Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7](Cl)([Cl:9])=[O:8]>C1(C)C=CC=CC=1>[N:1]1([C:7]([Cl:9])=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cl
Reactant: C1CSCCN1
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 10 g (97 mmol) of thiomorpholine in 200 ml of toluene is added dropwise at 0° to a solution of 85 ml (165 mmol) of 20% phosgene in toluene and the white suspension is stirred for 1 h at RT. Excess phosgene is driven off by introducing nitrogen, the suspension is filtered, and the filtrate is concentrated by evaporation. The title compound is obtained in the form of a yellow oil. IR (CH2Cl2, cm-1): 1735, 1450, 1440, 1405, 1370, 1290, 1180.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[C:13]([O:25][CH3:26])[C:12]([CH3:27])=[C:11]2[C:7]=1[C:8](=[O:28])[O:9][CH2:10]2)=[O:4].O[Li].O>CO.O>[CH3:1][O:2][C:3]([NH:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:13]([O:25][CH3:26])[C:12]([CH3:27])=[C:11]2[C:7]=1[C:8](=[O:28])[O:9][CH2:10]2)=[O:4]
Reactant: COC(=O)CC/C(C)=C/Cc1c(NC(=O)OC)c2c(c(C)c1OC)COC2=O
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COC(=O)Nc1c(C/C=C(\C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2
Yield: 62.2 %

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (1.0 g) in 10 ml methanol was heated to reflux for 4 hours and then evaporated to dryness. The residue was recrystallized from acetone/hexane to give 0.41 g of methyl (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate. The ester (0.35 g) and 0.05 g of LiOH-H2O in 9 ml 2:1 MeOH-H2O was heated at reflux for 4 hours. The mixture was acidified, extracted with ethyl acetate, and the organic layer was dried over MgSO4. The organic layer was concentrated and the residue was further purified by silica gel chromatography (eluant 60:40:2 hexane:ethyl acetate:acetic acid) to give 0.21 g of (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, mp 155°-158° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:20][C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Sc1nnc(-c2ccc3occc3c2)o1
Reactant: ClCc1cccc(Cl)c1
Product: Clc1cccc(CSc2nnc(-c3ccc4occc4c3)o2)c1
Yield: 89 %

Procedure:
In the same manner as in Example 1 and using 5-(1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-chlorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 89%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.[OH-].[K+].O>CO>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)CCc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Temperature: 62.5 °C
Reaction time: 0.25 h

Procedure:
2-(1H-indol-5-yl)-ethanesulfonic acid methylamide (100 g) was dissolved in methanol (1000 ml) and N-methyl-4-piperidone (200 ml) was added thereto at 25° C. The reaction mass was stirred for 15 minutes and potassium hydroxide (300 g) was added at 25° C. The reaction mass was heated to 60-65° C. for 8 hours and cooled gradually to 25° C. Water (1500 ml) was added slowly and stirred the mixture till solid was obtained. The solid was filtered and dried at 50-55° C. under vacuum to obtain the title compound. (Yield: 80 g, HPLC Purity: 99%)
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(N(CC)CC)C>[C:1]([O:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:17][CH:16]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 64.6 %

Procedure:
From the reaction of 52.3 g (0.5 m) methacryloyl chloride and 76.6 g (0.5 m) of p-nitrobenzyl alcohol and 50.6 g triethylamine was isolated 71.5 g (64.5%) of p-nitrobenzyl methacrylate as pale-yellow crystals, mp--87°-88° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([O-])=O.[C:34]([C@H:37]1[CH2:41][CH2:40][NH2+:39][CH2:38]1)([OH:36])=[O:35].CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:39]3[CH2:40][CH2:41][C@H:37]([C:34]([OH:36])=[O:35])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)[C@H]1CC[NH2+]C1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC[C@H](C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 2 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.2 g, 2.9 mmol) was added to a solution of (3S)-3-carboxypyrrolidinium trifluoroacetate (0.50 g, 2.3 mmol) and DIPEA (3 mL, 17 mmol) in DCE (20 mL) at 80° C. The reaction mixture was stirred for 2 hrs. and the solvent was concentrated. The product was purified by MPLC on silica gel using 30% acetone in DCM containing 1% of AcOH to provide the title compound as white solid. Yield: 600 mg (42%); MS (ESI) (M+H)+=484.1.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[C:5]([O:19][CH3:20])[CH:4]=2)=[CH:24][CH:23]=1
Reactant: NCCc1ccc(F)cc1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCc2ccc(F)cc2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 94.7 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 4-fluorophenethylamine (0.0256 g, 0.184 mmol) gives the title compound (0.0689 g. 94.9%): TOF MS ES+ 396.2 (M+H)+, HRMS calcd for C22H23N3O3F 396.1723 (M+H)+found 396.1714, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.1 min, 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:16].CO>[Ni]>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[S:11][C:10]([CH2:12][NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cc2ccc(F)cc2)s1
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(Cc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 15.1 %

Procedure:
7N ammonia/methanol (30 mL) and Raney nickel (500 mg) were added to 5-(4-fluorobenzyl)thiophene-2-carbaldehyde described in Preparation Example 37 (460 mg, 2.09 mmol), and the mixture was stirred for 14 hours under hydrogen atmosphere at room temperature. The catalyst was removed by filtering through Celite pad, then, purification by silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=4:1) was carried out, and the title compound (70 mg, 0.316 mol, 15.1%) was obtained as an oil.
Reaction SMILES: CO[CH:3]([O:7][CH3:8])N(C)C.O[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=C[C:11]=1[C:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18]>C1C=CC=CC=1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:17](=[O:18])[C:11]3[CH:10]=[CH:15][C:14]([OH:16])=[CH:13][C:3]=3[O:7][CH:8]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Yield: 85 %

Procedure:
Another known approach used for the synthesis of formononetin is the general method involving the addition of one carbon to 2-hydroxydeoxybenzoins and their cyclization to form isoflavones. The method introduced by Andrew Pelter (Pelter, Andrew, et al., Synthesis, 5:326 (1976)) involves the reaction of 2-hydroxydeoxybenzoins with N,N-dimethylformamide dimethylacetal (dimethoxydimethyl aminomethane) (two equivalents) in dry benzene. Refluxing a mixture of 2,4-dihydroxy-4'-methoxydeoxybenzoin with N,N-dimethylformamide dimethyl acetal in dry benzene for 4 hours gave formononetin in 85% yield. However, the use of the expensive reagent, N,N-dimethylformamide dimethyl acetal and dry benzene as solvent makes this an unattractive method for the commercial production of formononetin.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:14](Cl)=[O:15])=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:12]([O:13][C:14]([N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:15])[C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: C1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CC1
Reaction time: 14 h
Yield: 97.5 %

Procedure:
Commercially-obtained pyrrolidine 5 (6.7 g, 96 mmol) was dissolved in DCM (100 ml) at 0° C. Cbz-Cl (13.6 g, 80 mmol) was added slowly, and the reaction was allowed to stir for 14 hours. The solvent was removed under vacuum, and the residue was taken up in ethyl acetate. This ethyl acetate was washed with 0.5 N HCl two times, saturated sodium bicarbonate solution once, brine and dried over MgSO4. The solvent was removed under vacuum to yield the title product 6 (15.9 g (99%), 78 mmol). 1H NMR (DMSO-d6): δ 7.24 (m, 5H), 5.61 (m, 2H), 5.35 (s, 2H), 3.62 (d, J =4.3 Hz, 2H). MS (ESI-POS): [M+H]+=204.
Reaction SMILES: [C:1]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:44]=[C:43]([CH2:45][CH2:46][CH3:47])[C:27]([O:28][CH:29]([C:34]2[CH:39]=[CH:38][C:37]3[O:40][CH2:41][O:42][C:36]=3[CH:35]=2)[C:30]([O:32][CH3:33])=[O:31])=[C:26]([Cl:48])[CH:25]=1>CN(C=O)C>[C:30]([CH:29]([C:34]1[CH:39]=[CH:38][C:37]2[O:40][CH2:41][O:42][C:36]=2[CH:35]=1)[O:28][C:27]1[C:43]([CH2:45][CH2:46][CH3:47])=[CH:44][C:24]([CH2:23][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]2=[O:15])=[CH:25][C:26]=1[Cl:48])([O:32][CH3:33])=[O:31]
Reactant: CCCc1cc(CBr)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 0.069 g (0.33 mmol) of 1-carboethoxy-2-benzimidazolinone dissolved in 0.6 mL DMF was added 0.217 g (0.66 mmol) of powdered cesium carbonate and the resulting suspension was stirred under a nitrogen atmosphere at room temperature for 30 minutes. A solution of the product of step E in 0.5 mL DMF was then added and the reaction mixture was stirred for an additional 15 hours. The mixture was then partitioned between EtOAc and water and extracted. The organic layer was separated, dried (MgSO4), filtered and evaporated, and the residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.088 g (45%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH:11]([CH3:30])[C:12]([OH:29])([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)[C:13]([F:16])([F:15])[F:14].[CH3:31][O:32][C:33](=[O:41])[CH2:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:31][O:32][C:33](=[O:41])[CH2:34][CH:35]1[CH2:36][CH2:37][N:38]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:11]([CH3:30])[C:12]([OH:29])([C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=4[CH:28]=3)[C:13]([F:15])([F:14])[F:16])[CH:4]=2)[CH2:39][CH2:40]1
Reactant: CC(c1cc(C(=O)O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)CC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCN(C(=O)c2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
To a solution of 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-benzoic acid (74 mg) in tetrahydrofuran (0.63 ml) were added 4-piperidine acetic acid methyl ester (32 mg), N-ethyldiisopropylamine (65 mg) and benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, 113 mg). The mixture was stirred at room temperature for 18 h and then concentrated to dryness. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (82 mg) as colorless foam. MS (m/e)=583.2 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:20]3[CH:19]=[C:18]([CH3:27])[CH:23]=[CH:22][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Cc1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and m-tolylboronic acid to give (1H-pyrazol-3-yl)-(1-m-tolyl-isoquinolin-3-yl)-amine. LC-MS m/e 301(MH+).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.CN1CCN(C(=O)C=C[C:36]2[C:44]3[N:43]([C:45]4C=CC=C[CH:46]=4)C=N[C:40]=3C=C(C(F)(F)F)C=2)CC1>>[CH2:45]([N:43]([CH:44]([CH3:36])[CH3:40])[C:3](=[O:2])[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:23])([F:22])[F:24])[CH:7]=1)[CH3:46]
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: CCN(C(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)C(C)C
Yield: 6 %

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford the title compound as a white solid (7.2 mg, 6%), m/z 402.0 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]([CH3:11])([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:5].[OH-].[K+]>O.C(O)C>[CH3:11][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:5])[C:3]([OH:12])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccsc1

Procedure:
The 2 -methyl-2-(3-thienyl)propionic acid methyl ester obtained in the foregoing Example 7 was added to a water:ethanol (1:4) solution (200 ml) of potassium hydroxide (18.5 g). Then the mixture was refluxed under heating for one hour and concentrated under reduced pressure, followed by a further addition of water thereto. Then the mixture was washed with dichloromethane (100 ml). The aqueous layer was acidified with diluted hydrochloric acid and the liberated carboxylic acid was extracted with dichloromethane (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed by a water pump. The residue was recrystallized from hexane to obtain 2-methyl-2-(3-thienyl)propionic acid with mp. 78°-80.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:38]([NH:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:39])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)NCc3ccccc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][C:17]([C:27](=[O:29])[NH2:28])([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:37](N)=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][C:17]4([N:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:37][NH:28][C:27]4=[O:29])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: NC=O
Reactant: NC(=O)C1(Nc2ccccc2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC1)CC2
Temperature: 170 °C

Procedure:
To 16 g of 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-carbamoyl-4-anilinopiperidine is added 30 g of formamide, the temperature is raised slowly, and the mixture is heated at 170° C for 14 hours. After cooling water is added to the reaction mixture, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The precipitated crystals are collected by filtration and recrystallized from chloroform to give 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 249°-253° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:7]=1C=O)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:7]=1[OH:27])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCOc1ccc(C=O)c(OCOCC)c1
Solvent: ClCCl
Product: CCOCOc1ccc(O)c(OCOCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 282.4 %

Procedure:
A solution of 2a (3.78 g, 12.0 mmol) in anhydrous CH2Cl2 (4.0 mL) was slowly added to mCPBA (70%) (3.26 g, 13.2 mmol) in anhydrous CH2Cl2 (16.3 mL) at 0° C. The resulting solution was warmed to room temperature, then refluxed for 12 hours. After cooling to room temperature, the resulting solution was washed with saturated aqueous NaHCO3 solution (3×20 mL) and 10% aqueous Na2S2O3 (30 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was re-dissolved in MeOH (5 mL) and stirred with excess 10% aqueous NaOH for 3 hours at room temperature. The pH was adjusted to 2 with 6 M HCl and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated to give 3a as an orange oil (8.21 g, 94%): 1H NMR (CDCl3, 500 MHz) 6.89-6.85 (m, 2H), 6.67 (dd, J=8.8, 2.7 Hz, 1H), 5.81 (d, J=6.6 Hz, 1H), 5.23 (s, 2H), 5.15 (s, 2H), 3.80-3.73 (m, 4H), 1.29-1.24 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 151.0, 145.0, 141.5, 115.2, 110.6, 106.0, 94.9, 94.2, 64.8, 64.1, 15.1, 15.1; IR (film) νmax 3362, 2887, 1460, 1286, 1162, 735 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C12H18O5, 265.1052. found, 265.1045.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:27]=1)[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]([F:30])([F:31])[F:32])[CH:27]=1)/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cc(Br)cc(OC(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Br)cc(OC(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of compound 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 3-bromo-5-(trifluoromethoxy)benzaldehyde 29 (115.4 mg, 0.607 mmol). PTSA (230.9 mg, 1.214 mmol) was added to the reaction mixture, then stirred at 120° C. for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound (E)-2-(3-bromo-5-(trifluoromethoxy)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 30, which was purified through flash chromatography by using 100-200 mesh silica gel. Compound 30 was eluted at 25% ethyl acetate in hexane to afford a yellow coloured solid. To 30 (45 mg, 0.107 mmol), dissolved in methanol 20 mL, was added Pd/C 20 mg and stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude des-brominated compound 31. The crude 31 was purified by flash chromatography using 100-200 mesh silica gel. Compound 31 was eluted as des-brominated compound at 25% ethyl acetate in hexane as half white coloured solid compound 6-methoxy-5-morpholino-2-(3-(trifluoromethoxy)benzyl)-2,3-dihydro-1H-inden-1-one 31. 1HNMR (400 MHz, CDCl3) δ ppm 7.43 (m, 4H), 7.18 (s, 1H), 6.81 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.43 (m, 1H), 3.17 (m, 4H), 3.06 (m, 1H), 2.97 (m, 1H), 2.69 (m, 2H); MS (ESI) m/z 422.1 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([F:13])([F:12])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.[OH2:25]>>[F:12][C:9]1([F:13])[O:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH:2]=[O:25])[C:11]=2[O:10]1
Reactant: O
Reactant: FC1(F)Oc2cccc(CBr)c2O1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1cccc2c1OC(F)(F)O2

Procedure:
117 g of crude 4-bromomethyl-2,2-difluoro-1,3-benzodioxole are added to 120 g of urotropin in 250 ml of water and the mixture is heated under reflux for 3 hours. 120 ml of hydrochloric acid in 150 ml of water are then added and the mixture is heated for a further 3 hours. The crude product is then driven over with steam, removed from the receiver and shaken with 100 g of sodium bisulphate in 250 ml of water. After extraction with methylene chloride, the aqueous phase is acidified with 2N sulphuric acid and the aldehyde is separated off and distilled. The yield is 53 g.