Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([NH:18][CH2:19][C:20]([OH:22])=O)[CH:10]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:53]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH:58]1[C:63]([NH2:65])=[O:64])(=[O:56])[CH:54]=[CH2:55]>CN(C=O)C>[C:53]([N:57]1[CH2:62][CH2:61][N:60]([C:20](=[O:22])[CH2:19][NH:18][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]([Cl:15])=[CH:13][C:12]=2[O:16][CH3:17])[CH2:59][CH:58]1[C:63]([NH2:65])=[O:64])(=[O:56])[CH:54]=[CH2:55]
Reactant: C=CC(=O)N1CCNCC1C(N)=O
Reactant: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(-c3cc(Cl)ccc3Cl)c(Cl)cc2OC)CC1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
2-((2′,5′,6-Trichloro-4-methoxy-[1,1′-biphenyl]-3-yl)amino)acetic acid (231 mg, 0.641 mmol) and Et3N (592 mg, 2.564 mmol) in DMF (3 mL) at 0° C., EDCI.HCl (184 mg, 0.961 mmol) and HOBt (134 mg, 0.961 mmol) were added and the resulting mixture was stirred at 0° C. for 30 min. To this mixture, the above 1-acryloylpiperazine-2-carboxamide hydrochloride (160 mg) was added and stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (10 mg, 2.97% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.60-7.38 (m, 3H), 6.70-6.99 (m, 1H), 6.86-6.78 (m, 1H), 6.54-6.49 (m, 1H), 6.16-6.10 (m, 1H), 5.76-5.69 (m, 1H), 5.32-5.31 (m, 1H), 4.93-4.84 (m, 1H), 4.93-4.84 (m, 1H), 4.70-4.62 (m, 1H), 4.35-4.32 (m, 1H), 4.04-3.96 (m, 2H), 3.89-3.63 (m, 1H), 2.90-2.86 (m, 1H). ESI-MS m/z: 525.2[M+H]+.
Reaction SMILES: O.[OH-].[Li+].[O:4]=[C:5]1[C:13]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30]C)=[O:29]>O1CCCC1.O>[O:4]=[C:5]1[C:13]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (1.48 g, 35.2 mmol) was added to a solution of methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate (6.00 g, 14.2 mmol) in a mixed solvent (tetrahyrofuran/water=2/1 v/v, 180 mL), and stirred at ambient temperature for 16 h. Most of tetrahydrofuran was removed under vacuum, and 150 mL water was added. The solution was extracted with 50 mL of mixed solvent (ethyl acetate/hexanes: 1/3 v/v). The water layer was acidified with 1 N HCl solution until pH 2. After filtration and air dry, 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid was obtained (5.60 g, 96%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ13.2 (br s, 1H), 7.95 (dd, J=7.7, 1.2 Hz, 1H), 7.51 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.37 (dd, J=7.5, 7.5 Hz, 1H), 7.24-7.14 (m, 2H), 7.12-6.96 (m, 2H), 6.81 (d, J=7.7 Hz, 1H), 6.58 (s, 1H), 6.40 (s, 1H), 5.39-5.18 (m, 2H), 4.86 (d, J=8.9 Hz, 1H), 4.74 (d, J=8.9 Hz, 1H), 4.47 (t, J=8.7 Hz, 2H), 3.95 (s, 3H), 2.95 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 168.7, 161.6, 161.2, 143.0, 137.6, 133.0, 132.6, 131.5, 129.8, 129.2, 127.7, 126.4, 124.2, 123.6, 120.9, 120.4, 119.7, 109.7, 92.9, 80.5, 72.6, 57.5, 42.5, 28.8; MS (ES+) m/z 414.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.II.[O:15]1CC[CH2:17][CH2:16]1>BrCCBr>[CH3:17][CH:16]([C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[OH:15]
Reactant: C1CCOC1
Reactant: Brc1ccc2c(c1)OCCCC2
Agent: II
Solvent: BrCCBr
Product: CC(O)c1ccc2c(c1)OCCCC2
Temperature: -10 °C
Reaction time: 2 h

Procedure:
7.3 g of 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine in 30 ml of absolute tetrahydrofuran were added under argon to 930 mg of Mg shavings and a granule of iodine. The reaction was initiated by the addition of a few drops of 1,2-dibromoethane and had finished after 2 hours. Thereafter, the reaction mixture was cooled to -10° C. and excess acetaldehyde was distilled into the reaction vessel. After 10 minutes, the mixture was hydrolyzed with saturated sodium bicarbonate (NaHCO3) solution, extracted with ether, washed with water, dried and evaporated to dryness. Chromatography on silica gel (petroleum ether/ethyl acetate 3:1) yielded 4.93 g of 2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-8-methanol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](Cl)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:26][NH2:27])=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)NN)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
20 g of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carbonyl chloride in 100 ml of ethanol are placed under nitrogen and the mixture is heated at reflux for 2 hours. It is allowed to return to a temperature of 20-25° C., then 50 g of hydrazine hydrate are added and the mixture is again heated at reflux for 3 and a half hours. The reaction medium is filtered while hot and then the ethanol is evaporated. The reaction medium is concentrated, then taken up in 150 ml of DCM and separated by settling. The aqueous phase is discarded, the organic phase is washed twice with 100 ml of water and then the DCM is evaporated. After drying under vacuum, 16.9 g of the expected compound are obtained.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[C:23]([CH3:29])=[N:24][C:25](Cl)=[CH:26][CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[SH:36][CH2:37][CH2:38][OH:39]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[C:23]([CH3:29])=[N:24][C:25]([S:36][CH2:37][CH2:38][OH:39])=[CH:26][CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)ccc1Oc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(SCCO)ccc1Oc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Temperature: 80 °C
Reaction time: 17 h
Yield: 2 %

Procedure:
A mixture of 4-[6-(6-chloro-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (835 mg, 1.98 mmol) and potassium carbonate (305 mg, 2.2 mmol) in 3 mL of 2-mercapto-ethanol was stirred in microwave at 80° C. After 17 hours, mixture was continued to be stirred at 100° C. for 30 minutes and then 120° C. for 30 minutes. Mixture was purified by HPLC and column chromatography (hexane/AcOEt) to give Compound C12 as a white solid (16.4 mg, 2%). 1H NMR (CDCl3, 400 MHz) δ 1.07-1.09 (d, J=6.3 Hz, 6H), 1.68-1.78 (m, 2H), 1.90-1.99 (m, 2H), 2.12 (s, 3H), 2.29 (s, 3H), 3.23-3.25 (t, J=5.1 Hz, 2H), 3.32-3.38 (m, 2H), 3.68-3.71 (m, 2H), 3.91-3.94 (t, J=4.9 Hz, 2H), 4.84-4.90 (m, 1H), 5.24-5.30 (m, 1H), 7.12-7.21 (m, 2H), 8.12 (s, 1H). Exact mass calculated for C22H30N4O5S 462.19, found 463.3 (MH+).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([N:13]1[CH:22]2[CH2:23][CH2:24][CH:14]1[C:15]1[CH:16]=[C:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[CH:19][C:20]=1[CH2:21]2)=[O:12])([CH3:9])([CH3:8])[CH3:7].B(OC)(OC)[O:34]C.OO.Cl>C1COCC1.CO>[C:6]([O:10][C:11]([N:13]1[CH:22]2[CH2:23][CH2:24][CH:14]1[C:15]1[C:16]([OH:34])=[C:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[CH:19][C:20]=1[CH2:21]2)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1CCC(C2)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: OO
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1O)C1CCC(C2)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
Tert-butyllithium (1.7M, 2.3 mL, 4.0 mmol) was added dropwise to a solution of 4-tert-butoxycarbonylamino-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester (450 mg, 1.2 mmol) in THF (5 mL) at −78° C. The solution was then allowed to warm slowly to −20° C. and stir at that temperature for 1 h before cooling again to −78° C. and adding trimethyl borate (0.37 mL, 3.2 mmol) via syringe. The reaction was allowed to warm to room temperature slowly and stir overnight. The reaction was quenched with methanol (1 mL) and hydrogen peroxide (30% solution, 0.37 mL, 3.6 mmol) was added to the reaction and allowed to stir at room temperature for 2 h. The mixture was then adjusted to neutral pH with 1 N HCl, extracted with CH2Cl2 (3×10 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified with silica gel chromatography (0-50% EtOAc in hexanes) to obtain 4-tert-Butoxycarbonylamino-3-hydroxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester as a brown foam (260 mg, 55%). 1HNMR (400 MHz, CDCl3) δ 7.7 (m, 1H), 7.5 (s, 1H), 7.1 (d, 1H, J=8.1 Hz), 6.9 (m, 1H), 4.5 (d, 1H, J=7.8 Hz), 4.1 (m, 1H), 3.1 (dd, 1H, J=14.4, 4.9 Hz), 2.9 (dd, 1H, J=14.4, 4.9 Hz), 2.7 (dd, 1H, J=18.2, 8.1 Hz), 2.6 (dd, 1H, J=18.2, 10.6 Hz), 2.2-2.1 (m, 1H), 1.5-1.3 (m, 19H); 1H-1H COSY interactions between peak at 7.7 and 7.1 ppm; MS (m/e) 391 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](OB(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:21]2[CH2:22][CH2:23][C:19](=[O:24])[CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccc(OCc2ccccc2)cc1
Reactant: O=C1C=CCC1
Product: O=C1CC[C@@H](c2ccc(OCc3ccccc3)cc2)C1
Yield: 63.7 %

Procedure:
4-Benzyloxyphenylboric acid (15.1 g, 66 mmol) and cyclopentenone (2.5 mL, 30 mmol) were used and treated in a similar manner to (Step 1) of (Example 3) to give the title compound (5.09 g, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:17]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:16])=[CH:10][CH:11]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
To a solution of 4-[(5-bromo-2-chloro-phenyl)methyl]phenol 17b (2.0 g, 6.72 mmol, obtained from the synthetic method described in step 1 of example 17) and benzyl bromide (1.36 mL, 11.4 mmol) in tetrahydrofuran (20 mL) was added potassium carbonate (1.86 g, 13.4 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 25c as a white solid (1.83 g, 70.4%).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH2:14]([CH2:16][NH2:17])[OH:15]>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:17][CH2:16][CH2:14][OH:15])[NH:7][C:6]=2[CH:8]=1
Reactant: NCCO
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Product: O=S1(=O)N=C(NCCO)Nc2cc(Cl)sc21
Temperature: 0 °C
Yield: 60 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (206 mg, 0.8 mmol) in ethanolamine (1.0 ml) was stirred for 18 h at 100° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (5 ml) at 0° C. followed by adjustment to pH 2 with 4M hydrochloric acid. The product was isolated by filtration, washed with water, and recrystallised from ethanol/water to give 135 mg (60%) of the pure title compound; mp 260-261° C. dec.; 1H-NMR (DMSO-d6): δ3.26 (distorted q, 2H), 3.50 (t, 2H), 4.85 (br s, 1H), 7.07 (s, 1H), 7.20 (br s, 1H), 10.9 (br s, 1H); MS: m/e 281/283 (M+); (C7H8N3Cl1O3S2) calc C, 29.84; H, 2.86; N, 14.91; found C, 30.13; H, 2.84; N, 14.79.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1-BOC-homopiperazine (0.8 ml) was added methane sulphonyl chloride (0.34 ml) and triethylamine (0.68 ml). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then partitioned between dichloromethane and water. The combined organic extracts were then washed with brine and dried (MgSO4). The solvent was removed in vacuo to yield 1.23 g crude 4-methanesulfonyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([CH3:18])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:27])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].Cl[C:40]([O:42][CH3:43])=[O:41]>O1CCCC1>[CH3:43][O:42][C:40]([N:14]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])=[C:8]([CH3:27])[CH:9]=2)=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)([CH3:18])[O:15]1)=[O:41]
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(C)(c3cc(Cl)cc(Cl)c3)C2)ccc1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)N1OC(C)(c2cc(Cl)cc(Cl)c2)C=C1c1ccc(C(=O)OC(C)(C)C)c(C)c1
Temperature: -78 °C

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (1.3 g) in dry tetrahydrofuran (15 ml) stirred under argon at −78° C., was added lithium hexamethyldisilazane (“LHMDS”) (1 M in hexane) (3.45 ml). The solution was stirred at −78° C. until deprotonation was completed as monitored by thin layer chromatography. Then, to this solution was added methyl chloroformate (0.465 ml) and the reaction mixture was stirred at −78° C. for 2 hours. The mixture was quenched with saturated ammonium chloride and then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/diisopropylether 1:1) to give 3-(4-tert-butoxycarbonyl-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-methyl-5H-isoxazole-2-carboxylic acid methyl ester (472 mg) as a yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[S:10]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[N:19][C:15]=2[CH:14]=1)(=[O:12])=[O:11])=[O:5])[CH3:2].[ClH:39].C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[ClH:39].[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[S:10]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:44])[NH2:29])=[CH:24][CH:23]=3)=[N:19][C:15]=2[CH:14]=1)(=[O:12])=[O:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C

Procedure:
Prepared analogously to Example 32 from 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-sulfonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenylamide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mg].[CH:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.O>[CH3:17][CH:16]([OH:18])[C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CC=O
Reactant: Clc1cc(Br)ccc1-c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
2-Chloro-4-biphenylmagnesium bromide was prepared by known methods from 53.4 g of 2-chloro-4-bromobiphenyl and 5.0 g of magnesium turnings in tetrahydrofuran. A solution of 9.2 g of acetaldehyde in 100 ml of tetrahydrofuran was added dropwise to the cooled Grignard reagent solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture then was cooled, treated successively with 165 ml of saturated aqueous ammonium chloride and 100 ml of water, and poured onto ice. The reaction mixture was extracted with diethyl ether. The diethyl ether extracts were combined, washed three times with water, and dried over anhydrous sodium sulfate. The diethyl ether was evaporated under reduced pressure and the liquid residue was vacuum distilled to give 28.6 g of α-methyl-3-chloro-4-phenylbenzyl alcohol, bp 145°-157°C/0.09 mm. The following elemental analysis was obtained:
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:12]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:22](=[O:23])[C:21]3[CH:32]=[CH:33][C:18]([C:17]([F:16])([F:34])[F:35])=[CH:19][CH:20]=3)=[CH:25][CH:26]=2)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13]
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2 hours, after which a solution of 4-(4-trifluoromethylbenzoyl)benzyl bromide (754 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 15 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (448 mg, yield 47%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[S:18]>ClCCl>[CH3:15][NH:16][C:17]([NH:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[S:18]
Reactant: CN=C=S
Reactant: Cc1cccc(N2CCOCC2)c1N
Solvent: ClCCl
Product: CNC(=S)Nc1c(C)cccc1N1CCOCC1

Procedure:
Reaction of 6-methyl-2-morpholinoaniline (8.75 g) with methyl isothiocyanate (4.7 g) in dichloromethane (50 ml) at room temperature for four days yielded N-methyl-N'-(6-methyl-2-morpholinophenyl)thiourea (m.p. 182°-183° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25](C4C(Cl)=C(OC)C=C(OC)C=4Cl)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N1CCN(C2C=C(NC(C3C4N=CC=NC=4C([C:89]4[C:98]5[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=5)[CH:92]=[N:91][CH:90]=4)=CC=3)=O)C=CC=2)CC1)C>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:89]4[C:98]5[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=5)[CH:92]=[N:91][CH:90]=4)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 17 h at rt, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-isoquinolin-4-ylquinoxaline-5-carboxylic acid (Example 52). Title compound: ESI-MS: 490.0 [M+H]+; tR=2.21 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[N:21]#[C:22]Br>C1COCC1.CCOC(C)=O>[CH2:13]([N:6]([CH2:5][C@H:2]1[CH2:3][O:4][C:22]([NH2:21])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CCN(C[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(C[C@H]1COC(N)=N1)c1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 74.8 %

Procedure:
To a stirred solution of (S)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol (128 mg) at r.t. in THF (5 ml) under an argon atmosphere were added potassium carbonate (182 mg) and a solution of cyanogen bromide (140 mg) in THF (5 ml). Stirring at r.t. was continued for 21 h. The mixture (off-white suspension) was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to provide (S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (108 mg, 75%) as an off-white solid. MS (ISP): 220.4 ([M+H]+).