Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:26]([O:30][C:31](=[O:51])[NH:32][C:33]([CH3:50])([CH3:49])[CH2:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:51])[NH:32][C:33]([CH3:50])([CH3:49])[CH2:34][N:35]1[CH:39]=[C:38]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:21])[F:22])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:37]=[N:36]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1)NC(=O)OC(C)(C)C
Product: CC(C)(Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1)NC(=O)OC(C)(C)C

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with {1,1-Dimethyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-carbamic acid tert-butyl ester to give [1,1-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester. MS (ESI+) 590.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=2)[CH:21]=[N:20]1.C(Cl)CCl.CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:28][C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[NH:19][N:20]=[CH:21]3)=[O:18])=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(Cl)cc2)CC(=O)N1
Temperature: 80 °C
Yield: 16.9 %

Procedure:
The product of step 2 (494 mg, 1.86 mmol, 1.00 equiv), 1H-indazol-5-amine (296 mg, 2.23 mmol, 1.20 equiv), EDC (426 mg, 2.23 mmol, 1.20 equiv), and DMAP (10 mg, catalytic) were suspended in 8.0 mL DMF. Et3N (0.621 mL, 4.46 mmol, 1.00 equiv) was added and the solution was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (100% EtOAc) to provide 0.120 g (17%) of the title compound as a white solid. MS (ES+) m/e 399 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH:3]=1.C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:21])=[O:10])[CH2:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=CC[C@@H](C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1=CC[C@@H](C(=O)Cl)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(1S)-4-Methyl-cyclohex-3-ene-1-carboxylic acid (250 mg, 1.78 mmol), azeotropically dried by evaporation from toluene was dissolved in dichloromethane (4 mL) and treated with dimethylformamide (1 drop). The reaction mixture was cooled to 0° C. and treated dropwise with oxalyl chloride (0.42 mL, 4.5 mmol). The reaction mixture was allowed to warm to ambient temperature while stirring for 4 h. The solution was concentrated, treated with hexanes and concentrated again to afford (1S)-4-methyl-cyclohex-3-ene-1-carboxylic acid chloride as a light yellow oil which was used immediately in the next step.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](=[O:15])[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])(=O)[CH3:2].ClCC[S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.[OH-].[K+].CO>O>[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:7](=[O:15])[CH2:6][CH2:5][S:4][CH2:1][CH2:2][S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)(=[O:14])[CH3:13]
Reactant: CC(=O)NCCNC(=O)CCSC(C)=O
Reactant: ClCCSC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NCCNC(=O)CCSCCSC1CCCCO1
Temperature: 75 °C

Procedure:
A quantity of the S-{2-[N-(2-acetylaminoethyl)carbamoyl]ethyl} thioacetate, prepared above, (3.2 g, 23 mmol), 2-(2-chloroethylthio)tetrahydropyran (2 g, 11 mmol), potassium hydroxide (2.5 g, 44 mmol), methanol (10 cm3) and water (5 cm3) were mixed together and heated at 75° C. for 30 min. The mixture was allowed to cool and then partitioned between chloroform (50 cm3) and water (50 cm3). The organic layer was separated and the aqueous layer extracted with a further portion of chloroform. The combined chloroform extracts were then dried (MgSO4) and volatile components removed under reduced pressure to leave the crude product as an oily solid. A quantity of this material was purified firstly by chromatography on silica using a mixture of ethyl acetate, and methanol (95:5) as the eluant and then by reverse phase h.p.l.c. using aqueous methanol as the eluant. The pure N-(2-acetylaminoethyl)-3-[2-(tetrahydropyran-2-ylthio)ethylthi o]propionamide was obtained as a white solid (0.3 g).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:25])[C:7]([CH3:24])([C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)[CH3:8])[CH:2]([CH3:4])[CH3:3].Br[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:34]=1)[C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.CCOC(C)=O.O.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.O>[C:32]([C:31]1[CH:34]=[C:27]([C:12]2[CH:11]=[CH:10][C:9]([C:7]([CH3:8])([CH3:24])[C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:25])=[CH:14][CH:13]=2)[CH:28]=[N:29][CH:30]=1)#[N:33]
Reactant: N#Cc1cncc(Br)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cncc(C#N)c2)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
N-isobutyl-2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide (example 23a) (14.86 g, 43.03 mmol), 5-bromonicotinonitrile (7.50 g, 40.98 mmol) and potassium carbonate (11.33 g, 81.96 mmol) were mixed in toluene (75 mL), ethanol (15 mL) and water (11.25 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (950 mg, 0.82 mmol) was added. The reaction mixture was heated to reflux for 16 hr and cooled to room temperature then diluted with EtOAc/water, washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (eluant 40% EtOAc in hexane) twice, then recrystallized from EtOAC/hexane and co-evaporated with ethanol to give 11.6 g of the product as a white solid in 88% yield. 1H NMR (400 MHz, DMSO-d6): δ 0.75 (d, 6H)), 1.48 (s, 6H), 1.70 (m, 1H), 2.85 (t, 2H), 7.45 (m, 3H), 7.8 (d, 2H), 8.65 (t, 1H), 9 (d, 1H), 9.2 (d, 1H). MS(M+H, 322).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.C[O:43][C:44]([C:46]1[CH:51]=[CH:50][C:49](Br)=[CH:48][N:47]=1)=[O:45]>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:49]3[CH:50]=[CH:51][C:46]([C:44]([OH:43])=[O:45])=[N:47][CH:48]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(=O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (1.3 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (0.60 g) and 5-bromo-pyridine-2-carboxylic acid methyl ester (0.41 g) in dimethylformamide (4 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (61 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted with water and brine. The aqueous extracts were combined, acidified (pH ca. 5-6) using citric acid, and extracted with CH2Cl2/MeOH (ca. 10:1). The combined organic extracts were washed with brine and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->50:50) to afford the title compound as a resin-like solid. Yield: 0.44 g (73% of theory); Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]([C:25]1[S:29][C:28]([NH2:30])=[N:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:21]([C:25]1[S:29][C:28]([NH:30][C:15]([CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[O:17])=[N:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)Nc2nnc(C(C)(C)C)s2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C18H23N3O5S [M−H]−: 392.
Reaction SMILES: ClCC(=O)CCCC[N:8]1[C:12](=O)[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=C2C1=O.[F:20][C:21]([F:31])([F:30])[CH2:22][NH:23][C:24]([NH:26][C:27]([NH2:29])=[S:28])=[NH:25]>C(O)C>[F:31][C:21]([F:20])([F:30])[CH2:22][N:23]=[C:24]([NH2:25])[NH:26][C:27]1[S:28][CH:17]=[C:16]([CH2:15][CH2:14][CH2:11][CH2:12][NH2:8])[N:29]=1
Reactant: N=C(NCC(F)(F)F)NC(N)=S
Reactant: O=C(CCl)CCCCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a solution of N-(6-chloro-5-oxohexyl)phthalimide (3.4 g.) in ethanol was added N-(2,2,2-trifluoroethylamidino)-thiourea (2.75 g.) in ethanol (30 ml.). The mixture was heated under reflux for 2 hours and the reaction mixture concentrated to small volume by evaporation. Following treatment of the resulting solution with ether until the solution was just turbid, crystalline 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-phthalimidobutyl)thiazole hydrochloride (3.6 g.) was precipitated. This material (2.1 g.) in ethanol (20 ml.) and water (5 ml.) was heated to boiling and the solution pH was adjusted to 12 by addition of 2 N sodium hydroxide. After heating on a steam bath for 10 minutes, the solution pH was adjusted to 3 with conc. hydrochloric acid and heating continued for a further 0.5 hour. The solution was cooled, adjusted to pH 12 with 2 N sodium hydroxide and extracted with ethyl acetate (2×30 ml.). Evaporation of the washed (H2O), dried (magnesium sulphate) extract gave 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-thiazole as a pale yellow gum which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:12])=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:12][C:4]1[S:3][C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6][C:5]=1[C:7]1[O:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(-c2ccco2)c(Br)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(Br)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Compound g (10.0 g, 40.8 mmol) obtained in Reference Example 7 was dissolved in pyridine (136 mL), and under ice-cooling, 4-dimethylaminopyridine (250 mg, 2.04 mmol) and benzoyl chloride (8.05 mL, 69.4 mmol) were added thereto, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=10:1) to afford N-[5-bromo-4-(2-furyl)thiazol-2-yl]benzamide (12.0 g, 84%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([C@@H](C(C)C)C)[N:3]=1.[CH:16]1([NH:19][C:20]([C:22]2[CH:23]=[C:24]([F:32])[C:25]([CH3:31])=[C:26](B(O)O)[CH:27]=2)=[O:21])[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CC(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>[CH:16]1([NH:19][C:20]([C:22]2[CH:23]=[C:24]([F:32])[C:25]([CH3:31])=[C:26]([C:2]3[N:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([CH3:10])[CH:5]([CH3:6])[CH3:4])=[O:7])=[CH:9][CH:10]=3)[CH:27]=2)=[O:21])[CH2:18][CH2:17]1
Reactant: CC(C)[C@@H](C)c1nc(Cl)ccc1C(N)=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)C)cn1
Temperature: 90 °C

Procedure:
6-Chloro-[(R)-(−)-3-methyl-2-butyl]nicotinamide (Intermediate 18, 100 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 6, 100 mg), tetrakis(triphenylphosphine)palladium (10 mg) and aqueous sodium hydrogen carbonate (4 ml) were mixed in propan-2-ol (8 ml) and heated at 90° C. under nitrogen for 18 hrs. The solvents were evaporated from the cooled reaction under vacuum and the residue dissolved as far as possible in ethylacetate. The solution was applied to an SPE (SCX, 10 g) and washed with ethyl acetate. The product was eluted from the column with methanol/0.880 ammonia, and the solvents evaporated in vacuo. The residue was redissolved in ethyl acetate and filtered through an SPE (silica, 0.5 g). The filtrate was reduced to dryness under vacuum and triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-dimethylpropyl]-3-pyridinecarboxamide.
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Mg]Cl)(C)C.[Cu]C#N.[CH2:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:28]1[O:30][CH2:29]1>O1CCCC1>[CH2:32]([O:31][CH2:27][C@@H:28]([OH:30])[CH2:29][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[CH:5]=[C:6]([F:8])[CH:7]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1c(Br)cc(F)cc1-c1c(Cl)cccc1Cl
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1c(C[C@H](O)COCc2ccccc2)cc(F)cc1-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of 3-bromo-2′,6′-dichloro-5-fluoro-2-methoxy-biphenyl (2.2 g, 6.3 mmol) in anhydrous tetrahydrofuran at 0° C. was added isopropylmagnesium chloride (3.45 ml, 2.0 M in hexane) and the resulting mixture was allowed to stir at 0° C. for 4 h. The reaction mixture was cooled to −30° C. and copper(I) cyanide (0.28 g, 3.1 mmol) in tetrahydrofuran was added and the reaction mixture was allowed to stir at −30° C. for 1 h. Benzyl(S)-(+)-glycidyl ether (0.48 ml, 3.1 mmol) was then added at −30° C. and the reaction mixture was allowed to warm to room temperature for 12 h. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 1.28 g (94%) of (S)-1-benzyloxy-3-(2′,6′-dichlor-5-fluoro-2-methoxybiphenyl-3-yl)propan-2-ol as a colorless oil. HRMS ESI m/e 435.0946 [M−H]−, Calc'd 435.0930; [α]D25=+2.8 (c 8.14 in dimethylsulfoxide).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38](O)=[O:39])=[CH:5][CH:4]=1.[CH2:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH2:51])[CH3:44].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH:51][C:38]([C:10]1[N:11]=[C:12]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[C:33]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:26][CH2:27]2)[NH:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:41])([F:42])[F:1])=[CH:4][CH:5]=1)=[O:39])[CH3:44]
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Reactant: CCN1CCCC1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCCC1CNC(=O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (200. mg, 0.325 mmol, Example (16e)), (1-ethylpyrrolidin-2-yl)methanamine (83 mg, 0.65 mmol, Acros), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (216 mg, 0.487 mmol, Aldrich), and DIEA (0.170 mL, 0.975 mmol, Aldrich) in DCM (2 mL) reacted under the condition of Example 16(f) and Example 16(g) to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 596 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[C:12](OC)(OC)(OC)[CH3:13]>CO>[CH3:12][C:13]1[O:11][C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: COC(C)(OC)OC
Solvent: CO
Product: Cc1nc2ccc(C(=O)O)cc2o1
Temperature: 100 °C
Yield: 40.6 %

Procedure:
A mixture of 4-amino-3-hydroxybenzoic acid (500 mg, 3.7 mmol) and trimethyl orthoacetate (1.0 mL, 7.9 mmol) is heated in an oil bath to 100° C. for 2 h. The mixture is cooled to rt and diluted with MeOH. The resulting solution is filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give 2-methyl-1,3-benzoxazole-6-carboxylic acid as an off-white solid (266 mg, 46%): 1H NMR (DMSO-d6) δ 13.1, 8.2, 8.0, 7.7, 2.7.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4](F)[C:3]=1[CH3:13].O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>C(O)C.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[C:3]=1[CH3:13]
Reactant: Cc1c(F)c(F)cc([N+](=O)[O-])c1Cl
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(Cl)c([N+](=O)[O-])cc(F)c1N1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 2-chloro-5,6-difluoro-3-nitrotoluene (54 mg) are added ethanol (0.3 ml) and water (0.03 ml) at 0° C. and thereto further added dropwise a solution of N-methylpiperazine (0.04 ml) and triethylamine (0.06 ml) in ethanol (0.1 ml) at room temperature. The mixture is stirred at room temperature for 5 hours, at 60° C. for 5 hours and further at 80° C. overnight. The reaction mixture is acidified with 2N hydrochloric acid and washed with a small amount of diethyl ether and then neutralized with aqueous saturated sodium hydrogen carbonate and extracted with dichloromethane. The extract is washed with water and aqueous saturated sodium chloride in this order and dried over anhydrous magnesium sulfate, and then dichloromethane is disilled off to give 2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)-3-nitrotoluene (35 mg).
Reaction SMILES: [CH3:1][CH:2]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH:3](OS(C)(=O)=O)[CH3:4].[Cl:21][C:22]1[CH:23]=[C:24]([C:28]#[N:29])[NH:25][C:26]=1[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]#[N:29])[N:25]([CH2:4][CH2:3][CH:2]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH3:1])[C:26]=1[CH3:27]
Reactant: CC(OS(C)(=O)=O)C(C)N1C(=O)c2ccccc2C1=O
Reactant: Cc1[nH]c(C#N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(Cl)cc(C#N)n1CCC(C)N1C(=O)c2ccccc2C1=O
Yield: 65.9 %

Procedure:
A solution of 4.23 g (14.2 mmol) of 2-[1-methyl-2-[(methylsulfonyl)oxy]propyl]-1H-isoindole-1,3(2H)-dione, 2.05 g (14.2 mmol) of 4-chloro-5-methyl-1H-pyrrole-2-carbonitrile and 2.35 g (14.2 mmol) of K2CO3 in 60 mL DMF was heated at 60° C. overnight. The mixture was diluted with ether and washed 4 times with water. Drying (MgSO4) and removal of solvent gave an oil which was chromatographed on silica gel (15% ethyl acetate in hexanes) to give 3.2 g of 4-chloro-1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl]-5-methyl-1H-pyrrole-2-carbonitrile as a solid, 1NMR (CDCl3) δ1.5 (d, 3H), 2.2 (s, 3H and m, 1H), 2.7 (m, 1H), 3.9 (m, 1H), 4.05 (m, 1H), 4.4 (m, 1H), 6.6 (s, 1H), 7.85 (m, 2H), 7.9 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[C:19]([F:24])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[NH:27]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[C@H:26]([CH3:25])[CH2:30][CH2:29][S:28]4(=[O:32])=[O:31])=[C:19]([F:24])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)c(F)c3)CC2)c(C)c1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 8.4 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](3-fluoro-4-iodophenyl)methanone (600 mg) described in Preparation Example 159 and (R)-3-methylisothiazolidine 1,1-dioxide (185 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (51 mg) was obtained.