Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1=[O:11].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[S:24][C:23]=2[CH:31]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([S:27]([N:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[C:12]4[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=4)[C:6](=[O:11])[CH2:7]3)(=[O:29])=[O:28])[S:24][C:23]=2[CH:31]=1
Reactant: CN(CCN1CCNCC1=O)c1ccncc1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Product: CN(CCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1=O)c1ccncc1

Procedure:
A portion (˜50%) of the crude 1-[2-{(Methyl)-(pyridin-4-yl)-amino}-ethyl]-piperazin-2-one, EXAMPLE 93 is reacted with 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (54 mg, 0.20 mmol), EXAMPLE 1, using same procedure as described in EXAMPLE 719. The residue obtained after HPLC purification is subjected to silica gel chromatography using NH4OH/MeOH/CH2Cl2 (1:4:95) as eluant to give title compound (30 mg, 0.064 mmol) as a white solid. MS m/z 465, 457 (M+1); 1H NMR (CDCl3, 300 MHz) δ8.15 (d, 2H), 7.88 (s, 1H), 7.85 (d, 1H), 7.79 (s, 1H), 7.47 (d, 1H), 6.47 (d. 2H), 3.80 (s, 2H), 3.50 (m, 4H), 3.43 (d, 2H), 3.30 (d, 2H), 2.98 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:17][OH:18])[CH2:3][CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].[OH:20]O>C(O)(=O)C.O>[CH3:1][C:2]([CH3:19])([CH2:17][OH:18])[CH2:3][CH2:4][CH2:5][CH2:6][S:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:15])([CH3:16])[CH2:13][OH:14])=[O:20]
Reactant: CC(C)(CO)CCCCSCCCCC(C)(C)CO
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CO)CCCCS(=O)CCCCC(C)(C)CO
Temperature: 25 °C
Reaction time: 22 h
Yield: 104.4 %

Procedure:
To a solution of 6-(5,5-dimethyl-6-hydroxy-hexyl-sulfanyl)-2,2-dimethyl-hexan-1-ol 5.1 g, 17.5 mmol) in glacial acetic acid (25 ml) was added hydrogen peroxide (50 wt. % in water; 1.20 g; 17.5 mmol). The reaction mixture was stirred at rt for 22 h, then diluted with water (200 ml), and extracted with chloroform (2×150 ml). The combined organic phases were subsequently washed with saturated NaHCO3 solution (3×100 ml) and saturated NaCl solution (100 ml), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to give crude product (5.60 g; 105%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ ppp=3.29 (AB, 2 H, J=12.2); 3.27 (AB, 2 H, J=12.2); 2.70 (m, 4 H); 2.48 (s br, 2 H); 1.76 (m, 4 H); 1.44 (m, 4 H); 1.30 (4 H); 0.87 (s, 6 H); 0.86 (s, 6H). 13C NMR (75 MHz, CDCl3) δ ppp=76.80; 71.39; 52.20; 38.08; 35.15; 24.21; 24.03; 23.66; 23.26. Calcd. for C16H35SO3 (MH+): 307.2307, found 307.2309.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.CS(O[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=1)(=O)=O>CN(C)C=O>[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][N:24]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=3)[CH2:23][CH2:22]2)[N:12]=1
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Temperature: 100 °C
Yield: 64 %

Procedure:
N,N-Diisopropylethylamine (0.8 mL; 5 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)quinoline (D3) (0.2 g; 1 eq) and 2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.22; 1 eq) in dimethylformamide (1.5 mL). The reaction mixture was heated to 100° C. for 10 hours. The dark solution was concentrated under reduced pressure, diluted with water (3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography, eluting with a gradient from dichloromethane to dichloromethane/MeOH (98/2) affording the title compound in 64% yield (0.21 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:16][CH2:15][CH2:14]3)[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[F:33].C(O)(C(F)(F)F)=O>>[CH:17]1([N:7]2[CH2:8][C:9]3([CH2:16][CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[F:33])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1F
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Yield: 54.2 %

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 4) (0.20 g, 0.63 mmol, 1 eq), 4-amino-3-fluorobenzoic acid (0.30 g, 1.9 mmol, 3 eq) and TFA (0.24 mL, 3.2 mmol, 5 eq) were heated to reflux in TFE for 18 hours. Further 4-amino-3-fluorobenzoic acid (0.20 g) and TFA (0.1 mL) were added and the reaction was heated to reflux again for 2 days. Further TFA (0.24 mL) was added and the reaction was heated to reflux again for 3 days. Solvent was evaporated in vacuo and the resulting residue was triturated with EtOAc to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluorobenzoic acid (0.15 g, 55%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH2:19][CH2:20]I)[CH:16]=2)[C:11]([C:24]2[N:32]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=2)=[CH:10]1>>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH2:19][CH2:20][N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[CH:16]=2)[C:11]([C:24]2[N:32]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=2)=[CH:10]1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Reactant: OC1CCNCC1
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCN1CCC(O)CC1
Yield: 92.4 %

Procedure:
1-{2-[1-methyl-5-methoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-6-yloxy]ethyl}piperidin-4-ol is prepared by following the procedure described in example 147b, but using 0.089 g of 4-hydroxypiperidine and 0.265 g of 2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. After purification by flash-pack chromatography (silica, 90/10 by volume dichloromethane/methanol as eluents, argon), 0.234 g of 1-{2-[1-methyl-5-methoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-6-yloxy]ethyl}piperidin-4-ol is obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[NH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][N:10]=1
Reactant: COc1ccc(C(=O)CN)cc1
Reactant: O=C(Cl)c1sccc1Cl
Product: COc1ccc(-c2cnc(-c3sccc3Cl)o2)cc1

Procedure:
3-Choloro-thiophene-2-carboxylic acid-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-amide: The title compound was prepared from 3-chloro-thiophene-2-carbonyl chloride and 2-amino-4′-methoxy acetophenone by a procedure similar to Example 93a as an orange solid. 1H NMR (DMSO-d6): 8.30 (s, NH), 8.02 (d, J=9.0 Hz, 1H), 7.89 (d, J=6.6 Hz, 2H), 7.20 (d, J=6.0 Hz, 2H), 7.10 (d, J=8.7 Hz, 1H), 4.80 (d, J=5.4 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]=O)=[CH:4][CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was charged with 6-bromo-2-methylpyridine-3-carbaldehyde (2.50 g, 12.6 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (2.34 g, 12.6 mmol, 1.00 equiv), and dichloromethane (50 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (8.00 g, 37.8 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (30 mL). The resulting mixture was extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (22/78) to provide 3.80 g (82% yield) of tert-butyl 4-[(6-bromo-2-methylpyridin-3-yl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 370 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:25][C:26]([F:35])([F:34])[C:27]1[N:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:18])([F:17])[F:19])=[CH:12][N:11]=[C:10]([C:21]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([C:26]([F:35])([F:34])[F:25])[N:31]=3)=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: C[C@H](Oc1cnc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Product: C[C@H](Oc1cnc(C(=O)NCc2nc(C(F)(F)F)no2)nc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxylic acid (Example AQ) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAN 944905-93-5; example AK) as starting materials. MS: 496.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C1C=CC=CC=1>CO>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:24][CH2:25][N:26]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[N+:13]([O-:15])=[O:14])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1ccc(F)cc1[N+](=O)[O-])N1CC1
Solvent: c1ccccc1
Solvent: CO
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of 15 parts of 1-(4-fluoro-2-nitrobenzoyl)-aziridine, 11 parts of 4-(4-chlorophenyl)-4-piperidinol, 55.8 parts of benzene and 8.8 parts of methanol is stirred and refluxed for 1.50 hours. After stirring is continued overnight at room temperature, the reaction mixture is evaporated. The residue is dissolved in trichloromethane. The solution is washed with water and 8 parts of methanol are added. The whole is stirred for 10 minutes with silica gel. The latter is filtered off and the filtrate is evaporated. The residue is triturated with 2,2'-oxybis propane. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 9.5 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-4-fluoro-2-nitrobenzamide; mp. 144.3° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13]C)=[O:12].O.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1cccc(N2CCCCC2=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(N2CCCCC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of methyl 3-(2-oxopiperidin-1-yl)benzoate (114 mg) described in a document (J. Med. Chem. 1997, 40, 331.) in THF (3.0 mL)-water (0.5 mL) was added lithium hydroxide monohydrate (61.5 mg). The mixture was stirred at room temperature overnight, and 10% citric acid solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (34.7 mg).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:35][C:36](=[O:53])[CH2:37][CH:38]([NH:42][C:43]([NH:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:39][CH:40]=[CH2:41])[C:14](=[O:34])[N:15]([CH2:26][CH:27](OCC)OCC)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:25]=2[NH:24][N:23]=[CH:22]3)=[CH:8][CH:7]=1)(C)(C)C>C(O)=O>[CH2:46]([NH:45][C:43]([N:42]1[CH:38]([CH2:39][CH:40]=[CH2:41])[CH2:37][C:36](=[O:53])[N:35]2[CH:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=3)[C:14](=[O:34])[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[CH:22]4)[CH2:26][CH:27]12)=[O:44])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cn[nH]c12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Solvent: O=CO
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc4cn[nH]c34)CC2N1C(=O)NCc1ccccc1
Yield: 34.9 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid {2-(4-tert-butoxy-phenyl)-1-[(2,2-diethoxy-ethyl)-(1H-indazol-7-ylmethyl)-carbamoyl]-ethyl}-amide (3.60 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 2-Allyl-6-(4-hydroxy-benzyl)-8-(1H-indazol-7-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.0 g, 3 step yield: 30%), 1H NMR (CDCl3, 300 MHz) δ 8.20 (s, 1H), 7.4-7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.80 (m, 3H), 6.75 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 5.05 (d, J=10.75, 1H), 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.6˜2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 579 (M+H), 601 (M+Na).
Reaction SMILES: O=[C:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)(=O)C>O1CCCC1>[CH2:9]([O:8][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)CCCC(=O)c1cn(-c2cccnc2)c2ccccc12
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCc1cn(-c2cccnc2)c2ccccc12

Procedure:
To a solution of 0.5 g of 3-(1-oxo-4-ethoxycarbonylbutyl)-N-(3-pyridyl)-indole in 25 ml of tetrahydrofuran is added 0.6 g of borane-tert-butylamine complex and 0.6 ml of glacial acetic acid. The reaction mixture is heated at 90° and monitored by high pressure liquid chromatography. When complete, the reaction mixture is evaporated under reduced pressure, water and methylene chloride are added, the pH is adjusted to 7-8 with sodium carbonate solution, the organic layer is separated, washed with water, dried and evaporated to dryness to yield 3-(4-ethoxycarbonylbutyl)-N-(3-pyridyl)-indole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:20]Br>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:20][C:19]2[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(CBr)cc(OC)c1OC
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
4-Hydroxy thiophenol (12 g, 0.095 mol) and potassium carbonate (15.86 g, 0.115 mol) were dissolved in 250 ml of N,N-dimethylformamide, and cooled to 0° C. To the above solution at 0° C. was added dropwise 25 g (0.095 mol) of 3,4,5-trimethoxybenzyl bromide prepared in step (1) dissolved in 50 ml N,N-dimethylformamide. After stirring for 2 hr, the ice-bath was removed, and the solution was stirred overnight. The whole solution was poured into water, and extracted with 300 ml ethyl acetate. The organic layer was washed twice with 300 ml of water. Drying over magnesium sulfate, filtration, concentration, and chromatographic purification on silica gel column (ethyl acetate/n-hexane=2/3) gave 20 g (yield 68%) of 3,4,5-trimethoxybenzyl 4-hydroxyphenyl thioether as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([C:11]([NH:13][C@@H:14]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[O:12])[CH2:10][CH2:9]1>C(Cl)Cl>[NH:16]1[CH2:17][CH2:18][C@@H:14]([NH:13][C:11]([CH:8]2[CH2:9][CH2:10]2)=[O:12])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)C2CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCNC1)C1CC1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
TFA (1 mL) was added to a solution of (R)-tert-butyl 3-(cyclopropanecarboxamido)pyrrolidine-1-carboxylate (500 mg, 1.96 mmol) in 5 mL CH2Cl2. After stirring for 30 min, the reaction was quenched with 1M NaOH solution till neutral and extracted twice with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and concentrated to yield N-((R)-pyrrolidin-3-yl)cyclopropanecarboxamide (250 mg) which was used without further purification. LC/MS: m/z 155.3 (M+H)+ at 0.6 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].Cl>N1CCCCC1.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(Br)c1
Temperature: 100 °C
Yield: 94.4 %

Procedure:
3-Bromobenzaldehyde (10.0 g, 54 mmol), malonic acid (10.1 g, 97 mmol) and piperidine (0.267 mL, 2.7 mmol) are treated with pyridine (30 mL) and heated at 100° C. for 3.5 h. The reaction mixture is cooled to room temperature, poured into 200 ml of 20% hydrochloric acid at 0° C.; the resultant precipitate is collected, washed with copious amounts of water and dried in a vacuum dessicator overnight to afford the title compound (11.64 g, 51 mmol).
Reaction SMILES: CC(C)([O-])C.[K+].F[P-](F)(F)(F)(F)F.[CH:14]([N+:17]([CH:25]([CH3:27])[CH3:26])=[CH:18]N1CCCCC1)([CH3:16])[CH3:15].[C:28]([O:32][C:33]([N:35]1[C:39](=[O:40])[CH2:38][CH2:37][C@H:36]1[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1.C(OC(C)C)(=O)C>[C:28]([O:32][C:33]([N:35]1[C@H:36]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:46][CH:47]=2)[CH2:37]/[C:38](=[CH:18]\[N:17]([CH:14]([CH3:15])[CH3:16])[CH:25]([CH3:26])[CH3:27])/[C:39]1=[O:40])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)[N+](=CN1CCCCC1)C(C)C
Agent: CC(C)(C)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 M solution of potassium tert-butoxide in THF (11.7 ml) is added to diisopropyl(piperidin-1-ylmethylidene)ammonium hexafluorophosphate (5 g, prepared according to Example 12). The resulting mixture is then stirred for 1 h at 50° C. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (1 g) is then added to the reaction and the resulting mixture is stirred for 1 h at room temperature. The mixture is diluted with isopropyl acetate and filtered through silica. The residue is concentrated in vacuo then purified by column chromatography (ethyl acetate) to give (R)-5-biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr). Rf 0.55 (ethyl acetate). 1H NMR (DMSO-d6), 7.65-7.62 (2H), 7.61-7.58 (2H), 7.47-7.42 (2H), 7.37-7.31 (1H), 7.29-7.25 (2H), 7.01 (1H), 4.28-4.20 (1H), 3.84-3.70 (2H), 3.07-3.01 (1H), 2.82-2.73 (1H), 2.71-2.63 (1H) 2.49-2.44 (1H), 1.49 (9H), 1.13-1.08 (12H).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14](=[CH2:20])[CH2:15][N+](C)(C)C)=[CH:9][CH2:8][CH2:7]2.[CH3:21][OH:22]>[Ag]=O.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([CH2:15][C:13]1([CH3:12])[C:21](=[O:22])[CH2:6][CH2:5][C:4]1=[O:3])=[CH2:20])=[CH:9][CH2:8][CH2:7]2
Reactant: CO
Reactant: C=C(C[N+](C)(C)C)C1=CCCc2cc(OC)ccc21
Agent: O=[Ag]
Agent: [I-]
Solvent: O
Product: C=C(CC1(C)C(=O)CCC1=O)C1=CCCc2cc(OC)ccc21
Reaction time: 2 h

Procedure:
To a solution containing 13.3 parts of 2-(6-methoxy-3,4-dihydro-1-naphthyl)-2-propen-1-yl trimethylammonium iodide in 200 parts by volume of methanol and 1 part by volume of water is added 4.1 parts of silver oxide and the resulting reaction mixture is stirred for approximately 2 hours. At the end of that time the mixture is filtered into a container holding 4 parts of 2-methylcyclopentane-1,3-dione. The resulting solution is concentrated to a small volume and 500 parts by volume of xylene, 5 parts by volume of hexamethylphosphoramide and 5 parts by volume of triethylamine are added. Approximately 50 parts by volume of solvent is removed by distillation and the resulting mixture is heated gently at the reflux temperature for about 20 hours, then allowed to cool. That solution is washed successively with water, 5% hydrochloric acid, water, 5% aqueous sodium bicarbonate and water again, after which time the mixture is dried over anhydrous sodium sulfate and concentrated to a small residue. Crystallization of that crude product from methanol affords 2-(6-methoxy-3,4-dihydro-1-naphthyl)-3-(2-methylcyclopentane-1,3-dione-2-yl)propene, melting at about 81°-82° and displaying an ultraviolet absorption at about 274 millimicrons with a molecular extinction coefficient of approximately 10,400.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[C:9]([F:25])=[N:8]2)=[C:4]([C:20]([F:22])([F:23])[F:21])[CH:3]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=Cc1ccc2c(c1)c(F)nn2Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 140 °C

Procedure:
A suspension of 1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (0.9 mmol, from Example 1)) and SelectFluor® (2 eq., Aldrich) in CH3CN (3 mL) was heated in a microwave reactor at 140° C. for 30 min. The solvent was evaporated and the residue was washed with DCM. The insoluble solid was discarded. The combined organic washings were concentrated and the residue was purified by flash chromatography (0-20% EtOAc/Hex) to afford 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-fluoro-1H-indazol-5-carbaldehyde.