Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:34]1[N:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([C:21]3([O:32][CH3:33])[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[CH3:33][O:32][C:21]1([C:19]2[S:20][C:16]([C:11]3[CH:10]=[C:9]([NH:8][C:34]4[N:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=4)[CH:14]=[C:13]([CH3:15])[CH:12]=3)=[CH:17][N:18]=2)[CH2:22][CH2:23][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CCOC(=O)C1CCC(OC)(c2ncc(-c3cc(C)cc(N(C(=O)OC(C)(C)C)c4nccc(C(F)(F)F)n4)c3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCC(OC)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1

Procedure:
To the product of Step 1 (0.15 g, 0.243 mmol) in dichlormethane (2 mL) was added trifluoroacetic acid (1.48 g, 12.98 mmol) and the reaction was stirred until complete. The reaction was diluted with water and the mixture extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give ethyl 4-methoxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M+H]+ m/z 521.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25](O)=[O:26])=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[O:26])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: C1COCCN1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)N2CCOCC2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
A mixture of [3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetic acid (400 mg), 1-hydroxybenzotriazole hydrate (180 mg), WSC (230 mg), morpholine (100 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 4-[3-[4-[2-(2-furyl)-5-methyl1–4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetylmorpholine (440 mg, yield 96%), which was then recrystallized from ethyl acetate-hexane. melting point: 132–133° C.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH:7][C@@H:8]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([CH3:21])[CH:12]=1)[CH:9]=[CH2:10])=[O:6])([CH3:4])[CH3:3].[Li+].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:23][N:7]([C@@H:8]([C:11]1[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=[C:13]([CH3:21])[CH:12]=1)[CH:9]=[CH2:10])[S@:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(C)cc(C(F)(F)F)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C=C[C@H](c1cc(C)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of (S)-2-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)allyl) propane-2-sulfinamide (400 mg, 1.25 mmol) in THF (10 mL) under N2 atmosphere was dropwise added LiHMDS (1.9 ml, 1 M in THF, 1.9 mmol) at −60° C. The reaction was stirred for 30 min at −60° C. followed by addition of MeI (712 mg, 32 mmol). After stirring for another 3 h at room temperature, the reaction was quenched with water at 0° C. and then extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (300 mg, yield: 75%); m/z (ES+): 334 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2Br)[C:16]1=[O:25].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[C:16]1=[O:25]
Reactant: Nc1ccccc1NC(=O)CCCCCN1Cc2c(Br)cccc2C1=O
Reactant: OB(O)c1cccnc1
Product: Nc1ccccc1NC(=O)CCCCCN1Cc2c(cccc2-c2cccnc2)C1=O
Yield: 94 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-6-(4-bromo-1-oxoisoindolin-2-yl)hexanamide obtained in Example 36 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-pyridinyl boronic acid instead of phenyl boronic acid, to obtain the title compound (94%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[O:15])[C:13]3[CH:16]=[C:17]([C:20](=[O:24])[CH:21]([F:23])[F:22])[CH:18]=[CH:19][C:12]=3[CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[CH:14]([OH:15])[C:13]3[CH:16]=[C:17]([CH:20]([OH:24])[CH:21]([F:22])[F:23])[CH:18]=[CH:19][C:12]=3[CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: O=C(c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1)C(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1c2cc(C(O)C(F)F)ccc2C=Cc2ncc(Cl)cc21
Reaction time: 0.33 h

Procedure:
Sodium borohydride (15 mg, 0.4 mmol) was added to a slurry of 3-chloro-7-(difluoroacetyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (60 mg, 0.19 mmol) in methanol (2 mL) at room temperature. The mixture was stirred for 20 minutes at which time it was quenched via the dropwise addition of 2N aqueous hydrochloric acid. Once gas evolution ceased, the solvent was removed in vacuo. The resulting residue was taken up in ethyl acetate and poured into saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate three times. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 0-50% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.37 (s, 1H), 8.14 (s, 1H), 7.87 (d, 1H), 7.36 (m, 3H), 7.15 (dd, 1H), 5.82 (tt, 1H), 5.19 (s, 1H), 4.83-4.78 (m, 1H), 3.30 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1.[CH3:15]O.S(Cl)(Cl)=O>O>[CH3:15][O:12][C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH:8]=1)=[O:13]
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Reactant: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cc(OC)ccc2o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Methoxybenzofuran-2-carboxylic acid (5.04 g, 26 mmol) was weighed into a 200 ml round bottom flask fitted with a stir bar, septum and nitrogen inlet. Anhydrous MeOH (50 ml) was added under nitrogen atmosphere. The solution was cooled in an ice bath and thionyl chloride (2.3 ml, 32 mmol) was added dropwise with vigorous stirring. After stirring for 72 h at room temperature, the reaction mixture was poured into water (150 ml) and the white solid was collected. The solid was dissolved in toluene (100 ml) and the solution was washed with 1M NaHCO3 and brine and dried over MgSO4. Removal of the organic layer provided 5-methoxybenzofuran-2-carboxylic acid methyl ester as a white solid (5.15 g).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[C@@H:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=2)=[O:17])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.Br[C:41]1[S:42][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]([CH3:46])[N:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([NH:8][C@H:9]1[C@@H:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=2)=[O:17])[CH2:13][CH2:12][N:11]([C:41]2[S:42][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]([CH3:46])[N:45]=2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NCc2ccccc2)nc1Cl
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](NCc3ccccc3)C2)nc1C
Yield: 57.2 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-3-(benzylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (203a) (26.0 mg, 0.056 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (17 mg, 0.068 mmol) and sodium carbonate (60 mg, 0.563 mmol), to obtain 17 mg of the title compound (57%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]=[C:10]2[NH:14][CH2:13][CH2:12][NH:11]2)=[C:4]([Cl:15])[CH:3]=1.C([N:19]1[CH2:23][CH2:22][NH:21][C:20]1=O)(=O)C.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[Cl:15][C:4]1[CH2:3][C:2](=[N:1][CH:20]2[NH:21][CH2:22][CH2:23][NH:19]2)[CH:7]=[C:6]([Cl:8])[C:5]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1
Reactant: CC(=O)N1CCNC1=O
Reactant: Nc1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1=CC(=NC2NCCN2)CC(Cl)=C1N=C1NCCN1

Procedure:
A mixture of 2-(4-amino-2,6-dichlorophenylimino)imidazolidine (3.7 g, 0.015M) and 1-acetyl-2-imidazolidone (2.2 g, 0.02M) in phosphoryl chloride (25 ml) was heated under reflux for 3 days. After cooling to room temperature the phosphoryl chloride was evaporated to give an oily residue. The residue was basified with sodium hydroxide (50%) and the insoluble solid was filtered off. This solid was hydrolysed with dilute sodium hydroxide in methanol. After evaporation of the mixture the product was extracted into methylene chloride. Evaporation of the extract gave 2-[2,6-dichloro-4-(2-imidazolidinylimino)phenylimino]imidazolidine.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[CH:14][CH:13]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[C:18]1([CH2:17][N:16]2[C:12]([NH:11][C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]([OH:6])=[O:5])=[CH:13][CH:14]=[N:15]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccccc1I
Reactant: Nc1ccnn1Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccccc1Nc1ccnn1Cc1ccccc1

Procedure:
A mixture of 2-iodobenzoic acid (14 g, 0.057 mol), 5-amino-1-phenylmethylpyrazole (9.8 g, 0.057 mol), DMF (140 ml), potassium carbonate (8.3 g) and Cu(OAc)2 (0.1 g) was refluxed for about 2 days. The reaction mixture was poured into water, acidified with acetic acid to a pH of 5 and then the solid which formed was collected by filtration, washed with water, then ether and then was dried to afford N-(1-phenylmethylpyrazol-5-yl) anthranilic acid, m.p. 190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 99.5 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.0 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate (0.961 g, 4.0 mmol). Trituration in hexanes/ethyl acetate (3:2) gave the product (1.91 g); m.p. 172-173° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[O:19][CH2:20][CH2:21][CH:22]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CSc1nc(N)nc(C2=CCCO2)c1C#N
Temperature: 100 °C
Yield: 48.5 %

Procedure:
To a stirred solution of 700 mg (2.86 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 25 ml dry dioxane under argon at room temperature were added 1.13 g (3.14 mmol) tributyl-(4,5-dihydro-furan-2-yl)-stannane and 281 mg (0.40 mmol) bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/1) afforded 325 mg (49%) 2-amino-4-(4,5-dihydro-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow crystalline solid. ES-MS m/e (%): 257 (M+Na+, 47), 235 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([NH2:61])[CH:56]=[C:55]2[CH3:62]>CN(C=O)C.O.CCOC(C)=O>[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([NH:61][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:5][CH:6]=1)=[O:10])[CH:56]=[C:55]2[CH3:62]
Reactant: Cc1nc(-c2cccnc2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(F)cc12
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccnc2)ncc1C(=O)Nn1cc(C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
A solution of 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (502 mg, 2.33 mmol), HCTU (1.054 g, 2.55 mmol), and DIPEA (1.10 mL, 6.30 mmol) in DMF (10 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-3-methyl-indol-1-ylamine (341 mg, 2.08 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether (4 times) to afford 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (160 mg, 21%) as a solid. MS: 362 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 11.86 (s, 1H), 9.58 (s, 1H), 9.24 (s, 1H), 8.79-8.78 (m, 1H), 8.74 (td, 1H), 7.62 (dd, 1H), 7.44 (dd, 1H), 7.37-7.36 (m, 2H), 7.06 (td, 1H), 2.78 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C[Li].[CH2:18](OCC)C.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH:12]([OH:13])[CH3:18])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)nc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(Br)cc2)nc1
Reaction time: 1 h
Yield: 60 %

Procedure:
6-(4-Bromophenyl)nicotinaldehyde (3.2 g, 12 mmol) was dissolved in tetrahydrofuran (50 mL), and a solution of methyllithium in diethyl ether (1.0 M, 15 mL, 15 mmol) was added dropwise at −78° C. under a nitrogen atmosphere, followed by stirring at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.30 (hexane/ethyl acetate=2/1) by thin layer chromatography was concentrated under reduced pressure to afford 1-[6-(4-bromophenyl)pyridin-3-yl]ethanol (2.0 g, 7.2 mmol) as a white solid (yield 59%).
Reaction SMILES: [C:1]([N:5]1[C@H:9]([CH2:10]O)[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])(=[O:4])[CH2:2][CH3:3].C(N(CC)C(F)(F)C(F)C(F)(F)[F:30])C>C(Cl)Cl>[C:1]([N:5]1[C@H:9]([CH2:10][F:30])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N1[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Temperature: 22.5 °C

Procedure:
(4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound V: R1 is methylsulfonyl, R2 and R3 are methyl and R4 is ethyl) (70 g, 0.2050 moles) in methylene chloride (450 ml) reacts with N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) (73.2 g, 0.328 moles) at 95-105° C. for 2-4 hours. Cooling to 20-25° C., quenching with 25% aqueous sodium hydroxide and water (2000 mL) and separation of the methylene chloride layer gives a solution of (4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound IX: R1 is methylsulfonyl, R2 and R3 are methyl and R4 is ethyl) for use in the next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCCCCl)cc1
Yield: 98 %

Procedure:
To a solution of methyl 4-(3-chloropropoxy)benzoate ax13 (3 g, 13 mmol, 1 eq) in ethanol (30 ml) is added 2.5 M aqueous sodium hydroxide (10 ml, 25 mmol, 2 eq). The mixture is refluxed for 1 hour, concentrated under vacuum, acidified with 2 M aqueous hydrochloric acid to pH 1 and extracted with ethyl acetate (3×50 ml). The combined organic layers are evaporated to give 2.75 g of 4-(3-chloropropoxy)benzoic acid ax51.
Reaction SMILES: [CH2:1](O)[CH2:2][CH:3]=[CH2:4].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:18]([C:21]1[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23][C:22]=1[C:29]([C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([CH3:39])[CH:38]=1)[C:34]#[N:35])=[O:30])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.ClCCl.CN(C=O)C>[CH2:4]([N:23]1[C:22]([C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[C:37]([CH3:39])[CH:38]=2)[C:34]#[N:35])=[O:30])=[C:21]([CH:18]([CH3:20])[CH3:19])[C:26](=[O:27])[NH:25][C:24]1=[O:28])[CH2:3][CH:2]=[CH2:1]
Reactant: C=CCCO
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C=CCCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 1.1 h
Yield: 30.4 %

Procedure:
To a stirred solution of 3-butene-1-ol (216 mg, 3 mmol) in chloroform (20 mL) cooled in an ice bath under nitrogen atmosphere, was added triethylamine (630 μL, 4.5 mmol) and methanesulfonyl chloride (270 μL, 3.6 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was diluted with dichloromethane and washed with sat. aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuum for ca. 20 min. and mixed with 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (Compound 1) (891 mg, 3 mmol), powdered anhydrous potassium carbonate (414 mg, 3.6 mmol), and lithium iodide (402 mg, 3 mmol). DMF (15 mL) was then added to the mixture and stirred for overnight in an oil bath (40-50° C.). After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through a celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 320 mg (30%) of 3-(3-but-3-enyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (79) as a white foam. Recrystallization from ether-hexane resulted a white solid. m.p. 133-134° C.; 1H-NMR (300 MHz, CDCl3) δ 1.13 (3H, d, J=6.9 Hz), 1.22 (3H, d, J=6.9 Hz), 2.19-2.34 (3H, m), 2.54 (3H, s), 3.15 (1H, m), 3.90 (1H, m), 4.94-5.02 (2H, m), 5.58 (1H, m), 7.82 (1H, s), 7.96 (1H, s), 8.06 (1H, s), 8.99 (1H, s); m/z (EI) 351 (M+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO.O.CCOC(C)=O>C1COCC1>[CH:14]1([CH2:12][NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CS(=O)(=O)c1ccc(NC(=O)C2CCCC2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Temperature: 25 °C

Procedure:
In a nitrogen atmosphere a solution of cyclopentanecarboxylic acid (4-methanesulfonyl-phenyl)-amide (10 mmol) in THF (20 mL) was added a solution of 1M BH3 in THF (20 mL). The mixture was refluxed for 3H and cooled to RT. Addition of 10 mL of MeOH followed by reflux for 15 min. The mixture was cooled and added water (100 mL) and EtOAc (200 mL). The organic phase was isolated and washed with 1N NaOH, water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.Cl>C(O)CCC.O1CCOCC1>[F:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:22][C:19]3[CH:20]=[CH:21][C:16]([C:14]4[N:15]=[C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])[S:12][CH:13]=4)=[CH:17][CH:18]=3)[S:28][C:29]=2[CH:35]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cs1)C(C)C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 300 mg) in n-butanol (5 ml), 2-chloro-6-fluorobenzo[d]thiazole (202 mg) was added and the reaction mixture was heated at 70° C. and stirred for 10 minutes. 4M HCl in dioxane (0.131 gm) was added and the reaction mixture was stirred for 16 hours at 90° C. Organic solvent was concentrated to obtain a sticky solid, which was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 130 mg (29%). 1H NMR (CDCl3; 300 MHz): δ 7.97 (d, 2H), 7.83 (d, 1H), 7.67 (s, 1H), 7.64 (m, 4H), 7.38 (dd, 1H), 7.13 (td, 1H), 4.77 (q, 1H), 3.80 (s, 3H), 2.37 (m, 1H), 0.97 (dd, 6H).