Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].Cl.[F:10][C:11]([F:15])([F:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(#N)C>[F:1][C:2]([F:8])([F:7])[CH2:3][NH:4][C:5]([NH:13][CH2:12][C:11]([F:15])([F:14])[F:10])=[S:6]
Reactant: FC(F)(F)CN=C=S
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)CNC(=S)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,2,2-Trifluoroethylisothiocyanate (2.12 g.) was added to a mixture of 2,2,2-trifluoroethylamine hydrochloride (1.36 g), triethylamine (1.01 g) and acetonitrile (10 ml.), and the mixture stirred at room temperature for 4 hours and then evaporated to dryness. The residue was partitioned between water and ethyl acetate, and the ethyl acetate phase was dried and evaporated to dryness. The residue was recrystallised from a mixture of acetone and light petroleum ether (b.p. 60°-80°) to give 1,3-di(2,2,2-trifluoroethyl)thiourea, m.p. 152°-153°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[O:8]=[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:11][NH:10]1.[H-].[Na+].O>CN(C)C=O.[I-].[K+]>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:10]1[C:9](=[O:8])[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:11]1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1CCCCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
Potassium iodide (0.1 g) and 1,5-dibromopentane (4.6 g) were added to a suspension of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.88 g) and 60% sodium hydride (0.4 g) in N,N-dimethylformamide (40 ml). After being stirred for 3 hours at room temperature, the mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (100 g) using chloroform as an eluent to afford 3-[2-(5-bromopentyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (3.48 g).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1
Reactant: Cn1nnnc1SCCl
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1nnnc1SCI
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloromethylthio-1-methyltetrazole (987 mg: 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g: 12.0 mMol.), and the mixture is stirred at 50° C. for 3 hours. After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, filtered, and concentrated to give 5-iodomethylthio-1-methyltetrazole as yellow oil (1.33 g: containing about 20 Mol. % of the chloride).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([NH:53][C@H:54]([C@H:59]([CH2:61][C:62]([O:64][CH3:65])=[O:63])[OH:60])[CH2:55][CH:56]([CH3:58])[CH3:57])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([NH:53][C@H:54]([C@H:59]([CH2:61][C:62]([O:64][CH3:65])=[O:63])[OH:60])[CH2:55][CH:56]([CH3:57])[CH3:58])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 56 mg of Z-Phe-His-OH, 60 mg of H-Leu-Val-Ala-Sta-OCH3.HCl, 18 mg of HOBT, 0.24 ml of ethyldiisopropylamine and 34 mg of DCCI, the title compound is obtained in the form of a colourless powder after flash chromatography (30 g of silica gel 60, 40-63 μm, system N8). Rf (N9)=0.33.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[C:49]([N:57]2[N:61]=[CH:60][CH:59]=[N:58]2)=[C:50]([CH:54]=[CH:55][CH:56]=1)[C:51](O)=[O:52]>>[F:47][C:48]1[C:49]([N:57]2[N:61]=[CH:60][CH:59]=[N:58]2)=[C:50]([CH:54]=[CH:55][CH:56]=1)[C:51]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:52]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cccc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 126 mg, 0.45 mmol) and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1293284-51-1; 111 mg, 0.54 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1.[N+](C1C=CC=CC=1)([O-])=O>C(O)(=O)C.[Zn]>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10]
Reactant: COCc1cccc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CC(=O)O
Product: COCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
EX-514B) The 3-(methoxymethyl)nitrobenzene (4.18 g, 25 mmol) from EX-514A was dissolved in 160 mL of acetic acid. Zinc dust (5 g, 76.5 mmol) was added, and the solution was stirred at room temperature for 18 hours, at which time HPLC analysis indicated that no 3-methoxymethyl)nitrobenzene starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with water, then dried over MgSO4, and concentrated in vacuo to give 3.4 g (99%) of the desired 3-(methoxymethyl)aniline as a brown oil. The crude product was used without further purification. HRMS calod. for C8H12NO: 138.0919 [M+H]+, found: 138.0929. 1H NMR (CDCl3) δ 3.4 (s, 3H), 3.7 (s, 2H), 4.4 (s, 2H), 6.6 (d, 1H), 6.7 (m, 2H), 7.2 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.C(=O)=O>C1(OC)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:9])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ncc(Cl)c(C(=O)O)n1
Agent: O=C=O
Solvent: COc1ccccc1
Product: CS(=O)(=O)c1ncc(Cl)cn1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
5-Chloro-2-(methylsulfonyl)pyrimidine-4-carboxylic acid (5.7 g, 24 mmol) was refluxed in anisole (8 mL) until the evolution of carbon dioxide ceased. The reaction mixture was cooled to room temperature and filtered. The solid was washed with light petroleum ether (1×50 mL) and dried to obtain the title compound (4.10 g, 88% yield) as a light orange solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH2:8]([N:12]=[C:13]=[S:14])[CH:9]([CH3:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:12]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:13]1=[S:14])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: CC(C)CN=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(CC(C)C)C1=S
Yield: 23.2 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 5.7 g of isobutyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Title compound (2.3 g) was obtained as an oil. Anal. Calcd. for. C9H16N2O S: C, 53.97; H, 8.05; N, 13.99. Found: C, 54.01; H, 8.21; N, 14.00) Mass spectrum (El, M.+) m/z 200.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([Cl:17])=[O:4]
Reactant: O=C(O)C(F)(F)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(F)(F)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of 2,2-difluoro-2-(4-fluorophenyl)acetic acid (1.33 g, 7.0 mmol) in DCM (50 mL) was added oxalyl chloride (0.640 mL, 7.5 mmol) and a catalytic amount of DMF. After stirring for 3 h, the mixture was concentrated under reduced pressure to afford 2,2-difluoro-2-(4-fluorophenyl)acetyl chloride. To a solution of 2-aminobenzamide (0.857 g, 6.3 mmol) and TEA (1.04 mL, 0.0075 mol) in DCE (100 mL) at rt was added 2,2-difluoro-2-(4-fluorophenyl)acetyl chloride from above in DCE (100 mL) and the reaction mixture was stirred overnight. After adding EtOAc (200 mL) the mixture was washed with 1 N HCl, sat. NaHCO3 and brine. The organic solution was concentrated to yield an off-white solid (0.989 mg, 51%). 1H NMR (300 MHz, DMSO-d6) δ 7.15 (t, 1H), 7.27 (m, 2H), 7.54 (m, 1H), 7.74 (m, 2H), 7.92 (m, 2H), 8.44 (d, 2H), 13.37 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:24]C)[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:24])[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Agent: Cl
Agent: N
Product: CCCCCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 86.2 %

Procedure:
6-Amino-9-benzyl-8-methoxy-2-pentoxypurine (40 mg, 0.117 mmol) in concentrated hydrochloric acid (20 ml) was stirred for 12 hours at room temperature. The reaction mixture was made basic with 28% aqueous ammonia. The resulting crystals were filtered and washed with water to give the subject compound (33 mg, yield 86%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.150 mmol), 4-chloro-3-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL), and acetic acid (0.048 mL) was added NaBH3CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to afford (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.[CH:18]([C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1)=[O:19].C1CCN2C(=NCCC2)CC1>ClCCl>[OH:19][CH:18]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)[C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc(C=O)n1
Reactant: COc1ccc2cc(-c3cncnc3)[nH]c2c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cccc(C(O)c2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Temperature: 30 °C
Reaction time: 76 h
Yield: 61.4 %

Procedure:
To a suspension of 6-methoxy-2-pyrimidin-5-yl-1H-indole (779 mg) and methyl 6-formylpyridine-2-carboxylate (628 mg) in dichloromethane (17.3 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (0.052 mL), and the mixture was stirred at 30° C. for 76 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluting solvent: methanol-ethyl acetate) to obtain the title compound (829 mg). 1H-NMR (DMSO-d6) δ ppm: 3.75 (3H, s), 3.82 (3H, s), 5.99 (1H, d, J=3.5 Hz), 6.16 (1H, d, J=3.5 Hz), 6.61 (1H, dd, J=2.3, 8.8 Hz), 6.84 (1H, d, J=2.3 Hz), 7.49 (1H, d, J=8.8 Hz), 7.86-7.92 (1H, m), 8.06 (1H, t, J=7.8 Hz), 8.18-8.26 (1H, m), 9.23 (1H, s), 9.55 (2H, s), 11.40 (1H, br s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:18](=[O:19])[N:17]2[CH:12]1[S:13][CH2:14][C:15]([C:36]1[S:40][C:39]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)=[C:16]2[C:20]([O:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:23]([O:22][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[C:36]1[S:40][C:39]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)[CH:11]([NH:10][C:7](=[O:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:18]2=[O:19])=[O:21])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
Thien-2-yl-acetyl chloride (1.4 cc) is added to a solution of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyrid-3-ylmethyl)-thiazol-5-yl]-5-thia-1-azabicyclo [4.2.0]oct-2-ene (6.36 g) in dry tetrahydrofuran (200 cc), and triethylamine (1.58 cc) is then added. The mixture is stirred at 20° C. for 1 hour 20 minutes and is then poured into a 65:35 (by volume) mixture of ethyl acetate and a saturated sodium bicarbonate solution. The organic phase is decanted and then washed successively with distilled water (200 cc), and a saturated sodium chloride solution (200 cc) and dried over anhydrous sodium sulphate. The drying agent is filtered off and washed with ethyl acetate (10 cc) and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 30° C. The residue is purified by chromatography on a column (height: 24 cm, diameter: 3 cm) of silica gel (0.05-0.2 mm), elution being carried out with ethyl acetate (2.5 liters), and 60 cc fractions being collected. Fractions 12 to 35 are combined and concentrated to dryness under reduced pressure (30 mm Hg; B 4 kPa) at 30° C. to give 2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyrid-3-ylmethyl)-thiazol-5-yl]-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.45 g) in the form of a yellow froth.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)C=NC=1.Cl.Cl.N[C@H](C1C=C[N:39]=[C:38]([Cl:42])[N:37]=1)[C@@H](C1C=C(F)C=CC=1F)O>>[Cl:42][C:38]1[N:39]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:3]=[CH:2][N:37]=1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Reactant: N[C@H](c1ccnc(Cl)n1)[C@H](O)c1cc(F)ccc1F
Agent: Cl
Product: O=C1N[C@H](c2ccnc(Cl)n2)[C@@H](c2cc(F)ccc2F)O1

Procedure:
Prepared according to the same procedure as (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one, starting with (1R,2R)-2-amino-2-(2-chloropyrimidin-4-yl)-1-(2,5-difluorophenyl)ethanol 2HCl. 1H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J=4.9 Hz, 1H), 8.69 (s, 1H), 7.68 (d, J=5.2 Hz, 1H), 7.50-7.28 (m, 3H), 5.71 (d, J=5.5 Hz, 1H), 5.04 (d, J=5.5 Hz, 1H), Mass spec.: 312.1 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:30])[N:17](COC(=O)C(C)(C)C)[CH:18]=[N:19]3)=[CH:14][C:13]=2[O:31][CH3:32])[CH2:4][CH2:3]1.N>CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:30])[NH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:31][CH3:32])[CH2:6][CH2:7]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCN(C)CC1
Agent: N
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A suspension of 7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (31.8 g, 71.3 mmol) in methanol saturated with ammonia was stirred at ambient temperature overnight. The volatiles were removed under vacuum. The solid was triturated with ether containing about 10% of methylene chloride, filtered, washed with ether containing about 10% methylene chloride and dried under vacuum to give 7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (22.63 g, 95%).
Reaction SMILES: [CH:1]([N:4]([CH:23]([CH3:25])[CH3:24])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[O:21]C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(N(C(C)C)CCC(C1C=C(OC)C=CC=1C)C1C=CC=CC=1)(C)C.Br>C(O)(=O)C>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:23]([CH3:24])[CH3:25])[CH:19]=1
Reactant: COc1ccc(C)cc1C(CCN(C(C)C)C(C)C)c1ccccc1
Agent: Br
Agent: COc1ccc(C)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Solvent: CC(=O)O
Product: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 120 °C
Yield: 85.7 %

Procedure:
N,N-diisopropyl-3(2-methoxy-5-methylphenyl)-3-phenylpropanamine and N,N-diisopropyl-3-(5-methoxy-2-methylphenyl)-3-phenylpropanamine (11.0 g, 32.4 mmol) was dissolved in acetic acid (15 ml). After addition of 47% aqueous hydrobromic acid (25 ml), the mixture was heated to reflux for three hours (bath temperature, 120° C.). The reaction mixture was cooled to the room temperature. After the solvent was distilled off, water (120 ml) and toluene (110 ml) were added to the residue, to which sodium hydroxide (2.2 g) and sodium carbonate (26 g) were added to adjust pH to 11. After the aqueous layer was phase-separated to remove, the organic layer was washed with an aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent in the dried solution was distilled off under reduced pressure to obtain 9.04 g of racemic tolterodine (yield 85.7%).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][C:34]=1[CH2:43][CH2:44][CH2:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][C:34]=1[CH2:43][CH2:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:15]([OH:17])=[O:16])[CH2:4]2)[CH2:48][CH2:47]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc2nc(CCCC3CCNCC3)cnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3cnc4ccccc4n3)CC2)[C@@H](c2ccccc2)C1
Yield: 115.7 %

Procedure:
The title compound was prepared from 50 mg (0.12 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 33, Step E) and 55 mg (015 mmol) of 4-(3-(quinoxalin-2-yl)propyl)piperidine.2 TFA (from EXAMPLE 73, Step A) using a procedure analogous to that described in EXAMPLE 71, Step A. Flash chromatography using 19:1 v/v CH2Cl2/MeOH afforded 77 mg (100%) of the title compound: 1H NMR (500 MHz) 80.83-3.36(35H), 3.81 (s, 3H), 5.11 (ABq, J=11.9, 2H), 6.89 (d, J=8.7, 2H), 7.16-7.35 (7H), 7.70-7.78 (2H), 8.03-8.10 (2H), 8.73 (s, 1H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.F[B-](F)(F)F.[H+].O>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@H:19]([CH3:22])[CH2:20][O:21][CH3:1])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: C[C@H](CO)NS(=O)(=O)c1ccc(Br)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClCCl
Product: COC[C@@H](C)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
(Trimethylsilyl)diazomethane (10 mL, 10 mmol) was added to a vigorously stirred mixture of 4-bromo-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide (1.0 g, 3.4 mmol) and aqueous fluoroboric acid (conc. 42%, 6.8 mmol) in methylene chloride (25 mL), in 5 portions over 1 h at 0° C. The stirring was continued at 0° C. and another portion of trimethylsilyldiazomethane (5 mL, 5 mmol) was added over 30 min. The stirring was continued for 30 min, poured into water and extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and concentrated. Purification by column chromatography using gradient heptane to heptane/ethylacetate, (2:1), as the eluent gave 0.155 g (15% yield) of the title compound: MS (ESI) 309 m/z (M++1).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]([O:7][CH2:8][CH3:9])=[CH2:6]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:5]([O:7][CH2:8][CH3:9])[CH2:6][C:3]1=[O:4]
Reactant: C=COCC
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CCOC1CC(=O)N1C
Temperature: 130 °C
Yield: 16 %

Procedure:
A Teflon tube containing a mixture of 0.16 g (2.8 mmoles) of methyl isocyanate, 0.27 g (3.8 mmoles) of ethyl vinyl ether and 2 ml of toluene was sealed and introduced into a high-pressure reactor and the mixture was heated at 130° C. under a pressure of 8000 atmospheres for 20 hours. The reaction mixture taken out was evaporated and then purified by distillation under reduced pressure to obtain 1-methyl-4-ethoxy-2-azetidinone in a yield of 16% of the theoretical value.