Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>>[Cl:29][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1CCc1ccccc1
Product: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1CCc1ccccc1
Yield: 100 %

Procedure:
3-(4-Chlorophenyl)-3-hydroxy-2-phenethylisoindolin-1-one (250 mg, 0.687 mmol.) was reacted with thionyl chloride (0.055 mL, 0.756 mmol.) and a catalytic amount of DMF as for general procedure B, and the solvent removed to give a colourless oil of the crude 3-chloro-3-(4-chlorophenyl)-2-phenethylisoindolin-1-one (256 mg, 0.687 mmol., 100%).
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OCc1ccccc1
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Product: COC(=O)CC(N)c1ccc(OC)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-benzyloxy-4-methoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 7.26-7.44 (m, 5H), 6.82-6.93 (m, 3H), 5.13 (s, 2H), 4.31 (t, 1H, J=5 Hz), 3.85 (s, 3H), 3.64 (s, 3H), 2.57 (d, 2H, J=5 Hz), 1.80 (d, 2H, J=5 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.CC1C=C(C=C(C)C=1N(C)C)[CH:16]=[O:17]>O1CCOCC1>[CH3:11][C:2]1([CH3:1])[N:3]=[C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:16][O:17]1
Reactant: CC1(C)N=C1c1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1N(C)C
Solvent: C1COCCO1
Product: CC1(C)N=C(c2ccccc2)CO1

Procedure:
2.6 g of 2,2-dimethyl-3-phenyl-2H-azirine and 2,5 g of 3,5-dimethyl-4-(dimethylamino)benzaldehyde were exposed to light for 2 hours in 300 ml of 1,4-dioxane (with the light source described in Example 2). After purification as described in Example 12 and crystallization from n-pentane, there was obtained 5-[4-dimethylamino)-3,5-xylyl]-2,2-dimethyl-4-phenyl-3-oxazoline which melted at 91°-92° C. after drying for 2 hours at 50° C. and 13 Torr.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Br[C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1.IC1C=CC=CC=1>>[CH3:37][C:36]1[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])=[N:32][CH:33]=[CH:34][CH:35]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: Cc1cccnc1Br
Agent: Cl
Solvent: Ic1ccccc1
Product: Cc1cccnc1-n1ccc(Cn2cncc2Cc2ccc(C#N)cc2)cc1=O

Procedure:
4-[3-(3 '-Methyl-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-bromo-3-mehtylpyridine for the iodobenzene in Step 3.
Reaction SMILES: P(Cl)[Cl:2].P([O-])[O-].[CH2:7]([P:16](OCC)[O:17][CH2:18][CH3:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.C(P(Cl)Cl)C1C=CC(OC)=CC=1>CCOCC>[CH2:7]([P:16]([Cl:2])[O:17][CH2:18][CH3:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CCOP(Cc1ccc(OC)cc1)OCC
Reactant: ClPCl
Agent: COc1ccc(CP(Cl)Cl)cc1
Agent: [O-]P[O-]
Solvent: CCOCC
Product: CCOP(Cl)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This and other phosphonochloridous esters were best prepared by the procedure of Steininger (Chem. Ber., 1962, 95, 2993) for the comproportionation of the corresponding phosphonous dichloride and phosphonite. Thus, a solution of diethyl p-anisylphosphonite (7.5 g, 36 mmol) in dry ether (20 mL) was added to a solution of p-anisylphosphonous dichloride (8.2 g, 36 mmol) in ether (75 mL) at 5° C. The solution was warmed to room temperature and stirred two hours, then concentrated and distilled (Kugelrohr) at 105°-110° C. (0.1 mmHg). Yield: 9.4 g (60%); IR (neat) 1595, 1500, 1255, 1095, 1025, 930, 824 cm-1 ; 1H NMR (CDCl3) δ7.9-7.5 (m, 2H), 8.1-7.8 (m, 2H), 4.0 (m, 2H), 3.82, (s, 3H), 1.30 (t, J=7 Hz, 3H); 31P NMR (CDCl3) δ177.2 (ca. 90%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.CN[C@@H](C)[C@@H](C1C=CC=CC=1)O.[F:22][C:23]([F:40])([F:39])[C:24]1[CH:25]=[C:26](/[CH:30]=[N:31]/[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=[CH:28][CH:29]=1.CCCCC.[N+:46]([CH3:49])([O-:48])=[O:47]>FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O.C[C@H](N(C)C)[C@H](O)C1C=CC=CC=1>[N+:46]([CH2:49][CH:30]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:39])([F:40])[F:22])[CH:25]=1)([O-:48])=[O:47]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)/N=C/c1cccc(C(F)(F)F)c1
Agent: CN[C@@H](C)[C@H](O)c1ccccc1
Agent: C[C@@H]([C@H](O)c1ccccc1)N(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(C(F)(F)F)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Under argon, 9.75 ml (56 mmol) of N,N-diisopropylethylamine were added slowly dropwise to a suspension of 20.35 g (56 mmol) of zinc(II) trifluoromethanesulphonate in 300 ml of nitromethane at RT and the mixture was stirred for 1 h thereafter. The yellow suspension was subsequently admixed with 13.9 g (84 mmol) of (1R,2S)-(−)-2-(N-methylamino)-1-phenylpropan-1-ol [(−)-N-methylephedrine] and 18.4 g of molecular sieve and stirred for 1 h thereafter, then cooled to −20° C. A dropping funnel was charged with 51.0 g (186.6 mmol) of the compound from Example 11A, with addition of 75 ml of nitromethane. The initial solution underwent spontaneous warming to about 40° C., and the formation of a precipitate began. Thereafter the entire contents of the dropping funnel were added immediately in one portion to the cooled zinc(II) trifluoromethanesulphonate/(−)-N-methylephedrine mixture (no temperature control). The reaction mixture was stirred in a cooling bath (−20° C.) for a further 5 h, and then stirred overnight as well, the temperature slowly rising to 0° C. The work-up was carried out in analogy to variant 1. The crude product was purified using a short silica gel column (eluent dichloromethane/ethanol 100:2). The product-containing fractions were combined and freed from the solvents on a rotary evaporator, and the residue was dried in an HV. The solid obtained was stirred with 200 ml of n-pentane at RT, isolated again by filtration and dried in an HV. This gave 32.4 g of the title compound (approximately 82% purity according to LC-MS, 43% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][CH2:13]O)[N:8]([C:15](=[O:26])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:7]=2[CH:27]=1.S(Cl)([Cl:30])=O>ClCCl>[Cl:30][CH2:13][CH2:12][CH:9]1[N:8]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:7]2[CH:27]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(c1)N(C(=O)c1cccc(C(F)(F)F)c1)C(CCO)CO2
Solvent: ClCCl
Product: COc1ccc2c(c1)N(C(=O)c1cccc(C(F)(F)F)c1)C(CCCl)CO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 14.74 g (0.039 mol) of (±)-6-methoxy-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-3-ethanol dissolved in 165 ml of dichloromethane are added 14 ml (0.19 mol) of thionyl chloride and the mixture is stirred at room temperature for 5 h.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][OH:14])[CH:11]=2)[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22]>CCOC(C)=O>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:24][O:23][C:21](=[O:22])[NH:1][C:2]1[N:6]([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][OH:14])[CH:11]=2)[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)c1cc(N)n(-c2cnn(CCO)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCO)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A solution of Intermediate Ab (250 mg, 1.06 mmol) in EtOAc (3 mL) was treated with aqueous NaOH (1M, 1.9 mmol), followed by 2,2,2-trichloroethyl chloroformate (154 μL, 1.16 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with a further 10 mL EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-40% EtOAc in DCM to afford the title compound as a colorless oil (300 mg, 70%). LCMS (Method 3): Rt 3.42 min, m/z 410, 412 [MH+].
Reaction SMILES: FC1C=C(CN)C=NC=1.[CH3:10][N:11]1[CH:15]=[C:14]([CH2:16][NH2:17])[CH:13]=[N:12]1.[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:28]2=[O:39])[S:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38])[C:28]2=[O:39])[S:22][C:23]=1[C:24]([NH:17][CH2:16][C:14]1[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=1)=[O:25]
Reactant: Cn1cc(CN)cn1
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 49 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (1-methyl-1H-pyrazol-4-yl)methanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 49% yield: 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.37 (s, 1H), 5.79-5.76 (m, 1H), 4.40 (d, J=5.3 Hz, 2H), 4.15-4.09 (m, 2H), 3.87 (s, 3H), 3.62-3.57 (m, 2H), 3.42-3.37 (m, 2H), 2.60 (s, 3H), 2.19-2.11 (m, 2H), 1.88-1.83 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.2, 157.1, 155.6, 152.8, 138.7, 129.4, 118.2, 117.4, 42.9, 42.3, 42.0, 38.9, 34.4, 31.4, 30.9, 20.2, 17.2; MS (ES+) m/z 430.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([NH:50][CH2:51][CH2:52][N:53]6[CH2:58][CH2:57][O:56][CH2:55][CH2:54]6)=[O:35])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCN4CCOCC4)cc3)cn2)cc1
Yield: 56.4 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (50.0 mg, 0.0758 mmol) obtained in Step A in Example 1-D-19 and N-(aminoethyl)morpholine (19.7 mg, 0.152 mmol) instead of 3-(aminomethyl)pyridine, amidation was conducted in the same manner as Step B in Example 1-D-19, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide as a yellow solid (33.0 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-94) as a yellow powder (20.7 mg, 51%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][Sn:23]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH2:24]([Sn:23]([CH2:22][O:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)COc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of 1,1-dimethylethyl 4-hydroxybenzoate (0.20 g, 1.04 mmol) in N,N-dimethylformamide (4 ml) was treated with powdered anhydrous potassium carbonate (0.4 g) followed by iodomethyltributyltin (0.60 g, 1.4 mmol) [D. E. Seitz, et al, Synth. Commun. (1983) 13, 129-134] and the resulting mixture was stirred at 65° C. for 1 hour. The cooled reaction mixture was diluted with a mixture of hexane and ethyl acetate (9:1), washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent and chromotography of the residue on silica gel (elution hexane-toluene, 1:1) gave 0.494 g (96%) of the title material as an oil.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[C:28]([C:32](=[N:34]O)[NH2:33])[CH:29]=[CH:30][CH:31]=1>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:34]=[C:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[N:33]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(=NO)c1cccc(F)c1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 34 mg (0.22 mmol, 1.1 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 47 mg (53% of theory)
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([C:20]1[O:24][N:23]=[C:22]([OH:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:16]([C:20]1[O:24][N:23]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[C:22](=[O:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2oc(C(C)(C)C)cc2=O)c([N+](=O)[O-])c1
Yield: 94.7 %

Procedure:
In 100 ml of dimethyl sulfoxide were dissolved 23.0 g of ethyl 4-chloro-3-nitrobenzoate and 17 g of 5-t-butyl-3-hydroxyisoxazole and after adding thereto 17 g of potassium carbonate, the reaction was performed for 8 hours at 75° C. After the reaction was over, the reaction mixture obtained was poured into cold diluted hydrochloric acid followed by stirring, whereby colorless crystals deposited immediately. The crystals were recovered by filtration and recrystallized from ethanol to provide 31.7 g of the desired compound with a yield of 94.8%. The melting point thereof was 88° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28].O>ClCCl>[CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][N:27]([CH3:28])[CH3:26])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCBr)Nc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: CNC
Solvent: O
Solvent: ClCCl
Product: CN(C)CCCCC(=O)Nc1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 68 %

Procedure:
Compound 2 (5.88 g, 0.012 mol) was stirred in dichloromethane (150 mL) with 40% aqueous dimethylamine (10 mL) and water (25 mL) for 24 h. The solution was diluted with dichloromethane (50 mL) and washed with water (1×100 mL), 1 M aqueous sodium hydroxide (1×100 mL), and saturated brine (1×100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give 3 as a white solid (3 g, 68%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.S(=O)(=O)(O)O.[Br:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:12]=1[NH2:13].[BH4-].[Na+]>O1CCCC1>[Br:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:12]=1[NH:13][CH:2]([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: Cc1cc(N)c(Br)cc1C
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)c(NC(C)C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of acetone (5.60 mL, 76.3 mmol) and aqueous 4 M sulfuric acid (5.20 mL, 20.8 mmol) in tetrahydrofuran (15 mL) was added dropwise to a stirred solution of 2-bromo-4,5-dimethylaniline 1-8 (13.9 g, 69.3 mmol) in tetrahydrofuran (40 mL) at approximately 0° C. Sodium borohydride (2.62 g, 69.3 mmol) was added cautiously and the resulting mixture allowed to warm to ambient temperature. After 30 min, the reaction was quenched by the careful sequential addition of water (25 mL) and sodium hydroxide pellets (until strongly alkaline). The reaction mixture was extracted with tert-butyl methyl ether (150 mL) and the organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-20% ethyl acetate/hexanes as eluent) afforded 1-9 as a clear, pale orange oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11][CH2:12][CH3:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)=[CH:3][C:4]=1[CH2:11][CH2:12][CH3:13])([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCCc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 86.7 %

Procedure:
4-Chloro-1-nitro-2-propylbenzene (J. Organometallic Chem. 2001, 624(1-2), 167-171) (0.299 g, 1.50 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (0.553 g, 1.79 mmol), Na2CO3 (0.509 g, 4.80 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.0620 g, 0.0900 mmol) in dioxane (6 mL) and H2O (3 mL) was degassed for 10 min. The mixture was heated at 80° C. overnight. The reaction was filtered through Celite®, washed with EtOAc and H2O, dried (MgSO4), concentrated and purified by flash chromatography to provide the title compound of step A (0.451 g, 1.30 mmol, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.3 Hz, 3H), 1.46 (s, 9H), 1.65 (sextet, J=7.5 Hz, 2H), 2.50 (br. s., 2H), 2.83-2.88 (m, 2H), 3.62 (t, J=5.7 Hz, 2H), 4.08 (q, J=2.7 Hz, 2H), 6.14 (br. s., 1H), 7.25-7.29 (m, 2H), 7.87 (d, J=7.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34](=O)([O-])[O-].[K+].[K+]>CO.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:22][CH2:23][CH2:24][C:25]([O:27][CH3:34])=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)CCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
3.7 g of 5-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)pent-4-enoic acid are dissolved in 30 ml of methanol into which dry hydrogen chloride is introduced. The solution is stirred overnight and then rotary evaporated. Whilst cooling with ice, the base is liberated with aqueous potassium carbonate solution and then extracted with methylene chloride. The solution is rotary evaporated and the residue is chromatographed over a silica gel column.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:17][C:18]1[CH:23]=[C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][C:25]2=[O:38])[C:21]([O:39][CH3:40])=[CH:20][C:19]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1>C1COCC1>[F:17][C:18]1[CH:23]=[C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34]([NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][C:25]2=[O:38])[C:21]([O:39][CH3:40])=[CH:20][C:19]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1
Reactant: Nc1ccon1
Reactant: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Cl)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 13.9 %

Procedure:
A RBF was charged with isoxazol-3-amine (0.016 g, 0.191 mmol) and THF (1.6 mL), and the vessel was cooled to −78° C. for 15 minutes. Lithium bis(trimethylsilyl)amide (1.0 M in THF) (0.208 ml, 0.208 mmol) was then added dropwise over 1 minute. The reaction was stirred for 10 minutes, and then a solution of 1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (0.080 g, 0.173 mmol) in THF (1.6 mL) was added dropwise. The bath was removed, and the resulting mixture was stirred for 45 minutes. The reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via MPLC (ISCO, 40 g), eluting with 0 to 100% ethyl acetate in heptanes. The solid was dried under reduced pressure to provide 1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.012 g, 0.024 mmol, 13.60% yield) as a mixture of atropisomers. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27 (d, J=1.76 Hz, 1 H) 8.15 (d, J=2.05 Hz, 1 H) 7.97 (br. s., 1 H) 7.74-7.84 (m, 2 H) 7.43-7.53 (m, 1 H) 7.37-7.42 (m, 1 H) 7.33 (d, J=9.98 Hz, 1 H) 7.11-7.18 (m, 2 H) 7.09 (d, J=9.49 Hz, 1 H) 6.86 (dd, J=14.67, 9.29 Hz, 2 H) 6.61 (d, J=1.76 Hz, 1 H) 3.72-3.81 (m, 3 H). m/z (ESI) 510.0 (M+H)+.