Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=[CH:7]2)([O-])=O.[C:21]12([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[O:33]=[C:32]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=[CH:7]2)[CH2:31][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: CC(C)(C)OC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: CC(C)(C)OC(=O)Cn1ccc2cc(NC(=O)CC34CC5CC(CC(C5)C3)C4)ccc21
Yield: 60.4 %

Procedure:
Prepared according to the method of Example 15b) from 5-nitro-1H-indole-1-acetic acid, 1,1-dimethylethyl ester (0.29 g) and 1-adamantaneacetyl chloride (0.20 g) to give the title compound as a white solid (0.24 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][CH:42]([C@@H:67]1[CH2:71][C@H:70]([SH:72])[CH2:69][N:68]1[C:73]([O:75][CH2:76][C:77]1[CH:82]=[CH:81][C:80]([N+:83]([O-:85])=[O:84])=[CH:79][CH:78]=1)=[O:74])[CH2:43][C:44]([N:46]1[CH2:50][CH2:49][C@H:48]([CH2:51][N:52]([CH3:66])[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:72][C@@H:70]3[CH2:69][N:68]([C:73]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][C:80]([N+:83]([O-:85])=[O:84])=[CH:81][CH:82]=4)=[O:74])[C@H:67]([CH:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:50][CH2:49][C@H:48]([CH2:51][N:52]([CH3:66])[C:53]([O:55][CH2:56][C:57]5[CH:58]=[CH:59][C:60]([N+:63]([O-:65])=[O:64])=[CH:61][CH:62]=5)=[O:54])[CH2:47]4)=[O:45])[CH2:71]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CN(C[C@H]1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(O)CC(=O)N4CC[C@H](CN(C)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 80.3 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (660.8 mg) and (2S,4S)-2-[1-hydroxy-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl)ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (683.5 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[1-hydroxy-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (841.4 mg) was obtained.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C1([OH:20])C=CC=CC=1>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:20])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: Oc1ccccc1
Product: Oc1ccc(-c2cccnc2)cc1

Procedure:
Using the procedure described above, 3-(4'-aminophenyl)pyridine (10.0 g, 0.059 mol) is converted to the phenol. A total of 7.66 g of product is obtained, after chromatography, which is then recrystallized from acetone-hexane to give 6.52 g (65% of theory) of off-white crystals which have as melting point of 202°-203° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[C:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[CH:22]1[CH2:24][CH2:23]1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.[ClH:43].CCOCC>O1CCOCC1>[ClH:43].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[C:34]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[CH:22]1[CH2:24][CH2:23]1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3ccccc3nc2Cc2ccccc2)C2CC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3ccccc3nc2Cc2ccccc2)C2CC2)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of (±)-{3-[[(3-benzylquinoxalin-2-yl)cyclopropylmethyl]-(4-methyl-benzoyl)-amino]-propyl}carbamic acid tert-butyl ester 7 (0.40 g, 0.71 mmol) in dioxane (5 mL) at rt was added 4 N HCl in dioxane (2.0 mL, 8 mmol). The reaction mixture was stirred overnight. It was added with Et2O and the precipitated solid was collected, washed with Et2O and dried in vacuo over P2O5 to give 8 (0.32 g, 90%). 1H NMR (CD3OD) δ 8.15 (m, 2H), 7.87 (m, 2), 7.36 (m, 4H), 7.22 (m, 5H), 6.56 (m, 1H), 5.52 (m, 1H), 4.75 (m, 1H), 4.23 (m, 1H), 3.69 (m, 2H), 3.65 (s, 3H), 3.06 (m, 1H), 2.39 (m, 4H), 2.10 (m, 1H), 1.98 (m, 1H), 1.85 (m, 1H), 1.46 (m, 1H), 0.63 (m, 2H), 0.46 (m, 1H), 0.29 (m, 2H); 13C NMR (CD3OD) δ 155.5, 142.3, 141.2, 135.2, 131.9,130.5, 130.1, 130.0, 129.8, 129.6, 128.0, 127.3, 68.5, 43.2, 41.8, 38.9, 30.5, 21.7, 14.4, 5.78; MS (ESI), (M+H)+465.31.
Reaction SMILES: [CH:1]([CH:3]([CH3:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O)=O.O.[NH2:16][NH2:17]>C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]([CH3:14])=[CH:1][NH:17][N:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C(C)C=O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2n[nH]cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
9.8 g (51.0 mmol) of the 2-formyl-4′-methoxypropiophenone synthesized in Step 1 was dissolved in 150 ml of ethanol. At room temperature, 3.8 g (61.2 mmol) of 80% hydrazine hydrate was dropwise added to the solution, followed by stirring at the same temperature for 1 hour and further by heating under reflux for 2 hours. After reaction had been completed, the reaction mixture was cooled to room temperature and the solvent was distilled away. As a result, 8.4 g (44.9 mmol) of 3-(4′-methoxyphenyl)-4-methylpyrazole was obtained as an orange oily matter. The yield was 88%. The product synthesized was subjected to the next reaction without purification.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C@@H:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:18])[CH2:16][OH:17])[C:6]1=[O:25])([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.Cl>N1C=CC=CC=1>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C@@H:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:15]([OH:18])[CH2:16][O:17][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[C:6]1=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1c(=O)n([C@@H](c2ccccc2)[C@H](O)CO)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2c(=O)n(C(C)(C)C)c3ccccc32)cc1

Procedure:
A solution of 1-tert-butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimidazol-2-one (0.55 g, 1.6 mmol) and para-toluenesulfonyl chloride (0.37 g, 1.9 mmol) in anhydrous pyridine (5 mL) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a cold 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phenyl-propyl ester. To a solution of (2S,3S)-toluene-4-sulfonic acid 3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phenyl-propyl ester (0.8 g, 1.6 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (4 mL, 8 mmol) and the reaction mixture stirred for 12 hours at room temperature in a sealed tube. Upon completion, the reaction was partitioned between a saturated aqueous solution of sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (silica, 20% MeOH in dichloromethane) to give 1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-methylamino-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour s. The ethanol was removed in vacuo and the clear oil was triturated with diethyl ether/dichloromethane to give 1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride as a white solid. HRMS: calcd for C21H27N3O2+H+, 354.21760. Found (ESI, [M+H]+), 354.2179.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][C:11]1[C:15](B(O)O)=[C:14]([CH3:19])[O:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:10][C:11]1[C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[C:14]([CH3:19])[O:13][N:12]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cc(C=O)c(C)o1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 3,5-dimethylisoxazole-4-boronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.4 g, 69%) as a yellow crystal.
Reaction SMILES: NC1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:8]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].S(OC)(OC)(=O)=O.CC(C)=O.[CH3:48][N:49]([CH3:52])[CH:50]=O>CC(C)=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[C:9]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[N:8][N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:50]([N:49]([CH3:52])[CH3:48])=[CH:3][CH:4]=3)[C:12](=[O:13])[CH:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2cc(=O)n(Cc3ccc(N)cc3)nc2-c2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(=O)n(Cc3ccc(N(C)C)cc3)nc2-c2ccc(OC)cc2)cc1
Temperature: 60 °C
Yield: 30.8 %

Procedure:
To a solution of 2-(4-aminobenzyl)-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (245 mg, 0.6 mmol) in acetone/N,N-dimethylformamide (5/1) (6 ml), sodium hydrogencarbonate (378 mg, 4.5 mmol) and a solution of dimethyl sulfate in acetone [an acetone solution of dimethyl sulfate (631 mg) (total volume: 5 ml); 3.0 ml, 3.0 mmol)] was added, followed by stirring under heat at 60° C. for 90 minutes. After the acetone was distilled off, the residue was extracted with ethyl acetate. The organic layer was washed successively with water and a brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off. The pale orange oil (238 mg) was separated and purified by silica gel preparative chromatography [developer: chloroform/methanol (20/1)], whereby 5,6-bis(4-methoxyphenyl)-2-[4-(dimethylamino)benzyl]-2H-pyridazin-3-one (80.6 mg, 30.8%) was obtained as a reddish brown oil from fractions having large Rf values. 1H-NMR (CDCl3) δ: 2.94(6H,s), 3.79(6H,s), 5.32(2H,s), 6.71(2H,d,J=8.79 Hz), 6.78(2H,d,J=8.79 Hz), 6.79(2H,d,J=9.03 Hz), 6.85(1H,s), 7.07(2H,d,J=8.79 Hz), 7.11(2H,d,J=9.03 Hz), 7.48(2H,d,J=8.79 Hz).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: Cc1ccc(B(O)O)cc1
Product: CNCC1Cc2cccc(-c3ccc(C)cc3)c2O1

Procedure:
The title compound was prepared (0.071 g, 34%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-methylphenylboronic acid (0.168 g, 1.24 mmol). mp 210-213° C.
Reaction SMILES: [CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:23](I)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH-].[K+].C(O)CCC>CO>[CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCI
Reactant: CCCCCCC1Cc2ccc(-c3ccc(O)cn3)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Product: CCCCCCCCCCOc1ccc(-c2ccc3c(c2)CC(CCCCCC)C3)nc1
Yield: 39.2 %

Procedure:
0.045 g (0.15 mM) of 2-hexyl-5-(5-hydroxypyridine-2-yl)indan, 0.05 ml (0.23 mM) of decyl iodide, 0.013 g (0.20 mM) of 85%-KOH and 1 ml of n-butanol were mixed and heat-refluxed for 130 minutes under stirring. After the reaction, methanol was added to the reaction mixture, followed by filtration under cooling with ice to obtain an insoluble matter. The insoluble matter was dried and purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1), followed by recrystallization from acetone to obtain 0.026 g of 2-hexyl-5-(5-decyloxypyridine-2-yl)indan (Yield: 39.2%). ##STR308##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)C=O.[OH:11]O>[OH-].[Na+]>[Br:1][C:2]1[CH:9]=[C:6]([OH:11])[C:5]([OH:10])=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=Cc1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(Br)cc1O
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of 5-bromo-2-hydroxybenzaldehyde (10 g, 50 mmol) was dissolved in a 1 N aqeuous NaOH solution (55 mL). To this yellow solution was added hydrogen peroxide (36%, 12 mL) dropwise via addition funnel at room temperature. After stirring for 2 h, the reaction was quenched by adding saturated solution of Na2S2O3, and extracted with EtOAc. The organic extract was washed with 1N HCl, water, brine, and passed through a short pad of silica gel to obtain 4-bromobenzene-1,2-diol (7.0 g, 74%) as a brown solid. 1H NMR (300 MHz, CDCl3) 7.02 (d, J=2.1, 1H), 6.91 (dd, J=8.8, 2.1, 1H), 6.73 (d, J=8.8, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.C1COCC1.[NH3:25]>C(O)(C)C>[NH2:25][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CO)CC1
Temperature: -78 °C

Procedure:
trans-[4-(8-chloro-1-iodoimidazo-[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (26.50 g, 67.66 mmol) was charged in a 400 mL steel bomb and was dissolved in 2M NH3 in isopropanol (300 mL) and anhydrous THF (10 mL). The reaction mixture was cooled to −78° C. Ammonia gas was bubbled vigorously into the solution for 8 min; then the bomb was tightly sealed and heated to 120° C. for 20 h. The crude reaction mixture was concentrated in vacuo, then the reaction residue was taken up with MeOH/CHCl3, loaded onto silica gel. The mixture was purified by a silica gel glass column chromatography [eluted with 1:1 CH2Cl2/EtOAc to 10%˜7 N NH3 in MeOH/CHCl3] to afford the desired product as a beige cream white solid; MS (ES+): m/z 373.01 (100) [MH+], 373.98 (50) [MH+2]; tR(polar-5 min/openlynx) 1.57 min.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][C:20]1([CH2:33][CH2:34][OH:35])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Si:1]([O:35][CH2:34][CH2:33][C:20]1([OH:19])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCO)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of 21.50 ml (82.50 mmol) of tert-butyldiphenylsilyl chloride in 15 ml of dichloromethane is added dropwise, under an inert atmosphere, to a solution of 18.4 g (75 mmol) of tert-butyl 4-hydroxy-4-(2-hydroxyethyl)-1-piperidinecarboxylate, obtained in step 12.1, and 11.60 ml (82.50 mmol) of triethylamine in 100 ml of dichloromethane, cooled to about 0° C. The mixture is allowed to warm to room temperature and stifling is then continued for 12 hours. Saturated aqueous ammonium chloride solution is added to the reaction medium. The aqueous phase is separated out and extracted twice with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 10/90 and then 20/80 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14](OC)=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:15][CH2:14][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2
Reactant: COC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(CO)[nH]c3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A solution of methyl 5,6-dimethoxy-3-(4-methoxyphenyl)indole-2-carboxylate (0.25 g) in tetrahydrofuran (10 ml) was dropwise added to a suspension of lithium aluminum hydride (LiAlH4) (56 mg) in tetrahydrofuran (10 ml) at room temperature, followed by stirring for 2 hours at room temperature. After adding water, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from acetone to give 2-hydroxymethyl-5,6-dimethoxy-3-(4-methoxyphenyl)-indole (0.145 g, 63%) as colorless prisms.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH3:6][C:7]1([CH3:14])[O:11][C@@H:10]([CH:12]=[O:13])[CH2:9][O:8]1>O1CCCC1>[CH3:6][C:7]1([CH3:14])[O:11][CH:10]([CH:12]([CH2:3][CH:2]=[CH2:1])[OH:13])[CH2:9][O:8]1
Reactant: C=CC[Mg]Br
Reactant: CC1(C)OC[C@H](C=O)O1
Solvent: C1CCOC1
Product: C=CCC(O)C1COC(C)(C)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirring -78° C. solution, under argon, of 556 ml of 1M allylmagnesium bromide is added, dropwise over 20 minutes, a solution of 36.4 g of product from Example 330 in 17 ml of tetrahydrofuran. The reaction mixture is stirred at -78° C. for 2 hours. Thin layer chromatography indicates the presence of starting material. An additional 280 ml of 1M allylmagnesium bromide is added and the reaction is stirred overnight at -78° C. The reaction is quenched with dropwise addition of saturated ammonium chloride, filtered through diatomaceous earth and washed with diethyl ether, ethyl acetate and 20% isopropyl alcohol/chloroform. The combined extracts are washed with saturated sodium chloride, dried and concentrated in vacuo to give after Kugelrohr distillation at 85° C., 38.25 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)C#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].CN(C=[O:31])C>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)=[O:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(Br)c2)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(Br)c2)n1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a stirred solution of (26) (40 g, 0.1M) in anhydrous DMF (300 ml) in a water bath under an atmosphere of nitrogen, was portionwise added 60% sodium hydride (4.92 g, 0.12M). After 30 min., oxygen gas was bubbled into the reaction mixture for 2 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 34.6 g (89%) of a white solid; m.p. 122-123° C.; 1H NMR (200 MHz, CDCl3) δ 1.17 (6H, d, J=7.1 Hz), 2.36 (3H, s), 2.77 (1H, m), 3.92 (3H, s), 4.05 (3H, s), 7.54-7.56 (2H, m), 7.75 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2(O)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:24]>O1CCOCC1>[ClH:24].[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C2=CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
A solution of tert-butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate (0.5 g, 1.5 mmol) in 1,4-dioxane (20 mL) was chilled to 0° C. and treated with a solution of HCl in 1,4 dioxane (4.0 M, 10 mL, 40 mmol). The reaction mixture was stirred at rt for 12 h, and then the solvents were removed to provide a crude compound which was triturated with diethyl ether to provide the desired product as a solid (1.2 g, 82%). LC/MS (Method 109) RT=1.798 min. (M+H)+=207.8; 1H NMR (300 MHz, DMSO-d6) δ 9.51-9.09 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.79-6.71 (m, 2H), 5.52 (t, J=1.5 Hz, 1H), 3.73 (s, 3H), 3.67 (br. s., 2H), 3.26 (d, J=4.5 Hz, 2H), 2.45 (d, J=1.9 Hz, 2H), 2.25 (s, 3H)