Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][N:12]=2)=[CH:4][C:3]=1[F:13].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:4][C:3]=1[F:13]
Reactant: Fc1cc(C2=NCCC2)ccc1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1cc(C2CCCN2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 5-(4-bromo-3-fluorophenyl)-3,4-dihydro-2H-pyrrole ((12.7 g, 52.7 mmol) in 360 mL methanol was added NaBH3CN (6.6 g, 105 mmol) at 0° C. The resulting solution was adjusted to pH=6 with acetic acid. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with 2 N HCl and the methanol was removed by evaporation. The residue was diluted with water, the aqueous phase adjusted to pH=10 with NaOH, extracted with ethyl acetate, dried by Na2SO4, concentrated and the residue was purified by chromatography on silica gel to give 2-(4-bromo-3-fluorophenyl)pyrrolidine as a yellow solid (12.5 g, yield 98%). LC-MS (ESI) m/z: 244 (M+1)+.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][NH:3]1.P(Cl)(Cl)([Cl:15])=O>C(N(CC)CC)C>[Cl:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncnc1Cl
Yield: 86 %

Procedure:
To a mixture of ethyl 3,4-dihydro-4-oxopyrimidine-5-carboxylate (3.54 g) (synthesized according to the method reported by A. R. Todd and F. Bergel on J. Chem. Soc., 364 (1937)) and triethylamine (2.13 g) was added dropwise under ice-cooling phosphorus oxychloride (21 ml), and the mixture was then heated for 1.5 hour under reflux. The reaction mixture was concentrated to dryness, which was poured into ice-water, followed by partitioning between chloroform and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then dried. The solvent was distilled under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a pale yellow oil (3.42 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]([C:22]2([C:25]3[CH:35]=[CH:34][C:28]4[O:29][C:30]([F:33])([F:32])[O:31][C:27]=4[CH:26]=3)[CH2:24][CH2:23]2)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:36]>COCCOC.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>[F:33][C:30]1([F:32])[O:29][C:28]2[CH:34]=[CH:35][C:25]([C:22]3([C:20]([NH:19][C:17]4[CH:16]=[CH:15][C:14]([CH3:36])=[C:13]([C:6]5[CH:5]=[N:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=5)[N:18]=4)=[O:21])[CH2:24][CH2:23]3)=[CH:26][C:27]=2[O:31]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1ncc(B(O)O)cn1
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: COCCOC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cn1
Temperature: 120 °C
Yield: 63.6 %

Procedure:
To a mixture of 2-methoxypyrimidin-5-ylboronic acid (92 mg, 0.60 mmol) and N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (180 mg, 0.50 mmol) in DME (3 mL) and 2 M Na2CO3 (1 mL) was added Pd(PPh3)4 (29 mg, 0.025 mmol). The mixture was heated in a microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxypyrimidin-5-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide (140 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.18 (dd, J=8.6, 2.1 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 3.98 (s, 3H), 2.26 (s, 3H), 1.68 (q, J=3.6 Hz, 2H), 1.12 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 441.3.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1>O1CCOCC1>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:21]2[CH:22]=[C:23]([NH2:27])[N:24]=[CH:25][N:26]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(N)ncn1)c1nc2ccccc2n1-c1ccccc1
Yield: 66.5 %

Procedure:
A solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (321.6 mg, 1.36 mmol, 1.00 equiv) in dioxane (10 mL) and 6-chloropyrimidin-4-amine hydrochloride (456.3 mg, 2.71 mmol, 2.00 equiv, 98%) was stirred overnight at 130° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a C18 column with acetonitrile/water (0-40%) to afford 298.6 mg (60%) of 146 hydrochloride as yellow crystals. LC-MS (ES, m/z): 331 [M+H]+H-NMR: (400 MHz, CD3OD, ppm) δ: 8.15 (s, 1H), 7.87-7.58 (m, 8H), 7.38-7.36 (m, 1H), 5.88 (br s, 1H), 5.41-5.36 (q, 1H), 1.747-1.73 (d, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:18]([O:20][C:21](=[O:29])[CH:22](N)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]>N1C=CC=CC=1>[CH2:18]([O:20][C:21](=[O:29])[CH:22]([N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:16])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: N=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1O)C(=O)OCC

Procedure:
A suspension of 9.2 g. of 5-chloro-2-hydroxy-benzophenone imine in 60 ml. of ehtanol is treated with 12.6 g. of aminomalonic acid diethyl ester hyrochloride and 5.0 ml. of pyridine and the mixture boiled at reflux for 1 hour while stirring. The mixture is then concentrated to dryness under reduced pressure and the residue partitioned between toluene and water. The organic phase is washed with water, briefly dried over sodium sulfate and evaporated to dryness. The residual oily residue crystallizes upon trituration with hexane. There is obtained [(5-chloro-2-hydroxy-α-phenylbenzyliden)amino] malonic acid diethyl ester, having a melting point of 55°-56° C. Recrystallization from ethanol yields gold-yellowish leaflets having the same melting point.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:25]4[CH:26]=[CH:27][C:22]([C:20](=[O:21])[CH3:19])=[CH:23][CH:24]=4)[CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccc(F)cc3)c2)cc1
Temperature: 120 °C
Yield: 53.2 %

Procedure:
A mixture of 1-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-[1,2,3]triazole (100 mg, 0.411 mmol), 4-fluoroacetophenone (51 μL, 0.411 mmol) and potassium carbonate (114 mg, 0.82 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 48 h. After cooling to room temperature the mixture was poured into HCl (1 N) and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (79 mg, 53%) as an off white solid. MS: m/e=362.3 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)[CH3:3].C(N(CCCC)CCCC)CCC.[NH:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42](O)=[O:43])=[CH:41][C:36]=2[N:35]=[CH:34]1.[I-].ClC1C=CC=C[N+]=1C>CN(C)C=O>[CH2:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:42]([C:40]3[CH:39]=[CH:38][C:37]4[NH:33][CH:34]=[N:35][C:36]=4[CH:41]=3)=[O:43])=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)[CH3:3]
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CCc1nn(-c2ccccc2)c2cc(N)ccc12
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CCc1nn(-c2ccccc2)c2cc(NC(=O)c3ccc4[nH]cnc4c3)ccc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 3-ethyl-1-phenyl-1H-indazol-6-amine hydrochloride (300 mg, 1.10 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL), tributylamine (492 mg, 2.66 mmol, 2.50 equiv), 1H-benzo[d]imidazole-5-carboxylic acid (180 mg, 1.11 mmol, 1.00 equiv), 2-chloro-1-methylpyridinium iodide (330 mg, 1.29 mmol, 1.20 equiv). The resulting solution was stirred for 2 days at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1). The resulting mixture was diluted with methanol (10 mL) and the solids were washed with diethyl ether (1×50 mL) to yield N-(3-ethyl-1-phenyl-1H-indazol-6-yl)-1H-benzo[d]imidazole-5-carboxamide as a yellow solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH2:23]([O:15][C:12]1[CH:11]=[CH:10][C:9]([C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCBr
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C(C)(C)CC(C)(C)C)cc1
Temperature: 50 °C
Yield: 80.8 %

Procedure:
To 700 ml of N,N-dimethylformamide were added 206 g of 4-t-octylphenol and 207 g of anhydrous potassium carbonate and the mixture was stirred at 50° C. To the mixture was added dropwise 251 g of 1-bromooctane and thereafter the mixture was stirred for 7 hours at 65° to 80° C. Then, after removing insoluble matter by filtration, water was added to the filtrate thus obtained and the product was extracted with ethyl acetate. The organic solvent layer was collected, washed with a saturated aqueous sodium chloride solution, dried on anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily material thus obtained was distilled under reduced pressure (169°-172° C./0.05-0.06 mmHg) to provide 257 g (81% in yield) of 1-octyloxy-4-t-octylbenzene (Compound A).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([N:11]([CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=O)[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])(=[O:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN1CCOCC1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C>[CH2:4]([CH:3]1[CH2:2][NH:1][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23][N:11]1[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])(=[O:14])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccccc1S(=O)(=O)N(Cc1ccccc1C(=O)O)C(CN)Cc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccccc1S(=O)(=O)N1Cc2ccccc2C(=O)NCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
To a solution of compound 2f (45 mg, 0.1 mmol) in dry DMF (15 mL) was added 4-methylmorpholine (33 mg, 0.32 mmol). The mixture was stirred at rt for 10 min and DPPA (41 mg, 0.15 mmol) was added. This resulting mixture was stirred at rt for 24 h and then concentrated in vacuo to remove the solvent. The residue was dissolved in EA (10 mL), washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4. Concentration in vacuo and purification by prep-TLC gave compound 2g as a white solid (40 mg, 91% yield). 1H-NMR (400 MHz, CDCl3) δ 8.03 (dd, 1H, J=8.0, 1.6 Hz), 7.47-6.99 (m, 11H), 6.86 (d, 1H, J=8.0 Hz), 6.15 (m, 1H), 5.02 (d, J=15.6 Hz, 1H), 4.22 (d, J=15.6 Hz, 1H), 4.18 (m, 1H), 3.76 (s, 3H), 3.20 (dd, J=15.2, 8.8 Hz, 1H), 3.02-2.88 (m, 2H), 2.39 (d, J=8.8 Hz, 1H). MS (ESI+) m/z: 437 [M+H]+, 459 [M+Na]+.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:45]1[C:46]([OH:54])=[CH:47][C:48]3[O:52][CH2:51][CH2:50][C:49]=3[CH:53]=1)[C:31](=[O:44])[N:32]2[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:45]1[C:46]([OH:54])=[CH:47][C:48]3[O:52][CH2:51][CH2:50][C:49]=3[CH:53]=1)([CH2:5][OH:16])[C:31](=[O:44])[N:32]2[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2c(Br)cccc2N1Cc1ccccn1
Product: O=C1N(Cc2ccccn2)c2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (34%): MS (ES+) m/z 468.4 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]=CC=CC>>[CH3:12][CH:10]1[CH2:9][CH:8]=[CH:7][CH:3]2[C:4]([O:6][C:1](=[O:11])[CH:2]12)=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C=CC=CC
Product: CC1CC=CC2C(=O)OC(=O)C12

Procedure:
The Diels-Alder adduct from phthalic anhydride and piperylene is hydrolyzed and partially oxidized as in Example 1 and further oxidized as in Examples 1 and 2. Similar results are obtained.
Reaction SMILES: [C:1]([CH2:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30]>O1CCCC1>[C:1]([CH2:9]/[CH:10]=[CH:11]/[C:12]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/CC(=O)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(C/C=C/C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of 4-benzoylcrotonic acid (0.01 mole) in tetrahydrofuran is added 0.01 mole of N,N-carbonyldiimidazole. After stirring for 2 hours, 0.01 mole of L-proline is added. The mixture is stirred for 24 hours to give 1-(4-benzoylcrotonyl)-L-proline. The preceding compound is reacted with thiolacetic acid in carbontetrachloride for 24 hours to give the product of the example as a glass.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[C:35](O)([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[N:3]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:5]([C:35](=[O:36])[C:37]([F:40])([F:39])[F:38])[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:16])=[O:15]
Reactant: CCOC(=O)Cn1c(-c2ccccc2)cc(Cc2ccccc2S(=O)(=O)N2CCOCC2)c1C
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCOCC2)c(C(=O)C(F)(F)F)c1-c1ccccc1
Temperature: 0 °C
Yield: 67 %

Procedure:
Ethyl 2-(2-methyl-3-(2-(morpholinosulfonyl)benzyl)-5-phenyl-1H-pyrrol-1-yl)acetate (0.259 g, 0.537 mmol) (mixture of regioisomers—1.5:1.0) was dissolved in DCM (5.37 ml) and cooled to 0° C. DMAP (0.262 g, 2.147 mmol) was then added to the reaction in one portion, followed by TFA (0.758 ml, 5.37 mmol) in a drop-wise fashion. The ice bath was removed and the reaction was warmed to rt then refluxed for 16 h. At this time, the reaction was quenched with 1N HCl, and then diluted with 50 mL DCM. The layers were separated and the aqueous portion was then back-extracted with DCM (50 mL). The organics were combined, dried, filtered, and concentrated. The crude material ethyl 2-(2-methyl-3-(2-(morpholinosulfonyl)benzyl)-5-phenyl-4-(2,2,2-trifluoroacetyl)-1H-pyrrol-1-yl)acetate was then purified by silica gel chromatography using a 0-70% EtOAc/hexane gradient to furnish the desired material in 67% yield.
Reaction SMILES: C(C1N=C(OCC)C(C2N([C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:36])C(C3C=CC(Cl)=CC=3)(C)C(C3C=CC(Cl)=CC=3)(C)N=2)=CN=1)(C)(C)C.[CH2:43]1[O:45][C@@H:44]1[CH2:46][OH:47]>C(O)C>[OH:45][C@H:44]([CH2:46][OH:47])[CH2:43][N:40]1[CH2:39][CH2:38][N:37]([CH:35]=[O:36])[CH2:42][CH2:41]1
Reactant: OC[C@@H]1CO1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Solvent: CCO
Product: O=CN1CCN(C[C@H](O)CO)CC1
Temperature: 120 °C
Yield: 185.9 %

Procedure:
The mixture of [2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (170 mg, 0.28 mmol) and R-glycidol (63 mg, 0.84 mmol) in ethanol (1 mL) was heated in the microwave at 120° C. for 10 min. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (silica gel, eluting with 0-20% methanol in ethyl acetate) gave cis-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-[4-((S)-2,3-dihydroxy-propyl)-piperazin-1-yl]-methanone (98 mg). The diastereomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% ethanol in carbon dioxide) to give the title compound (post peak, 40 mg). HR-MS (ES, m/z) calculated for C35H45N6O4Cl2 [(M+H)+] 683.2874, observed 683.2871.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([NH2:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:12]([O:16][C:17]([NH:19][C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:18])[NH:19][C:20]1([C:23](=[O:24])[NH:9][CH:6]2[C:5]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[O:8][CH2:7]2)[CH2:21][CH2:22]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: NC1COc2cc(Br)ccc21
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2COc3cc(Br)ccc32)CC1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B] and for the preparation of example 12, (rac)-6-bromo-2,3-dihydro-benzofuran-3-ylamine (intermediate A-8 [B]) has been coupled with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid to give [1-((rac)-6-bromo-2,3-dihydro-benzofuran-3-ylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester, which was then reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) and (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and subsequently with 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) to give the title compound as light yellow solid. MS: 529.2 (MH+, 1Cl).
Reaction SMILES: Br[CH:2]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[N:10][CH:11]=1)[C:3]#[N:4].[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+].CN(C)C=O>O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6](/[CH:5]=[CH:2]/[C:3]#[N:4])=[CH:11][N:10]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(Br)C#N)cn1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C/C#N)cn1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A mixture of 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]propionitrile (4.5 g), lithium bromide (LiBr) (1.14 g), lithium carbonate (Li2CO3) (2.17 g) and N,N-dimethylformamide (50 ml) was stirred for 2.5 hours at 120° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure to leave (E)-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]acrylonitrile (3.2, 89%), which was recrystallized from ethyl acetate--hexane to give pale yellow crystals, m.p.116°-117° C.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][CH:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[S:37][C:36]([C:38](OCC)=[O:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)[CH3:25].CO>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:36]3[S:37][C:33]([N:29]4[CH2:30][CH2:31][CH2:32][N:26]([CH:24]([CH3:25])[CH3:23])[CH2:27][CH2:28]4)=[CH:34][CH:35]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCCN(C(C)C)CC2)s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C(C)C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
Trimethylaluminium (0.751 ml, 1.50 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (148 mg, 0.60 mmol) and ethyl 5-(4-propan-2-yl-1,4-diazepan-1-yl)thiophene-2-carboxylate (178 mg, 0.60 mmol) in toluene (3.002 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was added to methanol (50 mL) and treated with HCL (2M aqueous solution, to pH7 or below) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure material. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (123 mg, 41%) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])(=[O:8])=[O:7].C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])(=[O:8])=[O:7]
Reactant: O=S(=O)(CCCCCl)c1ccccc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1S(=O)(=O)CCCCCl
Yield: 88.2 %

Procedure:
2.8 g of 2-[(4-chlorobutyl)sulfonyl]benzyl alcohol was treated with 1.4 ml of oxalyl chloride, 2.4 ml of dimethylsulfoxide, and 7.8 ml of triethylamine in the same manner as described for Example 1, Part B. Purification of the crude product via column chromatography on silica gel, eluting with 60:10:30 toluene:ethyl acetate:hexane provided 2.45 g of the product. 1H-NMR (CDCl3) δ 1.91-1.97(m,4H); 3.35(t,2H,J=7 Hz); 3.54(t,2H,J=6 Hz); 7.80-7.85(m,2H); 8.07-8.14(m,2H); 10.75(s,1H). Mass spectrum: 261 (M+H).