Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Sn]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])(C)C.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:15][C:16]1[N:17]=[C:18]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[CH:19]=[CH:20][CH:21]=1
Reactant: Brc1cccc(Br)n1
Reactant: COC(=S)c1cc([Sn](C)(C)C)c(C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=S)c1cc(-c2cccc(Br)n2)c(C)s1
Temperature: 120 °C
Yield: 42.4 %

Procedure:
Methyl 4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-carboxylate (195 mg, 0.56 mmol) as prepared in previous step, and 2,6-dibromopyridine (398 mg, 1.7 mmol) were taken in anhydrous DMF (2 mL). To this mixture tetrakistriphenylphosphine-palladium (20 mg) was added and heated at 120° C. for 24 h. DMF was removed under vacuum and the residue was purified by preparative silica gel thin-layer chromatography to give 78 mg (41%) of methyl 4-(6-bromo(2-pyridyl))-5-methylthiothiophene-2-carboxylate as a solid. 1H-NMR (CDCl3; 300 MHz) δ2.60 (S, 3H), 3.78 (s, 3H), 7.19 (S, 1H), 7.47 (dd, J=1.09 and 7.67 Hz, 1H)), 7.58 (t, J=7.70, 1H), 7.65 (dd, J=1.12 and 7.43 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[CH:2]1.[CH3:8][CH:9]([Si:11](Cl)([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH3:10].N1C=CN=C1>C(Cl)Cl>[CH:9]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[O:7][CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)([CH3:10])[CH3:8]
Reactant: OCc1cscn1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](OCc1cscn1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a DCM solution of thiazol-4-ylmethanol (Combi-Blocks)(1 g, 8.69 mmol) stirred at 0° C., were added TIPSCl (2.2 mL, 10.43 mmol) and imidazole (1.48 g, 21.72 mmol). The resulting mixture was then warmed to room temperature and stirred for overnight. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, concentrated to a residue which was purified by flash column to give 4-((triisopropylsilyloxy)methyl)thiazole (2 g). 1H NMR (300 MHz, CDCl3), d: 8.794 (m, 1H), 7.338 (m, 1H), 5.065 (s, 2H), 1.209 (m, 3H), 1.133 (d, J=6 Hz, 18H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCCCCBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCCCCOc1ccccc1C=O
Yield: 43.5 %

Procedure:
A mixture of 12.2 g (0.1 mol) of salicylaldehyde, 23 g (0.11 mol) of 5-bromopentyl acetate, 44.2 g (0.3 mol) of anhydrous, granular potassium carbonate, and 700 mL of acetonitrile was stirred and refluxed for 20 hr. After being cooled, the resulting mixture was filtered with suction and the solids were washed well with ether. The filtrate and washes were combined and concentrated in vacuo giving a yellow oil which was purified by flash chromatography on silica gel, eluting with 4:1 hexane-ether. There was obtained 10.9 g (43.6%) of 2-[[5-(acetyloxy)pentyl]oxy]benzaldehyde as an oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:2]1.Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=2)[O:18][C:17](=[O:26])[CH:16]=1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[O:18][C:17](=[O:26])[CH:16]=2)=[O:11])[S:2]1
Reactant: O=c1cc(CCl)c2ccc(O)cc2o1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(CCCC[C@@H]1CCSS1)OCc1cc(=O)oc2cc(O)ccc12
Temperature: 80 °C
Yield: 24.9 %

Procedure:
To a room temperature solution of (R)-(+)-1,2-dithiolane-3-pentanoic acid (2.66 g, 12.9 mmol) and 4-Chloromethyl-7-hydroxy-2H-chromen-2-one (1) (2.40 g, 11.4 mmol) in anhydrous benzene (160 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.8 mL, 25 mmol) in one portion. The reaction mixture was heated to 80° C. (oil bath temperature) for 1 h, cooled to room temperature, then quenched with aqueous 15% citric acid (200 mL). The resulting suspension was filtered, and the collected insoluble material was suspended in acetone (100 mL), sonicated for 60 s, then filtered onto a bed of silica gel (˜10 g). The suspension-sonication-filtration step was repeated a second time. Concentration of the filtrate under reduced pressure followed by flash column chromatography (1% MeOH in CH2Cl2) provided the desired product as a pale yellow powder (1.08 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([OH:14])=[N:12][S:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Br.O>C(#N)C>[Br:21][CH2:22][CH2:23][O:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][S:11][N:12]=1
Reactant: Oc1nsnc1-c1c(Cl)cccc1Cl
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Clc1cccc(Cl)c1-c1nsnc1OCCBr
Yield: 148.1 %

Procedure:
In acetonitrile, were mixed and stirred 0.49 g of 3-(2,6-dichlorophenyl)-4-hydroxy-1,2,5-thiadiazole, 0.3 g of potassium carbonate, and 1.9 g of 1,2-dibromoethane at 80° C. for one hour. After spontaneous cooling, the reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute hydrochloric acid, 10% sodium hydrogencarbonate, and water successively,dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel chromatography to obtain 1.04 g of 3-(2-bromoethoxy)-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[C:34]5=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]5[N:32]=[C:31]4[CH2:41][CH3:42])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl>C(Cl)(Cl)Cl>[CH2:41]([C:31]1[N:30]([CH2:29][C:26]2[CH:25]=[CH:24][C:23]([NH:22][C@H:19]3[CH2:18][CH2:17][C@H:16]([C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:15])[CH2:21][CH2:20]3)=[CH:28][CH:27]=2)[C:34]2=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]2[N:32]=1)[CH3:42]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N[C@H]2CC[C@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N[C@H]2CC[C@H](C(=O)N3CCNCC3)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Compound 113 (261 mg, 0.454 mmol) was dissolved in chloroform (1.7 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (4.5 mL) was added to the solution, followed by stirring at 0° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added with a 2 mol/L aqueous sodium hydroxide solution, then extracted with ethyl acetate three times. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was recrystallized from ethanol-diisopropyl ether (1:20) to obtain Compound 114 (201 mg, 0.423 mmol, 93.3%).
Reaction SMILES: [BH4-].[Li+].[I:3][C:4]1[C:12]2[CH:11]=[N:10][CH:9]=[N:8][C:7]=2[N:6]([C:13]([CH3:19])([CH3:18])[C:14](OC)=[O:15])[CH:5]=1.O>C(O)C>[I:3][C:4]1[C:12]2[CH:11]=[N:10][CH:9]=[N:8][C:7]=2[N:6]([C:13]([CH3:19])([CH3:18])[CH2:14][OH:15])[CH:5]=1
Reactant: COC(=O)C(C)(C)n1cc(I)c2cncnc21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: CC(C)(CO)n1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
Lithium borohydride (32.3 mL, 64.6 mmol, 2.0 M in THF) was added to methyl 2-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropanoate (8.92 g, 25.9 mmol) (see Preparation 21) in ethanol (70 mL). The mixture was stirred at room temperature for 17 hours then water (70 mL) was added. The mixture was evaporated in vacuo then the residue was partitioned between DCM (250 mL) and water (50 mL). The aqueous phase was extracted with DCM:MeOH (90:10, 2×250 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford the title compound as an off-white solid in 100% yield, 8.20 g.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni].CO>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:23])[C:18]([NH:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N

Procedure:
A solution of 5 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N-methyl-2-nitrobenzenamine in 80 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 4.64 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -methyl-1,2-benzenediamine as a residue.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 48.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (8.0 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.8 mg) was obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:17][CH2:16][C:15]3[C:18]4[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=4[S:20][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1Br)(=O)C.[CH3:28][N:29]([CH3:58])[CH2:30][CH2:31][N:32]([CH3:57])[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40]2[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)=[N:37][CH:38]=1>>[CH3:28][N:29]([CH3:58])[CH2:30][CH2:31][N:32]([CH3:57])[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40]2[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=[C:44]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:17][CH2:16][C:15]5[C:18]6[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=6[S:20][C:14]=5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:45]=2)=[N:37][CH:38]=1
Reactant: CN(C)CCN(C)c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Product: CN(C)CCN(C)c1ccc(Nc2cc(-c3cc(F)cc(N4CCc5c(sc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Yield: 7.8 %

Procedure:
Following Example 270, reaction of 212a (550 mg, 1.20 mmol) and 270d (428 mg, 1.00 mmol) afforded a 8% yield (49 mg) of 286 as an off-white solid: mp 122-123° C.; 1H NMR (500 MHz, DMSO-d6) d 8.45 (d, 1H, J=2.0 Hz), 8.20 (s, 1H), 7.69 (d, 1H, J=2.4 Hz), 7.31 (m, 2H), 7.17 (m, 3H), 4.83 (t, 1H, J=4.6 Hz), 4.32 (d, 2H, J=4.3 Hz), 4.06 (m, 1H), 3.87 (m, 1H), 3.58 (s, 3H), 2.96 (m, 1H), 2.86 (m, 1H), 2.83 (s, 3H), 2.78 (m, 2H), 2.54 (m, 1H), 2.32 (t, 2H, J=7.0 Hz), 2.14 (s, 6H), 1.80 (m, 4H); MS (ESI+) m/z 631.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH2:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8]([NH:37][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])=[N:9][CH:10]=1
Reactant: CCS(N)(=O)=O
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O
Product: CCS(=O)(=O)Nc1ncc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3ccccc23)n1

Procedure:
The title compound of Example 151 was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.15 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 8.34 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.71-7.67 (m, 2H), 7.54 (t, J=7.6 Hz, 1H), 6.92-6.86 (m, 2H), 6.79-6.75 (m, 1H), 3.67 (s, 3H), 3.58 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H). LCMS: 473.0 (M+1)+
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].[CH3:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:34]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:42][C:39]2([C:35]3[N:34]=[C:33]([CH3:32])[CH:38]=[CH:37][N:36]=3)[CH2:40][CH2:41]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: Cc1ccnc(C2(N)CC2)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.024 g (46%). 1H NMR (400 MHz, CDCl3): δ 8.63 (d, J=6.0 Hz, 1H), 8.39 (bs, 1H), 7.99-7.95 (m, 2H), 7.82 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.41-7.36 (m, 2H), 7.34 (d, J=5.6 Hz, 1H), 7.21-7.15 (m, 3H), 6.39 (bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.71 (s, 3H), 2.24 (s, 3H), 2.06-2.03 (m, 2H), 1.74-1.71 (m, 2H). 19F NMR (376.47 MHz, CDCl3) δ−75.92 (TFA), −109.79, −119.33. LCMS: (ES+) m/z=553.2 (M+H)+
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[OH-].[Na+]>>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH3:10])[C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCOCC1

Procedure:
BOC-L-Alanine (3.50 mg, 20 mmol) and morpholine (1.74 g, 20 mmol) were coupled according to procedure A (washed with 1N NaOH after acid washes) giving a colorless oil which was used without further purification. Yield 3.94 g, 76%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14]([C:18]1[N:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[S:21][C:22]=1[CH2:23][OH:24])[CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:14]([C:18]1[N:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=2)[S:21][C:22]=1[CH2:23][O:24][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1)[CH2:15][CH2:16][CH3:17]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of 100 mg of 4-fluoro-2-trifluoromethyl benzonitrile in 5 ml of anhydrous dimethylformamide was added 200 mg of [4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol and 0.49 g of cesium carbonate. The resulting mixture was stirred at room temperature overnight, poured onto water and extracted with heptane 1/ethyl acetate 3. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 4/ethyl acetate 1) to give 180 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-trifluoromethyl-benzonitrile.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18]>C(O)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(OCCCCl)cc1

Procedure:
To a solution of 41 g of potassium hydroxide in 250 ml of ethanol is added 50 g of p-hydroxyphenylacetic acid. To this solution is added 32 ml of 3-bromo-1-chloropropane and the mixture is refluxed for 4 hours. The mixture is cooled in an ice bath and filtered. The filtrate is acidified to pH 2 with concentrated HCl. Filtration gives a solid which is washed with water to give 68 g of product. Recrystallization from acetic acid water gives white crystals, mp 89°-91° C.
Reaction SMILES: CO.[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:7][C:6](=[O:17])[C:5]=1[S:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH2:35][O:36][C:37](=[O:39])[CH3:38]>CN(C)C=O>[CH2:35]([O:36][C:37](=[O:39])[CH2:38][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:7][C:6](=[O:17])[C:5]([S:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:4]([OH:3])[CH:9]=2)=[CH:15][CH:14]=1)[CH3:34]
Reactant: CC(=O)OCCBr
Reactant: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1
Reaction time: 3 h

Procedure:
To a methanol solution (3 ml) of the 4-hydroxy-6-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (0.500 g, 1.47 mmol) was added cesium carbonate (0.955 g, 2.94 mmol). The reaction was stirred for 3 hrs. and is then concentrated in vacuo. Next, dimethylformamide (15 mL) is added and the residue is reconcentrated in vacuo to dryness. The solid is then diluted with dimethylformamide (3 mL) and bromoethylacetate (0.491 mL, 2.94 mmol) is added. The slurry is then stirred for 3 hrs. The reaction is quenched by dilution with ethyl acetate (100 mL). The organic layer is washed in succession with; 1 N HCl, water, saturated sodium chloride; dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by flash column chromatography (SiO2 -230 to 400 mesh) using a gradient of 15% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to 30% ethyl acetate/30% hexanes/40% methylene chloride.: m.p. 169-171° C.; 1H NMR (400 MHz, DMSO-d6) δ1.20 (t, 3 H), 2.75 (t, 2 H), 2.96 (t, 2 H), 4.16 (q, 2 H), 4.87 (s, 2 H), 6.69 (s, 1 H), 7.06 (d, 2 H), 7.19 (m, 5 H), 7.73 (d, 2 H), 11.85 (bs, 1 H).
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=[O:10])[CH:7]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[NH2:23]OS(O)(=O)=O>C1COCC1.O>[NH2:23][N:9]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)=[CH:7][C:8]1=[O:10]
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)[nH]1
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nn1c(C2CC2)cc(-c2ccc(C(F)(F)F)cc2)cc1=O
Temperature: 23 °C
Reaction time: 20 h
Yield: 63.7 %

Procedure:
To a solution of 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (example C.28 step 2) (4.19 g, 15.0 mmol) in THF (225 mL) and 1M NaOH (90.0 mL, 90.0 mmol) was added dropwise a solution of hydroxylamine-O-sulfonic acid (HOSA) (95%, 5.36 g, 45.0 mmol) in H2O (60 mL) at 0° C. The reaction mixture was stirred at 23° C. for 20 h (76% conversion). Added again at 0° C. 3N NaOH (30 mL, 30.0 mmol) and then hydroxylamine-O-sulfonic acid (HOSA) (95%, 5.36 g, 45.0 mmol) and the reaction mixture was stirred at 23° C. for 3 days (88% conversion). Poured into ice water, extracted with EtOAc, washed the organic layers with brine, dried over Na2SO4. Removal of the solvent in vacuum left a residue (5.17 g) which was purified by silica gel chromatography (400 g SiO2) to give the title compound as a light yellow solid (2.81 g, 64%). MS (ISP) 295.5 [(M+H)+]; mp 132° C.
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[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Se](=O)=[O:18]>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[CH:16]=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1nc2ccccc2n1-c1ccccc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1nc2ccccc2n1-c1ccccc1
Yield: 50.2 %

Procedure:
To a solution of 5.0 g (0.024 mole) of 1-phenyl-2methylbenzimidazole in 200 ml of dioxane was added 2.66 g (0.024 mole) of selenium dioxide and the reaction heated to reflux for 7 hours. The solids were filtered and the filtrate concentrated to a brown oil. The residue was chromatographed on 200 g of silica gel using 7% ethyl acetate in chloroform as the eluent to give 2.68 g of purified product.