Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=2)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:24]1([S:30]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][N:37]=[C:36]3[NH2:42])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C=O>[C:24]1([S:30]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][N:37]=[C:36]3[NH2:42])(=[O:32])=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[C:24]1([S:30]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][N:37]=[C:36]3[NH:42][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:9][C:10]=2[N+:17]([O-:19])=[O:18])(=[O:32])=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN1CCN(c2ccc(C(=O)O)c([N+](=O)[O-])c2)CC1
Agent: Nc1n[nH]c2ccc(S(=O)(=O)c3ccccc3)cc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c([N+](=O)[O-])c2)CC1
Temperature: 60 °C
Reaction time: 22 h
Yield: 43 %

Procedure:
4-(4-Methyl-piperazin-1-yl)-2-nitro-benzoic acid (5.54 g, 18.37 mmol) in dry tetrahydrofuran (100 mL) was treated with 0.070 mL of N,N-dimethylformamide followed by neat thionyl chloride (5.5 mL, 76.43 mmol) and refluxed for three hours. The volatiles were then removed by evaporation under reduced pressure and the solid was repeatedly taken up with anhydrous toluene (100 mL×3) and evaporated. The crude yellow acid chloride thus obtained was thoroughly dried under vacuum at room temperature then suspended in dry tetrahydrofuran (100 mL) and treated with a suspension of 5-benzenesulfonyl-indazol-3-ylamine (2.11 g, 7.71 mmol) and N,N-diisopropylethylamine (6.3 mL, 36.74 mmol). The reaction mixture was stirred at 60° C. (oil bath temperature) for 22 hours. The resulting almost clear solution was cooled to room temperature and the volatiles were removed by evaporation. The residue was treated with tetrahydrofuran (100 mL), methanol (100 mL) and 2N NaOH (30 mL). After stirring at room temperature for two hours, the organic solvents were removed by evaporation. The aqueous phase was adjusted to pH 7.5 and extracted several times with dichloromethane. A whitish solid present between the aqueous and the organic layer that could not be dissolved with dichloromethane was filtered off affording 0.4 g of crude product. The combined organic extracts were dried over sodium sulfate and evaporated giving 4.2 g of crude product. Purification of both the filtered solid and the organic extract by flash chromatography over silica gel (eluent: dichloromethane/methanol/33% NH4OH in 9:1:0.1 ratio) afforded 0.9 g of recovered 5-benzenesulfonyl-indazol-3-amine and 1.71 g of title compound as a yellow solid (43% yield).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH2:15][NH:16][C@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@H:18]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[N:11]([CH3:29])[C:10](=[O:30])[CH2:9][CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:38]1[O:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1>O1CCOCC1>[O:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=[C:38]1[N:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][CH2:15][C:14]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][C:10](=[O:30])[N:11]3[CH3:29])=[CH:6][C:5]=2[O:4][CH3:3])[C@@H:18]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1nc2ccccc2o1
Reactant: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1CN[C@H]1CCCN(c3nc4ccccc4o3)[C@H]1c1ccccc1)N(C)C(=O)CC2
Yield: 56.7 %

Procedure:
To 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one dihydrochloride (50 mg, 0.11 mmol), freshly ground potassium carbonate (61 mg, 0.44 mmol), and catalytic KI in 3 mL of 1,4-dioxane was added 2-chlorobenzoxazole (126 mg, 0.11 mmol). After heating at reflux for 5 days, the reaction was cooled and partitioned between ethyl acetate and water. The organic portion was separated, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (99:1 chloroform/methanol followed by 3:1 ethyl acetate/hexane) gave 31 mg (56%) of the title compound as a light brown oil. MS (M+H)+=497.2; 1H NMR (400 MHz, CDCl3): δ 1.75–1.85 (m, 1H), 1.85–1.95 (m, 3H), 2.55–2.60 (t, J=7 Hz, 2H), 2.80–2.85 (t, J=7 Hz, 2H), 3.15–3.25 (m, 1H), 3.30 (s, 3H), 3.30–3.40 (t, J=13 Hz, 1H), 3.71 (s, 3H), 3.82–3.92 (q, J=13.5 Hz, 2H), 4.16–4.21 (dd, J=13 Hz, 3.8 Hz, 1H), 5.74–5.76 (d, J=5.6 Hz, 1H), 6.62 (s, 1H), 6.90 (s, 1H), 6.95–6.99 (t, J=8.5 Hz, 1H), 7.10–7.14 (t, J=8.5 Hz, 1H), 7.19–7.21 (d, J=7.9 Hz, 1H), 7.24–7.28 (m, 4H), 7.68–7.70 (d, J=7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 24.2, 25.5, 26.8, 29.6, 31.7, 41.4, 46.0, 55.5, 56.9, 58.5, 108.5, 110.2, 116.0, 116.4, 120.3, 123.8, 125.7, 126.8, 127.5, 128.3, 129.3, 133.7, 137.7, 143.2, 148.5, 152.9, 162.3, 169.9. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid (Mp=181–183° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19](=[N:21][OH:22])[NH2:20])[CH2:5][N:6]([CH3:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][C:27]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41].C(Cl)CCl>CC#N.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]1[N:20]=[C:32]([C:30]2[CH:29]=[CH:28][C:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:31]=2)[O:22][N:21]=1)[CH2:5][N:6]([CH3:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)c(Cl)c1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)cc3Cl)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 65 (0.298 g, 0.91 mmol) and Intermediate 3 (0.79 g, 0.70 mmol) in MeCN (2 mL) was added EDC (0.188 g, 0.98 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with pyridine (2 mL) and heated at 150° C. under microwave irradiation for 20 minutes. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.43 (1H, d, J=1.8 Hz), 8.17 (1H, dd, J=7.9, 1.9 Hz), 7.99 (1H, d, J=7.9 Hz), 7.59 (1H, s), 7.42 (1H, dd, J=8.0, 1.6 Hz), 7.37-7.21 (4H, m), 7.13 (1H, d, J=7.4 Hz), 4.22 (2H, m), 3.75 (2H, s), 3.31 (3H, s), 3.22 (2H, s), 2.41 (3H, s), 2.08 (3H, s), 1.50 (9H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:4].[Br:20]Br>C(O)(=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:20][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1])=[C:7]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)[CH:8]=1
Reactant: BrBr
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1ncccn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ncccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 113 %

Procedure:
To a room temperature suspension of 2,2-dimethyl-N-(2-pyrimidin-2-yl-phenyl)-propionamide (˜117 grams, 437 mmoles) in acetic acid (1 L) was added bromine (67 mL, 1.31 moles) as a solution in 100 mL of acetic acid over a 1 hour period. The heterogenous mixture was stirred at room temperature for 5 hours over which time a thick precipitate formed. The mixture was then poured over ice, diluted with 1N Na2S2O3 (2 L), and stirred for 1 hour. The solids were filtered, resuspended in water (2 L), stirred for 1 hour, then filtered and washed with water again. The resulting solids were pumped to dryness at 50° C., resuspended in HOAc (1 L), and treated with bromine (22 mL, 430 mmoles) in acetic acid solution (20 mL) over a 20 minute period. The resulting heterogenous mixture was stirred for 5 hours, then quenched and treated as described above. The resulting solids were vacuum dried at 50° C. to afford the title compound (165 grams) as a tan powder.
Reaction SMILES: [CH2:1]([O:4][N:5]=[CH:6]/[C:7](/[CH3:21])=[CH:8]/[C@@H:9]1[C@@H:11]([C:12]([O:14]C(C)(C)C)=[O:13])[C:10]1([CH3:20])[CH3:19])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:4][N:5]=[CH:6]/[C:7](/[CH3:21])=[CH:8]/[C@@H:9]1[C@@H:11]([C:12]([OH:14])=[O:13])[C:10]1([CH3:20])[CH3:19])[CH:2]=[CH2:3]
Reactant: C=CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Under nitrogen atmosphere, a mixture of 0.74 g of t-butyl (1R)-trans-3-[(E)-3-(2-propenyloxyimino)-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate, catalytic amount of p-toluenesulfonic acid and 10 ml of toluene was stirred for 1 hour under reflux. The reaction mixture was cooled down to room temperature, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.47 g of (1R)-trans-3-[(E)-3-(2-propenyloxyimino)-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylic acid:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=2)=[CH:28][CH:29]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(O)C1CNCCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: O=C(O)C1CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 137 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 434. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.47 (s, 1H) 8.36 (d, 2H) 7.88 (d, 1H) 7.74 (t, 1H) 7.61 (d, 1H) 7.15 (d, 2H) 6.68 (d, 2H) 4.68 (dd, 1H) 4.39 (s, 2H) 3.96 (t, 2H) 3.84 (dd, 2H) 3.52 (t, 2H) 3.44 (t, 2H) 2.95 (t, 2H).
Reaction SMILES: [I:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5]I.[OH-].[K+].[OH-].[Na+].I>>[I:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH:4]=[CH2:5]
Reactant: FC(F)(I)C(F)(F)CCI
Agent: I
Agent: [K+]
Agent: [Na+]
Product: C=CC(F)(F)C(F)(F)I

Procedure:
the 1,4-diiodo-1,1,2,2-tetrafluorobutane reacting with at least a stoichiometric amount of potassium hydroxide or sodium hydroxide in the form of an approximately 10 to 60% strength by weight aqueous solution at a temperature of 20° to 100° C. and in the presence of a phase transfer catalyst in an amount of 0.1 to 5 mol %, relative to the amount of 1,4-diiodo-1,1,2,2-tetrafluorobutane, to eliminate hydrogen iodide, and isolating 1-iodo-1,1,2,2-tetrafluoro-3-butene from this reaction product,
Reaction SMILES: [C:1]1([N:7]2[C:11](=O)[CH2:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11](=[S:29])[CH2:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2=NN(c3ccccc3)C(=S)C2)cc1
Yield: 147.7 %

Procedure:
A mixture of 5.6 g (20 mmol) of 1-phenyl-3-(4-methylphenyl)-4, 5-dihydropyrazol-5-one, 6.1 g (15 mmol) of Lawesson's reagent and 50 ml of toluene was heated under reflux for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1 (v/v)) and recrystallized from diethyl ether-n-hexane to give quantitatively 5.9 g of the object compound as pale yellow crystals.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[C:22]1[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[N:25]=[C:24]([NH2:35])[N:23]=1)[CH2:18][NH:17][CH2:16][CH2:15]2>>[NH2:35][C:24]1[N:23]=[C:22]([C:21]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:8]([NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:9])[CH2:18]3)=[CH:13][C:12]=2[F:11])[CH:27]=[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:25]=1
Reactant: O=C=NC1CCCCC1
Reactant: CN1CCN(c2cc(-c3cc4c(cc3F)CCNC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3cc4c(cc3F)CCN(C(=O)NC3CCCCC3)C4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 75, Step 6 starting from cyclohexylisocyanate (Aldrich, Cat. #C105198) and 4-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=468.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(Cl)Cl.CC1(C)C(C)(C)OB([C:51]2[CH:56]=[CH:55][C:54]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])=[CH:53][CH:52]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:61][S:58]([NH:57][C:54]1[CH:53]=[CH:52][C:51]([C:2]2[CH:39]=[CH:38][CH:37]=[C:4]([CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]5[CH:26]=[CH:25][C:24]6[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=6)[N:18]=5)=[CH:14][C:9]=4[N:8]=[C:7]3[CH2:27][C:28]3([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]3)[CH:3]=2)=[CH:56][CH:55]=1)(=[O:60])=[O:59]
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccc(NS(C)(=O)=O)cc3)c2)CCCC1
Temperature: 25 °C

Procedure:
To a 5 mL microwave vial were added methyl 1-{[1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]methyl}cyclopentanecarboxylate (126 mg, 0.21 mmol), Pd(dppf)Cl2.DCM (18 mg, 0.02 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (192 mg, 0.65 mmol), Na2CO3 (0.3 mL, 2 M) and 1,4-dioxane (2.5 mL). The vial was flushed with N2 then capped and placed in a heating block at 80° C. After 16 h mixture was cooled to RT, transferred to a round-bottomed flask and was concentrated to dryness. The residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C39H38N4O5S, 674.82; m/z found, 675.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].I[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1]([O:5][C:6](=[O:16])[C@H:7]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCI
Reactant: CCCCCC[C@@H](O)CC(=O)OC(C)(C)C
Product: CCCCCC[C@@H](O)[C@@H](CCCCC)C(=O)OC(C)(C)C

Procedure:
The target compound (2.49 g, 38%) was obtained in the same manner as in Production Example C-1, except that the (R)-3-hydroxynonanoic acid t-butyl ester (5.00 g, 21.7 mmol) obtained in Production Example B-3 and 1-iodopentane (5.59 g, 28.2 mmol) were used.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.C(OCC)(=O)C>[CH:21]1([CH:20]=[C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[C:26]2[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C)cc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)c1
Yield: 101.6 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(3,5-dimethyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.28 mmol) in ethanol (3 mL), tetrahydrofuran (3 mL), and aqueous sodium hydroxide solution (10%, 1 mL) was heated at reflux for 24 h. The mixture was diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(3,5-dimethyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (90 mg, 99%) as a white solid: LC/MS m/e calcd for C22H24N2 [M+H]+ 317.45, observed 317.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=[NH:11])OCC)=[O:5])[CH3:2].[ClH:12].[CH3:13][NH:14][CH3:15]>C(O)C>[ClH:12].[CH3:13][N:14]([CH3:15])[C:7](=[NH:11])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CNC
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=N)N(C)C

Procedure:
107.3 g (0.67 mol) of the compound from Example 2 and 55 g (0.67 mol) of dimethylamine hydrochloride in 300 ml of ethanol are heated under reflux overnight. The solvent is removed by distillation and the residue is triturated with acetone
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[Si:25]([O:32][C:33]1[C:41]2[O:40][C:39](CO)=[CH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl>[C:28]([Si:25]([CH3:27])([CH3:26])[O:32][C:33]1[C:41]2[O:40][C:39]([CH2:20][Cl:24])=[CH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2cc(CO)oc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2cc(CCl)oc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.5 g (9.5 mmol) of triphenylphosphine and 0.92 ml (9.5 mmol) of carbon tetrachloride are added to a solution of [7-(tert-butyldimethylsilanyloxy)-benzofuran-2-yl]methanol (14) (1.78 g, 6.4 mmol) in methylene chloride (9 ml), kept at 0° C. The reaction mixture is stirred at 0° C. for 1 hour and then the solvent is evaporated under reduced pressure. The residue is taken up in 30 ml of cyclohexane and stirred for 1 hour. The precipitate formed is filtered and the filtrate concentrated. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 95/5). The title product is obtained in the form of a pale yellow liquid (1.5 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])=[O:5])C.[OH-].[Na+]>>[F:32][C:26]1[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:25]=1[NH:24][C:7]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cn2c(C(=O)O)c(Nc3ccc(I)cc3F)c3cnccc32)cc1
Temperature: 65 °C
Yield: 88.8 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1-(4-methoxy-benzyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (196 mg, 0.37 mmol), 1M aqueous sodium hydroxide solution (443 μl) and IMS (4 ml) was heated at 65° C. for 2.5 hours. After cooling to ambient temperature the solvent was evaporated, the residue was dissolved in water and the pH of the solution was adjusted to 7 by the addition of 1N HCl solution. The precipitated solid was collected by filtration, washed with water (5 mL), ethyl acetate (2 mL) and pentane (2 mL) then left to air dry to provide the title compound as a yellow solid (170 mg, 89%). LCMS (method A): RT=7.22 min, M+H+=518.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:26]=[CH:25][C:21]2[N:22]=[CH:23][S:24][C:20]=2[CH:19]=1>>[S:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:14](=[O:16])/[CH:13]=[CH:12]/[C:8]3[C:9]([CH3:11])=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23]1
Reactant: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)O
Reactant: Nc1ccc2ncsc2c1
Product: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)Nc1ccc2ncsc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (220 mg, 1.0 mmol) and 6-aminobenzothiazole (150 mg, 1.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z: 352 (M+1).
Reaction SMILES: [I-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10]C[N+](C)(C)C)=[CH:5][CH:4]=1.[ClH:17].[CH3:18][NH:19][CH3:20].Cl.FC1C=CC(C(=O)C)=CC=1>C(O)C.C(OCC)C>[ClH:17].[CH3:18][N:19]([CH3:20])[CH2:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)=[O:16]
Reactant: C[N+](C)(C)CCC(=O)c1ccc(F)cc1
Reactant: CNC
Agent: *CO*
Agent: CC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CC(=O)c1ccc(F)cc1
Temperature: 20 °C

Procedure:
3-(4-Fluorophenyl)-3-oxo-N,N,N-trimethylpropan-1-aminium iodide can be prepared in accordance with the following procedure: Dimethylamine hydrochloride (32.6 g), a 12 N aqueous solution of hydrochloric acid (1 cc) and polyoxymethylene (12.0 g) are added to a solution of 1-(4-fluorophenyl)-ethanone (56.0 g) in ethanol (200 cc). After heating under reflux for 3 hours, more polyoxymethylene (6.0 g) is added and the mixture is heated under reflux for a further 16 hours. The reaction mixture is cooled to 20° C. and diethyl ether (300 cc) is then added. The solid which precipitates is filtered off, washed 3 times with diethyl ether (300 cc in total) and dried under reduced pressure (20 mm Hg) at 25° C. for 16 hours. 2-Dimethylamino-1-(4-fluorophenyl)-ethan-1-one hydrochloride (65.0 g), which melts at 180° C., is thus obtained and this is dissolved in distilled water (60 cc). Diethyl ether (1,100 cc) and a 10 N aqueous solution of sodium hydroxide (30 cc) are added to the solution thus obtained, the mixture is stirred for 2 minutes and the organic phase is decanted. The aqueous phase is re-extracted twice with diethyl ether (300 cc in total). The ether extracts are combined, dried over sodium sulphate and evaporated under reduced pressure (20 mm Hg) at 40° C. Methyl iodide (42.5 g) is added, at between 20° and a maximum of 50° C., to a solution of the residual oil (52.2 g) in anhydrous acetonitrile (250 cc). The reaction is allowed to proceed for 2 hours at 20° C. and diethyl ether (300 cc) is then added. The solid which precipitates is filtered off, washed 3 times with diethyl ether (300 cc in total), and dried under reduced pressure (20 mm Hg) at 25° C. for 16 hours. 3-(4-Fluorophenyl)-3-oxo-N,N,N-trimethylpropan-1-aminium iodide (65.5 g), which melts at 230° C., is thus obtained.