Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].C(OCC)C>Cl.CC(O)=O.CO>[NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: N=C(NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Yield: 159.2 %

Procedure:
45.4 Grams (0.1 mole) of BOC-Arg(NO2)-CHA was dissolved in 300 ml (0.6 mole) of 2N-HCl/AcOH with a small amount of MeOH, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, 300 ml of dried diethyl ether was added to the reaction mixture so as to precipitate the crystals. There was obtained 34.9 g (89.4%) of H-Arg(NO2)-CHA.HCl.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH2:15][N:16]3[CH:20]([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:6](=[O:31])[N:7]2[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30].[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH2:15][N:16]3[CH:20]([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[C:6](=[O:31])[N:7]2[C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: OB(O)c1ccc(F)cc1Cl
Reactant: COc1ccc(CN2Cc3c(Br)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(CN2Cc3c(-c4ccc(F)cc4Cl)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
To a solution of 5-bromo-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (200 mg, 0.31 mmol) and 2-chloro-4-fluoro-benzene boronic acid (98 mg, 0.62 mmol) in toluene (3 mL) and ethanol (0.3 mL) was added sodium carbonate (2M solution, 0.39 mL) and tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.0155 mmol). The flask was evacuated and purged with nitrogen a few times. The reaction mixture was heated to reflux for 2 h and diluted with methylene chloride. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 5% of 2N ammonium in methanol/methylene chloride as eluent provided the 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.03 (s, 3H), 1.08 (s, 3H), 1.64 (m, 2H), 2.40 (m, 1H), 2.57 (brs, 1H), 2.83 (t, 1H, J=7.3 Hz), 2.90 (brs, 1H), 3.14 (s, 1H), 3.53 (m, 2H), 3.63 (t, 1H, J=13.2 Hz), 3.81 (s, 3H), 4.11 (abq, 2H, J=14.9 Hz), 4.55 (abq, 2H, J=14.9 Hz), 6.22 (s, 1H), 6.78 (s, 1H), 6.84 (d, 2H, J=8.4 Hz), 6.99 (t, 1H, J=8.0 Hz), 7.12 (dd, 1H, J1=8.4 Hz, J2=6.0 Hz), 7.21 (d, 3H, J=8.7 Hz), 7.38 (t, 1H, J=8.0 Hz), 7.54 (m, 2H). MS (API-ES+): 695 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:32][C:33]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[Cl:43][C:40]1[CH:41]=[CH:42][C:33]([N:32]2[C:7](=[O:9])[C:6]3[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=3[NH:1][C:14]2=[O:16])=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(-c3ccc(Cl)cc3C(=O)OC)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.4 g) in methylene chloride were added triphosgene (0.28 g) and triethylamine (0.48 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added methyl 2-amino-5-chlorobenzoate (1 mL), and the mixture was further stirred at room temperature for 1 hr, and extracted with water and chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (40 mL), sodium methoxide (0.58 g) was added, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.67 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][OH:11])=[N:6][CH:7]=1.C(O)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[N:6][CH:7]=1
Reactant: OCC#Cc1ccc(Br)cn1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: OCCCc1ccc(Br)cn1
Reaction time: 17 h
Yield: 82.4 %

Procedure:
To a suspension of 3-(5-bromo-2-pyridinyl)-2-propyn-1-ol (0.5 g) and dipotassium azadicarboxylate (3.66 g) in pyridine (40 ml) was added acetic acid (2 ml) and the mixture stirred at room temperature for 24 h, with further additions of acetic acid after 2 h (0.16 ml) and 17 h (2.16 ml). As reduction had only partially gone to completion, further dipotassium azadicarboxylate (3.2 g) and acetic acid (1.86 ml) were added, and stirring continued for 17 h. The mixture was quenched with water (15 ml) and evaporated in vacuo. The residue was co-evaporated with toluene (15 ml) and the residue partitioned between 8% sodium bicarbonate solution (60 ml) and ethyl acetate (60 ml) and the organic phase dried and evaporated in vacuo. The oily residue was purified by FCC using ether and ether-methanol (5%) eluants to afford the title compound as a yellow oil (0.42 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH3:35])=[C:17]([CH:23]4[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH:11]=[CH2:12])[C:3]=12.C[N+]1([O-])CC[O:40]CC1.[OH2:44].CCOC(C)=O>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH3:35])=[C:17]([CH:23]4[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH:11]([OH:40])[CH2:12][OH:44])[C:3]=12
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=Cc1nn(C(C)c2cc(Cl)c(C)c(C3CN(C(=O)OC(C)(C)C)C3)c2OC)c2ncnc(N)c12
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate (0.87 g, 1.7 mmol) in tert-butyl alcohol (11 mL) was added N-methylmorpholine N-oxide (225 mg, 1.92 mmol), water (5.5 mL), and osmium tetraoxide (26 mg, 0.10 mmol). The resulting mixture was stirred overnight at room temp. Water was added to the reaction followed by EtOAc. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated to give 0.93 g of the crude product. LCMS calculated for C25H34ClN6O5 (M+H)+: m/z=533.2; Found: 533.2.
Reaction SMILES: [NH2:1][C:2]1C=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22]N1C(=O)CCC1=O.[CH2:30]([Cl:32])Cl>>[NH2:1][C:2]1[C:30]([Cl:32])=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Reactant: ClCCl
Reactant: O=C1CCC(=O)N1Cl
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(N)c2Cl
Reaction time: 1 h

Procedure:
A solution of 50 g (0.175 mol) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one in 700 ml of methylene chloride is treated at room temperature with 27 g of N-chlorosuccinimide and the mixture is stirred for 1 hour. Subsequently, a further 27 g of N-chlorosuccinimide are added and the mixture obtained is stirred at room temperature for 17 hours. The mixture is diluted with methylene chloride, the organic phase is washed with 2 N sodium carbonate solution, dried and evaporated. After chromatography on 200 g of silica gel using methylene chloride for the elution, the residue gives 7-amino-6,8-dichloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one which melts at 234° C. after recrystallisation from methylene chloride/ethyl acetate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.B.C(N)(C)(C)C>CO>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: B
Solvent: CO
Solvent: CC(C)(C)N
Product: O=c1[nH]c2ccccc2n1C1CCN([C@H]2CC[C@H](O)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,3-dihydro-1-{1-[4-oxocyclohex-1-yl]piperidin-4-yl}-2H-benzimidazol-2-one (100 mg) in methanol (4 mL) at 0° C., under nitrogen, was added tert-butylamine-borane (28 mg). The reaction mixture was stirred at 0° C. for 1 h, then quenched with water (2 mL) and concentrated to remove the methanol. The resulting oil was dissolved in ethyl acetate (50 mL) and the organic solution was washed with saturated sodium carbonate (10 mL), then water (10 mL), then brine (10 mL) and then dried over sodium sulfate. Concentration under reduced pressure yielded trans-1,3-dihydro-1-{1-[4-hydroxycyclohex-1-yl]piperidin-4-yl}-2H-benzimidazol-2-one (75 mg) as a colorless solid: 1H NMR (400 MHz, CD3 OD) 7.42 (m, 1H), 7.04 (m, 3H), 4.28 (m, 1H), 3.50 (m, 1H), 3.09 (m, 2H), 2.45 (m, 5H), 2.03-1.94 (m, 4H), 1.78-1.75 (m, 2H), 1.44-1.26 (m, 4H). The hydrochloride salt was precipitated from diethyl ether/chloroform: analysis calculated for C18H25N3O2.HCl.0.50 H2O.0.70 CHCl3C: 50.54, H: 6.28, N: 9.45; found C: 50.54, H: 6.19, N: 9.64.
Reaction SMILES: Cl[C:2]1C=CC=C[C:3]=1CS(Cl)(=O)=O.[CH:13]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[C:28]([CH2:36][CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[C:41]([F:48])[CH:40]=2)=[C:27]1[CH2:49][CH2:50][NH:51][S:52]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1Cl)(=[O:54])=[O:53])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].[CH2:68]([Cl:70])Cl>O>[CH:13]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[C:28]([CH2:36][CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:42]([C:43]([O:45][CH2:2][CH3:3])=[O:44])=[C:41]([F:48])[CH:40]=2)=[C:27]1[CH2:49][CH2:50][NH:51][S:52]([CH2:55][C:60]1[CH:59]=[CH:58][CH:57]=[CH:56][C:68]=1[Cl:70])(=[O:53])=[O:54])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Reaction time: 2 h

Procedure:
[(2-chlorophenyl)methyl]sulfonyl chloride (0.14 g, 0.6 mmol) was added to a mixture of ethyl 4-{2-[2-(2-Aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoate (Step 6, Example 190, 0.12 g, 0.2 mmol) and K2CO3 (0.11 g, 0.8 mmol) in CH2Cl2 (2 mL) and water (1 mL) with stirring. After 2 hour at room temperature, the mixture was extracted with CH2Cl2 (10 mL) and the extract was washed with 0.5 N NaOH, and brine and dried over sodium sulfate. The CH2Cl2 solution was filtered through silica gel and the filtrate was evaporated. The resulting residue was triturated with a mixture of ether and hexanes to give 0.07 g of ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate as a white solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][N:7]([CH3:25])[C:8]1[CH:13]=[N:12][N:11]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[C:10](=[O:24])[CH:9]=1.CN([CH:29]=[O:30])C>>[CH3:25][N:7]([CH3:6])[C:8]1[CH:13]=[N:12][N:11]([CH:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[C:10](=[O:24])[C:9]=1[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: CN(C)c1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
POCl3 (0.9 mL, 9.75 mmol) was slowly added to precooled (0° C.), anhydrous DMF (5 mL). After stirring at room temperature for 30 min, a solution of 5-dimethylamino-2-(3,3,5,5-tetramethyl-cyclohexyl)-2H-pyridazin-3-one (749 mg, 2.70 mmol) in anhydrous DMF (6 mL) was added and the mixture was stirred at 70° C. for 1.5 h. After cooling, the mixture was poured over saturated NaHCO3/ice. The aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were dried (Na2SO4), filtered and evaporated in vacuo to provide 5-dimethylamino-3-oxo-2-(3,3,5,5-tetramethyl-cyclohexyl)-2,3-dihydro-pyridazine-4-carbaldehyde (1.19 g, 100%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.33 (1H, s), 7.80 (1H, s), 5.27 (1H, app tt, J=3.7, 11.7 Hz), 3.13 (6H, s), 1.63-1.44 (4H, m), 1.30 (2H, app t, J=11.0 Hz), 1.16 (6H, s), 0.98 (6H, s).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1.O>CC#N.C1(C)C=CC=CC=1>[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1)=[O:5]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(C=O)cc1
Reaction time: 5 h

Procedure:
To a mixture of N-methylmorpholine-N-oxide (63.9 g, 545 mmol) in MeCN (848 g) and toluene (742 g), was added a solution of methyl [4-(bromomethyl)phenyl]acetate (53.0 g) in toluene (212 g) at 0 to 25° C. After stirring for 5 hr, water (106 g) was added to the reaction mixture. The aqueous layer was removed and remaining MeCN in the organic layer was removed under reduced pressure. The remaining toluene solution was washed with water twice (530 g×2), and concentrated under reduced pressure at a temperature below 40° C. until the weight of the solution was 233 g. An activated charcoal (3 g) was added to the solution and removed by filtration. To the solution was added 2,6-dibutyl-4-hydroxytoluene (152 mg), and concentrated under reduced pressure to give the subtitle compound. Yield 30.9 g, 79% from methyl [4-(bromomethyl)phenyl]acetate; 1H NMR (DMSO-d6) δ 9.99 (s, 1H), 7.87 (d, 2H), 7.86 (d, 2H), 3.83 (s, 2H), 3.63 (s, 3H)
Reaction SMILES: C[Mg]Br.[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>O1CCCC1>[C:15]([C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([CH2:33][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[CH:29][C:27]=3[CH:28]=2)[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Agent: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 118 %

Procedure:
A solution of methylmagnesium bromide in tetrahydrofuran (1N, 15 ml) was added to diethyl malonate (7.33 g) at 0° C. for 10 minutes. The mixture was stirred for 2 hours at ambient temperature. To the mixture, 4-tert-butyl-2-(5-chloromethylbenzofuran-2-yl)thiazole (3.50 g) was added and stirred for 23 hours at 45° C. The resulting mixture was concentrated under reduced pressure and added to the solution of 4N hydrogen chloride in ethyl acetate. The resulting precipitates were collected by filtration and washed with n-hexane and diisopropyl ether to give the salt. The salt was added to the aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-tert-butyl-2-[5-(2,2-diethoxycarbonylethyl)benzofuran-2-yl]thiazole (5.80 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH:7]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>[Pd]>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:3]=[N:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(-c2cncc(Br)c2)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2cncc(-c3ccc(OC(F)(F)F)cc3)c2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of the product of step 1 with 4-formylphenyl boronic acid.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16](=[N:18][CH:19]([CH3:21])[CH3:20])[CH3:17])=[C:10](F)[CH:9]=1>CNC=O>[Br:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]2[N:15]=[C:16]([CH3:17])[N:18]([CH:19]([CH3:21])[CH3:20])[C:10]=2[CH:9]=1
Reactant: CC(=NC(C)C)Nc1c(F)cc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CNC=O
Product: Cc1nc2c(F)cc(Br)cc2n1C(C)C
Temperature: 30 °C
Yield: 72.9 %

Procedure:
Add potassium tert-butoxide (6.9 kg) in portions to a solution of N-(4-bromo-2,6-difluoro-phenyl)-N′-isopropyl-acetamidine (16.2 kg) in N-methyl formamide (76 kg) while maintaining the temperature at T<30° C. Heat the mixture at 70-75° C. until complete by HPLC. Cool to 20-30° C. and quench by adding into water (227 kg) then extract with MtBE (37×4 kg). Wash the combined organic phases with brine (49×2 kg) and concentrate to 25-30 L, add n-hexane (64 kg) and filter the slurry to give 11 kg of the title compound. MS (ES+): m/z=272 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([OH:15])=O)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].CN(C)C=O.C(Cl)(=O)C([Cl:24])=O.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2>ClCCl.ClCCl.CO>[CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([Cl:24])=[O:15])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C12CCC(C(=O)Cl)(CC1)CC2
Reaction time: 3 h

Procedure:
Bicyclo-[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (IV, Example 81, 1 wt) is dissolved in dichloromethane (6.25 vol) and dimethylformamide (0.025 vol) is added. Concomitantly oxalyl chloride (0.5125 vol) is dissolved in dichloromethane (0.625 vol) and the resulting mixture is added to the mixture containing the bicyclo-[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (IV) at between 12 to 17° C., taking care for gas evolution. The mixture is stirred at 15 to 25° for 2 to 4 hours which is monitored by (TLC; dichloromethane/methanol: 9/1, visualization Bromocresol green). The solvent is removed under reduced pressure at 40 to 45°, dichloromethane (5 vol) is added, stirred for 5 to 15 min and removed under reduced pressure at 40 to 45°. The process is repeated by adding dichloromethane (5 vol), stirring for 5 to 15 min and removing under reduced pressure at 40 to 45°. Acetonitrile (6.25 vol) is then added to give the title compound in solution.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][N:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.CC(O)=O.CCO>[Pd].CCOC(C)=O>[C:27]1([N:22]([CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[S:23]([CH3:26])(=[O:25])=[O:24])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)N(C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(C[C@H]1CNCCN1)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 119.7 %

Procedure:
A 150-mL round-bottomed flask was charged with N-(((2R)-1,4-dibenzyl-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.527 g, 1.172 mmol, step 2), AcOH (0.10 mL, 1.7 mmol), Pd (10 wt. % (dry basis) on activated carbon, wet, Degussa type, 0.528 g), EtOH (10 mL) and EtOAc (2 mL). The reaction mixture was evacuated under vacuum and refilled with hydrogen. The mixture was stirred under an atmosphere of hydrogen at room temperature for 4.5 h then at 50° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated and re-subjected to the reaction condition (Pd/C 0.683 g and EtOH 10 mL). The reaction mixture was evacuated under vacuum and refilled with hydrogen. The mixture was stirred under an atmosphere of hydrogen at 50° C. for 12 h. The reaction mixture was filtered through a pad of filter agent. The filtrate was concentrated to give N-phenyl-N-((2R)-2-piperazinylmethyl)methanesulfonamide (0.378 g) as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([N:14]([CH:28]1[CH2:30][CH2:29]1)[C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)[C:6](=O)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:39]>CCO>[CH2:1]([O:3][C:4]([C:5]1[N:14]([CH:28]2[CH2:30][CH2:29]2)[C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=2)=[N:39][C:6]=1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:31])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C(=O)c1cccnc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccnc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Temperature: 110 °C
Yield: 71.9 %

Procedure:
To 1.2 g (3 mmol) of 2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-3-pyridin-3-yl-propionic acid ethyl ester in 10 ml of EtOH was added 1.4 g (11 mmol) of ammonium trifluoroacetate. The EtOH was evaporated and the residue heated to 110° C. for 4 h. The cooled residue was partitioned between saturated sodium hydrogen carbonate solution and CH2Cl2. The organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 3:7 to 1:1] afforded 0.9 g (80%) of the title compound as a colorless solid. MS: 418.2 (MH+).