Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH2:13]1[C:17]2[CH2:18][NH:19][CH2:20][C:16]=2[CH2:15][N:14]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:19]2[CH2:18][C:17]3[CH2:13][N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][C:16]=3[CH2:20]2)=[N:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC2=C(CNC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CC3=C(CN(C(=O)OC(C)(C)C)C3)C2)nc1
Yield: 72 %

Procedure:
Ethyl 6-chloronicotinate (567 mg, 3.05 mmol), tert-butyl 3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrole-2-carboxylate (565.9 mg, 2.7 mmol) and cesium carbonate (878 mg, 2.7 mmol) were stirred in 20 ml of DMF at 100° C. for 8 h and at 120° C. for 8 h. The residue was filtered off, washed with water and ethyl acetate, and dried. The first filtrate was concentrated and stirred with ethyl acetate, and the product was filtered off. Yield: 72%, M+H+: 360.20.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:15])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[F-].[Cs+].[CH3:18]I.O>C1COCC1>[C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:18])=[C:10]([Br:15])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1oc2ccc(O)c(Br)c2c1N
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a mixture of 12F (5.6 g, 0.020 mol) and CsF (9.5 g, 0.0625 mol) in THF (20 mL) was added MeI (2.9 g) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then added dropwise into water. The solids were precipitated out dissolved in ethyl acetate and purified by column chromatography on silica gel to give 12G (2.4 g, 40.7% yield).
Reaction SMILES: COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=O.CO.[OH-].[K+]>O.Cl>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ncnc3cc(OC)c(OC)cc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Temperature: 100 °C
Yield: 66.7 %

Procedure:
A mixture of crude 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (33 g), as prepared in the previous step, MeOH (100 mL), and KOH pellets (26 g, 400 mmol assuming 87% w/w water) was stirred at reflux (100° C. oil bath) for 1 h, at which point the translucent reddish-amber solution was allowed to cool to rt and diluted with water (100 mL) and 6 M HCl (100 mL). The solution was stirred at 100° C. for 10 min (Caution: Initial vigorous bubbling), allowed to cool to rt, diluted with 2.5 M NaOH (90 mL) and extracted with DCM (1×150 mL; 1×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to afford the title compound as a beige powder (13.95 g, 76% from 4-chloro-6,7-dimethoxyquinazoline). 1H-NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.69 (m, 1H), 3.05 (m, 2H), 2.84-2.71 (m, 2H), 1.88-1.65 (m, 4H). LC/MS (ESI): calcd mass 273.2, found 274.2 (MH)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][Si:12](Cl)([CH3:14])[CH3:13].C(N(CC)CC)C.CCCCCC>O1CCCC1>[Cl:1][CH2:2][C:3]([O:10][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=C(CCl)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of ethyl 4-chloro-3-oxobutanoate (30 g, 0.183 mol, 24.7 mL) and trimethylsilyl chloride (30.2 mL, 0.234 mol) in tetrahydrofuran (360 mL) was added dropwise triethylamine (30.61 mL, 0.23 mol) at -20° C. with mechanical stirring. After the addition was complete (~15 minutes), the mixture was stirred for an additional 30 minutes at -20° C., 30 minutes at 0° C., and then one hour at room temperature. The reaction was diluted with a large excess of hexane (1L). The resulting precipitate was filtered and the solution was concentrated on a rotavap to an oily residue. It was diluted with hexane (400 mL), filtered and the filtrate was concentrated on a rotavap to an oily residue. This process was repeated until no further precipitation occurred. Distillation of the residue (b.p. 70° C. to 78° C./1 mm Hg) gave the title compound (33 g, 80%) as a mixture of cis,trans isomers.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[NH:9]([C:16]1[N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]2[C:23]([C:24](=[O:26])[CH:25]=1)=[C:22]([CH3:27])[CH:21]=[C:20]([Cl:28])[N:19]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Cl:28][C:20]1[N:19]=[C:18]2[C:23]([C:24](=[O:26])[CH:25]=[C:16]([N:9]([CH3:3])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:22]([CH3:27])[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(Cl)nc2c1c(=O)cc(N(C)c1ccccc1)n2-c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
MeI (0.10 mL, 228 mg, 1.6 mmol) was added to a stirred suspension of K2CO3 (23.5 mg, 0.17 mmol) and 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (50 mg, 0.14 mmol) in THF (3 mL). The suspension was heated to 40° C. and stirred was overnight. The reaction was quenched with water (5.0 mL) and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Recrystallization of the residue using EtOAc afforded 7-chloro-5-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one (18 mg, 35%): LCMS RT: 2.24 min, MH+: 376.6, Rf=0.76 (4:1 Hex:EtOAc).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1.CN(C=O)C.C(N(CC)CC)C.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>CCCCCCC>[CH:40]([O:39][C:37](=[O:38])[NH:2][C@@H:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)([CH3:42])[CH3:41]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2ccccn2)C[C@@H](N)C1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccccn3)c3ccc(C#N)cc23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
Equip a 2 L reaction flask with a cooling bath, air stirrer, temperature probe, and addition funnel Charge the flask with (S)-2-amino-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile hydrochloride (62.8 g, 0.218 moles), DMF (188 mL), and triethylamine (33.4 mL, 0.240 mol). Cool the resulting solution to 0° C. using an ice/acetone bath. While maintaining the temp at <10° C., add isopropyl chloroformate (218 mL, 0.218 mol, 1 M in toluene) drop-wise via an addition funnel. When the addition is complete, remove the cooling bath was removed and allow the mixture to warm to ambient temperature. After 1 hour, analyze by HPLC to indicate the reaction is complete, and pour the mixture into a solution of deionized water (1256 mL) and EtOAc (1884 mL). Separate the layers, filter the organic layer, and re-wash with a 1:1 water:brine solution, then dry over Na2SO4. Concentrate in vacuo at 55° C. to about 15 volumes, and allow the resulting to cool to ambient temperature, affording a white precipitate. Add heptane (628 mL) and stir for 20 min. Concentrate the mixture back to about 15 volumes. Filter the solids, wash with heptane, and dry to give the titled compound as a fluffy white solid (68.9 g, 84.5%). 1H NMR (500 MHz, DMSO-d6), δ 8.49 (dd, 1H), 7.86 (d, 1H, J=1.5), 7.71-7.75 (m, 1H), 7.60 (d, 1H, J=9.0), 7.57 (d, 1H, J=9.0), 7.36 (dd, 1H), 7.28-7.26 (m, 1H), 7.14 (d, 1H, J=7.5), 5.44 (s, 2H), 4.79-4.72 (m, 1H), 4.71-4.66 (m, 1H), 3.22-3.20 (m, 1H), 3.16-3.12 (m, 1H), 2.73-2.66 (m, 2H), 1.16 (dd, 6H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH3:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>C(OCC)(=O)C>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][C:28]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:18][CH3:19])=[N:7][N:8]3[C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)([OH:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCc1nn(-c2ccc(F)cc2)c2cc(Br)ccc12
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(O)(c2ccc3c(CC)nn(-c4ccc(F)cc4)c3c2)CC1
Yield: 56.2 %

Procedure:
This compound was prepared according to the method described in Example 6 of U.S. Ser. No. 08/046,858, filed May 8, 1997 as Attorney Docket No. PC9798, starting with 3.0 grams (9.4 mmol) of 6-bromo-3-ethyl-1-(4-fluoro-phenyl)-1H-indazole and 2.0 grams (11.7 mmol) of 4-oxo-cyclohexanecarboxylic acid ethyl ester to give after silica gel flash column chromatography (using 20% ethyl acetate 80% hexane as elutant) 2.17 grams of light yellow semi-solid which was a mixture of diastereoisomers. 1H NMR (400 MHz, CDCl3) δ1.25-1.3 (t, 3H); 1.4-1.5 (t, 3H); 1.6-1.78 (m, 2H); 1.8-2.5 (m, 7H); 2.70 (m, 1H); 3.04 (m, 2H); 4.16 (m, 2H); 7.17-7.28 (m, 3H); 7.61-7.79 (m, 4H); MS, m/z 324.4 (M+H+, base).
Reaction SMILES: CCCC[N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])(CCCC)CCCC.[F-].O1C2C=CC=CC=2C=C1[C:28]1[C:29](=[O:64])[NH:30][C:31](=[O:63])[C:32]=1[C:33]1[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH2:42][CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:34]=1>C1COCC1>[OH:45][CH2:44][CH2:43][CH2:42][N:35]1[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:41]2[C:33]([C:32]2[C:31](=[O:63])[NH:30][C:29](=[O:64])[C:28]=2[C:16]2[CH:15]=[CH:14][NH:5][CH:17]=2)=[CH:34]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](OCCCn1cc(C2=C(c3cc4ccccc4o3)C(=O)NC2=O)c2cccnc21)(c1ccccc1)c1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1c1cc[nH]c1
Yield: 84 %

Procedure:
TBAF (0.12 mL, 1 M solution in THF, 0.12 mmol) as added dropwise to a solution of 3-benzofuran-2-yl-4-{1-[3-(tert-butyidiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyrrole-2,5-dione Compound 16a (0.044 g, 0.06 mmol) in THF (1 mL) under nitrogen. After 18 hours the mixture was concentrated and purified by column chromatography (SiO2) to give Compound 24 (0.017 g, 84%) as an orange solid. 1H NMR (300 MHz, Acetone-d6) δ 10.47 (s, 1H), 9.57 (s, 1H), 8.3 (dd, J=4.7, 1.5 Hz, 1H), 7.9 (s, 1H), 7.56 (m, 1H), 7.49 (dd, J=7.9, 1.5 Hz, 1H), 7.01 (dd, J=7.9, 4.7 Hz, 1H), 6.75 (m, 1H), 6.22 (m, 1H), 4.55 (t, J=6.6 Hz, 2H), 4.02 (t, J=5.7 Hz, 1H), 3.56 (q, J=5.8 Hz, 2H), 2.11 (m, 2H); MS (ES) m/z: 388 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=1>>[CH3:34][O:33][C:31]([CH:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:22]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:12]=2[O:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:39][CH:38]=3)=[CH:3][CH:4]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:23])[CH2:26]1)=[O:32]
Reactant: FC(F)(F)Oc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(OC(F)(F)F)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-[3-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)propoxy]benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-trifluoromethoxybenzene.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH:20]1[C:28]2[C:27]3[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=3[O:25][C:24]=2[CH:23]=[C:22]([S:33](Cl)(=[O:35])=[O:34])[CH:21]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:4][CH:3]([CH3:5])[CH:2]([NH:1][S:33]([C:22]1[CH:21]=[CH:20][C:28]2[C:27]3[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=3[O:25][C:24]=2[CH:23]=1)(=[O:34])=[O:35])[C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: O=S(=O)(Cl)c1ccc2c3c(oc2c1)CCCC3
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(NS(=O)(=O)c1ccc2c3c(oc2c1)CCCC3)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.6 %

Procedure:
To a solution of (D)-valine, tert-butyl ester (0.13 g, 0.74 mmol) and triethylamine (0.075 g, 0.74 mmol) in tetrahydrofuran/water (5 mL, 1:1) was added in one portion at room temperature 6,7,8,9-tetrahydro-dibenzofuran-3-sulfonyl chloride (0.20 g, 0.74 mmol). The reaction mixture was stirred at room temperature for 14 hours, followed by the addition of aqueous HCl (1 M, 5 mL) and ethyl acetate (10 mL). The organic phase was separated and washed with brine, dried (MgSO4), and concentrated to dryness to give the title compound as a white solid (0.24 g, 80%).
Reaction SMILES: C([N:4]1[C:13]([C:14]#[N:15])=[C:12](C2C=CC=C(F)C=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:23]C)[CH:10]=2)[C:5]1=[O:25])C=C.[C-]#N.[Na+]>CS(C)=O.[OH-].[Na+].C(Cl)Cl>[OH:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:25])[NH:4][C:13]([C:14]#[N:15])=[CH:12]2
Reactant: C=CCn1c(C#N)c(-c2cccc(F)c2)c2cc(OC)ccc2c1=O
Agent: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1cc2cc(O)ccc2c(=O)[nH]1

Procedure:
To a solution of 2-allyl-4-(3-fluorophenyl)-6-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile (2.0 g) in 24 mL DMSO was added NaCN (1.47 g). The reaction was heated to 150 C for 6.5 h, then diluted with 1N NaOH and extracted with EtOAc (2×). The organic solutions were extracted once with 1N NaOH. The combine aqueous solutions were acidified with conc. HCl and extracted with EtOAc (3×). All organic solutions were combined and dried (MgSO4), then concentrated to give a dark solid. The solid was suspended in CH2Cl2 and filtered to give 1.04 g of 2-allyl-4-3-fluorophenyl)-6-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CC(O)C.[OH-].[Na+].O>[CH3:26][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:1][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: ClCC1CO1
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)cc1-c1ccccc1
Reaction time: 24 h
Yield: 47 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (296 mg, 0.81 mmol) in 2-propanol (2.5 mL) and 3 N aq. NaOH (1 mL) is treated with epichlorohydrine (150 mg, 1.63 mmol) and the mixture is stirred at it for 24 h, then diluted with water and extracted with EA. The solvent of the organic extract is evaporated and the residue is purified by CC on silica gel eluting with hepaten:EA 4:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (160 mg) as a pale yellow oil; LC-MS: tR=1.16 min, [M+1]+=421.22, 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.45-7.30 (m, 5H), 6.88 (m, 2H), 3.99 (dd, J=2.9, 11.1 Hz, 1H), 3.72 (dd, J=5.8, 11.1 Hz, 1H), 3.38-3.31 (m, 1H), 3.19-3.11 (m, 2H), 2.98-2.85 (m, 5H), 2.72-2.67 (m, 1H), 2.26 (s, 6H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(NO)c1cccnc1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3cccnc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-nicotinamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.57 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:25][Sn:26](Cl)([CH3:28])[CH3:27]>C1COCC1>[CH3:25][Sn:26]([CH3:28])([CH3:27])[C:22]1[S:21][C:20]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:24][CH:23]=1
Reactant: CCCCCCCCCCCCCCc1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc([Sn](C)(C)C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
n-BuLi (1.6 M, 42 mL, 67 mmol) was added slowly to a solution of 2-tetradecyl-thiophene (17.0 g, 237 mmol) in THF (150 mL) at −78° C. and stirred for 30 min. Trimethyltin chloride (13.3 g, 67 mmol) in THF (30 mL) was added dropwise to the resultant suspension and then gradually warmed to room temperature. The reaction mixture was stirred for 18 h and quenched with saturated ammonium chloride solution (100 mL). The mixture was extracted with diethyl ether (2×100 mL) and the combined organic extracts were washed with brine (100 mL). The organic phase was dried and concentrated to give brown oil (26.8 g, 99%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.02 (d, 1H, J=3.2 Hz), 6.90 (d, 1H, J=3.2 Hz), 2.85 (t, 2H, J=8 Hz), 1.68 (q, 2H, J=7.6 Hz), 1.50-1.20 (m, 22H), 0.88 (t, 3H, J=6.8 Hz), 0.344 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:12](=[CH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-:20].[Na+].OO.Cl>C1COCC1.O>[CH3:19][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][OH:20])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: C=C(CCCCC)c1ccc2c(c1)OCCC2(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4,4-dimethyl-7-(1-methylene-hexyl)-chroman (0.442 g, 1.71 mmole) in 8 mL of THF at 0° C. was treated with 1.71 mL of 1M BH3.THF complex. The reaction mixture was stirred at room temperature for three hours and then cooled to 0° C. The mixture was treated successively with 0.3 mL of water, 0.34 mL of 3M sodium hydroxide and 0.34 mL of 30% hydrogen peroxide, stirred at room temperature for two hours and then diluted with 10 mL of water. The pH was adjusted to 4.0 with 10% HCl and extracted with three 12.5 ML portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The product was purified by flash chromatography (SiO2, 10-20% ethyl acetate in hexanes) to yield 0.366 g of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol as a colorless oil.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11](=[O:48])[C:12]([O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47])([CH3:39])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]2[CH2:27][N:26](CC3C=CC(OC)=CC=3)[C:25](=[O:37])[N:24]2[CH3:38])=[CH:16][CH:15]=1)[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11](=[O:48])[C:12]([O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47])([CH3:39])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]2[CH2:27][NH:26][C:25](=[O:37])[N:24]2[CH3:38])=[CH:16][CH:15]=1)[CH3:9]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)Oc1ccccc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1F
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Trifluoroacetic acid (70 mL) is added dropwise to a solution of triethylsilane (2.5 mL, 15.73 mmol, d=0.728) and 2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (4.44 g, 7.86 mmol). The reaction mixture is stirred 2 h, then concentrated in vacuo. The residue is diluted with ethyl acetate, then washed with a saturated solution of aqueous sodium carbonate, water, and brine. The organic layer is dried and concentrated to provide the title compound (3.5 g, 100%). 1H NMR (400 MHz, CDCl3): δ 7.20 (d, 2H, J=8.7 Hz), 7.06-7.01 (m, 1H), 6.97-6.87 (m, 3H), 6.79 (d, 2H, J=8.7 Hz), 5.04-4.98 (m, 1H), 4.20 (q, 2H, J=6.8 Hz), 4.02 (t, 2H, J=6.8 Hz), 3.76-3.69 (m, 1H), 3.55 (t, 1H, J=8.7 Hz), 3.26, 3.14 (ABq, 2H, J=14.5 Hz), 3.21 (t, 1H, J=8.7 Hz), 2.78 (s, 3H), 2.27-2.20 (m, 1H), 1.99-1.90 (m, 1H), 1.38 (s, 3H), 1.23 (t, 3H, J=6.8 Hz), 0.96 (t, 2H, J=7.7 Hz). MS [EI+] 445 (M+H)+. Rf=0.50 in 10% methanol in methylene chloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:4]=1.[SH:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:22]([CH3:33])[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:33][C:22]1[CH:21]=[C:20]([S:19][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:4]=2)[CH:32]=[CH:31][C:23]=1[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: FC(F)(F)c1ccc(-c2cccc(CBr)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Yield: 93.7 %

Procedure:
A solution of the 2-(bromomethyl)-6-[4-(trifluoromethyl)phenyl]pyridine (238 mg, 0.75 mmol), ethyl (4-mercapto-2-methylphenoxy)acetate (84 mg, 0.37 mmol) and K2CO3 (57 mg, 0.41 mmol) in MeCN (5 mL) was stirred at rt, under nitrogen overnight. The mixture was then partitioned between water and EtOAc and the layers separated. The organic layer was then washed with water and brine, dried (MgSO4), filtered and reduced. Purification by SPE (silica, 2 g cartridge) eluting with CHCl3:cyclohexane (5:1) afforded the title compound (160 mg).