Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[O:6][C@H:5]([C@H:9]([C@@H:11]2[C@@:15]3([CH3:45])[CH2:16][CH2:17][C@@:18]45[CH2:24][C@:23]64[CH2:25][CH2:26][C@H:27]([O:33][C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@:28]([C:30]([OH:32])=[O:31])([CH3:29])[C@@H:22]6[CH2:21][CH2:20][C@H:19]5[C@:14]3([CH3:46])[CH2:13][CH2:12]2)[CH3:10])[CH2:4][CH:3]=1.Cl>>[CH3:1][C:2]1[C:7](=[O:8])[O:6][C@H:5]([C@H:9]([C@@H:11]2[C@@:15]3([CH3:45])[CH2:16][CH2:17][C@@:18]45[CH2:24][C@:23]64[CH2:25][CH2:26][C@H:27]([OH:33])[C@:28]([C:30]([OH:32])=[O:31])([CH3:29])[C@@H:22]6[CH2:21][CH2:20][C@H:19]5[C@:14]3([CH3:46])[CH2:13][CH2:12]2)[CH3:10])[CH2:4][CH:3]=1
Reactant: CC1=CC[C@@H]([C@@H](C)[C@H]2CC[C@@]3(C)[C@@H]4CC[C@H]5[C@](C)(C(=O)O)[C@@H](O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)CC[C@@]56C[C@@]46CC[C@]23C)OC1=O
Agent: Cl
Product: CC1=CC[C@@H]([C@@H](C)[C@H]2CC[C@@]3(C)[C@@H]4CC[C@H]5[C@](C)(C(=O)O)[C@@H](O)CC[C@@]56C[C@@]46CC[C@]23C)OC1=O
Yield: 93.4 %

Procedure:
Abrusoside A [30 mg] is hydrolyzed by treatment with 1 N HCl (8 ml) for 4 hr at 100° C., to produce an aglycone, abrusogenin [21 mg], which is recrystallized from MeOH as colorless, needle-shaped crystals, and is shown to be homogeneous by tlc in solvent 2 (Rf 0.35), cyclohexaneEtOAc-CHCl3 -MeOH (6:4:2:3, solvent 5, Rf 0.49), and CHCl3 -MeOH (10:1, solvent 6, Rf 0.23). The H2O layer containing the saccharide portion of abrusoside A is neutralized with silver carbonate, with the filtrate subjected to gc/ms and tlc, and found to contain only D-glucose. Abrusogenin exhibited the following data: mp 278°-280°; [α]D +37° (c 0.1 CHCl3 -MeOH, 1:1), uv, (EtOH) end absorption; ir, vmax (KBr) 3430 (OH), 1707 (C=O), 1384, 1259, 1147, 1046 cm-1 ; 1H nmr, (360 MHz, CDCl3 +CD3OD) δ6.63 (1H, m, H-24), 4.50 (1H, dd, J=13.2 Hz, J=2.8 Hz, H-22), 4.09 (1H, dd, J=11.1 Hz, J=4.3 Hz, H-3), 2.58 (1H, m, H-23a), 1.91 (3H, br. s, 27-Me), 1.13 (3H, s, 30Me), 1.00 (3H, d, J=6.7 Hz, 21-Me), 0.97 (3H, s, 18-Me), 0.93 (3H, s, 28-Me), 0.61, 0.39 (2H, d, J=4.0 Hz, 19-H2) ppm; 13C nmr, (90.8 MHz, CDCl3) δ 180.19 (s, C-29), 167.13 (s, C-26), 140.29 (d, C-24), 127.96 (s, C-25), 80.51 (d, C-22), 75.22 (d, C-3), 54.57 (s, C-4), 48.87 (s, C-14), 47.92 (d, C-8), 47.54 (d, C-17), 45.24 (s, C-13), 44.10 (d, C-5), 40.02 (d, C-20), 35.44 (t, C-12), 32.68 (t, C-15), 31.58 (t, C-1), 29.92 (t, C-19), 29.21 (t, C-2), 27.86 (t, C-23), 27.58 (t, C-7), 26.37 (t, C-11), 25.60 (t, C-16), 25.09 (s, C-10), 23.00 (t, C-6), 19.95 (s, C-9), 19.37 (q, C-28), 17.89 (q, C-18), 17.07 (q, C-27), 12.85 (q, C-21), 9.18 (q, C-30) ppm; ei-ms, (70 eV) m/z 484 (M+, 10%), 469 (M+ -Me, 16), 466 (M+ -H2O, 19), 448 (17), 423 (11), 385 (19), 367 (11), 344 (10), 314 (81), 299 (18), 233 (28), 215 (22), 203 (15), 187 (28), 173 (38), 161 (44), 147 (52), 119 (59), 111 (58), 107 (81), 95 (100) 93 (67), 91 (38), 81 (50), 79 (32) 69 (24), 67 (25), 55 (80); hr-ms, mass measurement, found, 484.3189, (calcd. for C30H44O5, 484.3186); 367.2630, (C25H35O2, 367.2635); 314.2245, (C21H30O2, 314.224); 181.1223 , (C11H17O2, 181.1227); 167.1072, (C10H15O2, 167.1071); 139.0764, (C8H11O3, 139.0768); 111.0445, (C6H7O2, 111.0445);95.0131, (C5H3O2, 95.0133).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20](C)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([C:35]2[CH:36]=[N:31][CH:32]=[N:33][CH:34]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1cncnc1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(pyrimidin-5-yl)naphthalen-2-yl)acetic acid (139) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using pyrimidin-5-yl-boronic acid in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO-d6): δ 12.87 (s, broad, 1H), 9.39 (s, 1H), 8.89-8.86 (m, 2H), 7.76-7.68 (m, 2H), 7.58-7.55 (s, 1H), 7.49-7.44 (m, 3H), 7.28 (d, J=8.2 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 5.15 (s, 1H), 2.27 (s, 3H), 0.97 (s, 9H). 19F-NMR: (377 MHz, DMSO-d6): δ−73.9 (s) LCMS-ESI+ (m/z): [M+H]+ calcd for C27H26ClN2O3: 461.2; Found: 461.2.
Reaction SMILES: [CH:1]1([C:7](N(C2C=CC=CC=2OC(F)(F)F)CCN2CCN(C3C=CC([N+]([O-])=O)=CC=3OC)CC2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:40][C:41]([F:69])([F:68])[O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=2[Br:67])[CH2:54][CH2:53]1>>[CH:1]1([C:7]([N:49]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][C:41]([F:40])([F:68])[F:69])[CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][N:55]([CH2:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[Br:67])[CH2:54][CH2:53]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Br)c(CN2CCN(CCNc3ccccc3OC(F)(F)F)CC2)c1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2OC(F)(F)F)CC1
Product: COc1ccc(Br)c(CN2CCN(CCN(C(=O)C3CCCCC3)c3ccccc3OC(F)(F)F)CC2)c1
Yield: 67 %

Procedure:
The title compound was prepared following the procedure described for the compound of example 55, substituting the compound of example 74 for the compound of example 54. The residue was purified by flash chromatography (CHCl3-2 N methanolic NH3 100:1). Yield: 67%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=[CH:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Rh]>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=Cc2cccnc2OCc2ccccc2)cc1
Agent: [Rh]
Solvent: CCO
Product: O=C(O)c1ccc(CCc2cccnc2OCc2ccccc2)cc1
Yield: 51.7 %

Procedure:
A suspension of rhodium on alumina (5%, 0.1 g) in ethanol (20 ml) was flushed well with argon. A solution of the methyl 4-[2-(2-benzyloxypyrid-3-yl)ethenyl]benzoate (1.0 g, 2.9 mmol) in ethanol (60 ml) was added. The reaction was transferred to a manometer under an atmosphere of hydrogen and the reaction was stirred at ambient temperature until 1.4 equivalents hydrogen had been taken up. The reaction mixture was filtered and evaporated and the residue subjected to chromatography on SiO2 (CH2Cl2 /hexane) to give 4-[2-(2-benzyloxypyrid-3-yl)ethyl]benzoic acid (0.5 g, 49%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][C:19]=2[CH3:20])[NH:16][C:15]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:44]([CH3:46])[CH3:45])(=O)=O>>[CH:44]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]3)=[C:19]([CH3:20])[CH:18]=2)[CH:14]=[C:15]1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]1)=[O:22])([CH3:46])[CH3:45]
Reactant: Cc1cc2[nH]c(C(=O)N3CCN(S(C)(=O)=O)CC3)cc2cc1OC1CCN(C(C)C)CC1
Reactant: CC(C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc2c(cc1OC1CCN(C(C)C)CC1)cc(C(=O)N1CCN(S(C)(=O)=O)CC1)n2C(C)C
Yield: 9 %

Procedure:
The title compound was synthesized in analogy to example 4, from [5-(1-isopropyl-piperidin-4-yloxy)-6-methyl-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 29), cesium carbonate and isopropyl methanesulfonate, to afford the title compound as a light-yellow oil (9%).
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C@H:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][C:8]([OH:10])=[O:9].[CH3:21]O>>[NH2:5][C@@H:6]([CH2:7][C:8]([O:10][CH3:21])=[O:9])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CO
Reactant: N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@H](N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 29 h

Procedure:
SOCl2 (6.60 mL, 90.5 mmol) was added drop-wise over 15 min to a cooled (ice-water) mixture of (S)-3-amino-4-(benzyloxy)-4-oxobutanoic acid (10.04 g, 44.98 mmol) and MeOH (300 mL), the cooling bath was removed and the reaction mixture was stirred at ambient condition for 29 hr. Most of the volatile component was removed in vacuo and the residue was carefully partitioned between EtOAc (150 mL) and saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (150 mL, 2×), and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford (S)-1-benzyl 4-methyl 2-aminosuccinate as a colorless oil (9.706 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 7.40-7.32 (m, 5H), 5.11 (s, 2H), 3.72 (app t, J=6.6, 1H), 3.55 (s, 3H), 2.68 (dd, J=15.9, 6.3, 1H), 2.58 (dd, J=15.9, 6.8, 1H), 1.96 (s, 2H). LC (Cond. 1): RT=0.90 min; LC/MS: Anal. Calcd. for [M+H]+ C12H16NO4: 238.11; found 238.22.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].C(O)(=O)C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[Cl:13][C:6]1[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]2[NH:1][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:4][C:3]=2[CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Solvent: CCO
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2[nH]c(-c3ccccc3)nc2cc1Cl

Procedure:
A mixture of 2.21 g. of 2-amino-4-chloro-5-sulfamylaniline (VI), 50 ml. of glacial acetic acid, and 1.05 g. of benzaldehyde was refluxed for 16 hours and then decanted into water. The precipitate was collected by filtration, dissolved in ethanol, treated with Darco, filtered through filter paper and then through Celite. Concentration in vacuo provided a solid which was dissolved in ethanol, filtered, and forced out with water. Treatment of this beige solid with boiling acetronitrile provided an off-white solid mp 314°-316°.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[F:9][C:2]([F:1])([F:8])[C:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:5]
Reactant: C1CNCCN1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(N1CCNCC1)C(F)(F)F
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
Ethyl trifluoroacetate (34.54 mL, 287.33 mmol) was added to a suspension of piperazine (25.0 g, 287.33 mmol) in THF (250 mL) at room temperature under nitrogen and stirred for 30 min and concentrated to remove solvent. The oily residue was taken up in ether and filtered and the filter cake was washed with ether. The filtrate was concentrated to give a clear oil (24.37 g, 47%). LC-MS [M+H]+=183.1, RT=1.07 min.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(#N)C.CO>[CH3:2][N:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: Clc1ccccn1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(CCNC(=O)OC(C)(C)C)c1ccccn1

Procedure:
A solution of tert-butyl [2-(methylamino)ethyl]carbamate hydrochloride (0.30 g, 0.0014 mol), 2-chloropyridine (160 mg, 0.0014 mol), and triethylamine (300 μL, 0.0021 mol) in acetonitrile (5 mL) was heated at 90° C. overnight. The mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=252.1
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.CN1CCN(C)C1=O.O>C(O)(=O)C>[N:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc2c1=O
Temperature: 140 °C
Yield: 35.1 %

Procedure:
A mixture of 530 mg (1.665 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 567 mg (8.325 mmol) of imidazole and 7.7 ml of dry 1,3-dimethyl-2-imidazolidinone is heated to 140° C. (oil bath temperature) for 90 minutes in a closed vial. After cooling, the dark solution is poured on 130 ml of water and the pH adjusted to ˜5 by adding 2 M acetic acid. The precipitate formed is filtered and recrystallized four times from DMSO/water, yielding 214 mg of the title compound as a red powder, m.p. >270° C.
Reaction SMILES: [Li].C([O:4][C:5](=O)[CH:6]=[C:7]1[CH2:10][N:9]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8]1)C.O.[OH-].[Na+]>O1CCCC1>[CH:11]([N:9]1[CH2:10][CH:7]([CH2:6][CH2:5][OH:4])[CH2:8]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 75.7 %

Procedure:
Lithium aluminumhydride (889 mg, 23.4 mmol) was suspended in tetrahydrofuran (50 mL), and under a nitrogen stream, a tetrahydrofuran (30 mL) solution of (1-benzhydrylazetidin-3-ylidene)acetic acid ethyl ester (2.40 g, 7.81 mmol) was added dropwise over 20 minutes at 0° C. with stirring. The reaction liquor was stirred for two hours at the same temperature, and then while cooling the reaction liquor in ice, water (889 μl), 1 N sodium hydroxide (889 μl) and water (8.57 mL) were added in this order. The resulting mixture was dried over anhydrous sodium sulfate. The insoluble was separated by filtration, and the mother liquor was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40M, ethyl acetate:n-hexane=1:1 to ethyl acetate), to obtain the title compound (1.58 g, 76%) as an oily matter.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH3:31])[C:17](=[O:27])[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OCc2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)C(=O)c2ccc([N+](=O)[O-])cc2)c(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of N-(2-benzyloxy-4-methylphenyl)-4-nitrobenzamide (4.7 g) in N,N-dimethylformamide (50 ml) was treated with sodium hydride (623 mg, 60% w/w in mineral oil) at 0° C. After 30 minutes, iodomethane (1.21 ml) was added, and the reaction mixture was stirred for 3 hours. The reaction was quenched with water and the mixture diluted with ethyl acetate. The organic phase was washed with water and brine. The organic solution was dried over magnesium sulfate and concentrated to give N-(2-benzyloxy-4-methylphenyl)-N-methyl-4-nitrobenzamide (4.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([NH2:8])[CH:7]=1.[CH2:10]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>C(#N)C.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.[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH3:19])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Br)ccc1I
Reactant: C#CCCN1CCC[C@H]1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CCCN1CCC#Cc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of Example 168B (0.2 g, 0.67 mmol), 1-but-3-ynyl-(2R)-2-methyl-pyrrolidine (7.4 mL as a 0.1 M solution in acetonitrile, 0.74 mmol), and triethylamine (10 mL, 72.0 mmol) was degassed with nitrogen for 10 minutes while stirring at r.t. Next, Pd(PPh3)2Cl2 (0.010 g, 0.013 mmol) and CuI (0.003 g, 0.013 mmol) were added and the resulting mixture was degassed for an additional. 10 minutes, sealed, and stirred at r.t. for 18 hours. Contents were then concentrated under reduced pressure and the residue was dissolved in 100 mL dichloromethane, washed twice with each: 50 mL sat. NaHCO3, 50 mL water, and 50 mL brine, dried with Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to afford the product in 30% yield as a light yellow oil. 1H NMR (CD3OD, 300 MHz) δ 7.03 (d, J=9 Hz, 1H), 6.88 (d, J=3 Hz, 1H), 6.68 (dd, J=3, 9 Hz, 1H), 3.41–3.20 (m, 2H), 2.79–2.52 (m, 5H), 2.12–2.04 (m, 1H), 1.92–1.82 (m, 2H), 1.56–1.47 (m, 1H), 1.25 (d, J=6 Hz, 3H). MS (ESI) [M+H)+ at 308.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Cl)=[CH:5][C:3]=1[NH2:4].[CH3:13][O-:14]>>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:14][CH3:13])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: C[O-]
Product: COc1cc(N)c(Cl)cc1[N+](=O)[O-]

Procedure:
Similarly, 2,5-dichloro-4-nitroaniline is allowed to react with methoxide ion to afford 2-chloro-4-nitro-5-methoxyaniline, m.p. 150°-152° C. Also by allowing 2,3-dichloro-4-nitroaniline to react with sodium ethoxide, sodium propoxide, sodium butoxide and sodium benzyloxide, 3 ethoxy-, 3-propoxy-, 3-isopropoxy-, 3-butoxy- and 3-benzyloxy-4-nitroaniline are obtained.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][CH:5]1[C:13]2([C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])[CH2:12][C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:23]([O-:25])=[O:24])[CH:10]=2.CO>C1COCC1>[CH3:4][CH:5]1[C:13]2([C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])[CH2:12][C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:23]([OH:25])=[O:24])[CH:10]=2
Reactant: CC1c2ccc(C(=O)[O-])cc2CC12C(=O)Nc1ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1c2ccc(C(=O)O)cc2CC12C(=O)Nc1ncccc12

Procedure:
A mixture of lithium hydroxide monohydrate (31 mg, 0.73 mmol) and methyl (1R,2S and 1S,2R)-1-methyl-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate (75 mg, 0.24 mmol) in THF (5 mL) and methanol (5 mL) was stirred at 23° C. for 5 h, concentrated. The residue was acidified with saturated aqueous citric acid solution to pH 2, and extracted with ethyl acetate (2×). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a racemic mixture. MS: m/z=295.2 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 12.75 (br. s, 1H), 10.96 (s, 1H), 8.10 (d, 1H, J=3.9 Hz), 7.76-7.87 (m, 3H), 7.30 (d, 1H, J=7.9 Hz), 7.01 (dd, 1H, J=5.1, 7.3 Hz), 3.75 (q, 1H, J=7.0 Hz), 3.39 (d, 1H, J=16.1 Hz), 3.27 (d, 1H, J=16.1 Hz), 1.11 (d, 3H, J=7.0 Hz).
Reaction SMILES: COC1C=CC(N2C3C(=CC=CC=3)C(=O)C=C2C2C=CC=CC=2)=CC=1.[CH2:26]([N:28]([CH2:55][CH3:56])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41](=O)[CH:40]=[C:39]2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:34][CH:33]=1)[CH3:27]>>[CH2:55]([N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][CH:39]2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:34][CH:33]=1)[CH3:56]
Reactant: CCN(CC)CCOc1ccc(-n2c(-c3ccccc3)cc(=O)c3ccccc32)cc1
Agent: COc1ccc(-n2c(-c3ccccc3)cc(=O)c3ccccc32)cc1
Product: CCN(CC)CCOc1ccc(N2c3ccccc3CCC2c2ccccc2)cc1

Procedure:
By following a procedure similar to that described in Example 7 (Procedure 2) and substituting for 1-(4-methoxyphenyl)-2-phenyl-4(1H)-quinolone an equivalent amount of 1-{4-[2-(diethylamino)ethoxy]phenyl}-2-phenyl-4(1H)-quinolone there can be obtained 1-{4-[2-(diethylamino)ethoxy]phenyl}-2-phenyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[C:22]([O:23][CH3:24])=[N:21][C:20]2[C:15](=[CH:16][C:17]([CH3:30])=[C:18]([CH3:29])[C:19]=2[C:25](OC)=[O:26])[N:14]=1.[Cl-].[NH4+]>ClCCl>[CH3:11][O:12][C:13]1[C:22]([O:23][CH3:24])=[N:21][C:20]2[C:15](=[CH:16][C:17]([CH3:30])=[C:18]([CH3:29])[C:19]=2[CH2:25][OH:26])[N:14]=1
Reactant: COC(=O)c1c(C)c(C)cc2nc(OC)c(OC)nc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: COc1nc2cc(C)c(C)c(CO)c2nc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
Diisobutylaluminium hydride (19.9 mL, 1M in dichloromethane, 19.9 mmol) was added dropwise over 30 minutes to a stirred solution of 2,3-dimethoxy-6,7-dimethyl-5-(methoxycarbonyl)quinoxaline (5.0 g, 18.1 mmol) in dry dichloromethane (300 mL) under nitrogen at -90° C. After 1 hour, another portion of diisobutylaluminium hydride (19.9 mL) was added, and the mixture was stirred for a further 1.5 hours. Saturated aqueous ammonium chloride (100 mL) was added, and the mixture was allow to warm to room temperature. The mixture was filtered through Arbocel filter aid, and the filtrate was washed thoroughly with dichloromethane. The aqueous layer was separated and extracted with two portions of dichloromethane. The combined organic solutions were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography to give 2,3-dimethoxy-6,7-dimethyl-5-hydroxymethyl quinoxaline (1.25 g, 28%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:21][CH3:22])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.O1CCCC1.C(O)(C)C.[CH3:32][NH2:33]>CO>[NH2:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:21][CH3:22])=[C:7]([O:19][CH3:20])[CH:8]=3)[N:3]=[C:2]([CH2:32][NH2:33])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CN
Reactant: COc1cc2nc(Cl)nc(-c3cccc(N)c3)c2cc1OC
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1cc2nc(CN)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 90 °C
Reaction time: 15 h
Yield: 38.7 %

Procedure:
Two hundred grams of crude 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine (content 124 g; 0.394 mol) was suspended in a mixed solution consisting of 1.2 L of tetrahydrofuran and 0.6 L of isopropanol. To the mixture was added 1.2 L of a methylamine solution in methanol, and the mixture was stirred in a SUS autoclave at 90° C. for 15 hours. The reaction mixture was allowed to cool down to 25° C., and concentrated under reduced pressure. To the residue were added 1.0 L of water and 4.0 L of chloroform, and the mixture was stirred at 50° C. for 0.5 hours and allowed to cool down to 25° C. The mixture was filtered through celite to remove the insoluble matter, and the filtrate was transferred to separatory funnel and the organic layer was separated. To the separated organic layer were added 50.0 g of anhydrous magnesium sulfate and 20.0 g of activated carbon, and the mixture was stirred at 50° C. for 1 hour and allowed to cool down to 25° C. The mixture was filtered through celite to remove the insoluble matter, and the filtrate was concentrated under reduced pressure. To the residue was added 904 mL of chloroform, and the mixture was stirred at 50° C. for 1 hour and stirred overnight after turning off the heater. Then the mixture was stirred in an ice bath for 2 hours and precipitated crystals were collected by filtration. The collected crystals were dried at 50° C. under reduced pressure to yield 76.3 g of a product of interest. Yield: 38.7%