Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:2]([C:17]([O:19]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[NH2:38][C@H:39]([C:47]([NH:49][C@@H:50]([C:52]([OH:54])=[O:53])[CH3:51])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCOCC1.O>[NH:1]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C@@H:2]([C:17]([NH:38][C@H:39]([C:47]([NH:49][C@@H:50]([C:52]([OH:54])=[O:53])[CH3:51])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:19])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: C[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
8.0 g (15.0 mmol) of pentafluorophenyl ester of Boc-D-Orn(Z)-OPfp was dissolved in 15 ml dioxane. To this was added with mixing 4.3 g (17.7 mmol) H-Phe-D-Ala-OH dissolved in water with pH 8.5. The reaction mixture was stirred for a day and a night at room temperature. The solvents were evaporated under vacuum, 70 ml ethyl acetate was added, and the mixture was acidified to pH 2-3 by the addition of 2% sulfuric acid solution. The peptide was extracted twice with 70 ml ethyl acetate, washed with saturated sodium chloride solution to neutral pH and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum leaving a thick oil. The product was crystallized from ethyl acetate with ether and hexane. The yield was 6.92 g (74.4%), and the melting point was 145° C. Rf=0.44 in acetic acid:chloroform;methanol=0.5:16:1. Rf=0.32 in chloroform:ethyl acetate:methanol=6:3:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](N(OC)C)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9].[CH3:30][Mg]Cl.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([C:24](=[O:25])[CH3:30])[CH:3]=1
Reactant: C[Mg]Cl
Reactant: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1c(Cl)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluoro-N-methoxy-N-methylbiphenyl-2-carboxamide (2.7 g, 6.6 mmol) in tetrahydrofuran (26 mL) at 0° C. was treated with 3 M of methylmagnesium chloride in tetrahydrofuran (6.6 mL, 20 mmol) dropwise and stirred at 20° C. for 1 hour. The reaction mixture still contained some starting material and was, therefore, cooled to 0° C., treated with additional 3 M of methylmagnesium chloride in tetrahydrofuran (2.2 mL, 6.6 mmol) dropwise, and stirred at 20 ° C. for 2 hours. The reaction mixture was cooled to 0° C., quenched with 1 M hydrogen chloride in water (26 mL, 26 mmol), poured into 0.1 M hydrogen chloride in water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography using ethyl acetate in hexanes (0%-20%) gave the desired product (2.3 g, 93%). LCMS for C20H20ClFN3O (M+H)+: m/z=372.1; Found: 371.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([C:21](OCC)=[O:22])=[CH:19][N:18]=[C:17]3[S:26][C:27]([CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:28][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(C1C=C2C(=CC=1)NC(C#N)=C2)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:33][C:30]([F:31])([F:32])[CH2:29][C:27]1[S:26][C:17]2=[N:18][CH:19]=[C:20]([CH2:21][OH:22])[C:15]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[C:16]2[CH:28]=1
Reactant: CCOC(=O)c1cnc2sc(CC(F)(F)F)cc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N#Cc1cc2cc(C=O)ccc2[nH]1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(CO)cnc3sc(CC(F)(F)F)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
Ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carboxylate (45 mg, 0.1 mmol) was dissolved in CH2Cl2 (3 mL). Trifluoroacetic acid (2 mL) was added to the solution. After 2 hours, the solution was concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL), and washed with a 10% solution of K2CO3 (2×1 mL), and dried over anhydrous K2CO3. The organic phase was concentrated to give tan residue, which was used in the next step without further purification. This residue was dissolved in 1,2-dichloroethane (1 mL). 5-formyl-1H-indole-2-carbonitrile (23 mg, 0.14 mmol) and sodium tri(acetoxy)borohydride (32 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 2 hours. The solution was diluted with EtOAc (10 mL) and washed with 0.1 N NaOH (1×5 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by reversed-phase preparative HPLC (95:5-5:95 MeCN/H2O with 0.1% HCl buffer). The product containing fractions were lyophilized to afford the product as a white solid (1.4 mg, 2.5% yield), Compound 278. LC-MS: 1.45 min, 500.2 m/z [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4].C([Li])CCC.[B:19](OC)([O:22]C)[O:20]C.Cl>C(OCC)(=O)C.C1COCC1.CCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([B:19]([OH:22])[OH:20])=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(F)c1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(B(O)O)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
The compound (22) (84.6 g) and THF (500 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. n-Butyllithium (1.65 M in a n-hexane solution; 303.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, the mixture was added dropwise to a THF (200 ml) solution of trimethyl borate (56.7 g) in the temperature range of −74° C. to −65° C., and the stirring was continued for another 8 hours while the mixture was allowed to return to 25° C. Subsequently, the reaction mixture was poured into a vessel containing 1N—HCl (100 ml) and ice-water (500 ml), and mixed. Ethyl acetate (300 ml) was added thereto and the mixture was allowed to separate into organic and aqueous phases, and the extraction was carried out. The organic phase obtained was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure, giving 4-butoxy-2,3-difluorophenylboronic acid (23) (6.4 g). The yield based on the compound (22) was 69.2%.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:31][C:30]([CH3:33])([CH3:32])[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:23][CH:24]=1)=[O:34]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: CC(C)(C)C(=O)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(NC(=O)C(C)(C)C)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with N-(4-Hydroxy-phenyl)-2,2-dimethyl-propionamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C24H31NO6 [M+H]+: 430.
Reaction SMILES: [NH2:1][C@@H:2]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C@@H:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[F:31][C:32]1[CH:33]=[C:34]([CH2:39][C:40](O)=[O:41])[CH:35]=[C:36]([F:38])[CH:37]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:31][C:32]1[CH:33]=[C:34]([CH2:39][C:40]([NH:1][C@@H:2]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:3]([NH:5][C@@H:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8][C@@H:7]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:4])=[O:41])[CH:35]=[C:36]([F:38])[CH:37]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a stirred solution of (2S)-2-amino-2-(4-fluorophenyl)-N-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]acetamide (65b) (81 mg, 0.199 mmol) in dichloromethane (2 mL) under nitrogen was added 3,5-difluorophenylacetic acid (40 mg, 0.232 mmol), HOBt (35 mg, 0.259 mmol), NMM (30 mg, 0.297 mmol) and EDAC-HCl (50 mg, 0.261 mmol). The mixture was stirred 5 h at ambient temperature then evaporated. The residue was dissolved in ethyl acetate and extracted in succession with saturated sodium bicarbonate, 1N aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6:1 (v/v) dichloromethane: ethyl acetate (TLC Rf=0.42) to afford the title compound (85 mg, 76%) as a white solid. 1H NMR (300 MHz, CDCl3) δ3.54 (s, 2H), 5.08 (t, 1H, J=7.0 Hz), 5.19 (d, 1H, J=6.5 Hz), 5.79 (d, 1H, J=7.0 Hz), 6.16 (br d, 1H, J=6.5 Hz), 6.62 (br d, 1H, J=7.0 Hz), 6.66-6.86 (m, 3H), 6.87-7.04 (m, 3H), 7.08-7.39 (m, 10H), 7.50 (br s, 1H). MS APCI, m/z=560 (M+1). LC/MS: 2.61 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[C@H:4]([CH:46]([CH3:48])[CH3:47])[NH:5][C:6](=[O:45])[C@H:7]([CH:42]([CH3:44])[CH3:43])[NH:8][C:9](=[O:41])[CH2:10][CH:11]1[CH2:17][CH2:16][C:15]([C@@H:18]([NH:20][C:21](=[O:32])[C@H:22]([CH3:31])[NH:23]C(OC(C)(C)C)=O)[CH3:19])=[CH:14][CH:13]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:12]1[OH:40].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:49])[C@H:4]([CH:46]([CH3:48])[CH3:47])[NH:5][C:6](=[O:45])[C@H:7]([CH:42]([CH3:43])[CH3:44])[NH:8][C:9](=[O:41])[CH2:10][CH:11]1[CH2:17][CH2:16][C:15]([C@@H:18]([NH:20][C:21](=[O:32])[C@H:22]([CH3:31])[NH2:23])[CH3:19])=[CH:14][CH:13]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:12]1[OH:40]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC([C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)=CC(Cc2ccccc2)C1O)C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC([C@H](C)NC(=O)[C@H](C)N)=CC(Cc2ccccc2)C1O)C(C)C)C(C)C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 30 mg of (40) in CH2Cl2 (1 mL) was added trifluoroacetic acid (10 mL). After stirring for 45 min the reaction was evaporated to dryness, triturated with ether, filtered and dried under vacuum to give the title compound (41) as a mixture of isomers (24rag, 75%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].S([O-])([O-])(=O)=O.CS[C:12]([NH2:24])=[NH+:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[CH3:23].CS[C:27]([NH2:39])=[NH+:28][CH2:29][CH2:30][S:31][CH2:32][C:33]1[N:34]=[CH:35][NH:36][C:37]=1[CH3:38]>>[CH3:38][C:37]1[NH:36][CH:35]=[N:34][C:33]=1[CH2:32][S:31][CH2:30][CH2:29][N:28]=[C:27]([NH2:39])[NH:1][CH2:2][CH2:3][NH:4][C:12]([NH2:24])=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[CH3:23]
Reactant: NCCN
Reactant: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Agent: O=S(=O)([O-])[O-]
Product: Cc1[nH]cnc1CSCCN=C(N)NCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
The reaction of 1,2-diaminoethane (0.60 g) with S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate (5.86 g) by the method described in Example 5 afforded the title compound which was isolated as the dipicrate (3.5 g), m.p. 201°-203°.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:26]=[C:25]([N:27]([C:32]4[CH:37]=[CH:36][C:35]([B:38]5[O:42]C(C)(C)C(C)(C)[O:39]5)=[C:34]([F:47])[CH:33]=4)[S:28]([CH3:31])(=[O:30])=[O:29])[C:24]([CH:48]4[CH2:50][CH2:49]4)=[CH:23][C:17]=3[C:18]=2[C:19]([NH:21][CH3:22])=[O:20])=[CH:10][CH:9]=1.Cl.CCOC(C)=O>C1COCC1.O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:26]=[C:25]([N:27]([C:32]4[CH:37]=[CH:36][C:35]([B:38]([OH:39])[OH:42])=[C:34]([F:47])[CH:33]=4)[S:28]([CH3:31])(=[O:30])=[O:29])[C:24]([CH:48]4[CH2:49][CH2:50]4)=[CH:23][C:17]=3[C:18]=2[C:19](=[O:20])[NH:21][CH3:22])=[CH:10][CH:9]=1
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(B4OC(C)(C)C(C)(C)O4)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(B(O)O)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Sodium periodate (549 mg, 2.57 mmol) was added to a mixture of 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (164 mg, 0.257 mmol) in THF (6 mL) and 1N HCl (3.21 mL, 3.21 mmol). The mixture was stirred at room temperature overnight and EtOAc and water were added. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with 10% aq. Na2S2O3, brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (MeCN/H2O with 0.1% TFA) to give the title compound as a white solid (80 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (q, 1H) 8.23 (br. s., 1H) 8.07 (s, 1H) 7.94 (d, 2H) 7.64 (d, 2H) 7.55 (t, 1H) 7.22 (s, 1H) 7.11 (s, 1H) 7.07-7.10 (m, 1H) 3.45 (s, 4H) 2.85 (d, 3H) 2.04-2.15 (m, 1H) 1.00 (br. s., 1H) 0.82 (d, 2H) 0.54 (br. s., 1H). LCMS (m/z, ES+)=557 (M+H+).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:2])=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C)cc1
Solvent: O
Product: COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.1 %

Procedure:
In this example an undivided cell was used, said cell being provided with a platinum anode and a lead cathode. A solution of 250 grams of water, 10 grams of sulfuric acid and 50 grams of manganous sulfate was placed in the cell and 50 grams of p-methoxytoluene slowly added thereto. The electrical energy which was used consisted of an E applied voltage of 5.5 volts along with about 4.0 amps while maintaining the current density at a rate of about 80 milliamps/cm2. The reaction was effected for a period of about 3.5 hours while maintaining the cell at ambient temperature and atmospheric pressure. A work-up of the results disclosed that there had been a 47.1% yield of anisaldehyde with a 50.5% selectivity to said aldehyde, a current efficiency of 93.3% being observed.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:12][CH:13]=[CH:14][C:5]=3[C:4](=[O:15])[N:3]1[CH2:16][C:17]([OH:19])=[O:18])[CH:8]=[CH:9][CH:10]=2.O.[C:21]1(C)C=CC(S(O)(=O)=O)=C[CH:22]=1.C(O)C>C1(C)C=CC=CC=1>[CH2:21]([O:18][C:17](=[O:19])[CH2:16][N:3]1[C:4](=[O:15])[C:5]2[CH:14]=[CH:13][CH:12]=[C:7]3[C:6]=2[C:11](=[CH:10][CH:9]=[CH:8]3)[C:2]1=[O:1])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CN1C(=O)c2cccc3cccc(c23)C1=O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CN1C(=O)c2cccc3cccc(c23)C1=O
Temperature: 25 °C

Procedure:
A mechanically-stirred mixture of 1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid (125.0 g, 0.49 mole), p-toluenesulfonic acid hydrate (9.3 g, 0.049 mole), anhydrous pure ethanol (226 g, 288 ml, 0.49 mole) and dry toluene (750 ml) was heated at reflux for 16 hr in a Soxhlet apparatus in which the thimble was filled with hydrated alkali-aluminium silicate (3 A Molecular Sieves). The title compound was crystallized from the reaction mixture after cooling to room temperature. The crystals were collected and a second crop of crystals were obtained from the mother liquors. Recrystallization of the two crops of crystals from ethyl acetate gave the title compound; mp 160°-162° C.; UV (MeOH) 232, 332 and 341 nm, ε=48,613, 13,470 and 12,920, respectively; IR (CHCl3) 1745, 1705 and 1665 cm-1 ; Anal. Calc'd.: C, 67.84%; H, 4.63%; N, 4.94%; Found: C, 67.89%; H, 4.60 %; N, 4.87%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]([C:33]([CH3:35])=[CH2:34])=[CH:21][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:39][C:40]([NH:42][CH3:43])=[O:41]>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]([C:33]([CH3:35])=[CH2:34])=[CH:21][C:10]=1[C:11]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:39][C:40](=[O:41])[NH:42][CH3:43])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCl
Reactant: C=C(C)c1cc(C(=O)Nc2ccc(F)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)c1cc(C(=O)N(CC(=O)NC)c2ccc(F)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 116 %

Procedure:
2,4-Bis-benzyloxy-N-(4-fluoro-phenyl)-5-isopropenyl-benzamide (0.1 g, 0.21 mmol) [Using method A2 from (2,4-bis-benzyloxy-5-isopropenyl)-benzoic acid (Preparation B5) and 4-fluoro-aniline] was dissolved in DMF (1 ml), treated with 60% NaH in mineral oil (13 mg, 1.5 eq) and stirred at room temperature for 15 min. 2-chloro-N-methyl acetamide (33 mg, 0.12 mmol) was added and the reaction stirred for a further 60 minutes, then diluted with EtOAc and water. The EtOAc layer was separated, washed with brine, dried (MgSO4) and evaporated. The crude material was purified by flash column chromatography eluting with EtOAc to give 75 mg of title compound. MS: [M+H]+ 539.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)c(F)cc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a11) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[O:22])[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[BH4-].[Na+]>CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3c(CO)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 4.9 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde in 100 cm3 of methanol, at a temperature in the region of 20° C., is added 0.57 g of sodium borohydride. The reaction medium is stirred at room temperature for 3 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 100 cm3 of water and 100 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 4.92 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methanol are obtained with the following characteristics:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10]([F:13])([F:12])[CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[N:3]=1.[H-].[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:10]([F:13])([F:12])[CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][CH:27]=2)[N:3]=1
Reactant: CCCCCCCCC1CCc2cc(-c3ccc(O)cc3)nc(F)c2C1(F)F
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cc3c(c(F)n2)C(F)(F)C(CCCCCCCC)CC3)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1,8,8-trifluoro-3-(4-hydroxyphenyl)-7-octyl-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1,8,8-trifluoro-3-[4-(octyloxy)phenyl]-7-octyl-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[CH3:20][C:21]([CH3:25])=[CH:22][CH2:23][NH2:24].C(N(CC)CC)C>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:24][CH2:23][CH:22]=[C:21]([CH3:25])[CH3:20])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CC(C)=CCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCNc1nc(NCC=C(C)C)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To 10 ml of a solution of 150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline in acetonitrile were added 137 mg (1.13 mmol) of 3-methyl-2-butenylamine hydrochloride and 288 mg (2.85 mmol) of triethylamine, followed by heating at room temperature for 4.5 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with chloroform (10 ml×3). After the organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography to give 133 mg (yield: 75.1%) of the title compound.