Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([OH:14])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1.[OH-].[Na+]>CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([O:14][C:16](=[O:18])[CH3:17])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(O)c1ccc(C)nc1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCOC(=O)CC(OC(C)=O)c1ccc(C)nc1
Yield: 90.4 %

Procedure:
4.3 g (0.021 mol) of 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester, 3.0 g (0.03 mol) of acetic anhydride, 2.7 g (0.034 mol) of pyridine and 0.17 g (0.0017 mol) of 4-dimethylaminopyridine were stirred at 0° C. for 24 hours. The solution was mixed with 25 ml of 5 percent sodium hydroxide solution and extracted twice, each time with 25 ml of methylene chloride. The organic extracts were evaporated; the residue (4.7 g) contained 3-acetoxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester (yield 90.4 percent).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([O:17]C)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(s1)-c1cc(Br)ccc1OC2
Reaction time: 15 h
Yield: 93.4 %

Procedure:
To a suspension of methyl 8-bromo-4H-thieno[3,2-c]chromene-2-carboxylate 2 (2.64 g, 8.12 mmol, 1 equiv) in 4:1 tetrahydrofuran/water (80 mL) was added aqueous potassium hydroxide (24 mL, 24 mmol, 3.0 equiv, 1.0 M solution in water) at 24° C. After 15 hr, the tetrahydrofuran was removed in vacuo (<20 mm Hg). The resulting aqueous suspension was diluted with water until all the solids were dissolved. To the resulting solution was added concentrated hydrochloric acid until the solution reached pH=1. The resulting solids were collected by filtration and dried in vacuo (<1 mm Hg) to afford 3bp as a yellow solid (2.36 g, 93%). 1H NMR (500 MHz, CDCl3), δ: 13.28 (br s, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.60 (s, 1H), 7.40 (dd, J=8.7, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:38])[N:7]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:8]([C@H:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][C:14]#[CH:15])=[N:9]2)=[CH:4][CH:3]=1.[CH3:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1>ClC(Cl)C.ClCCCl>[NH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:39][C:40]1[CH:47]=[CH:46][C:43]([CH3:44])=[CH:42][CH:41]=1)[C@@H:12]([C:8]1[N:7]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:6](=[O:38])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][C:14]#[CH:15]
Reactant: Cc1ccc(C=O)cc1
Reactant: C#CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (52.6 mg, 0.10 μmol) in dichloroethane (0.5 mL) was treated with respective aldehydes (in this case 4-methyl benzaldehyde, 0.25M solution in DCE, 0.8 mL, 0.2 μmol). The mixture was stirred at room temperature for 16 h. Solvent was removed under reduced pressure. Residue was taken in MeOH (1.0 mL) and treated with hydrazine (0.25 mL). Reaction mixture was stirred at room temperature for 16 h and solvent removed under reduced pressure. The product was purified with reverse phase chromatography to give final product. Yield (14 mg, 24%). LCMS: m/e 500 [M+H].
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:54])[C:51]#[C:52][CH3:53])[CH2:11][O:12]2)C1C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:50]([OH:54])[C:51]#[C:52][CH3:53])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CC#CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC#CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: -78 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]but-2-yn-1-ol 5a (0.71 g, 0.95 mmol) in dichloromethane (30 mL) was added dropwsie boron trichloride (9.5 mL, 9.5 mmol, 1 M in dichloromethane) at −78° C. The mixture was stirred at −78° C. for 2 hours. The reaction mixture was then stirred at room temperature for 3 hours and quenched with 5 mL of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water (20 mL×2) and then saturated aqueous sodium chloride (20 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by prep-HPLC to afford title compound as a pale yellow solid (42 mg, 10.0%, HPLC: 91.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 475[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.63 (d, 1H), 7.48 (m, 1H), 7.39 (m, 1H), 7.02 (m, 2H), 6.79 (m, 2H), 5.07 (d, 1H), 5.06 (d, 1H), 4.79 (d, 1H), 4.62 (d, 1H), 4.48 (t, 1H), 4.46 (d, 1H), 3.95 (m, 4H), 3.82 (m, 2H), 3.71 (m, 1H), 3.53 (m, 1H), 1.45 (s, 3H), 1.28 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=O)[O:23]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-thiophen-3-yl-phenyl)-carbamic acid tert.-butyl ester (Example G6) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a brown solid (104 mg) and used crude in the next step (Example 7).
Reaction SMILES: [Zn](C)[CH3:2].[C:4]1([CH:10]=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1>>[C:4]1([C@@H:10]([OH:11])[CH3:2])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1
Reactant: O=CC1=CCCCC1
Reactant: C[Zn]C
Product: C[C@H](O)C1=CCCCC1
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A 10 mL Schlenk flask was charged with bis(sulfonamide) ligand L*2 (3.8 mg, 0.01 mmol), Ti(OtBu)4 (193 □L, 0.50 mmol), and 0.5 mL hexanes and stirred for 30 min at room temp. A hexanes solution of Me2Zn (0.32 mL, 0.63 mmol) was then added, and after stirring for 10 min, cyclohexenecarboxaldehyde (28 □L, 0.25 mmol) was added. The reaction was stirred at room temp for 19 h and quenched with a saturated solution of aq NH4Cl. The organic and aqueous layers were separated, and the aqueous layer was extracted with hexanes (3×10 mL). The combined organic layers were then washed with brine and H2O and dried over MgSO4. The filtrate was concentrated in vacuo and the residue was chromatographed on silica (10% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 94% yield (30 mg, 0.23 mmol). 1H NMR and 13C{1H} NMR spectra for this compound were identical to the previously reported literature data.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1.O.O.Cl[Sn]Cl>Cl>[Cl:1][CH2:2][CH2:3][N:4]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])[CH2:14][CH3:15]
Reactant: CCN(CCCl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CCN(CCCl)c1cccc(N)c1
Temperature: 90 °C
Yield: 88 %

Procedure:
A solution of the above nitro mustard (XII; R=H) (2.51 g, 11 mmol) in 12 N HCl (25 mL) was treated portionwise at 25 ° C. with SnCl2.2H2O (9.9 g, 44 mmol), heated on a steam bath at 90° C. for 1 h, then evaporated to dryness under reduced pressure. The residue as shaken vigorously With a mixture of CH2Cl2, 2 N NH4OH and ice, and filtered through a celite pad. Workup of the organic layer gave essentially pure 3-[N-(2-chloroethyl) -N-ethylamino]aniline (XIII; R=H) (1.92 g, 88%) as an oil, which was used immediately.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17]COC)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>C1COCC1.C(O)(C)C.O>[C:1]12([C:11]3[CH:12]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([CH:25]=[O:26])=[CH:27][CH:28]=4)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COCOc1ccc(-c2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reaction time: 57 h
Yield: 98.6 %

Procedure:
To a solution of 4-[3-(1-adamantyl)-4-methoxymethoxyphenyl]benzaldehyde (6.88 g, 18.30 mmol) in 200 mL of THF:isopropanol (1:1) was a added 30 mL of6 N HCl at room temperature. After 20 hours 30 mL of 12 N HCl was added. After 57 hours starting material was still present, 60 mL of additional 12 N HCl was added and stirred for 16 hours. The resulting mixture was diluted with water and extracted with ether (2×200 mL). The combined organics were washed with water (150 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give 6.00 g (99%) of 4-[3-(1-adamantyl)-4-hydroxyphenyl]benzaldehyde as a solid. 1H NMR (300 MHz; DMSO-d6): δ 1.72 (brs, 6H), 2.00–2.20 (m, 9H), 6.88 (d, J=8.7 Hz, 1H), 7.36–7.48 (m, 2H), 7.78 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H), 9.67 (s, 1H), 9.98 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.[Li][CH2:16][CH2:17]CC.C(I)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CO>[CH2:16]([C:8]1[S:7][C:6]([C:9]([OH:11])=[O:10])=[C:5]2[CH2:12][CH2:13][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=12)[CH3:17]
Reactant: [Li]CCCC
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCI
Solvent: O
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cooled solution (−78° C.) of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (960 mg, 4.57 mmol) in THF (19 mL), tert.-BuLi (8 mL, 1.5 M solution in pentane) is added. The mixture is stirred at −78° C. for 10 min before ethyliodide (3.80 g, 24.37 mmol) is added. The reaction mixture is stirred at −78° C. for 3 h. Water/MeOH 1:1 (8 mL) followed by 10% aq. citric acid solution is added and the mixture is extracted with EA. The combined organic extracts are washed with brine, dried over Na2SO4 and evaporated. The remaining solid is suspended in acetonitrile (6 mL), heated to 60° C., cooled to rt, filtered and dried to give 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (640 mg) as a slightly beige solid; LC-MS: tR=1.01 min, [M+1+CH3CN]=280.10.
Reaction SMILES: Cl(O)(=O)(=O)=O.[C:6]([NH:9][NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:7]>C(OC(=O)C)(=O)C>[CH3:7][C:6]1[O:18][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:10][N:9]=1
Reactant: CC(=O)NNC(=O)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cc1nnc(-c2ccccc2)o1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
60% Perchloric acid (12 ml) was added to a stirred suspension of 1-acetyl-2-benzoyl hydrazine (31 g, 0.174 mole) in acetic anhydride (150 ml) over 45 minutes at 5°±5° C. The solution was brought to ambient temperature over 1 hour, then filtered. The precipitate was dissolved in water (200 ml), solid sodium carbonate added to pH 9 and the product extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and concentrated to an oil. Chromatography gave 2-methyl-5-phenyl-1,3,4-oxadiazole as a gum (9 g, 30%). This was reacted with ethanolamine following the procedure of Preparation (a) above to give the title compound as an oil (5 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52](O)=[C:51]([O:56][CH3:57])[CH:50]=1)(=[O:46])[CH3:45].N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:44]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:7][C@@H:6]2[O:8][C@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])=[C:51]([O:56][CH3:57])[CH:50]=1)(=[O:46])[CH3:45]
Reactant: COc1cc(COC(C)=O)ccc1O
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(COC(C)=O)ccc1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
Under an argon atmosphere, 2,3,4,6-tetra-O-acetyl-D-glucopyranose (2) (576 mg, 1.65 mmol) was dissolved in toluene (5 ml) at room temperature, and triphenylphosphine (423 mg, 1.61 mmol) and 4-acetoxymethyl-2-methoxyphenol (6) (204 mg, 1.04 mmol) were added. Then, the reaction mixture was cooled in an ice bath, diethyl azodicarboxylate 2.2 M toluene solution (0.75 ml, 1.65 mmol) was added dropwise, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient; ethyl acetate:n-hexane=20:80→61:39) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-methoxybenzyl acetate (7) (335 mg, 0.637 mmol, yield 61%) as a colorless oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:28])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[C:14]([O:26][CH3:27])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:28])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[C:14]([O:26][CH3:27])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: CCN(CC)CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCOc1ccc(CCC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 1.5 g of N-(trans-4-methylcyclohexyl)-4-(2-diethylaminoethoxy)-3-methoxycinnamamide (Example 140), 0.075 g of 10% palladium-carbon, and 100 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. As a result, 1.21 g of N-(trans-4-methylcyclohexyl)-3-[4-(2-diethylaminoethoxy) -3-methoxyphenyl]propionamide (a compound of the present invention) was obtained as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NCc1ccc(OC)cc1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
A stirred solution of 6.0 mL (0.046 mole) of 4-methoxyphenylmethyl-amine and 6.5 mL (0.047 mole) of triethylamine in 200 mL of tetrahydrofuran was cooled to about 5° C., and a solution of 4.4 mL (0.046 mole) of ethyl chloroformate in 10 mL of tetrahydrofuran was added. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, then was poured into a mixture of 200 mL of ice and 200 mL of an aqueous solution saturated with ammonium chloride. This mixture was extracted with 300 mL of diethyl ether, and the extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 4.2 grams (43.8% yield) of ethyl (4-methoxyphenylmethyl)-carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:16]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][N:32]2[CH2:33][CH2:34][N:29]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)Nc1ccc(Cl)cc1C(=O)O
Yield: 11 %

Procedure:
1.0 g (4.0 mmol) of 5-chloro-2-[(chloroacetyl)amino]benzoic acid obtained in Example 72-(i), 1.0 g (4.0 mmol) of 1-benzhydrylpiperazine, 1.1 g (8.8 mmol) of N,N-diisopropylethylamine, and 60 mg (0.4 mmol) of sodium iodide were stirred in 5 mL of DMF solution at 80° C. for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, H2O was added to the residue, and solids were collected by filtration and dried. The obtained crude product was separated and purified by silica gel column chromatography, and the resultant was then recrystallized using ethyl acetate/n-hexane, thereby giving 198 mg of the target 5-chloro-2-({[4-(diphenylmethyl)piperazine-1-yl]acetyl}amino)benzoic acid (yield: 11%).
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[C:26](=[O:28])[CH3:27])=[CH:6][C:5]=3[CH2:4][O:3][CH2:2]1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[CH:26]([OH:28])[CH3:27])=[CH:6][C:5]=3[CH2:4][O:3][CH2:2]1
Reactant: CC(=O)c1cc(C)ccc1Nc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C(C)O)c1
Temperature: 25 °C

Procedure:
To a solution of 1-{2-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-ylamino]-5-methylphenyl}ethanone from EXAMPLE 116 (20 mg, 0.05 mmol) in 5 ml methanol at 0° C. was added sodium borohydride (5.5 mg, 0.15 mmol). The solution was stirred with warming to room temperature for 2 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 117 as a mixture of diastereomers at the alcohol center. LRMS (ES)+: 380.3 (M+H)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][C:3]=2[O:2]1>C(O)(=O)C>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][NH:8]3)=[CH:4][C:3]=2[O:2]1
Reactant: c1cc2cc3c(cc2[nH]1)OCO3
Solvent: CC(=O)O
Product: c1c2c(cc3c1OCO3)NCC2
Yield: 42.1 %

Procedure:
5,6-methylenedioxyindole (1.3 g, 8 mmol) dissolved in 25 ml glacial acetic acid was reduced catalytically (1 atm., 22° C.) using 370 mg PtO2 hydrate to give 550 mg of crude 2,3-dihydro-5,6-methylenedioxyindole which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([NH2:55])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[C:67](Cl)(=[O:70])[CH2:68][CH3:69]>C1COCC1>[CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)[NH:55][C:67](=[O:70])[CH2:68][CH3:69])=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.05 g, 0.057 mmol) was suspended in THF (0.572 mL). Upon addition of DIPEA (0.050 mL, 0.286 mmol), the slurry partially clarified. Propionyl chloride (0.005 mL, 0.057 mmol) was added at room temperature and the reaction was allowed to stir at room temperature overnight. Upon completion, the reaction was quenched with a small amount of formic acid and purified by reverse phase HPLC (10-45% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving [2-Methyl-1-(2-{5-[6-(4-{2-[1-(2-phenyl-2-propionylamino-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.008 g, 17%) as a white solid. LCMS-ESI+: calc'd for C48H52N8O5: 820.41 (M+); Found: 821.51 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(C#N)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[OH-].[Na+].C1C[O:29]CC1.C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([OH:29])[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)cccc32)n1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.8 g of 7-chloro-3-cyano-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide, 50 ml of 1% NaOH and 50 ml of THF are stirred at room temperature for 3 hrs. The THF is removed by evaporation and the mixture is diluted with water and extracted twice with ethyl acetate. The aqueous solution is acidified with 2N--H2SO4. The resulting acid solution is extracted with 3×100 ml ethyl acetate and the organic phases combined, dried over Na2SO4 and concentrated to give a pale yellow solid. This residue is taken up in ethyl acetate and treated with activated charcoal until the yellow base line material is removed to give the title product as a white solid m.p. 188°-190° C.