Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:18])[C:5]2=O.CCOCC>CCCCCC>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccc(F)cc21
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C1Cc2cc(F)ccc2N1Cc1ccccc1
Yield: 75.2 %

Procedure:
In a manner similar to the method of N-benzylisatin, 5-fluoroisatin (10.0 g, 60.5 mmol) yielded 5-fluoro-N-benzylisatin as an orange red powder (14.5 g, 93%). The crude product was used for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.33-7.21 (m, 5H), 6.95 (d, J=7.6 Hz, 1H), 6.84 (t, 1H), 6.60 (m, 1H), 4.89 (s, 2H); MS ESI 255.9 [M+H]+, calcd for [C15H10FNO2+H]+ 255.07. The title compound was prepared in a manner similar to the method of N-Benzyl-oxindole using 5-fluoro-N-benzylisatin (14.5 g, 56.8 mmol). Trituration using Et2O:hexane yielded the title compound as a pale yellow solid (10.3 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 5H), 7.00 (d, J=7.6 Hz, 1H), 6.87 (t, 1H), 6.63 (m, 1H), 4.91 (s, 2H), 3.63 (s, 2H); MS ESI 241.9 [M+H]+, calcd for [C15H10FNO2+H]+ 241.09.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].C([O-])(O)=O.[Na+]>CO>[OH:13][NH:12][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc(CO)cc1
Yield: 113.6 %

Procedure:
A mixture of 4-hydroxymethylbenzonitrile (5.0 g, 37.6 mmol), hydroxylamine hydrochloride (2.87 g, 41.3 mmol) and NaHCO3 (4.10 g, 48.8 mmol) in methanol (200 mL) is refluxed for 20 h, filtered and the solvent of the filtrate is evaporated to give N-hydroxy-4-hydroxymethyl-benzamidine (7.1 g) as a white solid; LC-MS: tR=0.22 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[Li+].[CH3:15][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C1Cc2ccccc2C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)Cc2ccccc2C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
Indane-2-carboxylic acid methyl ester (550 mg, 3.125 mmol) was dissolved in THF (20 mL). At −78° C. LiHMDS (1M solution in THF, 3.75 mL) was added into the reaction mixture. The solution was stirred for 15 min at −78° C., warmed to 0° C. for 15 min and then −78° C. for an additional 15 min. Methyl iodide (250 μL, 4.01 mmol) was then added into the reaction mixture followed by stirring at −78° C. for 15 min, room temperature for 30 min and then quenched with saturated ammonium chloride. The solution was then diluted with diethyl ether and washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and concentrated. The crude mixture was then purified by silica gel flash column chromatography to afford 2-methyl-indan-2-carboxylic acid methyl ester (52 mg, 9%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.16 (m, 4H), 3.72 (t, 3H), 3.48 (d, 2H), 2.81 (d, 2H), 1.36 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[O:6][C:7]1[CH:8]=[C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=1)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N+:26]([C:25]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:15])=[O:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:1][NH:32][CH2:29][CH2:30][CH3:31])([O-:28])=[O:27]
Reactant: CCCN
Reactant: O=Cc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under N2, a mixture of N-[3-(3-formyl-4-nitrophenoxy)-phenyl]-benzenesulfonamide (0.0060 mol) and propylamine (0.0085 mol) in DCE (50 mL) was stirred at room temperature, then NaBH(OAc)3 (0.0080 mol) was added and the reaction mixture was stirred overnight at room temperature. A saturated NaHCO3 solution (50 mL) was added and the layers were separated. The organic layer was dried, filtered off and the solvent was evaporated. The residue was purified over silica gel filter (eluent: 98:2 CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].C1COCC1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC.[BH4-].[Na+]>CO>[CH2:17]([NH:6][C@@H:5]([C@@H:7]([CH3:8])[CH2:9][CH3:10])[C:4]([O:3][CH3:2])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](C)[C@H](NCc1ccccc1)C(=O)OC
Yield: 68 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-isoleucine methyl ester hydrochloride (1 gm, 5.5 mmol), THF (20 mL) MgSO4 (1.12 gm, 9.35 mmol), benzaldehyde (1.12 mL, 11.0 mmol), Et3N (767 μL, 5.5 mmol), sodium borohydride (416 mg, 11.0 mmol), and methanol (30 mL) to give 11a (880 mg, 68%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.88-0.943 (6H, m), 1.16-1.3 (1H, m), 1.55-1.64 (1H, m), 1.68-1.88 (2H, m), 3.13 (1H, d, J=6.10 Hz), 3.62 (1H, d, J=12.93 Hz), 3.74 (3H, s), 3.84 (1H, d, J=12.93 Hz), 7.24-7.29 (1H, m), 7.31-7.39 (4H, m). ESI-MS: 258.0 (M+23).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([Cl:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-].[Na+]>COC(O)C>[ClH:18].[CH2:11]([N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[NH:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Nc1nc2ccccc2s1
Agent: COC(C)O
Agent: [I-]
Agent: [Na+]
Product: Cl
Product: N=c1sc2ccccc2n1Cc1ccccc1
Yield: 39 %

Procedure:
A mixture of 2-aminobenzothiazole (2.116 g, 13.7 mmol), benzyl chloride (2.1 mL, 18.2 mmol) and sodium iodide (200 mg) were refluxed for 8 hours in methoxyethanol (25 mL). Crystallization occurred upon cooling. The crystals were filtered off and thoroughly washed with ether to give yellow crystals in 39% yield: mp 275-278° C.; 1H-NMR (DMSO-d6) 5.65 (s, 2H), 7.28, (d, 2H), 7.36 (m, 4H), 7.50 (t, 1H), 7.55 (d, 1H) 8.02 (s, 1H); HR-MS (EI) m/z 240.0719 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]=1[C:8]#[N:9].[C:18]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:23][CH2:22]1)(=O)[CH3:19]>>[F:13][C:12]([F:14])([F:15])[CH2:11][O:10][C:6]1[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=[C:2]([N:1]=[C:18]([N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[O:29])[CH2:23][CH2:22]2)[CH3:19])[C:7]=1[C:8]#[N:9]
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Reactant: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 95 %

Procedure:
The subtitle compound was prepared from 3-amino-4-cyano-5-(2,2,2-trifluoroethoxy)-anisole and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following a similar procedure to that described in Example 10(g) allowing the reaction to stir for 60 hours at room temperature. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 to 95:5, v/v). The product was dissolved in a minimum volume of dichloromethane and an excess of ethereal hydrogen chloride added. The resulting precipitate was filtered off and partitioned between saturated aqueous sodium hydroxide solution (100 ml ) and dichloromethane (200 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound (1.83 g, 95%). Rf 0.58 (dichloromethane:methanol:0.880 aqueous ammonia 92:7:1, v/v). MS m/z 484 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13].Cl.[NH2:18][OH:19].C(N(CC)CC)C>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:18][OH:19])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13]
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)cc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=NO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a suspension of 4-formyl-2-trifluoromethyl-benzoic acid methyl ester (Example I10) (5.98 g) and hydroxylamine hydrochloride (1.79 g) in methanol (80 ml) was added triethylamine (5.4 ml). The reaction mixture was stirred at ambient temperature for 1 hour. More hydroxylamine hydrochloride (5.4 g) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed and the residue diluted with ethyl acetate (200 ml) and water (150 ml). The phases were separated and the organic layer was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was dissolved in a mixture of dichloromethane and heptane and crystallized by slowly evaporating the dichloromethane to give 4-(hydroxyimino-methyl)-2-trifluoromethyl-benzoic acid methyl ester (3.90 g) as a white crystalline powder. 1H-NMR (CDCl3, 400 MHz): 8.18 (s, 1H), 7.97-7.64 (m, 4H), 3.95 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2CCCCC.BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[NH:6]2
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Agent: O=C1Nc2cccc(Br)c2C1(O)c1cc2c(cc1O)OCO2
Product: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 4-bromo-3hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (95%) as a cream solid: MS (ES+) m/z 348.5 (M+1), 346.3 (M+1).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=O)[OH:3].S(=O)(=O)(O)O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:3][CH:2]1[CH2:4][C:5](=[O:7])[O:8][C:1]1=[O:9])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=S(=O)(O)O
Product: CC(=O)OC1CC(=O)OC1=O
Temperature: 140 °C
Yield: 60 %

Procedure:
250 g (1.86 mole) of malic acid are dissolved in 500 ml of acetic anhydride and a further 1 ml of concentrated sulphuric acid is added thereto. The mixture is then heated at 140° C. for four hours. Finally, it is concentrated in vacuo and the residue is fractionally distilled. 2-acetoxysuccinic acid anhydride is obtained in a 60% yield. Boiling point at 0.01 torr: 108° to 113° C.; melting point: 56° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([NH2:26])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C[Si]([N:31]=[C:32]=[O:33])(C)C>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([NH:26][C:32]([NH2:31])=[O:33])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(N)cc2c1CCCNC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(NC(N)=O)cc2c1CCCNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
5-Amino-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (40 mg, 0.11 mmol, 1.0 equiv) was dissolved in 10 mL of methylene chloride and 1 mL of triethylamine. Trimethylsilyl isocyanate was added and the solution was stirred overnight. In the morning the reaction was washed with 10 mL of water and the organic layer was concentrated. The crude residue was purified by flash chromatography on silica (10 g of SiO2) using 0% ethyl acetate in methylene chloride to 100% ethyl acetate graded over 25 min at a flow rate of 15 mL/min-then 100% ethylacetate for another 15 min. The fractions with pure product (TLC) were combined and concentrated to provide 5-ureido-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester as a white solid (41 mg). This material was used without further purification.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:23])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][C:7]3=[CH2:22].[OH-:24].[Na+]>CO>[CH2:1]1[C@@H:3]2[C:4](=[O:23])[CH:5]3[O:24][C:6]43[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][C:7]4=[CH2:22]
Reactant: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@]2(C)C1=CC(=O)[C@H]1CC12
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C3C[C@@H]3C(=O)C3OC132
Temperature: 0 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
1,2β-methylen-6-methylenandrost-4-ene-3,17-dione (3.104 g, 10 mmol) is dissolved in 120 ml of methanol and cooled to 0° C. Thereupon ice cold 36% H2O2 (10 ml) and 2% NaOH (5 ml) is added gradually, the reaction mixture kept for about 20 hours at 5° C. and then poured into 900 ml of ice water. The raw product is filtered off, washed with water, dried and then chromatographed on silica gel using CHCl3 as eluant. Thus pure title compound is obtained in 60% yield (1.959 g).
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[N:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:25][N:24]=3)=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:39][C:40](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:41]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[N:13]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:34][CH2:33][N:32]([CH:40]([CH3:41])[CH3:39])[CH2:31]4)=[CH:25][N:24]=3)=[CH:19][CH:20]=2)[CH3:14])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CN(C(=O)Nc1cc(C(C)(C)C)on1)c1ccc(NC(=O)c2ccc(OC3CCNC3)cn2)cc1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc(C(=O)Nc3ccc(N(C)C(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 68 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)-1-methylureido)phenyl)-5-(1-isopropylpyrrolidin-3-yloxy)picolinamide (45 mg, 68%) was prepared using a procedure analogous to that described in Example 20, substituting N-(4-(3-(5-tert-butylisoxazol-3-yl)-1-methylureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride from the Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 521 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].I[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9](=[O:10])[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CI
Reactant: O=C(Cc1ccc(Cl)cc1)N1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CC(C(=O)N1CCCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
16.8 g (0.075 mol) of 2-(4-chloro-phenyl)-1-pyrrolidin-1-yl-ethanone are dissolved in 175 ml dimethylsulphoxide and after the addition of 8.9 g (0.08 mol) of potassium tert.butoxide stirred for 15 minutes at ambient temperature. After the addition of 18.1 ml (0.085 mol) of ethyl iodoacetate the reaction mixture is stirred for 45 hours at ambient temperature. The solution is poured onto ice water and extracted with ethyl acetate. The combined organic extracts are washed with sodium chloride solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel, initially eluting with petroleum ether and later with petroleum ether/ethyl acetate (8:2 and 1:1). The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH:19]=O)[O:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])[CH3:2].[CH2:25]([NH:27][CH3:28])[CH3:26]>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[N:15]=[C:14]([C:16]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:18]([CH2:19][N:27]([CH2:25][CH3:26])[CH3:28])[CH:17]=3)[O:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(C=O)c3)n2)cc(C)c1O
Reactant: CCNC
Product: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Yield: 88.6 %

Procedure:
The title compound (2.14 g) was prepared starting from 3-[3-(3-ethyl-4-hydroxy-5-methyl-phenyl)-[1,2,4]oxadiazol-5-yl]-5-methyl-benzaldehyde (2.13 g, 6.61 mmol) and N-ethyl-methylamine (1.56 g, 26.4 mmol) according to Method B. LC-MS: tR=0.61 min; [M+1]+=366.22; 1H NMR δ 1.06 (t, J=7.0 Hz, 3H), 1.19 (t, J=7.3 Hz, 3H), 2.14 (s, 3H), 2.28 (s, 3H), 2.41-2.48 (m, 5H), 2.65-2.72 (m, 2H), 3.54 (s, 2H), 7.46 (s, 1H), 7.67-7.71 (m, 2H), 7.89 (s, 1H), 7.93 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:14])[CH:9]([NH2:13])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[F:16][CH2:17][CH2:18][O:19][C:20]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:21]=1[C:22](=N)OCC.ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:14][C:22]([C:21]3[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:20]=3[O:19][CH2:18][CH2:17][F:16])=[N:13][CH:9]2[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OC)cc1OCCF
Reactant: CCCC(N)C(N)c1ccc(Cl)cc1
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCCC1N=C(c2ccc(OC)cc2OCCF)NC1c1ccc(Cl)cc1

Procedure:
5-(4-Chloro-phenyl)-2-[2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4-propyl-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-pentane-1,2-diamine and ethyl 2-(2-fluoro-ethoxy)-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 391.1587, calculated for C21H25N2O2FCl [(M+H)+]391.1583.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7])=[O:4].[I-].[OH:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([S+:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]3[CH:33]=[CH:34][CH:35]=[CH:36][C:25]2=3)=[CH:19][C:18]=1[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br-:1].[CH3:37][C:18]1[CH:19]=[C:20]([S+:24]2[C:25]3[CH:36]=[CH:35][CH:34]=[CH:33][C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=3)[CH:21]=[C:22]([CH3:23])[C:17]=1[O:16][CH2:2][C:3](=[O:4])[O:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)(OC(=O)CBr)c1ccccc1
Reactant: Cc1cc(-[s+]2c3ccccc3c3ccccc32)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-[s+]2c3ccccc3c3ccccc32)cc(C)c1OCC(=O)OC(C)(C)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
2-phenylpropan-2-yl 2-bromoacetate (1.96 g, 7.63 mmol) was added to a solution of 5-(4-hydroxy-3,5-dimethylphenyl)-5H-dibenzo[b,d]thiophenium iodide (3.00 g, 6.94 mmol) and cesium carbonate (2.94 g, 9.02 mmol) in DMF (40 mL) at 0° C., warmed to r.t. and stirred overnight. The reaction mixture was diluted with water (200 mL) and washed with DCM (3×200 mL). The organic layers were washed with water (3×300 mL), concentrate and poured onto MTBE. The precipitate was filtered and dried to afford the title compound (3.80 g, 97%) as a white solid. 1H NMR (300 MHz, ((CD3)2SO) δ: 8.52 (d, J=7.5 Hz, 2H), 8.33 (d, J=7.5 Hz, 2H), 7.96 (t, J=7.2 Hz, 2H), 7.5 (d, J=7.9 Hz, 2H), 7.20-7.39 (m, 5H), 4.61 (s, 2H), 2.19 (s, 6H), 1.71 (s, 6H).
Reaction SMILES: C[Si](C)(C)Cl.[CH:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Br[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18].Cl>C(OCC)(=O)C.[Zn]>[OH:14][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(C)Br
Reactant: CCCCCCCC=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CCCCCCCC(O)C(C)C(=O)OC
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 5.5 g of zinc powder (84 mmol) in 34 ml of ethyl acetate. After 1.6 ml of trimethylchlorosilane (12.5 mmol) had been added, the mixture was heated at 65° C. Following cooling to 60° C., 7.2 g of octanal (56 mmol) were added, and over the course of 4 min, 11.2 g of methyl 2-bromopropionate (67 mmol) were added dropwise, the temperature being maintained at 65° C. by external cooling. The mixture was then stirred at 60° C. for 5 min and, after cooling to 0° C., acidified with 40 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was removed by filtration and the organic phase separated. The organic phase was then stirred at 0° C. with 40 ml of 0.5 N hydrochloric acid and finally washed with 20 ml of saturated sodium hydrogen carbonate solution. Following phase separation and drying over sodium sulfate, the solvent was removed by distillation under reduced pressure. Methyl 3-hydroxy-2-methyldecanoate was obtained in a yield of 10.2 g (85% of theory) with a boiling point of 68° C. (0.04 mbar). The diastereomer ratio was 2:1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]1[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:18])=[CH:16][N:6]1[C:5]2=[O:30].[I:31][CH3:32]>>[I-:31].[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]1[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N+:26]([CH3:32])[CH:27]=[CH:28][CH:29]=3)=[O:18])=[CH:16][N:6]1[C:5]2=[O:30]
Reactant: CI
Reactant: Cc1cc2nc3ccc(C(=O)NCCCCc4cccnc4)cn3c(=O)c2cc1C
Product: Cc1cc2nc3ccc(C(=O)NCCCCc4ccc[n+](C)c4)cn3c(=O)c2cc1C
Product: [I-]
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 2.2 g of 2,3-dimethyl-11-oxo-N-[4-(3-pyridinyl)butyl]-11H-pyrido[2,1-b]quinazoline-8-carboxamide and 10 ml of iodomethane was stirred at room temperature, under argon form 3 days. An orange gum was obtained after removal of the excess iodomethane which was crystallized from methanol to yield 2.3 g (77.2%) of orange crystals, m.p. 129° dec.