Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](C=CC3C=NC=CC=3)[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:29]([CH:31]1[O:33][CH2:32]1)Cl.ClCCl.[Br:37]N1C(=O)CCC1=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>>[C:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:33][CH3:32])=[CH:19][CH:20]=2)[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2].[Br:37][C:17]1[CH:16]=[C:15]([CH:20]=[CH:29][C:31]=1[O:33][CH3:32])[CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: ClCC1CO1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CC2CN(C(=O)OC(C)(C)C)CCO2)cc1
Product: COc1ccc(CC2CNCCO2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Boc-2-(4-methoxybenzyl)morpholine was prepared using the same procedure as described for example 9, intermediate (a), but starting with racemic epichlorohydrin. N-Boc-2-(4-methoxybenzyl) (0.16 mmol) was dissolved in dichloromethane (1.5 mmol) and N-bromosuccinimide (28 mg, 0.16 mmol) added. The reaction was shaken for 18 hrs at room temperature and then further N-bromosuccinimide (11 mg, 0.06 mmol) added. The reaction was shaken for a further 2 hrs, Na2S2O3 (10% w/v aqueous solution, 1 mL) added and the mixture shaken for 40 minutes. The mixture was poured on to an HMN column (25 g) and washed with dichloromethane (10 mL) and the liquors concentrated in vacuo. The residue was dissolved in dichloromethane (1.5 mL), treated with TFA (1 mL) and shaken for 90 minutes at room temperature. The reaction mixture was added directly to an SCX-2 column (5 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL and 2×2.5 mL). Combined ammonia washes were concentrated in vacuo. The residue was dissolved in IPA (2 mL) and diethyl ether (2 mL) and treated with MP-carbonate (3.1 mmol/g, 300 mg) and shaken for 30 minutes. The suspensions were filtered and the concentrated in vacuo to yield the desired 2-(3-Bromo-4-methoxy-benzyl)-morpholine example 72, as a beige gum (18 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]1([C:21]2[N:22]=[C:23]([SH:32])[NH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[N:5]1([C:3](=[O:4])[CH2:2][S:32][C:23]2[NH:24][C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Product: O=C(CSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)N1CCCc2ccccc21
Yield: 26 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4,5-diphenyl-1H-imidazole-2-thiol as the nucleophile to yield 19 as a off-white solid (26%): MS m/z: 426 (M+H)+. Anal. Calcd. For, C26H23N3OS.0.2H2O: C, 72.77; H, 5.50; N, 9.79; S, 7.47. Found: C, 72.58; H, 5.33; N, 9.74; S, 7.48.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[F:6][C:7]1[CH:8]=[C:9]([C:15](=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].O>C(O)C.C1(C)C=CC=CC=1>[F:6][C:7]1[CH:8]=[C:9]([C:15](=[N:2][OH:3])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(Cc2ccccc2)=NO)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydroxylamine hydrochloride (3.7 g, 53.2 mmol) and potassium hydroxide (2.98 g, 53.2 mmol) were suspended in absolute ethanol (25 mL) and stirred for 30 minutes. To this, a suspension of 1-(3-fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one from Step 1 (10.0 g, 40.9 mmol) in toluene (150 mL) was added in one portion. The yellow suspension was warmed to reflux for 16 hours, then the suspension was cooled to room temperature. Water (100 mL) was added, and the resulting solution was extracted with ethyl acetate (2×100 mL). The combined organic solution was washed with brine (100 mL), dried over magnesium sulfate and filtered. The resulting solution was evaporated under reduced pressure to yield a crude residue. The residue was crystallized from boiling ethanol/water to yield, upon filtration and drying 1-(3-fluoro-4-methoxyphenyl)-2 phenyl-ethan-1-one oxime as ivory-colored crystals (10.0 g, 94%): 1H NMR (CDCl3 /300 MHz) δ 7.42 (dd, J=12.69, 2.01, 1H), 7.36-7.19 (m, 6H), 6.89 (dd, J=8.66, 8.46 HZ, 1H), 4.16 (s, 2H), 3.88 (s, 3H). 19F NMR (CDCl3 /282.2 MHz): 135.517 (m).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][NH:9][C:10](=[O:13])[NH:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][NH:9][C:10](=[O:13])[NH:11][CH2:12][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=C1NCc2ccc([N+](=O)[O-])cc2CN1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CNC(=O)NC2
Yield: 70.2 %

Procedure:
Compound 7-nitro-1,2,4,5-tetrahydro-benzo(e)(1,3)diazepin-3-one (2.00 g, 9.65 mmol) was dissolved in methanol (60 mL) and the solution was carefully added to a Parr shaker vessel containing 10% Palladium/Carbon (200 mg) under nitrogen. The reaction was then shaken under 50 psi of hydrogen until uptake of hydrogen had ceased (˜3 hours). Catalyst was then removed via filtration through a Celite pad. The filter cake was rinsed with methanol (3×50 mL) and the filtrate was reduced en vacuo to afford 1.20 g of 7-amino-1,2,4,5-tetrahydro-(2,4)-benzodiazepin-3-one as a white solid. LC/MS (ESI)=178.32 (M+H). Rf: (10% MeOH/DCM)=0.31.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1>C1(C)C=CC=CC=1.CCCCCCC>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of omeprazole (5 g, 14.5 mmol) and (S)-1,1,2-triphenyl-1,2-ethanediol (6.30 g, 21.7 mmol) was dissolved in a minimum of a toluene/heptane mixture (0.84:0.16, 190 ml) at 100° C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with a toluene/heptane mixture (3:1, 2×50 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] inclusion complex (6.108 g, 91%, 96.3% e.e.) as an off-white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[C:16](=[C:17]([CH:22]=C)[CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:33])[C:16]=2[CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2c1CCN2S(=O)(=O)c1cc(C)ccc1OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: COc1ccc(C)cc1S(=O)(=O)N1CCc2c(C=O)cccc21
Reaction time: 0.42 h

Procedure:
OsO4 (9 mg, 0.05 mmol) was added to a stirred mixture of 1-[(2-methoxy-5-methylphenyl)sulfonyl]-4-vinylindoline (240 mg, 0.73 mmol; Intermediate 10) and 2,6-lutidine (170 μL, 1.46 mmol) in dioxane (12 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.625 g, 2.92 mmol) in water (4 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 25 min, combined with an earlier batch of this intermediate (followed this experimental and starting from Intermediate 10; 60 mg, 18 mmol), and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered and concentrated to give the title compound (360 mg, still some dioxane according to HNMR) as a black sticky oil. MS (ESI+) for C17H17NO4S m/z 332 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=1.O>CC(C)=O.CCOC(C)=O>[CH2:2]([O:22][C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=1[F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
1-(Bromomethyl)benzene (4.92 g, 28.8 mmol) and K2CO3 (3.98 g, 28.8 mmol) were added to a solution of 4-bromo-2-fluorophenol (5.0 g, 26 mmol) in acetone. The reaction mixture was stirred at room temperature for 18 hours. Water (100 mL) and EtOAc (100 mL) were added, the organic layer was separated and dried over MgSO4 and concentrated to give 1-(benzyloxy)-4-bromo-2-fluorobenzene as a yellow solid 7.06 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.ClCCl.O>CN1C(=O)CCC1>[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCCNCC1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN1CCCN(c2ccn3ncc(C=O)c3n2)CC1
Temperature: 140 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in NMP was added 1-methylhomopiperazine (103 μL, 0.829 mmol). The mixture was heated in microwave for 10 minutes at 140° C. Dichloromethane and water were added, and the product extracted in dichloromethane. The organic layer was then washed with water and dried over Na2SO4 and concentrated under reduced pressure to yield 5-(4-methyl-1,4-diazepan-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=260)
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15])([CH3:10])[CH3:9].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br-:1].[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=2)=[O:15])([CH3:9])[CH3:10])=[O:41])=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[N+](C)(CCCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A solution of (5-amino-pentyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate O) (1.0 g, 2.35 mmol), 4-benzyloxy phenyl acetic acid (0.57 g, 2.35 mmol), N-methylmorpholine (1.0 mL, 9.09 mmol), DCC (0.49 g, 2.35 mmol) and HOBt (0.32 g, 2.36 mmol) in DMF (20 mL) is stirred at RT for 1 h. The reaction mixture is concentrated in vacuo, and the residue is purified by column chromatography (basic alumina, 0-4% methanol in DCM) to afford a brown solid which is crystallised from methanol and EtOAc to afford the title compound. M+ 568.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[C:15]2[C:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[S:25](=[O:33])(=[O:32])[NH:24][N:23]=1.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CC#N.O.C(Cl)Cl>[C:39]([O:38][C:36](=[O:37])[CH2:35][N:17]1[C:18]2[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=2)[C:15]([C:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25](=[O:32])(=[O:33])[N:24]([CH2:2][CH2:3][CH3:4])[N:23]=2)=[C:16]1[CH3:21])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCI
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCCN1N=C(c2c(C)n(CC(=O)OC(C)(C)C)c3ccc(F)cc23)c2ccccc2S1(=O)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Iodopropane (7 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[F:35][C:36]1([F:43])[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[F:35][C:36]1([F:43])[CH2:41][CH2:40][CH:39]([O:34][C:31]2[CH:32]=[CH:33][C:28]([N:4]3[C:5](=[O:27])[C:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]3[CH2:1][CH3:2])=[CH:29][CH:30]=2)[CH2:38][CH2:37]1
Reactant: OC1CCC(F)(F)CC1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(F)(F)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (600 mg), 4,4-difluorocyclohexanol (362 mg), diisopropyl azodicarboxylate (1.9 M in toluene, 1.4 mL), triphenylphosphine (698 mg) and tetrahydrofuran (10 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow oil (635 mg, 86%).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[C:37]([O:39][CH3:40])[C:36](B(O)O)=[CH:35][N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:36]4[C:37]([O:39][CH3:40])=[N:38][C:33]([O:32][CH3:31])=[N:34][CH:35]=4)=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C:14]2[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=2)=[CH:24][C:25]=1[F:30]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)c(F)c1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)c(F)c2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-3-fluoro-phenyl)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AZ) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([O:17][C:18]4[C:23]5[N:24]=[C:25]([NH2:27])[S:26][C:22]=5[CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[CH:10][C:4]=2[O:3]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([O:17][C:18]4[C:23]5[N:24]=[C:25]([NH:27][C:29](=[O:31])[CH3:30])[S:26][C:22]=5[CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Cc2ccc(-c3cc(Oc4cccc5sc(N)nc45)ncn3)cc2O1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc5c(c4)OC(C)(C)C5)ncn3)cccc2s1
Temperature: 85 °C

Procedure:
To a 100-mL, round-bottomed flask containing 4-[6-(2,2-dimethyl-2,3-dihydro-benzofuran-6-yl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 133(b)), (0.50 g, 1.3 mmol) was added toluene (7 mL) and acetic anhydride (0.40 mL, 3.8 mmol, Aldrich). The reaction mixture was heated at 85° C. for 2 h. The toluene was removed in vacuum and the resulting orange solid was re-dissolved in dichloromethane (125 mL), washed with water (150 mL), dried over Na2SO4 and concentrated in vacuum. The resulting orange solid was suspended in dichloromethane (100 mL), collected by filtration, and dried under vacuum to obtain the title compound as a white solid. Mp: 224–225° C. MS (ESI, pos. ion.) m/z: 433 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.[CH2:37]([OH:40])[CH2:38][OH:39].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:39][CH2:38][CH2:37][O:40][C:23]1[N:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(OCCO)n1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and ethylene glycol (1.0 equiv.) in acetonitrile (0.10M) was added potassium carbonate (1.0 equiv.) and the allowed to stir at 120° C. for 24 hours. LCMS analysis indicated formation of the desired product. The volatiles were removed in vacuo. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(4-methyl-3-(2-(methylsulfonamido)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 6% yield. LCMS (m/z) (M+H)=536.3, Rt=0.80 min, 1H NMR (400 MHz, <cd3od>) δ ppm 2.37 (s, 3H) 3.79-3.85 (m, 4H) 3.86-3.97 (m, 6H) 4.60-4.65 (m, 2H) 6.78 (s, 1H) 7.41 (d, J=8.22 Hz, 1H) 7.67 (dd, J=8.22, 2.35 Hz, 1H) 7.74 (t, J=7.83 Hz, 1H) 7.91 (d, J=8.22 Hz, 1H) 7.94 (d, J=1.96 Hz, 1H) 8.21 (d, J=7.83 Hz, 1H) 8.26 (s, 1H). LCMS (m/z) (M+H)=503.1, Rt=0.73 min. The compounds listed below were prepared using methods similar to those described above using the appropriate starting materials.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@@H:22]1[CH2:27][C@H:26]([CH3:28])[C@H:25]([N:29]([CH3:34])[C:30](=[O:33])[O:31][CH3:32])[C@H:24]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:23]1.[F:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=1[C:51]1[N:56]=[C:55]([C:57]([OH:59])=[O:58])[CH:54]=[CH:53][C:52]=1[F:60]>CN(C=O)C.O>[C:39]([O:38][C:36]([NH:35][C@@H:24]1[CH2:23][C@H:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:57](=[O:58])[C:55]2[CH:54]=[CH:53][C:52]([F:60])=[C:51]([C:45]3[C:44]([F:43])=[CH:49][CH:48]=[CH:47][C:46]=3[F:50])[N:56]=2)[CH2:27][C@H:26]([CH3:28])[C@@H:25]1[N:29]([CH3:34])[C:30](=[O:33])[O:31][CH3:32])=[O:37])([CH3:41])([CH3:40])[CH3:42].[C:39]([O:38][C:36]([NH:35][C@H:24]1[CH2:23][C@@H:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:57](=[O:59])[C:55]2[CH:54]=[CH:53][C:52]([F:60])=[C:51]([C:45]3[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=3[F:43])[N:56]=2)[CH2:27][C@@H:26]([CH3:28])[C@H:25]1[N:29]([CH3:34])[C:30](=[O:33])[O:31][CH3:32])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)N(C)[C@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(C)[C@@H]1[C@H](C)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H]1NC(=O)OC(C)(C)C
Product: COC(=O)N(C)[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %
Yield: 15 %

Procedure:
EDC (1.1 equiv.) and HOAt (1.1 equiv.) were added to a solution of (+/−)-methyl ((1S,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl)(methyl)carbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.5 equiv.) in DMF (0.05 M). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, concentrated and purified by ISCO SiO2 chromatography. Purification was completed via SFC (40% EtOH, 100 mL/min, IC column) to yield methyl ((1S,2R,4R,6S)-2-((tert-butoxycarbonyl)amino)-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl)(methyl)carbamate (15% yield, 99% ee) and methyl ((1R,2S,4S,6R)-2-((tert-butoxycarbonyl)amino)-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl)(methyl)carbamate (15% yield, 99% ee). LC/MS (m/z)=628.3 (MH+), Rt=0.89 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Cl-].[NH4+:32]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:32][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=4[CH:17]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)[nH]2)cc1
Yield: 46.4 %

Procedure:
8.0 g (20 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) and 5.5 g (0.1 mole) of ammonium chloride in 150 ml of dry dimethylformamide were heated for 6 hours at 150° C. After cooling, the mixture was poured onto water and the precipitated crystals were filtered off under suction, washed several times with water and dried in a stream of nitrogen. Purification by column chromatography (silica gel; n-heptane plus increasing amounts of ethyl acetate) and recrystallization from ethanol gave 3.6 g of the title compound of melting point 176°-179° C.