Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:31]([F:34])([F:33])[F:32])=[N:4][CH:5]=[C:6](Cl)[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]2[C:27]3[C:22](=[C:23]([F:29])[CH:24]=[CH:25][C:26]=3[F:28])[N:21]=[CH:20][N:19]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CCO.[Pd]>[Cl:1][C:2]1[C:3]([C:31]([F:33])([F:34])[F:32])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:18]2[C:27]3[C:22](=[C:23]([F:29])[CH:24]=[CH:25][C:26]=3[F:28])[N:21]=[CH:20][N:19]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(F)c2c(NCCc3ccc(Oc4c(Cl)cnc(C(F)(F)F)c4Cl)cc3)ncnc12
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c2c(NCCc3ccc(Oc4ccnc(C(F)(F)F)c4Cl)cc3)ncnc12
Reaction time: 0.17 h
Yield: 0 %

Procedure:
{2-[4-(3,5-dichloro-2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine (700 mg, 1.4 mol) was dissolved in 2B EtOH (100 mL) under nitrogen in a Parr shaker bottle. Triethylamine (130 mg) and 10% Pd/C (200 mg) were added and the bottle was charged with H2 to an initial pressure of 50 psi. After shaking for approx. 10 min (approx 1 psi H2 uptake), the reaction was filtered through Celite and concentrated in vacuo to provide a white solid. The solid was partitioned between water and EtOAc twice, and the pooled fractions were dried and concentrated in vacuo. The residue was triturated with Et2O, to afford 310 mg of {2-[4-(3-chloro-2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine as a white crystalline solid, M.P. 129-131°. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1 H), 8.35 (d, J=5.4 Hz, 1 H), 7.40-7.31 (m, 3 H), 7.12-7.06 (m, 2 H), 7.05-6.97 (m, 1 H), 6.85-6.66 (m, 2 H), 4.01-3.92 (m, 2 H), 3.09 (t, J=7.1 Hz, 2 H); MS: m/z 480.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Cl:13][C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH2:15]1>>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:10][CH:9]2[CH2:8][N:7]([CH3:11])[CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:16][CH:15]=1
Reactant: OC1(Cl)C=CC=CC1
Reactant: Cc1cc2c(o1)CN(C)CC2O
Product: Cc1cc2c(o1)CN(C)CC2Oc1ccc(Cl)cc1
Product: Cl

Procedure:
The same method as in Example 47 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 1-chlorophenol instead of 4-chloro-3-methylphenol to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:9])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[N:21]=[CH:20][C:19]=1[C:33](Cl)=[O:34]>O1CCCC1>[Br:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2]([NH:1][C:33]([C:19]2[CH:20]=[N:21][N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=3)[C:18]=2[CH3:17])=[O:34])=[CH:3][CH:4]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: Cc1nc(Br)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(Br)ccc1NC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
To a solution of 5-amino-2-bromo-6-picoline (701 mg) and triethylamine (1.57 ml) in tetrahydrofuran (20 ml) was added 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (1.34 g) described in Reference Example 180 under ice-cooling, and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was evaporated, and saturated sodium bicarbonate water was added thereto. The insoluble matter was collected by filtration, washed with water, and then dried in vacuo to give the titled compound as a pale yellow solid (1.66 g). MS (ESI) m/z: 440 (M+H)+.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:33]([O:40][CH:41]1[CH:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:44]([CH2:63][O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[O:43][C:42]1=[O:72])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>C1COCC1>[S:28]1[C:24]([CH2:23][C:15]2[CH:14]=[C:13]([C:42]3([OH:72])[C@H:41]([O:40][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C@@H:46]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C@@H:45]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C@@H:44]([CH2:63][O:64][CH2:65][C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[O:43]3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]1=2
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: Brc1cc(Cc2cc3ccccc3s2)cc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2cc(Cc3cc4ccccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
Under a nitrogen atmosphere, an n-butyllithium hexane solution (1.6 M, 1.58 ml, 2.53 mmol) was added dropwise to a solution of 2-(4-bromonaphthalen-2-ylmethyl)-benzo[b]thiophene (0.81 g, 2.29 mmol) in anhydrous THF (15 ml) at −78° C. over five minutes. The reaction mixture was stirred at −78° C. for 5 minutes, and then a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydropyran-2-one (1.36 g, 2.52 mmol) in anhydrous THF (10 ml) was added dropwise thereto at −78° C. and the reaction solution was stirred at −78° C. for 2 hours. To the obtained reaction mixture was added a saturated ammonium chloride aqueous solution and the mixture was extracted with diethyl ether and the organic layer was washed with a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel flash column chromatography [n-hexane:ethyl acetate (10:1)] to obtain the title compound (1.4 g, 75%).
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([O:11]C)=[N:6]2.Cl.N1C=CC=CC=1.[H-].[Na+].Br[CH:30]([F:32])[F:31]>CN(C=O)C.C(OCC)(=O)C>[F:31][CH:30]([F:32])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:5]([N:4]=[C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[CH:2]=2)[N:6]=1
Reactant: COc1ccc2c(Br)c(-c3cccc(F)c3)nn2n1
Reactant: FC(F)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2cc3ccc(OC(F)F)nn3n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
Portions of 3-bromo-2-(3-fluoro-phenyl )-6-methoxy-pyrazolo[1,5-b]pyridazine (400 mg, 2.1 g total) were placed in individual Reactivials equipped with a magnetic stirrer bar. Pyridine hydrochloride (10 eq) was added to each vial, the vials sealed, and heated to 200° for 3 hours. The vials were allowed to cool to ˜140° before opening and the contents poured into ice/water. The resulting mixture was extracted into ethyl acetate (3×100 ml) and the combined organic extracts washed with water (7×75 ml), dried (Na2SO4) and evaporated to give the des-bromo phenol as a brown solid (1.0 g, MH+230). This solid was dissolved in anhydrous DMF (10 ml) and sodium hydride (60% dispersion in mineral oil, 200 mg) added portionwise. After stirring for 20 minutes at ambient temperature the solution was transferred to a small cooled autoclave and bromodifluoromethane (5 ml, xs, condensed at −30°) added. The autoclave was then sealed, allowed to warm to ambient temperature and stirred for 36 hours. The resulting solution was diluted with ethyl acetate (200 ml), washed with water (10×20 ml), dried (Na2SO4), concentrated and the residual gum purified by flash column chromatography with cyclohexane:ethyl acetate (4:1) as eluant. This gave the title compound as a solid (652 mg, 60%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[O:17])=[CH:4][C:3]=1[F:28]>CCO.[Pd]>[F:28][C:3]1[CH:4]=[C:5]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[O:17])[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[N:7][CH:2]=1
Reactant: CC(C)c1ccc(NC(=O)c2cc(F)c(Cl)nc2NCc2ccncc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc(NC(=O)c2cc(F)cnc2NCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
{6-Chloro-5-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(methylethyl)phenyl]carboxamide (50 mg, 0.125 mmol, from Example 66) dissolved in EtOH (10 mL) with TEA (0.5 mL) and suspended with Pd/C (10%, 5 mg). The mixture was stirred at RT under a H2 balloon for 45 min. The mixture was filtered through a layer of Celite® and the filtrate was concentrated in vacuo. The residue was partitioned between CH2Cl2 and aq. NaHCO3 (sat.). The organic solution was dried over Na2SO4 and concentrated in vacuo to give the title compound. MS:365 (M+1). Calc'd. for C21H21FN4O—364.42.
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([C:16]2[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.[Cl:24][C:25]1[C:30](C=O)=[C:29](Cl)[N:28]=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]2[N:9]([C@H:10]3[CH2:11][CH2:12][C@H:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:22])[CH3:23])[N:17]=4)[CH2:14][CH2:15]3)[N:8]=[CH:6][C:30]=12
Reactant: CC(C)c1noc([C@H]2CC[C@@H](NNC(=O)OC(C)(C)C)CC2)n1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1noc([C@H]2CC[C@H](n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-hydrazinecarboxylic acid tert-butyl ester (Intermediate 13; 691 mg, 2.03 mmol) in tetrahydrofuran (3 mL) was added to a cooled (0° C.) solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 361 mg, 2.03 mmol) and diisopropylethylamine (718 μL, 4.06 mmol) in anhydrous tetrahydrofuran (6 mL), and the mixture was stirred at 0° C. for 30 min and then at room temperature for 5 h. The mixture was filtered, and the filtrate was washed with brine. The aqueous layer was extracted with methyl tert-butyl ether and the organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, evaporated, and held under high vacuum. Toluene (15 mL) was added and the mixture was held at 110° C. overnight. The solvent was evaporated and the residue was purified on a Supelco 50 g column, eluting with 0-3% methanol/dichloromethane to give 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclo-hexyl]-1H-pyrazolo[3,4-d]pyrimidine (489 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 1.24 (d, 6H, J=6.9 Hz), 1.74-1.88 (m, 2H), 2.04-2.28 (m, 6H), 2.98-3.08 (m, 1H), 3.11-3.22 (m, 1H), 4.91-4.97 (m, 1H), 8.49 (s, 1H), 8.86 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>C(O)(=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:4]2[C:5](=[CH:9][C:10]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]([OH:7])=[N:2][C:1]([NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1)=[CH:3]2
Reactant: Cc1cc(N)n[nH]1
Reactant: COCCOc1cc(C(=O)O)c(CC#N)cc1OC
Solvent: CC(=O)O
Product: COCCOc1cc2c(O)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Temperature: 130 °C
Yield: 61.6 %

Procedure:
A mixture of 2-Cyanomethyl-4-methoxy-5-(2-methoxy-ethoxy)-benzoic acid (1.0 g, 3.77 mmol), 3-amino-5-methylpyrazol (0.73 g, 7.54 mmol) in acetic acid (10 ml) were sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. After removal of acetic acid, the residue was dissolved in 2 ml MeOH. This solution was added dropwise to 100 ml water, and the solid was collected and dried to give product (0.8 g, 61.6%). LC-MS: m/e 345 (MH+).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH3:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O.C(Cl)Cl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:3][CH3:4])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOCCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 3-neck, 2 L rbf, NaOH (135 g, 3.37 mol) was added slowly to water (1 L). After the addition was complete, the solution was cooled to room temperature and DCM (2 L) added, followed by triethylene glycol monoethyl ether (500 g, 2.81 mol). p-Toluenesulfonyl chloride (535 g, 2.81 mol) was added portion-wise over a period of 10 minutes, and the mixture refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (2 L), mixed well and separated. The organic phase was washed with water (2×2 L), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting clear, colourless oil was stirred at room temperature with a 10% aqueous NaOH solution (1 L) to hydrolyze unreacted p-toluenesulfonyl chloride. After 18 hours, the material was poured into water (1 L), extracted with chloroform (500 mL) and separated. The organic portion was washed with water (2 L), 10% HCl (2 L) and water (2 L). The material was dried over anhydrous MgSO4, filtered and solvent removed by rotavap to afford (103) as a clear, colourless oil (595 g, 64%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[CH:4]=1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:16]([F:25])[C:15]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[F:25][C:16]1[C:15]2[O:2][C:1]([C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]([CH3:12])[CH:4]=3)=[N:13][C:14]=2[CH:19]=[CH:18][C:17]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Solvent: CC(=O)O
Solvent: CO
Solvent: Ic1ccccc1
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccccc34)oc2c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
In methanol (50 ml), 3-formyl-1-methylindole (796 mg, 5.0 mmol), methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.0 mmol) and Molecular Sieves 4A (10 g) were stirred at room temperature for 5 hours and then, at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and iodobenzene diacetate (5.0 mmol) was added thereto. After stirring at room temperature for 14 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (3/1) eluate fractions, methyl 7-fluoro-2-(1-methyl-3-indolyl)-6-benzoxazolylacetate (860 mg, including impurities) was obtained as a pale brown solid. The compound was provided for the subsequent reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([OH:27])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[N+:31]([O-:58])[CH:32]=[C:33]([Cl:57])[C:34]=1[CH2:35][C@@H:36]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]2[CH2:56][CH2:55]2)[CH:43]=1)[O:37][C:38](=[O:41])[CH2:39]O.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH2:39][C:38]([O:37][C@H:36]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]3[CH2:56][CH2:55]3)[CH:43]=2)[CH2:35][C:34]2[C:33]([Cl:57])=[CH:32][N+:31]([O-:58])=[CH:30][C:29]=2[Cl:28])=[O:41])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:22][CH2:23]1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1cc(CC(=O)O)ccc1OCC1CC1)S(C)(=O)=O
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1cc(CC(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)ccc1OCC1CC1)S(C)(=O)=O

Procedure:
To a solution of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-(cyclopropylmethoxy)phenyl)acetic acid (0.200 g, 0.501 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (0.239 g, 0.501 mmol), EDC (0.288 g, 1.502 mmol), and DMAP (0.0306 g, 0.250 mmol) were added, and the mixture was reacted for 5 hours. A 1N solution of HCl was added, and the desired compound was extracted with DCM (3×) recovering the crude desired product (0.450 g, yield considered to be quantitative, MS/ESI+ 859.3 [MH]+) that was used in the following step without further purification.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([Br:15])[S:11][C:10]=2[CH:16]=1)(=[O:5])[CH3:4]>CCOCC.O1CCOCC1.O>[Br:15][C:12]1[S:11][C:10]2[CH:16]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[CH:7]=[CH:8][C:9]=2[C:13]=1[CH3:14]
Reactant: CC(=O)c1ccc2c(C)c(Br)sc2c1
Reactant: BrBr
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(Br)sc2cc(C(=O)CBr)ccc12
Reaction time: 0.75 h
Yield: 85.1 %

Procedure:
Bromine (1.67 g.) was added dropwise to a stirred solution of 6-acetyl-2-bromo-3-methylbenzo[b]-thiophene (2.50 g.) in a mixture of ether (15 ml.) and dioxan (15 ml.). The solution was stirred for 45 minutes and then diluted with water (100 ml.). The layers were separated and the aqueous layer was washed several times with ethyl acetate. The combined organic layer and extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform gave 2-bromo-6-bromoacetyl-3-methylbenzo[b]thiophene (2.75 g.) pure enough for further reaction. A sample crystallized from ethyl acetate/petrol (b.p. 60°-80°) had m.p. 126°-128° C.
Reaction SMILES: B.CSC.[CH2:5]([O:9][S:10]([CH:13]1[CH2:16][C:15](=[C:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[CH2:14]1)(=[O:12])=[O:11])[CH2:6][CH2:7][CH3:8].C(OCC)(=O)C>C1COCC1>[OH:19][CH2:18][CH:17]([CH:15]1[CH2:14][CH:13]([S:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])=[O:11])[CH2:16]1)[CH2:23][OH:24]
Reactant: CCCCOS(=O)(=O)C1CC(=C(C(=O)OCC)C(=O)OCC)C1
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCOS(=O)(=O)C1CC(C(CO)CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Borane-DMS (0.2 mL, 2.3 mmol) was added to a solution of diethyl 2-(3-(butoxysulfonyl)cyclobutylidene)malonate (0.2 g, 0.575 mmol) in THF (5 mL) and the resulting reaction mass was stirred at room temperature overnight. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was quenched with 1N HCl and extracted using ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated. Purification by column chromatography on silica gel (70% ethyl acetate in hexane) afforded 0.13 g of the product (74% yield).
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.CN(C)C=O.[CH2:45]([S:47]([NH:50][C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([N+:59]([O-])=O)[CH:54]=1)=[O:52])(=[O:49])=[O:48])[CH3:46]>CO>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:59][C:55]3[CH:56]=[CH:57][CH:58]=[C:53]([C:51]([NH:50][S:47]([CH2:45][CH3:46])(=[O:49])=[O:48])=[O:52])[CH:54]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: CCS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: CCS(=O)(=O)NC(=O)c1cccc(NC(=O)NC2(C3CCCCC3)N=Cc3ccccc3N(C)C2=O)c1

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 4, using 5-cyclohexyl-1,3-dihydro-1-methyl-3(R,S)-[(4nitrophenyloxycarbonyl)amino]-2H- 1,4-benzodiazepin-2-one (0.25 g, 0.57 mmol), triethylamine (80 μl, 0.57 mmol), dimethylformamide (5ml) and 1-(ethylsulphonylaminocarbonyl)-3-nitrobenzene (0.14 g, 0.63 mmol). After trituration with hot methanol, the compound (125 mg, 42%) was afforded as a colourless solid. mp 210° C. (dec.). 1H NMR (360 MHz, D6 -DMSO) δ 0.86-0.98 (1H, m), 1.10-1.25 (2H, m), 1.23 (3H, t, J=7.4 Hz), 1.26-1.64 (5H, m), 1.72-1.80 (1H, m), 1.87-1.96 (1H, m), 2.88-2.99 (1H, m), 3.33 (3H, s), 3.48 (2H, q, J=7.4 Hz), 5.08 (1H, d, J=8.3 Hz), 7.31-7.42 (3H, m), 7.47 (1H, d, J=7.9 Hz), 7.52-7.58 (2H, m), 7.67 (1H, dd, J=7.9 and 7.8 Hz), 8.76-8.80 (1H, m), 7.92 (1H, dd, J=1.8 and 1.8 Hz), 9.21 (1H, s), 11.98 (1H, brs).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:10]2[Cl:29].[CH3:30][N:31]1[C:35]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:37])=[CH:34][N:33]=[CH:32]1>C1COCC1>[Cl:29][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:36]([C:35]3[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[OH:37])[CH:8]=2)[N:13]=[C:12]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1cncc1C(=O)c1ccccn1
Reactant: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Oc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(CC)c1nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc2c(Cl)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.49 mL, 1.2 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (0.500 g, 1.23 mmol, Intermediate 5: step d) in dry THF (20.5 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (230.9 mg, 1.233 mmol, Intermediate 6: step b) in dry THF (1.5 mL) was added dropwise. The reaction was stirred for 2 minutes, then moved into an ice bath for 7 minutes, and finally allowed to warm to ambient temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water/brine and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 100% EtOAc), followed by reverse phase chromatography (ACN/H20+0.05% TFA). Product fractions were basified with saturated aqueous sodium bicarbonate and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.54 (d, J=3.9 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.84 (dd, J=9.5, 7.7 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.32 (dd, J=14.1, 5.4 Hz, 3H), 7.05 (t, J=7.3 Hz, 1H), 6.93 (s, 1H), 6.79 (d, J=7.8 Hz, 2H), 6.22 (d, J=1.1 Hz, 1H), 3.51 (q, J=14.6, 7.3 Hz, 4H), 3.25 (s, 3H), 1.05 (t, J=7.0 Hz, 6H); MS m/e 514.3 [M+H]+.