Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[NH:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[NH2:12]>>[C:2]1([C:1]([O:8][CH2:9][CH3:10])=[O:7])[N:14]2[C:15]3[C:20]([CH:21]=[CH:22][C:13]2=[N:11][N:12]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CCOC(=O)C(=O)OCC
Reactant: NNc1ccc2ccccc2n1
Product: CCOC(=O)c1nnc2ccc3ccccc3n12

Procedure:
Ethyl s-triazolo(4,3-a)quinoline-1-carboxylate was prepared by reacting diethyl oxalate with 2-hydrazinoquinoline, in the manner described in Examples 1 and 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-:15])=[O:14])=[C:7]([CH2:9][C:10]([OH:12])=O)[CH:8]=1.[C:16]1([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCl.N>O1CCCC1.C1CCCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-:15])=[O:14])=[C:7]([CH2:9][C:10]([NH:29][CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:24][CH2:25]2)=[O:12])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(CC(=O)O)c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(CC(=O)NC2CCN(Cc3ccccc3)CC2)c1
Temperature: 40 °C
Reaction time: 0.67 h

Procedure:
9.24 g (56.98 mmol) of N,N′-carbonyldiimidazole were added to a solution of 12.0 g (56.8 mmol) of 5-methoxy-2-nitrobenzene-acetic acid in 100 ml of tetrahydrofuran and the mixture was stirred for 40 minutes at a reaction temperature of 40° C. After the addition of 11.6 g (56.88 mmol) of 1-(phenylmethyl)-4-piperidineamine the mixture was heated to 40° C. for another hour. The reaction mixture was concentrated by evaporation in vacuo, the solid residue was digested with 50 ml of water and tert.butylmethylether, suction filtered and dried in a circulating air dryer at 50° C. 19.9 g (91% of theoretical) of pale yellow crystals were obtained, Rf 0.6 (eluant: dichloromethane/EE/cyclohexane/methanol/conc. ammonia 300/80/25/25/3 v/v/v/v/v).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[N:25]=[C:26]=[O:27])[CH2:22]2>C(Cl)Cl.C(N(CC)CC)C>[CH:17]12[CH2:23][CH:21]3[CH2:20][CH:19]([CH2:24][CH:15]([CH2:22]3)[CH:16]1[NH:25][C:26]([N:1]1[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]1)=[O:27])[CH2:18]2
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: C1=CC2(CCNCC2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (20 mg, 0.108 mmol) and 2-adamantyl isocyanate (18 mg, 0.10 mmol) were combined in CH2Cl2 and stirred overnight at ambient temperature. An additional 5 mg (0.028 mmol) of 2-adamantyl isocyanate and 2 drops of triethylamine were added and the mixture again stirred overnight at ambient temperature. The mixture was chromatographed directly on a silica gel column eluted with CH2Cl2 followed by 0.5% and 1% methanol in CH2Cl2. The product fractions were combined and evaporated to dryness in vacuo, and the residue was crystallized from petroleum ether to provide the title compound as a solid: (mp 189°-191°).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)[C:15](=[O:44])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)[C:15](=[O:44])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(OCCCOCc3ccccc3)cc2=O)C(OCc2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(OCCCOCc2ccccc2)ccn1C1CCNCC1OCc1ccc2ccccc2c1

Procedure:
In an analogous manner to that described in Example 145(i), from tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-3'-(naphthalen-2-ylmethoxy)-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,4']bipyridine-1'-carboxylate by cleavage of the BOC group by means of trifluoroacetic acid there was obtained (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-3'-(naphthalen-2-ylmethoxy)-1',2',3',4',5',6'-hexahydro-[1,4']bipyridin-2-one trifluoroacetate as a colourless solid; MS: 499 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3]1([C:11]#[N:12])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1.C(=O)([O-])O.[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][C:27](Cl)=[O:28]>C(OCC)(=O)C.O>[C:11]([C:3]1([N:2]([OH:1])[C:27](=[O:28])[CH2:26][C:20]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=2[CH3:18])[CH2:4][CH2:5][N:6]([O:9][CH3:10])[CH2:7][CH2:8]1)#[N:12]
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Reactant: CON1CCC(C#N)(NO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CON1CCC(C#N)(N(O)C(=O)Cc2cc(C)ccc2C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxyamino-1-methoxy-piperidine-4-carbonitrile (preparation example 11, step 2) (4.0 g, 23.4 mmol) and sodium hydrogen carbonate (3.0 g, 35.7 mmol) in ethyl acetate (35 ml) and water (25 ml) at 0° C. was added a solution of (2,5-dimethyl-phenyl)-acetyl chloride (4.2 g, 23.0 mmol) in ethyl acetate (35 ml) dropwise over one hour. The reaction mixture was stirred at 0° C. for one hour and at room temperature for two hours. The layers of the biphasic system were separated, the aqueous phase extracted with ethyl acetate (3×), the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (gradient ethyl acetate/hexane 1:2→1:1→2:1). Yield: 1.55 g of N-(4-cyano-1-methoxy-piperidin-4-yl)-2-(2,5-dimethyl-phenyl)-N-hydroxy-acetamide (compound P3ii.2) as a white solid, mp 153-156° C.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1C=C(C(F)(F)F)C=CN=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][N:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cc(C(F)(F)F)ccn2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: FC(F)(F)c1ccnc(Cl)c1
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2cc(C(F)(F)F)ccn2)o1
Yield: 77 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(4-(trifluoromethyl)pyridin-2-yl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (130 mg, 0.196 mmol) and 2-chloro-4-(trifluoromethyl)pyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (80 mg, 77%): 1H NMR (CDCl3, 400 MHz) δ 8.79 (d, 1H, J=5.0 Hz), 7.84 (s, 1H), 7.73 (s, 1H), 7.43 (dd, 1H, J=5.0, 0.9 Hz), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 4.88 (dd, 1H, J=7.3, 5.9 Hz), 2.60 (t, 2H, J=7.8 Hz), 1.93 (m, 2H), 1.61 (m, 2H), 1.36 (m, 4H), 0.91 (s, 9H), 0.11 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.5, 150.9, 149.6, 148.6, 142.8, 139.3 (q, J=33.9 Hz), 128.4, 128.2, 126.6, 125.6, 118.1 (q, J=3.5 Hz), 114.6 (q, J=3.0 Hz), 68.7, 36.4, 35.9, 31.4, 29.1, 25.7, 25.7, 18.2, −5.0, −5.1.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.FC(F)(F)C(O)=O.[Br:57][C:58]1[CH:70]=[CH:69][CH:68]=[CH:67][C:59]=1[O:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[Br:57][C:58]1[CH:70]=[CH:69][CH:68]=[CH:67][C:59]=1[O:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:63][CH2:62]1
Reactant: Brc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Br)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.038 g, 0.000135 mol) in DMF (2 mL) was added DIPEA (0.0872 g, 0.00068 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0325 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-bromophenoxy)-piperidine trifluoroacetate (0.05 g, 0.0001349 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.044 g (68%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-bromo-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 483.1 (M+1)+, 99.71%, 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.02 (s, 1H), 7.79 (d, 1H), 7.6 (m, 1H), 7.42 (m, 2H), 7.3 (m, 2H), 7.26 (d, 1H), 7.0 (s, 1H), 6.9 (t, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.4 (m, 4H), 1.7 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C@H:11]([NH:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:16])[C@H:10]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:9]1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C@H:11]([NH:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:16])[C@H:10]([C:27]([OH:29])=[O:28])[CH2:9]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2F)C(=O)[C@@H]1NC(=O)c1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1C(=O)N(c2ccccc2F)C[C@H]1C(=O)O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
The tert-butyl ester of Example 20 (388 mg, 0.865 mmol) was dissolved in 3 ml of trifluoroacetic acid and stirred for 18 h at room temperature. Concentration in vacuo gave a solid which was chromatographed on a silica gel chromatotron plate (4 mm) eluting with 3/1/96 EtOH/CH2Cl2 /HOAc to give the title compound (183 mg, 54%) as a solid. Anal calcd for C22H17N2O4F. H2O: C, 66.40; H, 4.67; N, 6.83. Found C, 64.55; H, 4.42; N, 6.71. MS calcd for C22H17N2O4F 392, found 392. DSC=182.9°-185.2° C.@94.1 J/g.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[CH3:15])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](=[O:23])=[O:22].O>C1COCC1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]2[C:5]3[C:6](=[CH:14][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:7]([C:21]([OH:23])=[O:22])[C:8]=2[CH:13]=1
Reactant: O=C=O
Reactant: Cc1cccc2c1-c1c(C)cccc1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)C(C(=O)O)c1cc(C)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
A solution of 4,5-dimethylfluorene (5.2 g, 27.0 mmol) in 100 mL of THF at -78° C. was charged with butyl lithium (18.7 mL, 29.0 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5 g, 113.6 mmol) was introduced via cannula over a period of 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred overnight. Water was added (150 mL) and the layers were separated, the water layer was washed with ethyl acetate (5×20 mL), then acidified with conc. HCl. The precipitate was collected, washed with water and dried to give 2,7-dimethyl-9-fluorenecarboxylic acid (4.24 g, 65.9 %).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[N:23][CH:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34]>CO.O>[CH3:34][N+:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][OH:30].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[N:23][CH:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:26])[C:6]([C:27]([O-:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4cncn4)C3)c(F)cc2c1=O
Agent: C[N+](C)(C)CCO
Solvent: O
Solvent: CO
Product: O=C([O-])c1cn(C2CC2)c2c(F)c(N3CCC(n4cncn4)C3)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
To a suspension of 100.25 mg (0.25 mmol) of 1-cyclopropyl-6,8-difluoro-7-[3-(1,2,4-triazol-1-yl) pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 0.625 ml of methanol and 0.2 ml of water was added at room temperature slowly 0.075 ml of 45% choline in methanol. The solution was stirred at room temperature for an additional hour and after being through a cotton filter, the supernatant was evaporated to dryness under reduced pressure (30° C.). The residue was crystallized from acetone-methanol and dried to give 85 mg of off white solid, m.p. 193°-194° C. 1H NMR (CD3OD) δ: 8.61 (s, 1H), 8.42 (bs, 1H), 8.01 (s, 1H), 7.76 (dd, 14Hz, 1.8Hz, 1H), 5.3-5.15 (m, 1H), 4.3-3.75 (m, 7H), 3.5-3.44 (m, 2H), 3.21 (s, 9H), 2.62-2.45 (m, 2H), 1.22-1.02 (m, 4H). Anal. calcd. for C24H30F2N6O4H2O: C, 55.16; H, 6.13; N, 16.07. Found: C, 54.46; H, 5.91; N, 15.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH3:13])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:14]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH3:17])=[O:15]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:17][O:16][C:14](=[O:15])/[CH:18]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH3:13]
Reactant: COc1ccc(/C(C)=C/C=O)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/C=C(\C)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-butenal (8 g) was treated with (carbomethoxymethylene)triphenylphosphorane (17 g) in carbon tetrachloride (70 mL) and dichloromethane (15 mL) overnight at room temperature. The ester was isolated in the normal fashion and crystallized from hexane to afford 7.2 g of (E,E)-5-(4-methoxyphenyl)-2,4hexadienoic acid methyl ester, mp 84°-86° C.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][C:38]=1[N+:47]([O-:49])=[O:48]>[Pd]>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:11][CH:12]([CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)=[O:14])(=[O:45])=[O:44])=[CH:39][C:38]=1[N+:47]([O-:49])=[O:48]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Yield: 33.7 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (500 mg) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-chloro-3-nitrobenzenesulfonyl chloride (524 mg) to obtain (RS)-2-(4-chloro-3-nitrobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (198.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:34][C:33]2[CH:35]=[CH:36][C:30]([C:29]([F:28])([F:37])[F:38])=[CH:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Oc1cc(Nc2ccc(C(F)(F)F)cc2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 4-(trifluoromethyl)aniline (78.9 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[4-(trifluoromethyl)phenyl]amino]quinolin-2-ol as a light yellow solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[CH2:20][CH:19]3[CH:15]([CH2:16][N:17]([C:21](=[O:37])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:18]3)[C:14]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[F:45])([OH:38])[CH2:13]2)(=O)=O)=CC=1.[C-:47]#[N:48].[K+]>>[C:47]([CH2:11][CH:12]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:21](=[O:37])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18]2)[C:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])([OH:38])[CH2:13]1)#[N:48]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC3CN(C(=O)Cc4ccccc4OCc4ccccc4)CC3C(O)(c3ccccc3F)C2)cc1
Reactant: [C-]#N
Agent: [K+]
Product: N#CCC1CC2CN(C(=O)Cc3ccccc3OCc3ccccc3)CC2C(O)(c2ccccc2F)C1
Yield: 44 %

Procedure:
The procedure is as described for Example 13, starting from 1.67 g of (3aRS,4RS,6RS,7aSR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-(2-benzyloxyphenylacetyl)perhydroisoindol-4-ol and 0.104 g of potassium cyanide, and gives 0.35 g of (3aRS,4RS,6SR,7aSR)-6-cyanomethyl-4-(2-fluorophenyl)-2-(2-benzyloxyphenylacetyl)perhydroisoindol-4-ol in the form of a thick pink foam.
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][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>CN(C=O)C>[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][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2(Cl)c2ccc(Cl)cc2)cc1

Procedure:
Distilled THF (10 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-(4-methylbenzyl)-isoindolin-1-one (400 mg, 1.13 mmol), thionyl chloride (295.8 mg, 2.48 mmol, 0.18 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-methylbenzyl)isoindolin-1-one was produced as a viscous yellow oil (418 mg, 1.13 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-methylbenzyl)isoindolin-1-one (418.1 mg, 1.13 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (285 mg, 2.85 mmol) and dried K2CO3 (390.41 mg, 2.85 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a green oil (359 g). Purification by flash column chromatography yielded the title product as a colourless viscous oil (242.1 mg, 0.55 mmol, 50%) 1H NMR: (300 MHz, DMSO) δ ppm 1.19 (m, 1H, H16/16′), 1.67, 2.05 (m, 1H, H16/16′) 2.21 (s, 3H, H12), 3.85 (m, 1H, H17), 4.06 (d, 1H, J=15.21 Hz, H9/9′), 4.32 (m, 1H, H15) 4.53 (d, 1H, J=15.21 Hz, H9/9′), 4.81, 5.74, (dd, 1H, H18/19) 5.20, 5.66 (dd, 1H, H18/19), 6.95 (m, 4H, H10, H11, H13, H14), 7.25 (m, 5H, H1-H5), 7.65 (m, 2H, H6-H7) 7.74 (d, 1H, H8). IR: 1380, 1467, 1699, 2922 cm−1. HR-MS (EI): Calculated mass: [M+H]+ 446.1517. Found: 446.1517.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2([CH3:18])[CH3:17].C(N(CC)CC)C.Cl[C:27]1C=C(Cl)C=[C:32](Cl)[C:28]=1[C:29](Cl)=O.CC(O)(C)C>O1CCCC1.C1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CCCCCC>[C:28]([O:13][C:12]([C:10]1[CH:11]=[C:2]([Br:1])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2([CH3:18])[CH3:17])=[O:14])([CH3:32])([CH3:29])[CH3:27]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C(=O)O)c2O1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
A solution of 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 41, 0.3 g, 0.96 mmol) and triethyl amine (0.1 g, 0.96 mmol) in anhydrous tetrahydrofuran (3 mL) was treated with 2,4,6-trichlorobenzoyl chloride (0.23 g, 0.96 mmol) and the reaction mixture was allowed to stir for 20 minutes. The precipitated solid was filtered off and the filtrate was evaporated in vacuo to afford a residue that was dissolved in benzene (3 mL) under argon and treated with 4-(dimethylamino)pyridine (0.47 g, 3.84 mmol) and 2-methyl-2-propanol (0.14 g, 1.92 mmol). After 18 h, the reaction mixture was diluted with ethyl acetate and washed with 2N hydrochloric acid, 2N sodium hydroxide and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title product as a white solid (0.14 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](O)=[O:27])[CH:21]=[CH:22][C:23]=1[OH:24]>>[OH:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:27])[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(Cc1ccc(O)c(O)c1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 17 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3,4-dihydroxyphenylacetic acid in 17% yield. The product was chromatographed on silica. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=359, 1H NMR (MeOH-d4): 3.56 s (2H), 6.10 s (1H), 6.59 dd, 8, 2 Hz (1H), 6.66 d, 8 Hz (1H), 6.78 d, 2 Hz (1H), 7.03 t, 8 Hz (1H), 7.11 t, 8 Hz (1H), 7.25 t, 8 Hz (1H), 7.31–7.35 m (2H), 7.51 d, 7 Hz (1H), 7.55 dd, 8.1 Hz (1H), 7.99 d, 8 Hz (1H).