Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Br:20][C:12]1[S:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCc1nccs1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ncc(Br)s1

Procedure:
A solution (2 L) of 1.33 kg of 2-t-butoxycarbonylaminomethylthiazole in ethyl acetate was added to an aqueous solution (20 L) of 8.6 kg of sodium acetate, and the mixture was stirred. Bromine (1.35 L) was added dropwise to this solution (internal temperature: 19 to 24° C.) over a period of 3.5 hr, and the mixture was stirred at an internal temperature of 25.5±5° C. for 14 hr. Sodium sulfite pentahydrate (180 g) was added thereto, the mixture was then extracted with 3 L of ethyl acetate, and the organic layer was washed with 1 L of water and 1.53 L of a 6 M aqueous sodium hydroxide solution. The aqueous layer was then extracted with 3 L of ethyl acetate. The organic layers were combined, were dried over anhydrous magnesium sulfate, and were filtered. The solvent was removed from the filtrate by evaporation under the reduced pressure, followed by substitution concentration twice with 2 L of ethanol to give 944 g of 5-bromo-2-t-butoxycarbonylaminomethylthiazole.
Reaction SMILES: [CH3:1][N:2]([S:25]([CH3:28])(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][C:14]2=O)[CH:12]=1)[C:6]([O:8]C)=[O:7].O1CCCC1.O1CCCC1.CO>O1CCCC1>[CH3:1][N:2]([S:25]([CH3:28])(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH2:14][CH2:15][CH:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:17]2)[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(N2CC(c3ccccc3)CC2=O)cc(N(C)S(C)(=O)=O)c1
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cc(C(=O)O)cc(N2CCC(c3ccccc3)C2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of methyl 3-[methyl(methylsulfonyl)amino]-5-(2-oxo-4-phenylpyrrolidin-1-yl)benzoate obtained in Reference Example 18 0.20 g (0.50 mmol) in tetrahydrofuran (3 mL) was added 1.0 M BH3.tetrahydrofuran/tetrahydrofuran solution (1.5 mL) dropwise under ice-cooling and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added methanol (3 mL) under ice-cooling, and the solvent was evaporated. The residue was dissolved in methanol (10 mL), and the mixture was stirred at 80° C. for 7 hours and the solvent was evaporated. The resulting solid was dissolved in a mixture of 2N aqueous sodium hydroxide solution (0.5 mL), methanol (0.5 mL) and tetrahydrofuran (0.5 mL) and the mixture was stirred at room temperature for 15 hours. The solvent was concentrated and the residue was adjusted by adding 1N hydrochloric acid to pH=3 and the mixture was extracted with ethyl acetate. After drying of the mixture on magnesium sulfate, the solvent was evaporated to give 165 mg (0.176 mmol) of the title compound (yield: 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7](C)[C:4]=1[CH:5]=O.[C:18](O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH3:16][O:15][C:8]1([CH:7]=[C:4]([CH3:5])[C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]1[O:13][CH3:14])[CH:18]=[CH:19][C:20]([OH:22])=[O:21]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC1=C(OC)C(OC)C(C=CC(=O)O)(OC)C=C1C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
2,3,4,5-Tetramethoxy-6-methylbenzaldehyde (17.3 g, 72.1 mmol), malonic acid (22.5 g, 216 mmol) and piperidine (1.7 ml) were dissolved in pyridine (50 ml). The reaction was conducted for 5 hours, while the temperature was gradually raised from 50° C. to 100° C. The solvent was removed under reduced pressure. The residue was acidfified with 2 N hydrochloric acid, extracted and concentrated. Recrystallization of the product from ethyl acetate-isopropyl ether gave 1,2,3,4-tetramethoxy-5-methylcinnamic acid (Compound 20, 14.3 g, 70%). m.p. 117°-118° C. δ 2.31 (3H), 3.78 (3H), 3.83 (3H), 3.90 (3H), 3.96 (3H), 6.59 (1H), 7.94 (1H), 11.2 (1H).
Reaction SMILES: [NH3:1].[Si:2]([O:9][CH:10]([CH:23]=[CH2:24])[CH2:11][N:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20](Cl)[C:15]=2[C:14]([I:22])=[CH:13]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]>C1COCC1.O>[Si:2]([O:9][CH:10]([CH:23]=[CH2:24])[CH2:11][N:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([NH2:1])[C:15]=2[C:14]([I:22])=[CH:13]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: C=CC(Cn1cc(I)c2c(Cl)ncnc21)O[Si](C)(C)C(C)(C)C
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: C=CC(Cn1cc(I)c2c(N)ncnc21)O[Si](C)(C)C(C)(C)C
Temperature: 120 °C
Reaction time: 5 h

Procedure:
25% aqueous ammonia (9 ml) was added to a solution of 7-(2-(tert-butyldimethylsilyloxy)-3-butenyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.12 g) obtained in Step 3 in THF (7 ml). The mixture was stirred at 120° C. for 5 hours using a microwave reactor. The reaction mixture was cooled, and then diluted with water. The resulting precipitate was collected by filtration, washed with water, and then dried to obtain the title compound as a white solid (1.06 g).
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])[C:4](OCC)=O)#[N:2].[OH2:18].[NH2:19][NH2:20]>C(O)C>[NH2:2][C:1]1[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[C:4]([OH:18])[NH:20][N:19]=1
Reactant: CCOC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Reactant: NN
Reactant: O
Solvent: CCO
Product: Nc1n[nH]c(O)c1Cc1cccc(Cl)c1Cl
Yield: 66.9 %

Procedure:
A mixture of ethyl 2-cyano-3-(2,3-dichlorophenyl)propanoate (30 g, 0.11 mol) and hydrazine hydrate (11 g, 0.22 mol) in ethanol (300 mL), was stirred under reflux for 16 h. The reaction mixture was cooled and filtered to provide the titled compound (19 g) and the filtrate was concentrated to provide the crude titled compound (18 g); LC/MS: MS (ES+) m/e 258 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.47 (s, 2H), 4.12 (s, 2H), 7.02 (dd, J=1.5, 7.8 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.36 (s, 1H), 7.44 (dd, J=1.5, 7.8 Hz, 1H), 9.06 (s, 1H).
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:21])[NH:9][CH:10]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)[CH2:11]O)(C)(C)C>C1COCC1>[F:19][C:17]1[CH:18]=[C:13]([CH:10]2[CH2:11][O:21][C:8](=[O:7])[NH:9]2)[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: CC(C)(C)OC(=O)NC(CO)c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(c2cc(F)cc(F)c2)CO1
Reaction time: 3 h

Procedure:
Into a well-stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) at R.T. was added a solution of [1-(3,5-difluorophenyl)-2-hydroxy- ethyl]-carbamic acid-tert-butyl ester (5.0 g, 18.3 mmol) in THF (20 mL) via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 100 mL of Et2O, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf=0.15, 3:2 hexane-EtOAc) to obtain 4-(3,5-difluorophenyl)-oxazolidin-2-one as a white flaky solid (2.8 g, 77% yield). M.P. 81-83° C.; 1H NMR (300 MHz, CDCl3) δ 7.23-7.03 (m, 3H), 6.08 (br s, 1H), 4.94 (dd, J=6.6 Hz, J=8.7 Hz, 1H), 4.73 (t, J=8.7 Hz, 1H), 4.13 (dd, J=6.6 Hz, J=8.7 Hz, 1H). The enantiomers were separated by HPLC on a Chiralcel OD (20×250 mm) column using 80% hexane/20% isopropyl alcohol as the eluting system at 12.0 mL/min (U.V. 254 nm). The retention times for the two isomers were 16.19 min and 20.08 min respectively.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9](C)(C)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH2:2].C[O-].[Na+].CO>Cl>[CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:12]=1[C:11]([O:10][CH3:9])=[O:13])=[CH2:2]
Reactant: C=Cc1cccc2c1C(=O)OC(C)(C)O2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=Cc1cccc(O)c1C(=O)OC
Yield: 57.3 %

Procedure:
To 5-ethenyl-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.01 g, 19.6 mmol) was added 0.5 M sodium methoxide in methanol (85 mL, 42.5 mmol) at rt. Aqueous 1 N HCl (100 mL) was added to the solution after 15 min. The cloudy solution was extracted with ether (2×100 mL). The combined organic extracts were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford 2-ethenyl-6-hydroxybenzoic acid, methyl ester (2.0 g, 57%) as a yellow oil. This material was used without further purification in the next step: 1H NMR (CDCl3) δ3.96 (s, 3H), 5.26 (dd, J=10.8, 1.5 Hz, 1H), 5.49 (dd, J=17.3, 1.5 Hz, 1H), 6.95 (m, 2H), 7.23-7.39 (m, 2H), 11.12 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[N:7]=[C:8]([O:18][CH:19]3[CH2:36][CH:35]4[N:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([OH:40])=O)([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=3)[CH:5]=[CH:4][CH:3]=[N:2]1.ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:78][S:79]([CH:82]5[CH2:84][CH2:83]5)(=[O:81])=[O:80])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[N:1]1([C:6]2[N:7]=[C:8]([O:18][CH:19]3[CH2:36][CH:35]4[N:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:78][S:79]([CH:82]6[CH2:84][CH2:83]6)(=[O:81])=[O:80])=[O:40])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=3)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-n3cccn3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-n3cccn3)cc2c1

Procedure:
The title product 68 was prepared from 17-(3-pyrazol-1-yl-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (67) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=678 (M+H)+; 1H-NMR (CDCl3): 10.5 (br s, 1H), 8.4 (dd, J=2.5 Hz, 0.5, 1H), 8 (d, J=9.8 Hz, 1H), 7.75 (s, 2H), 7.00-7.10 (m, 2H), 6.55 (s, 1H), 6.45 (dd, J=2.5 Hz, 0.5, 1H), 5.95 (br s, 1H), 5.75 (dd, J=18.1 Hz, 8 Hz, 1H), 5.1 (t, J=10.3 Hz, 1H), 4.75 (t, J=7.0 Hz, 1H), 4.1 (dd, J=11.0 Hz, 4.3, 1H), 3.90 (s, 3H), 3.70 (d, J=11.0 Hz, 1H), 3.10-3.20 (m, 1H), 2.90-3.01 (m, 1H), 2.85 (s, 3H), 2.50-2.62 (m, 3H), 2.20-2.30 (m, 1H), 1.90-2.00 (m, 2H), 1.55-1.60 (m, 4H), 1.30-1.50 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[Br:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CCOCC>[Br-:11].[CH2:16]([O:15][C:13]([CH2:12][N+:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[CH:3]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: Cn1cnc2ccccc21
Solvent: CCOCC
Product: CCOC(=O)C[n+]1cn(C)c2ccccc21
Product: [Br-]
Yield: 62 %

Procedure:
The 1-methyl-benzimidazole of Step A was dissolved in ether and 1.4 equivalents of ethyl bromoacetate were added thereto. The ether solution was allowed to stand for several days and the crystals formed were recovered for a 62% yield of 1-ethoxycarbonylmethyl-3-methyl-benzimidazolium bromide. After crystallization from an ethyl acetate-methanol mixture, the product melted at 160°-161° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2].[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>ClCCl>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:20](=[O:22])[CH3:21])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2]
Reactant: CC(=S)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Yield: 95 %

Procedure:
A solution of 5-(S)-thioacetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazoli-dine-2-one (0.070 g, 0.247 mmol), acetic anhydride (0.25 mL), pyridine (0.38 mL), and dichloromethane (0.75 mL) was stirred at r.t. for 4 h. Solvent was removed under vacuum and the crude product purified by PTLC (10% MeOH in DCM) to give a white solid (0.076 g, 95%). M.p. 200-1° C.; MS (m/z): (M+H)+=326.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:21][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([C:18](O)=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:22])[NH:4][C:3]1=[O:23].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][N:2]1[C:6]2([CH2:21][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([C:18]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:22])[NH:4][C:3]1=[O:23]
Reactant: CN1C(=O)NC(=O)C12Cc1cc3ccc(C(=O)O)nc3cc1C2
Reactant: Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN1C(=O)NC(=O)C12Cc1cc3ccc(C(=O)Nc4ccccc4)nc3cc1C2

Procedure:
A mixture of (±)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carboxylic acid (14 mg, 0.045 mmol, described in Intermediate 18), aniline (4 mg, 0.045 mmol), EDC (26 mg, 0.136 mmol), HOBT (21 mg, 0.136 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.226 mmol) is stirred in DMF (1 mL) at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and concentrated to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH2:8][NH2:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:26]>>[ClH:26].[NH2:9][CH2:8][CH:7]([C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[C:6]([OH:17])=[O:5]
Reactant: CC(C)(C)OC(=O)C(CN)c1ccc(F)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCC(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-amino-2-(4-fluoro-phenyl)-propionic acid tert-butyl ester (1.3 g) and TFA (10 mL) in DCM (10 mL) was stirred at rt for 1.5 h. Then concentrated, HCl aqueous solution (50 mL, 2 M) was added and concentrated; then acetonitrile was added, and concentrated; then ether was added, solids were collected via filtration and air dried to give HCl salt of 3-amino-2-(4-fluoro-phenyl)-propionic acid (1.21 g).
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3[N:14]=[N:15][N:16]=[C:17]([N:18]=CN(C)C)[C:12]=3[N:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.CO[CH:25](OC)[N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30].C(Cl)Cl.CO.CO>O>[C@@H:1]1([N:9]2[C:13]3[N:14]=[N:15][N:16]=[C:17]([N:18]=[CH:25][N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])[C:12]=3[N:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: CN(C)C=Nc1nnnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CCCCN(CCCC)C(OC)OC
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCCCN(C=Nc1nnnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)CCCC

Procedure:
As described for 9a but using N,N-di-n-butylformamide dimethylacetal. Colorless needles (75%). M.p. 107-109° C. TLC (silica gel, CH2Cl2-MeOH, 9:1): Rf 0.42. UV: (10% MeOH in water): λmax 235 (10200), 325 nm (25700). 1H NMR ([D6]DMSO): δ 0.93 (t, 6H, CH3), 1.33, 1.64, 3.70 (3m, 12H, —CH2—); 2.45, 2.80 (2m, 2H, H2—C(2′)); 3.60 (m, 2H, H2—C(5′)); 3.92 (m, 1H, H—C(4′)); 4.48 (m, 1H, H C(3′)); 5.04 (t, 1H, 3J(H,H)=5.8 Hz, 5′-OH); 5.39 (d, 1H, 3J(H,H)=4.0 Hz, 3′-OH); 6.55 (pt, 1H, 3J(H,H)=6.3 Hz, H—C(1′)); 8.78 (s, 1H, N═CH); 9.08 (s, 1H, H—C(8)). Anal. calcd. for C18H29N7O3 (391.5): C 55.23, H 7.47, N 25.05; found: C 55.36, H 7.66, N 24.97.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:22]=[C:21]([Cl:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C1(SC2C=CC=CC=2)C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]#[N:28])[CH:22]=[C:21]([Cl:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: N#C/C=C/c1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CCCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 68.1 %

Procedure:
A solution of 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(E)-2-cyanoethenyl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide (32 mg, 0.069 mmol), diphenylsulfide (1.145 μl, 6.87 μmol) and Pd/C (7.31 mg, 6.87 μmol) in methanol (5 ml) and ethyl acetate (5 ml) was stirred under hydrogen gas (45 psi pressure) overnight. The palladium was filtered off, the solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-chloro-5-(2-cyanoethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (22 mg, 0.047 mmol, 69% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.69 (s, 1H), 7.15-7.40 (m, 2H), 7.04 (s, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 4.61 (s, 2H), 2.87 (t, 2H), 2.69 (t, 2H). LC-MS (ES+) m/z 467.02, [M+H].
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C@H:15]1[C@@H:19]([CH2:20][OH:21])[O:18][C:17](=[O:22])[NH:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>CC(C)=O>[CH2:8]([C@H:15]1[C@@H:19]([CH2:20][O:21][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[O:18][C:17](=[O:22])[NH:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2OC(=O)N[C@H]2Cc2ccccc2)cc1
Temperature: 22 °C
Reaction time: 6.5 h
Yield: 93.9 %

Procedure:
5.6 ml of triethylamine are added at 22° C. to a stirred suspension of 5.55 g of the alcohol from Example 8 in 27 ml of acetone and 6.64 g of p-toluenesulphonyl chloride and stirred at 22° C. for 6.5 hours. The suspension is treated with water, stirred at 10° C., filtered, the residue is washed with a water/acetone solution (3:2) and dried to give 9.09 g (94%) of 99% p-toluenesulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester, m.p. 148.7-150.3° C., [α]D20 : +3.0(1% acetone).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][C:12]12[CH2:19][CH2:18][CH2:17][N:16]1[CH2:15][CH2:14][CH2:13]2>>[N:16]12[CH2:17][CH2:18][CH2:19][C:12]1([CH2:11][NH:10][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:13][CH2:14][CH2:15]2
Reactant: N#Cc1ccccc1F
Reactant: NCC12CCCN1CCC2
Product: N#Cc1ccccc1NCC12CCCN1CCC2

Procedure:
The procedures described in Example 1 were repeated except that 2-fluorobenzonitrile (671 mg, 5.54 mmol) and 5-aminomethyl-1-azabicyclo[3.3.0]octane (1.94 g, 13.9 mmol) were employed. In this case, the desired compound was obtained as a colorless liquid (1.26 g, 94.2%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[O:5])C.[CH3:6][O:7][CH:8]([CH2:25][CH2:26][CH3:27])[CH2:9][CH2:10][C:11]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:12]=1[CH2:13][CH2:14][C:15]1[S:19]C(N)=[N:17][C:16]=12.Br[C:29]1[CH:34]=[C:33]([F:35])[C:32]([CH:36]=[C:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:31]([F:44])[CH:30]=1.C(N(CC)CC)C>O>[F:35][C:33]1[CH:34]=[C:29]([C:4](=[O:5])[NH:2][C:1]2[S:19][C:15]3[CH2:14][CH2:13][C:12]4[C:21](=[CH:22][CH:23]=[CH:24][C:11]=4[CH2:10][CH2:9][CH:8]([O:7][CH3:6])[CH2:25][CH2:26][CH3:27])[C:16]=3[N:17]=2)[CH:30]=[C:31]([F:44])[C:32]=1[CH:36]=[C:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCCC(CCc1cccc2c1CCc1sc(N)nc1-2)OC
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)=Cc1c(F)cc(Br)cc1F
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(CCc1cccc2c1CCc1sc(NC(=O)c3cc(F)c(C=C(C)C(=O)OCC)c(F)c3)nc1-2)OC
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a DMF (25 mL) solution of 4,5-dihydro-6-(3-methyloxyhexyl)naphtho[1,2-d]thiazol-2-ylamine (7) (4.5 g), 3-(4-bromo-2,6-difluorophenyl)-2-methylacrylic acid ethyl ester (3) (4.35 g), and dichlorobistriphenylphosphinepalladium (0.8 g) was added triethylamine (10 mL), and the reaction mixture was stirred under carbon monoxide atomosphere at 85° C. for 16 h. To the reaction mixture was added water, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=4:1) to obtain the compoumd (8) 7.1 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:21])=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29](O)=[O:30].CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([CH3:21])=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:22])=[O:30]
Reactant: O=C(O)c1[nH]cnc1Cl
Reactant: C=C(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 13.5 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethenyl)benzonitrile (0.068 g, 0.215 mmol), 4-chloro-1H-imidazole-5-carboxylic acid (0.040 g, 0.273 mmol), and DIPEA (0.075 mL, 0.429 mmol) were combined in THF (6 mL) and treated with EDC (0.082 g, 0.429 mmol) at 50° C. for three days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and brine. The organic phase was isolated, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 40 to 100% EtOAc/hexanes to give impure product. This material was repurified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1-methylethenyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.013 g, 0.029 mmol, 13.60% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br. s., 1H), 8.30 (br. s., 1H), 7.73-7.78 (m, 2H), 7.50 (d, J=8.52 Hz, 1H), 7.43 (s, 1H), 7.36 (t, J=7.76 Hz, 1H), 7.26 (s, 1H), 5.57 (s, 1H), 5.25 (s, 1H), 4.52 (d, J=5.36 Hz, 2H), 2.10 (s, 3H). LC-MS (ES−) m/z 443.08, 445.16 [M−1]. LC-MS (ES+) m/z 445.07, 447.07 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][C:3]1=[O:15].[C:17](OCCl)(=O)C(C)(C)C.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:39]#[C:40][CH3:41])[CH2:34][C:35]([O:37]C)=[O:36])=[CH:29][CH:28]=1>>[CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=2)[N:4]([CH2:17][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]([C:39]#[C:40][CH3:41])[CH2:34][C:35]([OH:37])=[O:36])=[CH:29][CH:28]=2)[C:3]1=[O:15]
Reactant: CC1(C)C(=O)Nc2ccc(C(F)(F)F)cc21
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)OCCl
Product: CC#CC(CC(=O)O)c1ccc(OCN2C(=O)C(C)(C)c3cc(C(F)(F)F)ccc32)cc1

Procedure:
Analogously to example 1, 3,3-dimethyl-5-trifluoromethyl-1,3-dihydroindol-2-one, chloromethyl pivalate and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-[4-(3,3-dimethyl-2-oxo-5-trifluoromethyl-2,3-dihydroindol-1-ylmethoxy)phenyl]hex-4-ynoic acid.