.59, 147.67, 143.18, 140.86, 140.78, 137.85, 133.48, 131.38, 131.36, 127.85, 127.82, 127.18, 127.13, 124.75, 118.35, 114.29, 33.36, 30.20.
Reaction SMILES: CC1(C)C(CC)CC1CC(Cl)=O.C1(C(Cl)=O)CCCCC1.[C:22]([NH:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37](=[O:47])[CH2:38][CH:39]2[CH2:42][CH:41]([CH2:43][CH3:44])[C:40]2([CH3:46])[CH3:45])=[C:32]([O:48][C:49](=[O:59])[CH2:50][CH:51]2[CH2:54][CH:53]([CH2:55][CH3:56])[C:52]2([CH3:58])[CH3:57])[CH:31]=1)=[O:29])([CH3:25])([CH3:24])[CH3:23]>>[CH3:58][C:52]1([CH3:57])[CH:53]([CH2:55][CH3:56])[CH2:54][CH:51]1[CH2:50][C:49]([O:48][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[O:36][C:37](=[O:47])[CH2:38][CH:39]1[CH2:42][CH:41]([CH2:43][CH3:44])[C:40]1([CH3:46])[CH3:45])[CH:28]([OH:29])[CH2:27][NH:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:59]
Reactant: CCC1CC(CC(=O)Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)CC2CC(CC)C2(C)C)C1(C)C
Agent: CCC1CC(CC(=O)Cl)C1(C)C
Agent: O=C(Cl)C1CCCCC1
Product: CCC1CC(CC(=O)Oc2ccc(C(O)CNC(C)(C)C)cc2OC(=O)CC2CC(CC)C2(C)C)C1(C)C

Procedure:
When 2,2-dimethyl-3-ethylcyclobutaneacetyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(2,2-dimethyl-3-ethylcyclobutaneacetoxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(2,2-dimethyl-3-ethylcyclobutaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.F[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[F:30]>CN(C)C=O>[F:30][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[N:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=[C:2]1[CH3:1]
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: Cc1nc(C(=O)O)c[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)O)cn1-c1ccc(S(C)(=O)=O)cc1F

Procedure:
A mixture of 2-methyl-1H-imidazole-4-carboxylic acid (500 mg), N,N-diisopropyl-ethyl-amine (4 mL), and 1,2-difluoro-4-methanesulfonylbenzene (1.2 g), in N,N-dimethylformamide (6 mL) is heated to 120° C. overnight. The crude product is purified by HPLC. LC (method 20): tR=0.90 min; Mass spectrum (APCI): m/z=299 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].[CH3:20][C:21]([O:24][C:25]([NH:27][C@H:28]([CH2:32][CH3:33])[C:29](O)=[O:30])=[O:26])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:29]([C@H:28]([NH:27][C:25](=[O:26])[O:24][C:21]([CH3:23])([CH3:22])[CH3:20])[CH2:32][CH3:33])=[O:30])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc2cccc(Oc3ccc(N)cn3)c12
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1noc2cccc(Oc3ccc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn3)c12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinamine (Intermediate 33) was dissolved in DMF (0.5 mL) and added to a mixture of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (7.7 mg, 0.038 mmol), DIPEA (0.008 mL, 0.047 mmol) and HATU (14.4 mg, 0.038 mmol) in 1 ml of DMF. The reaction mixture was then stirred at 50° C. for 2 hours. After the removal of DMF, water was added and the mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue was then charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/EtOAc (from all 10/0 to 7/3, then 7/3) to afford the title compound (4.4 mg).