Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[N:1]1([C:6]2[CH:11]=[C:10]([CH2:12][NH2:13])[CH:9]=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCCC2)c1
Temperature: 0 °C
Yield: 78.2 %

Procedure:
A solution of nitrile 26C (1.1 g, 3.3 mmol) in diethyl ether (30 mL) was added in small amounts to a mixture of LiAlH4 (0.25 g, 2 mol eq) in diethyl ether (30 mL) stirred at 0° C. After the addition was completed, the mixture was stirred at room temperature overnight. The excess of LiAlH4 was destroyed at 0° C. by addition of small amount of water (30 mL), the solid formed was filtered off and the organic filtrate was separated, washed with brine (50 mL) and dried over Na2SO4. The organic phase was evaporated under reduced pressure and the residue was purified by flash chromatography (7:3 EtOAc:MeOH) to afford 27C as a pale yellow oil (0.87 g, 77% yield). 1HNMR (DMSO, 400 MHz) δ 1.97 (m, 4H), 3.48 (m, 4H), 3.68 (s, 2H), 4.15 (bs, 2H), 6.44 (s, 1H), 7.15 (s, 1H), 7.43 (d, 2H, J=8), 8.17 (d, 2H, J=8).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)c1

Procedure:
The title compound was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 3-methoxyphenylboronic acid (9 mg, 0.06 mmol). MS (ESI+) calcd mass for C18H15N5O3S2 413.061631, found 413.062021.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[N:24]([CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](=[O:39])[C:22]2=[O:40]>O1CCCC1>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[N:24]([CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23](=[O:39])[C:22]2([OH:40])[C:8]1[C:7]([OH:10])=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc21
Reactant: Oc1ccc2c(c1)OCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc2C1(O)c1cc2c(cc1O)OCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 387.2 %

Procedure:
To a cooled (0° C.) solution of 2,3-dihydrobenzofuran-6-ol (0.52 g, 3.8 mmol) in anhydrous tetrahydrofuran (25 mL) was added isopropylmagnesium chloride (2.1 mL, 2 M solution in tetrahydrofuran, 4.2 mmol). The resultant suspension was stirred at 0° C. for 0.5 h and followed by the addition of 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione (2.11 g, 15.5 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 3 h and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 50% gradient) to afford 7-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one (7.12 g, 95%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ9.43 (s, 1H), 7.56-7.18 (m, 13H), 6.99-6.86 (m, 2H), 6.60 (s, 1H), 6.08 (s, 1H), 4.56 (t, J=8.6 Hz, 2H), 3.10 (t, J=8.6 Hz, 2H).
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([OH:45])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:5][NH:6][C:7]([C@:9]1([OH:45])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 137.2 %

Procedure:
To a solution of tert-butyl (3R,4R)-3-[(tert-butoxyamino)carbonyl]-3-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-1-carboxylate (740 mg, 1.15 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred at room temperature for 1.5 h. The solvent was concentrated in vacuo and methanol was used to chase residual trifluoroacetic acid. The residue was precipitated from ether as a white solid to yield 856 mg (97%) of (3R,4R)-N-tert-butoxy-3-hydroxy-4-(4-((2-methylquinolin-4-yl) methoxy)phenylsulfonamido)piperidine-3-carboxamide as the trifluoroacetic acid salt. MS: (M+H)+=543.1.
Reaction SMILES: [Cl:1]Cl.[CH3:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3>C(O)(=O)C>[Cl:1][C@@H:17]1[CH2:18][C@@:19]2([CH3:20])[C@@H:14]([CH2:13][CH2:12][C@@H:11]3[C@@H:21]2[CH2:22][CH2:23][C@@:6]2([CH3:7])[C@H:8]3[CH2:9][CH2:10][C@@H:5]2[O:4][CH3:3])[CH2:15][C:16]1=[O:24]
Reactant: ClCl
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)O
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@H](Cl)C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Chlorine in acetic acid (0.84 M, 12 ml.) is added dropwise with stirring to 17β-methoxy-5α-androstan-3-one (3.0 g.) in acetic acid (10 ml.). When the addition is complete the reaction mixture is chilled, and the precipitate which forms is filtered off, washed with water, dried and recrystallized from acetone-methylene chloride to give the title compound, m.p. 202°-210°; MS (m/e) 338, 306, 302, 291 and 265; NMR (CDCl3) 0.77, 1.10, 3.20, 3.30 and 4.06 δ.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(O)C>CCCCCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1cncn1C
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cncn1C
Yield: 44 %

Procedure:
Racemic compound 4.4 (680 mg, 2.5 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 15% i-PrOH in hexane as eluant. Eluant containing the peak with less retention time was concentrated and compound 4.5 (300 mg, 1.1 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 275.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([Cl:17])[N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O-:21].[Na+]>CO>[CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([Cl:17])[N:14]=[C:15]([O:21][CH3:20])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (6.38 g, 21.69 mmol) in anhydrous methanol (100 mL), was added 4.67 N sodium methoxide (5.57 mL, 26 mmol) slowly at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then at rt for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with brine, dried over Na2SO4, filtered, and concentrated to give 6-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine which was used without the need for purification. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.31-7.40 (m, 4 H), 7.23-7.31 (m, 1 H), 3.95 (s, 3 H), 3.72 (br. s., 2 H), 3.43 (br. s., 2 H), 2.84 (d, J=4.5 Hz, 2 H), 2.78 (d, J=4.0 Hz, 2 H). MS (ESI+) m/z 290.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I>C1COCC1>[CH3:13][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH:6]=[N:7]1.[CH3:13][N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[C:2]([Br:1])[CH:3]=[CH:4]2)=[N:8]1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc2ccc(Br)cc2n1
Product: Cn1ncc2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 51 %
Yield: 43 %

Procedure:
To 6-bromoindazole (402A) (5.0 g, 25.4 mmol) in THF (50 mL) was added sodium hydride (95%, 672 mg, 26.6 mmol) with ice bath cooling. The mixture was stirred for 30 minutes. Methyl iodide (6.36 mL, 102 mmol) was added at room temperature. The reaction mixture was quenched with ammonium chloride solution and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, ethyl acetate/hexane gradient) afforded 1-methyl-6-bromoindazole (402B) (2.71 g, 51%) as a yellow oil and 2-methyl-6-bromoindazole (402C) (2.28 g, 43%) as a yellow crystalline solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.C(O)(C(F)(F)F)=O.[K+].[Br-]>C(#N)C.O>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)[O:21][N:20]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)COc1ccc(SCc2cc(-c3ccc(C(F)(F)F)cc3)no2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(C(F)(F)F)cc3)no2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 89A. mp 166-168° C.; HPLC: area %=96.95, r.t.=3.140 min, γ=214 nm, mobile phase=acetonitrile/water w/0.10% TFA. IR (KBr) cm−1: 3140, 3085, 1742, 1322, 1255, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12.96 (br(s), 1H), 7.99 (d, 2H, J=8.3 Hz), 7.81 (d, 2H, J=8.3 Hz), 7.14 (d, 1H, J=8.4 Hz), 6.81 (s, 1H), 6.61 (d, 1H, J=8.4 Hz), 4.63 (s, 2H), 4.23 (s, 2H), 2.76 (t, 4H, J=7.5 Hz), 1.91 (pentet, 2H); MS m/z 450 (M+1). Anal. Calc'd for C22H18F3NO4S: C, 58.79; H, 4.04; N, 3.12. found: C, 58.38; H, 3.92; N, 2.95.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[O:30][C:31]([F:34])([F:33])[F:32].Cl[C:36](OC1C=CC([N+]([O-])=O)=CC=1)=[O:37].[CH2:48]([NH2:52])[CH:49]([CH3:51])[CH3:50]>ClCCl.O>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:36]([NH:52][CH2:48][CH:49]([CH3:51])[CH3:50])=[O:37])=[C:3]([O:30][C:31]([F:33])([F:34])[F:32])[CH:4]=3)[CH2:13][CH2:12]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(OC(F)(F)F)c3)CC2)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: O
Product: CC(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)cc1OC(F)(F)F
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
3-((4-(4-Amino-3-(trifluoromethoxy)benzoyl)piperazin-1-yl)methyl)—N-tert-butyl-benzamide (250 mg, 0.525 mmol) and 4-nitrophenol chloroformate (106 mg, 0.525 mmol) were combined and stirred in dichloromethane for 1 hour. Isobutylamine (0.115 g, 1.6 mmol, 0.156 mL) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with water and flushed through a hydrophobic frit. The organic phase was concentrated under vacuum and purified by basic reverse phase HPLC to afford the title compound (20 mg), MS (ESI) m/z 578.5 [M+H]+
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>O>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:26][CH:25]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
Carbazole (0.80 g, 4.80 mmol) and sodium hydride (NaH) (60% in mineral oil, 0.25 g, 6.2 mmol) were added to a flask, which was charged with argon. DMF (dimethylformamide) (12 mL) was added and the mixture was stirred at 60° C. for 1 hour (h), after which 4-bromomethyl benzoic acid methyl ester (1.16 g, 4.8 mmol) was added, and the mixture was stirred at 80° C. overnight. Water was added and the product was extracted with CH2Cl2 (dichloromethane), dried (Na2SO4, sodium sulfate) and concentrated. The product was purified by column chromatography to give 310 mg of compound 28 as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][C:15]([F:22])([F:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-])=O>O1CCCC1.[Pd]>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]=1[NH:13][CH2:14][C:15]([F:21])([F:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
To a solution of ethyl 3-[(2,6-dinitrophenyl)amino]-2,2-difluoropropanoate (2.44 g, 7.644 mmol) in tetrahydrofuran (50 mL) was added 10% palladium on carbon (50% wet; 588.0 mg), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 16 hrs. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (2.00 g, 7.715 mmol, quant.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].CC(C)([O-])C.[K+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:41][C:42](OC)=O)[CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38]>C(O)C>[CH3:40][O:39][C:35]1[CH:34]=[C:33]([CH:32]=[C:31]([O:30][CH3:29])[C:36]=1[O:37][CH3:38])[CH2:41][C:42]1[NH:22][C:20](=[O:21])[C:3]2[C:4]([CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: CCc1nn(C(C)CCCc2ccccc2)c(N)c1C(N)=O
Reactant: COC(=O)Cc1cc(OC)c(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCc1nn(C(C)CCCc2ccccc2)c2nc(Cc3cc(OC)c(OC)c(OC)c3)[nH]c(=O)c12
Yield: 41.6 %

Procedure:
400 mg (1.4mmol) of 5-amino-3-ethyl-1-(1-methyl-4-phenyl-butyl)-1H-pyrazole-4-carboxamide, 750 mg (6.7 mmol) of potassium tert-butoxide and 720 mg (3.0 mmol) of methyl 3,4,5-trimethoxy-phenylacetate are refluxed for 16 hours in 10 ml of ethanol. After the solvent has been removed, the mixture is acidified with 1N HCl, extracted 3 times with dichloromethane, the organic phase is dried over sodium sulphate and the solvent is removed in vacuo. Purification by chromatography gives 286 mg (40%) of a solid, Rf=0.62 (ethyl acetate/cyclohexane=2:1).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].[Cl-].C[CH:20]=[N+:21]=[CH:22]C.[CH3:24]COCC>C(#N)C>[CH3:20][N:21]([CH2:22][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][CH2:6][S:3]([N:2]([CH3:1])[CH3:17])(=[O:5])=[O:4])[CH:9]=2)[NH:13][CH:12]=1)[CH3:24]
Reactant: CCOCC
Reactant: CN(C)S(=O)(=O)CCc1ccc2[nH]ccc2c1
Reactant: CC=[N+]=CC
Agent: [Cl-]
Solvent: CC#N
Product: CN(C)Cc1c[nH]c2ccc(CCS(=O)(=O)N(C)C)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product of Stage (ii) (0.8 g) in acetonitrile (40 ml) containing N,N-dimethylmethyleneammonium chloride (0.6 g) was stirred at room temperature for 3 h. The resulting solution was partitioned between sodium carbonate (2N, 50 ml) and ethyl acetate (2×50 ml). The organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid. Trituration with ether gave the title compound as a solid (0.9 g) m.p. 156°-159°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[C:20]=2[CH3:26])(=[O:18])=[O:17])[CH:7]=1.[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>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.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([S:16]([C:19]2[C:20]([CH3:26])=[C:21]([C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:40])[F:41])=[CH:36][CH:35]=3)[CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:7]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2cccc(Br)c2C)c2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cn(S(=O)(=O)c2cccc(-c3ccc(OC(F)(F)F)cc3)c2C)c2ccc(F)cc12
Temperature: 110 °C
Yield: 65.2 %

Procedure:
Into a 50 mL oven dried round bottom flask, 3-[1-(3-Bromo-2-methyl-benzenesulfonyl)-5-fluoro-1H-indol-3-yl]-propionic acid methyl ester (5, 52.062 mg, 1.1459E-4 mol), 4-trifluoromethoxy-phenyl boronic acid (6, 35.397 mg, 1.7189E-4 mol) and Tetrakis(triphenylphosphine)palladium(0) (13.24 mg, 1.146E-5 mol) were combined. A volume of 0.3 mL of 1N K2CO3 was added and the reaction was heated to 110° C. for 90 minutes. TLC analysis showed co-elution of product and starting material. Ethyl acetate was added and washed 5× with saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered and concentrated at reduced pressure. The crude material was purified using prep plate chromatography (7:3 hexane:ethyl acetate) to provide the desired compound (40 mg isolated, 65% yield). 1H NMR consistent with compound structure. MS(ESI) [M+H+]+=536.1 (calculated 535.51).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:40]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[CH:40]1([NH:47][C:18](=[O:20])[C@@H:17]2[CH2:21][CH2:22][CH2:23][N:16]2[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NC1CCCCCC1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
6.4 g (0.02 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 75 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 2.54 ml (0.02 mol) of N-ethylmorpholine and 2.62 ml (0.02 mol) of isobutyl chloroformate were added and the solution was stirred at -10° C. for 20 minutes. A solution of 2.25 g (0.02 mol) of cycloheptylamine in 25 ml of dry tetrahydrofuran was then added. The mixture was stirred at 0° C. for 1 hour and then left to stand at room temperature for 16 hours. The mixture was then evaporated and the residue extracted twice with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed successively with 1-N hydrochloric acid, water, 5% sodium bicarbonate solution and water and then dried over magnesium sulphate. Evaporation yielded an oil which solidified upon trituration with petroleum ether. The solid was recrystallised from ethyl acetate/petroleum ether to yield 5.6 g (67.5%) of N-benzyloxycarbonyl-L-alanyl-L-proline cycloheptylamide of melting point 110°-113° C.; [α]D20 =-92.4° (c=1.05% in methanol).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])(C)C)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[CH3:17][CH:18]([CH3:29])[CH2:19]CCC1C=CC(Br)=CC=1>>[CH3:4][Si:2]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:16][CH2:17][CH:18]([CH3:29])[CH3:19])=[CH:11][CH:12]=1)([CH3:1])[CH3:3]
Reactant: CC(C)CCCc1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Product: CC(C)CCCc1ccc(C#C[Si](C)(C)C)cc1

Procedure:
Using the same general procedure as described for Compound 23, but using instead 4-(4-methylpentyl) bromobenzene (Compound 32), the title copound was synthesized as a colorless oil. PMR (CDCl3): & 0.32 (9H, s), 0.93 (6H, d, J~6.6 Hz), 1.18-1.29 (2H, m), 1.52-1.70 (3H, m), 2.58 (2H, t, J~7.7 Hz), 7.12 (2H, d, J~8.1 Hz), 7.43 (2H, d, J~8.1 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=O)/[CH:27]=[C:28](\O)/[CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:22]=[CH:23][C:24]=1[Cl:25]>C1COCC1.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:28]([CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[CH:27]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C(/C=C(\O)COC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(COC3CCCCO3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenylhydrazine hydrochloride (3.88 kg, 21.8 mol) and K2CO3 (3.21 kg, 23.2 mol) were added to a THF/EtOAc solution containing (Z)-1-(3,4-dichlorophenyl)-3-hydroxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-buten-1-one (Example 514) at 0-10° C. The resultant suspension was stirred and allowed to warm to rt overnight (16 h). When HPLC analysis indicated the disappearance of the starting material, the reaction mixture was filtered. The organic reaction filtrate was washed with 1 M aq. citric acid (34.0 L), followed by 10% aq. NaCl (50.0 L) and the resulting product solution was used in the next synthetic step without isolation. HPLC (Method U): Rt=16.22 min. MS (ES+): mass calculated for C22H22Cl2N2O3, 432.10; m/z found, 455.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.19 (dd, J=6.8, 2.2 Hz, 2H), 6.96 (dd, J=8.1, 2.1 Hz, 1H), 6.87 (dd, J=2.1, 7 Hz, 2H), 6.58 (s, 1H), 4.86 (d, J=12 Hz, 1H), 4.83-4.81(m, 1H), 4.60 (d, J=12 Hz, 1H), 3.99-3.84 (m, 1H), 3.82 (s, 3H), 3.78-3.74 (m, 1H), 1.91-1.52 (m, 6H). 13C NMR (100 MHz, CDCl3): 159.5, 150.7, 141.8, 133.0, 132.7, 130.9, 130.8, 130.6, 128.1, 127.1, 114.7, 107.7, 98.6, 63.2, 62.6, 60.8, 55.9, 30.9, 25.8, 21.4, 19.7, 14.6.