Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:35]1[N:36]=[C:37]2[CH:43]=[CH:42][N:41]([S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[C:38]2=[N:39][CH:40]=1)[CH2:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:13]1)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>>[S:44]([N:41]1[C:38]2[N:39]=[CH:40][C:35]3[N:36]([C:10]([C@@H:12]4[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][CH:22]5[C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=6[C:29]6[C:34]5=[CH:33][CH:32]=[CH:31][CH:30]=6)=[O:19])[CH2:13]4)=[CH:9][N:8]=3)[C:37]=2[CH:43]=[CH:42]1)([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:45])=[O:46]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)[C@@H]4CCCN(C(=O)OCC5c6ccccc6-c6ccccc65)C4)C(=O)OC(C)(C)C)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc([C@@H]4CCCN(C(=O)OCC5c6ccccc6-c6ccccc65)C4)n23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
A mixture of (R)-(9H-fluoren-9-yl)methyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)piperidine-1-carboxylate (0.20 g, 0.27 mmol), TFA (1.0 mL, 13 mmol) and TFAA (1.0 mL, 7.1 mmol) was stirred at about 25° C. for about 16 h. The reaction mixture was partitioned between EtOAc (50 mL) and aqueous saturated NaHCO3 (2×50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (R)-(9H-fluoren-9-yl)methyl 3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate as a clear oil (0.17 g, 99%): LC/MS (Table 2, Method a) Rt=2.68 min; MS m/z: 618 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:29](Cl)(Cl)=[S:30]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:29]=[S:30])[C:14]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: S=C(Cl)Cl
Reactant: CC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2 g of 6-amino-2-tert-butyl-5-[4-acetylpiperazin-1-yl]benzothiazole and 1.5 g of sodium bicarbonate in 150 ml of chloroform is cooled to 0° and 4 ml of thiophosgene is added dropwise and stirred at ambient temperature overnight. The solid is filtered off and the filtrate is evaporated under reduced pressure. The oil so obtained is applied on a silica gel column and eluted with 1% methanol in chloroform to yield 2-tert-butyl-6-isothiocyanato-5-[4-acetylpiperazin-1-yl]benzothiazole, melting at 100°-102°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([NH:8][C:9]1[C:10]([CH3:20])=[N:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]3[NH:12][N:11]=[C:10]([CH3:20])[C:9]=3[N:8]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccccc2)c1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nc3c(C)n[nH]c3c3ccccc23)c1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
128 mg of 3-methoxy-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)benzamide (4) were suspended in 5 ml of xylene and the suspension was boiled at 160° C.; 119 mg of phosphorus pentoxide were then added and the mixture was subsequently stirred at 160° C. for 15 min. 27 μl of phosphorus oxychloride were added dropwise to the suspension, which was then stirred at 160° C. for 12 h; a saturated solution of sodium hydrogen carbonate was then added and the whole was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 3. C18H15N3O (298.34); MS (ESI 290 (M+H)
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH3:12][N:13]([CH3:16])[CH:14]=O>>[CH3:12][N:13]([CH:16]=[C:9]1[CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][C:8]1=[O:11])[CH3:14]
Reactant: CC(=O)NC1CCC(=O)CC1
Reactant: CN(C)C=O
Product: CC(=O)NC1CCC(=O)C(=CN(C)C)C1

Procedure:
According to Reaction Scheme I, 4-acetamido cyclohexanone, prepared by the procedure of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970) is reacted with the dimethylacetal of dimethylformamide to yield 2-dimethylaminomethylene-4-acetamidocyclohexanone (III). Reacting this compound with sodium glycinate followed by a ring closure reaction in the presence of acetic anhydride yields, when R3 is methyl, dl-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (IV). Treatment of this latter compound with base gives dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (V). This latter compound can be preferentially alkylated on the amino group at C-5 using a reductive alkylation procedure; i.e., reaction with an aldehyde (formaldehyde, acetaldehyde, acrolein, or propionaldehyde) in the presence of a strong organometallic reducing agent such as sodium cyanoborohydride. The dialkylated compound, for instance, dl-5-di(n-propyl)amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (VI) can also be alkylated on the pyrrole ring nitrogen under basic conditions using an alkyl halide R2X (methyl iodide, allyl chloride, ethyl bromide, or the like) to yield a dl-2-(C1 -C3 alkyl or allyl)-5 -disubstituted-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole of Formula VII.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:15][C@H:14]([OH:16])[CH2:13][CH2:12][C@@H:11]1[NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.CCOCC>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][C@@H:11]1[NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
The compound benzyl (1S,2R,4R)-2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxycyclohexylcarbamate (4.15 g) in CH2Cl2 (30 mL) was added to Dess-Martin periodane (13.4 g, 31.6 mmol) in CH2Cl2 (100 mL) at 0° C. After 1 h, the ice bath was removed and the reaction aws stirred overnight. This mixture was diluted with ether (425 mL) and washed with water (2×50 mL), sat'd Na2S2O3 (2×50 mL), 1N sodium hydroxide (2×50 mL), and brine (1×50 mL). The organic layer was dried over MgSO4, filtered, and then evaporated to dryness to give benzyl (1S,2R)-2-((tert-butyldimethylsilyloxy)methyl)-4-oxocyclohexylcarbamate (4.05 g) as a clear viscous oil after drying under vacuum overnight. MS found: (M+H)+=392.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[OH-].[Na+]>N1C=CC=CC=1>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][S:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:17])=[O:18]
Reactant: Nc1nncs1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nncs2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
To a stirred suspension of 2-amino-1,3,4-thiadiazole (1.5 g, 15 mmol) in anhydrous pyridine (6 ml) at 0° C., under nitrogen, was added 3-nitrobenzenesulphonyl chloride (3.5 g, 16 mmol) portionwise. The mixture turned yellow and set solid. The mixture was then heated at 120° C. for 1 h before aqueous sodium hydroxide (20% (w/w), 3.3 ml) was added cautiously. Heating was continued for a further 15 min then the solution allowed to cool to ambient temperature. The mixture was evaporated in vacuo and the residue evaporated with water (2×50 ml) followed by toluene (2×50 ml). The residue was then taken up in water and the resultant brown solid collected by filtration. This was then recrystallised from glacial acetic acid. The title compound (1.4 g, 37%) was isolated as a yellow solid, which contained one mole of acetic acid. mp 189°-192° C. 1H NMR (250 MHz, D6 -DMSO) δ 7.88 (1H, dd, J=8 and 8 Hz), 8.23 (1H, dd, J=8 and 1 Hz), 8.45 (2H, m), 8.83 (1H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:14][C:15]1[CH:19]=[N:18][N:17]([CH3:20])[C:16]=1[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]([CH3:35])([N+:32]([O-])=O)[CH3:31])[NH2:24].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH2:32])([CH3:35])[CH3:31])=[C:21]([C:16]3[N:17]([CH3:20])[N:18]=[CH:19][C:15]=3[Br:14])[CH:22]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc(OCC(C)(C)N)c(-c3c(Br)cnn3C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
4-Acetamidobenzoyl chloride (11 mg, 0.06 mmol) was added to a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was added followed by zinc dust (33 mg) and the mixture was stirred at room temperature. After 4 h, the suspension was made basic with ammonium hydroxide and extracted twice with ethyl acetate. The combined extracts were evaporated to dryness, purified by preparative LCMS and lyophilized to give the product (5.6 mg, 22%) as a TFA-salt. LCMS m/z (%)=502.3 (M+H 81Br 42.9%), 500.4 (M+H 79Br 52.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 3 H), 1.18 (s, 3 H), 2.08 (s, 3 H), 3.67 (s, 3 H), 3.82 (d, J=9.60 Hz, 1 H), 3.98 (d, J=9.85 Hz, 1 H), 7.27 (d, J=9.09 Hz, 1 H), 7.67 (s, 1 H), 7.69 (d, J=2.78 Hz, 1 H), 731 (d, J=8.84 Hz, 2 H), 7.85-7.91 (m, 3 H), 7.91 (d, J=8.84 Hz, 2 H), 7.95 (dd, J=8.97, 2.65 Hz, 1 H), 10.22 (s, 1 H), 10.23 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:22]=[C:23]=[N:24][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8]1)[CH2:6]/[C:5]/2=[N:24]\[C:23]#[N:22]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1CCC2(C/C(=N\C#N)c3cc(Br)ccc3O2)C1
Temperature: 0 °C
Yield: 96.6 %

Procedure:
To a solution of 6-bromo-3′-methylspiro[chroman-2,1′-cyclopentan]-4-one (216 mg, 0.73 mmol) in anhydrous DCM (5.7 mL) was added TiCl4 (1 M solution in DCM, 1.5 mL, 1.49 mmol) dropwise within 15 min at room temperature. The mixture was stirred forl h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (300 mg, 0.36 mL, 1.61 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (20 g) and extracted with DCM (3×20 mL). The combined organic phases were dried over anhydrous Na2S O4, filtered, and concentrated to give (E)-N-(6-bromo-3′-methylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide as light brown solid (225 mg), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][NH2:12])[C:4]=2[O:3]1.C(N(C(C)C)C(C)C)C.Cl[C:24]([O:26]C)=[O:25]>O1CCCC1>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][NH:12][C:24]([OH:26])=[O:25])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(NN)c2O1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2cccc(NNC(=O)O)c2O1
Reaction time: 1 h

Procedure:
17.8 g of (1C) thus prepared and 12.9 g of ethyldiisopropylamine were dissolved in 200 ml of tetrahydrofuran. 9.45 g of methyl chloroformate was added drop-by-drop to the stirred solution, and the resulting mixture was stirred for one hour. The solvent then was evaporated, the residue was washed with water and extracted with ether, and the extract was dried. Part of the ether was evaporated from the extract and the remaining solution was cooled. The resulting solid was collected to give the methyl ester of 2-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)hydrazinecarboxylic acid (1D), as a white solid, m.p.; 101°-102° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]2[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:25](O)=[O:26])=[O:22])[NH:18][C:15]2=[CH:16][N:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[C:25](=[O:26])[C@@H:24]([NH:23][C:21]([C:19]1[NH:18][C:15]2=[CH:16][N:17]=[C:12]([Cl:11])[CH:13]=[C:14]2[CH:20]=1)=[O:22])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)C1CCCCN1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)C1CCCCN1C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of piperidine-2-carboxylic acid amide hydrochloride (Preparation 80, 24 mg, 0.17 mmol) in DMF (3 mL) was added 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 230, 52 mg, 0.14 mmol), followed by HATU (65.6 mg, 0.17 mmol) and DIPEA (63 μL, 0.36 mmol), and the reaction stirred at rt for 16 h. Solvent was removed in vacuo, purification via preparative HPLC gave the title compound as an off-white powder. m/z (ES+)=472.31 [M+H]+; RT=3.19 min.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][CH:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C@H:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:25][CH:24]=3)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:36](=[NH:41])(OCC)[CH3:37].C(N(CC)CC)C.Cl>C(O)C>[ClH:1].[ClH:1].[C:36]([N:32]1[CH2:33][CH2:34][C@H:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([CH:17]([CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][CH:8]=4)[CH:13]=3)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:24][CH:25]=2)[CH2:31]1)(=[NH:41])[CH3:37]
Reactant: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCNC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCN(C(C)=N)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 193.4 %

Procedure:
In 1,000 ml of ethanol was dissolved 105.3 g of ethyl (+)-3-(7-amidino-2-naphthyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride. With stirring at room temperature, the thus prepared solution was mixed with 51.5 g of ethyl acetimidate hydrochloride. With ice cooling and stirring, 89 ml of triethylamine was added dropwise to the above solution while keeping the inner temperature at 3° to 5° C., and the stirring was continued for 2.5 hours while keeping the temperature at 5° C. or below. After distilling off the solvent under a reduced pressure at a low temperature, the resulting reaction solution was adjusted to pH 4-5 with dilute hydrochloric acid, followed by further distillation under a reduced pressure to remove the solvent. The resulting residue was purified by subjecting it to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. Thereafter, thus eluted fractions of interest were pooled, mixed with a small amount of dilute hydrochloric acid, and then concentrated to dryness. In this way, 110.1 g of the title compound was obtained in the form of a colorless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH:14]([C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([NH2:20])=[O:19])[CH2:13]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(O)CCC.Br>C(O)(=O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][C@@H:14]([C:17]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([NH2:20])=[O:19])[CH2:13]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3occc3c2)C1
Agent: [Pd]
Agent: Br
Solvent: CC(=O)O
Solvent: CCCCO
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3c(c2)CCO3)C1
Reaction time: 6.5 h
Yield: 85 %

Procedure:
Pd/C 10% (0.8 g) was added to a solution of S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide (8 g) in acetic acid (160 ml). The mixture was hydrogenated at 45-50° C. and at atmospheric pressure for about 6-7 hrs. Catalyst was filtered off and solution was concentrated under vacuum obtaining an oily residue. n-Butanol (40 ml) was added and stirred to obtain a solution. 48% HBr (3.5 g) was added and a mixture n-Butanol/water was eliminated by distillation to reduce water content to less then 1%. Darifenacin .HBr crystallizes and after 2 hrs at 15-20° C. was filtered and washed with n-Butanol (3×5 ml). After drying at 55-60° C. under vacuum 8.1 g of Darifenacin hydrobromide were obtained. (Yield 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.CS(O[CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1cccc(CCOS(C)(=O)=O)c1
Product: COc1ccc(C2CCc3cc(C)ccc3C2=O)cc1

Procedure:
The process described in the third and fourth paragraphs of Example 1 was repeated using p-methoxyphenylacetic acid and 2-m-tolylethyl methanesulphonate as starting materials. The 3,4-dihydro-2-p-methoxyphenyl-6-methylnaphthalen-1(2H)-one thus obtained (1.33 g., m.p. 125°-126° C. after crystallisation from methanol) was added to a stirred solution of lithium diisopropylamide in tetrahydrofuran [prepared from n-butyllithium (5 ml. of a 1.5 molar solution in hexane) and a solution of diisopropylamine (0.8 g.; freshly distilled from potassium hydroxide) in tetrahydrofuran (20 ml.)] which was cooled to -20° C. under an atmosphere of argon. The mixture was stirred at -20° C. for 1 hour, methyl iodide (1.27 g.) was added and the mixture was stirred at laboratory temperature for 18 hours. Aqueous N-hydrochloric acid (50 ml.) was added and the mixture was extracted twice with diethyl ether (50 ml. each time). The combined extracts were dried and evaporated to dryness and the residue was purified by medium pressure chromatography on a silica gel column using a 12.5:1 v/v mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluent. The product was crystallised from petroleum ether (b.p. 60°-80° C.) and there was thus obtained 3,4-dihydro-2-p-methoxyphenyl-2,6-dimethylnaphthalen-1(2H)-one, m.p. 80°-82° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:16])=[C:4]2[C:8]3=[C:9]([CH2:11][NH:12][CH2:13][C:14](=[O:15])[N:7]3[CH:6]=[CH:5]2)[CH:10]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([C:2]2[C:3]([CH3:16])=[C:4]3[C:8]4=[C:9]([CH2:11][NH:12][CH2:13][C:14](=[O:15])[N:7]4[CH:6]=[CH:5]3)[CH:10]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(I)cc2c3c1ccn3C(=O)CNC2
Solvent: O
Product: Cc1c(-c2ccccc2)cc2c3c1ccn3C(=O)CNC2
Yield: 70 %

Procedure:
Using a procedure as described in Example 50(b), the title compound was synthesized from 6-iodo-7-methyl-3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 50(a)), and phenylboronic acid to give a white solid in 70% yield: 1H NMR (DMSO-d6) δ 2.23 (s, 3H), 3.46 (bs, 2H), 4.13 (bs, 2H), 7.17 (t, 1H, J=7.5 Hz), 7.45-7.56 (m, 5H), 7.76 (d, 1H, J=7.5 Hz), 7.84 (d, 1H, J=7.5 Hz), 8.29-8.31 (m, 1H). LRMS (M+) 276. Anal. (C18H16N2).0.4 H2O) C, H, N.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]([CH3:37])=[C:20]([CH:36]=2)[C:21]([NH:23][C:24]2[C:25]([CH3:35])=[C:26]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:27]([O:29][CH3:30])=[O:28])=[O:22])[CH2:11]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]([CH3:37])=[C:20]([CH:36]=2)[C:21]([NH:23][C:24]2[C:25]([CH3:35])=[C:26]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:27]([O:29][CH3:30])=[O:28])=[O:22])[CH2:11]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of methyl 3-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidyl]-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (0.60 g, 1.14 mmol) in THF (15 ml) is added Bu4NF 1.0 M in THF (0.596 g, 2.28 mmol) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 1 hour, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 4% methanol in dichloromethane as eluent to afford the title compound as a white solid (0.4 g, 85.5%). Mass spectrum (m/z): 411.4 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][NH:5][C:6]([CH3:9])([CH3:8])[CH3:7].[OH-].[Li+].Cl>O1CCOCC1.O>[C:6]([NH:5][CH2:4][C:3]([OH:10])=[O:2])([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)CNC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NCC(=O)O
Reaction time: 2 h

Procedure:
To a solution of tert-Butylamino-acetic acid methyl ester (Maybridge), 122 mg (0.84 mmol) in 10 mL of dioxane was added a solution of 60 mg (2.52 mmol) of lithium hydroxide in 10 mL of water. The reaction mixture was stirred for two hours, acidified to pH=1 with 5 N HCl and concentrated to dryness to yield the crude desired product which was carried on without further purification. MS (IS) 132.1 (M+1).