Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[N:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1)([O-:14])=[O:13]
Reactant: NC1CCOc2ccccc21
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=NC2CCOc3ccccc32)c1

Procedure:
An 80 g, (0.54 mole) portion of 4-chromanamine, and 650 ml of ethanol were placed in a 2-l, 3-necked flask, equipped with a stirrer and reflux condenser fitted with a drying tube. The slurry was treated with 85 g (0.56 mole) portion of m-nitrobenzaldehyde using rapid mechanical stirring. The reaction mixture was refluxed for 5 hrs., cooled 1 hr. and filtered. The yellow crystalline solid was washed with 100 ml of ethanol, ether, and dried, m.p. 117°-118°. Yield: 115 g (76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:35]1[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4ccc(F)cc4nc3OC)CC2)cc(OC)c1OC
Yield: 83 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 83%).
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li][CH2:13]CCC.IC>C1COCC1>[CH3:13][C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: CCCCOS(=O)(=O)C1CC1
Solvent: CI
Solvent: C1CCOC1
Product: CCCCOS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a solution of butyl cyclopropanesulfonate (1.5 g, 8.4 mmol) in THF (8 mL) at about −78° C., n-BuLi (1.6 M in hexanes, 5.26 mL, 8.42 mmol) and iodomethane (0.684 mL, 10.9 mmol) were added simultaneously and the resulting mixture was stirred at about −78° C. for about 2 h and then at ambient temperature for about 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (7 mL) and the layers were separated. The aqueous layer was back extracted with EtOAc (15 mL) and the combined organic extracts were dried over anhydrous MgSO4 and concd under reduced pressure. The residue was subjected to silica gel column chromatography (5 to 25% EtOAc in heptane over 30 min) to yield butyl 1-methylcyclopropane-1-sulfonate (0.8 g, 49%) as a colorless oil. 1H NMR (DMSO-d6) δ 4.17 (t, 2H), 1.62 (m, 2H), 1.43 (s, 3H), 1.35 (m, 2H), 1.22 (m, 2H), 0.94 (m, 2H), 0.88 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]([CH2:25][C:26]3[CH:38]=[CH:37][C:29]4[NH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:28]=4[CH:27]=3)[C:22]([OH:24])=O)=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[N:81]1([CH:87]2[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]2)[CH2:86][CH2:85][CH2:84][CH2:83][CH2:82]1>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]1[NH:30][C:29]2[CH:37]=[CH:38][C:26]([CH2:25][C@@H:21]([NH:20][C:18]([N:15]3[CH2:16][CH2:17][CH:12]([N:11]4[CH2:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[NH:3][C:2]4=[O:1])[CH2:13][CH2:14]3)=[O:19])[C:22](=[O:24])[N:90]3[CH2:91][CH2:92][CH:87]([N:81]4[CH2:86][CH2:85][CH2:84][CH2:83][CH2:82]4)[CH2:88][CH2:89]3)=[CH:27][C:28]=2[N:32]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(O)[C@@H](Cc1ccc2[nH]c(C(F)(F)F)nc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc2[nH]c(C(F)(F)F)nc2c1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.3 %

Procedure:
To a stirred solution of the acid (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propanoic acid (33 mg, 0.06 mmol) and diisopropylethylamine (33 mg, 0.25 mmol) in methylene chloride (2 mL) was added a solution of PyBOP® (33 mg, 0.06 mmol) and 4-piperidinopiperidine (12 mg, 0.07 mmol) in methylene chloride (1 mL). The reaction mixture was stirred at room temperature for 16 h and was subjected to preparative thin layer chromatography for purification (1:10 2M ammonia in methanol/methylene chloride) to give the title compound (4.6 mg, 12% yield). 1H-NMR (CD3OD, 500 MHz) δ 7.73-7.71 (m, 1H), 7.62 (bs, 1H), 7.39-7.36 (m, 1H), 7.19-7.11 (m, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 5.06-5.02 (m, 1H), 4.67-4.58 (m, 1H), 4.49-4.40 (m, 1H), 4.38 (s, 1H), 4.33 (bs, 1H), 4.25-4.16 (m, 2H), 4.10-4.03 (m, 1H), 3.22-3.14 (m, 3H), 3.04-2.87 (m, 4H), 2.79-2.71 (m, 1H), 2.58-2.48 (m, 1H), 2.44-2.33 (m, 1H), 2.31-2.22 (m, 1H), 2.04-1.92 (m, 1H), 1.86-1.43 (m, 11H), 1.33-1.29 (m, 1H), 0.94-0.84 (m, 1H), −0.04-0.12 (m, 1H). LC/MS: tR=1.97 min, 681 (MH)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1cccc(-c2cccnc2)c1F
Product: Fc1c(-c2cccnc2)cccc1-c1cnc2nc(C(F)(F)F)ccn12

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-fluoro-3-(pyridin-3-yl)benzeneboronic acid as described in Example 1 to give 3-[2-fluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as an off-white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 7.62 (2H, dd, J 7 and 7), 7.85-7.96 (3H, m), 8.36 (1H, s), 8.58 (1H, d, J 8), 8.86 (1H, dd, J 5 and 1), 9.14 (1H, s), 9.33 (1H, dd, J 7 and 3); m/z (ES+) 359 (M++H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:31])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)N2CCCC2)cc1
Yield: 52.8 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with pyrrolidine (available from Aldrich Chemical Company, Inc.; 44 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(pyrrolidine-1-carbonyl)-biphenyl-2-carboxylic acid (58 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 8.46 (s, 1H), 8.35 (dd, J=11.7, 1.9 Hz, 2H), 8.23 (dd, J=8.2, 1.9 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (dd, J=8.3, 2.3 Hz, 3H), 7.46 (d, J=8.0 Hz, 2H), 3.40-3.54 (m, 4H), 1.73-2.01 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=2)/[CH:10]=[C:11]2\[CH2:12][CH2:13][C:14]3[NH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]\2=3)[CH:2]=1.[OH-].[Li+].CO>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=2)[CH2:10][CH:11]2[C:18]3[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[NH:15][C:14]=3[CH2:13][CH2:12]2)[CH:2]=1
Reactant: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(-c2cccnc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2cccnc2)c1

Procedure:
The title compound was synthesized from (E)-methyl 4-(3-(pyridin-3-yl)benzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.051 g, 0.15 mmol) and lithium hydroxide (0.067 g, 1.6 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound. 15.0 mg, 31% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.08-2.21 (m, 1H), 2.52-2.63 (m, 3H), 2.79-2.94 (m, 2H), 3.33-3.36 (m, 1H), 6.34 (s, 1H), 7.28 (d, J=7.57 Hz, 1H), 7.39-7.44 (m, 2H), 7.46-7.51 (m, 2H), 8.04 (dt, J=8.02, 1.90 Hz, 1H), 8.49 (dd, J=4.88, 1.46 Hz, 1H), 8.76 (d, J=2.00 Hz, 1H); LCMS-MS (ESI−) 317.2 (M−H); HPLC (UV=96.4%), (ELSD=100%).
Reaction SMILES: C(O[CH:5]1[C:9]2[CH:10]=[C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=2[O:7][C:6]1=[O:22])(=O)C.[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1>O>[C:18]([C:11]1[CH:12]=[C:13]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:8]2[O:7][C:6](=[O:22])[CH:5]([C:29]3[CH:28]=[C:27]([CH3:30])[CH:26]=[CH:25][C:24]=3[CH3:23])[C:9]=2[CH:10]=1)([CH3:20])([CH3:19])[CH3:21]
Reactant: Cc1ccc(C)cc1
Reactant: CC(=O)OC1C(=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Solvent: O
Product: Cc1ccc(C)c(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)c1
Yield: 59.9 %

Procedure:
To a solution of 15.3 g (50.0 mmol) of 3-acetoxy-5,7-di-tert-butyl-3H-benzofuran-2-one (compound (206), Table 2, Example 2a) in 25 ml (0.20 mol) of p-xylene is added 1.0 g of Fulcat 22B and the mixture is refluxed for 17 hours on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess p-xylene is removed by distillation on a vacuum rotaray evaporator. Crystallisation of the residue from 20 ml of methanol yields 10.5 g (60%) of 5,7-di-tert-butyl-3-(2,5-dimethylphenyl)-3H-benzofuran-2-one, m.p. 93-97° C. (compound (101), Table 1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: COc1ccccc1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1ccccc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Methoxy-benzoic acid.
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:38][CH2:37][C:36]1=[O:40]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[CH:21][C:22]([NH:23][C:36](=[O:40])[CH2:37][CH3:38])=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Reactant: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 77 %

Procedure:
N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide was prepared from 4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and pyridine instead of N,N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (77% yield). HPLC: 98%, RT=4.157 min. MS: m/z=411 [M+H]+, RT=3.39 min.
Reaction SMILES: O1CCOCC1.[OH-].[Na+].C([O:17][CH2:18][C@@H:19]1[O:24][C@@H:23]([O:25][CH:26]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])[CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH2:22][CH2:21][CH2:20]1)(=O)C1C=CC=CC=1>O>[OH:17][CH2:18][C@@H:19]1[O:24][C@@H:23]([O:25][CH:26]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])[CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1
Yield: 74.7 %

Procedure:
90 ml of dioxan and 20 ml of a 25% w/v aqueous solution of sodium hydroxide were added to 9.15 g of 1-[trans-β-(6-benzoyloxymethyltetrahydropyran-2-yloxy)-2,4-dichlorophenethyl]imidazole, and the mixture was refluxed for 6 hours. At the end of this time, the reaction mixture was cooled, diluted with water and extracted with diethyl ether. The ethereal extract was washed with aqueous sodium chloride and dried over anhydrous sodium sulphate, after which the solvent was evaporated off. The residue was purified by column chromatography through silica gel eluted with a 10:20:3 by volume mixture of benzene, ethyl acetate and ethanol, to give 5.34 g of the title compound as a liquid.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(C)C[C@H](N)C(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CC(C)C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 4.40 of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 60-2 (crude form) as starting material, respectively 2.09 g (Isomer A: colorless powder) and 3.26 g (Isomer B: colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10](=S(C)(C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[CH:10]([Br:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)=S(C)(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 20 %

Procedure:
To a stirred solution of 2.73 grams (0.01 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-(dimethyloxosulfuranylidene)-3-oxopropanoate prepared in Example XLVII (Compound 205) in 35 milliliters of chloroform was added a solution of 1.37 grams (0.01 mole) of bromine in 35 milliliters of chloroform, dropwise, at ambient temperature. The mixture became dark orange and showed a slight exothermic effect during the feed period. Stirring was continued for 20 minutes, at which time the solution was a clear light yellow in color. It was then evaporated free of solvent and stored at 5° C. for a period of about 64 hours causing the residue to crystallize. Two recrystallizations from hexane-ethyl acetate (10:1) gave 0.58 gram (0.002 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-bromo-3-oxopropanoate having a melting point of 117° C.-119° C.
Reaction SMILES: CON(C)[C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1.[CH3:32][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH3:29][N:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([O:8][CH2:7][CH2:6][CH2:5][C:4](=[O:30])[CH3:32])[CH2:14][CH2:13]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CON(C)C(=O)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 260 mg (0.56 mmol) trans-N-Methoxy-N-methyl-4-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyramide in 10 ml THF were added 0.56 ml 3M (1.67 mmol, 3 eq) methylmagnesiumbromide in THF at −78° C. The solution was slowly warmed to RT over night, a saturated aqueous solution of NH4Cl was added and the mixture stirred for 30 min. The phases were separated and the inorganic phase was extracted with EtOAc. The combined organic ones were dried over Na2SO4 and evaporated. Column chromatography on silica gel with EtOAc/hexane 1:1 yielded 143 mg (61%) trans-N-Methyl-N-[4-(4-oxo-pentyloxy)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide as white solid, MS: 422 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCC1C=C[C:30]([S:33](C)(=[O:35])=[O:34])=CC=1>>[CH3:20][O:19][C:18]1[C:17]2[N:16]=[C:15]([NH2:21])[N:14]3[CH2:22][CH2:23][N:24]=[C:13]3[C:12]=2[CH:11]=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:33]([CH3:30])(=[O:35])=[O:34])=[CH:6][CH:7]=1
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Product: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(N)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bistrifluoroacetate salt (Intermediate A) and 1-(chloromethyl)-4-(methylsulfonyl)benzene. High vacuum drying gave the title compound (970 mg, 56%): HPLC MS RT=1.59 min, MH+=401.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.21 (3H, s), 3.85 (3H, s), 4.16-4.19 (2H, m), 4.32-4.35 (2H, m), 5.47 (2H, s), 7.36 (1H, d), 7.74 (2H, d), 7.88 (1H, d), 7.97 (2H, d).
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=O>CC1CCCO1.O>[C:2]1([C:1]2[N:8]=[C:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(Cl)c1ccco1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: c1ccc(-c2noc(-c3ccco3)n2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
Benzamide oxime (2.00 g, 14.7 mmol) and a 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) were combined in 2-methyltetrahydrofuran (20 mL) and water (2 mL). The solution was warmed to 50° C. and 50% aqueous solution of sodium hydroxide (1.52 g, 19.1 mmol) and 2-furoyl chloride (2.00 g, 15.3 mmol) were added dropwise simultaneously over 10 min. The pot temperature rose to 74° C. The mixture was stirred at 60° C. for 48 hours and the solids dissolved. The mixture was cooled to room temperature and poured into water (25 mL). The 2-methyltetrahydrofuran was removed at reduced pressure and solids formed in the aqueous solution. The solids were collected by vacuum filtration. 3-phenyl-5-(2-furanyl)-1,2,4-oxadiazole (2.33 g, 9.5 mmol) was obtained as a white solid. (64% yield).
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]3[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][N:28]=[C:27]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[N:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:47](Cl)[C:48]#[CH:49]>CC(C)=O>[N:1]1([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]3[C:30]([N:31]([CH2:49][C:48]#[CH:47])[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][N:28]=[C:27]([N:36]([CH2:37][CH3:38])[CH2:39][CH3:40])[N:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC)c1ncc(NS(C)(=O)=O)c(N[C@@H](Cc2ccc(OC(=O)N3CCCC3)cc2)C(=O)OC(C)(C)C)n1
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN(c1cnc(N(CC)CC)nc1N[C@@H](Cc1ccc(OC(=O)N2CCCC2)cc1)C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Compound 11 (0.20 g, 0.35 mmol), K2CO3 (0.073 g, 0.53 mmol), and acetone (3 mL) were placed in a sealed tube and stirred at room temperature for one hour. Propargyl chloride (0.26 mL, 3.5 mmol) was added and the reaction was sealed and heated at reflux for 48 hours. The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate. The solution was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield crude product as an orange film. The residue was purified by flash chromatography (1:1 ethyl acetate/hexanes) to yield 0.11 g (51%) of compound 12 as a transparent film.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][O:42][C:43]1[CH:44]=[CH:45][C:46]([S:49](Cl)(=[O:51])=[O:50])=[N:47][CH:48]=1>O1CCCC1>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:49]([C:46]2[CH:45]=[CH:44][C:43]([O:42][CH3:41])=[CH:48][N:47]=2)(=[O:50])=[O:51])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(S(=O)(=O)Cl)nc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)nc1
Yield: 93 %

Procedure:
To a suspension of sodium hydride (60% in oil, 168 mg) in tetrahydrofuran (10 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (970 mg), 15-crown-5 (925 mg) and a solution of 5-methoxypyridine-2-sulfonyl chloride (984 mg) in tetrahydrofuran (15 mL) at room temperature, and the mixture was stirred for 30 min. The reaction mixture concentrated under reduced pressure to a half volume, diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=17:3→1:1) to give the title compound as a yellow oil (yield 1.38 g, 93%).