Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17](OS(C)(=O)=O)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)([O-:27])=[O:26]>CN(C=O)C>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][CH:17]([S:34][C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)[CH2:18][CH2:19]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Yield: 87.5 %

Procedure:
Potassium carbonate (0.45 g, 3.5 mmol) was added in one portion to a stirred solution of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.75 g, 2.5 mmol) and 4-nitrothiophenol (0.5 g, 3.2 mmol) in DMF (25 ml) and the mixture heated to 70° C. for 7 hours. After this time, the reaction mixture was concentrated under vacuum and re-dissolved in ethyl acetate (25 ml) and washed with NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The resulting residue was purified by column chromatography (elution: 60% heptane, 40% ethyl acetate) to afford the title compound (0.74 g, 68% yield) as an off-white solid. δH (250 MHz, DMSO) 8.14 (2H, d), 7.55 (2H, d), 3.89-3.69 (3H, m), 3.07-2.90 (2H, m), 2.04-1.89 (2H, m), 1.51-1.33 (10H, m).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1)(=[O:25])[CH3:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][CH:15]=[N:16][C:8]=2[C:7]1[C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[N:28][CH:29]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)cn1
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A mixture of 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (300 mg, 1002 μmol) and 2-acetamido-5-aminopyridine (Aldrich, St. Louis, Mo.) (152 mg, 1002 μmol) was suspended in THF (2 mL) and treated with LiHMDS (1.0 M in THF, Aldrich, St. Louis, Mo.) (4009 μl, 4009 μmol). The mixture was stirred for 16 h and then poured into saturated aqueous NaHCO3, extracting with EtOAc. Some dark orange insoluble material was observed. The EtOAc extract was dried (MgSO4), filtered and concentrated to give N-(5-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)pyridin-2-yl)acetamide (324 mg, 75% yield) as an orange solid. 1H NMR (CDCl3, 300 MHz) δ 12.35 (s, 1H), 9.73 (dd, 1H), 9.04 (s, 1H), 8.69 (bs, 1H), 8.37 (s, 1H), 8.35 (dd, 1H), 8.21 (bs, 2H), 8.00 (bs, 1H), 6.96 (dd, 1H), 5.89 (dd, 1H), 4.23 (m, 1H), 3.84 (m, 1H), 2.21 (s, 3H), 2.3-17 (m, 8H); m/z (API-ES) 431, (M+H)+.
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].[CH3:41][N:42]([CH2:72][C:73]([NH:75][C@H:76]1[CH2:80][CH2:79][N:78]([C:81]([C@@H:83]2[CH2:87][C@H:86]([SH:88])[CH2:85][N:84]2[C:89]([O:91][CH2:92][C:93]2[CH:98]=[CH:97][C:96]([N+:99]([O-:101])=[O:100])=[CH:95][CH:94]=2)=[O:90])=[O:82])[CH2:77]1)=[O:74])[C:43]([NH:58][C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=1)=[O:60])=[N:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=1)=[O:46]>>[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:88][C@@H:86]3[CH2:85][N:84]([C:89]([O:91][CH2:92][C:93]4[CH:98]=[CH:97][C:96]([N+:99]([O-:101])=[O:100])=[CH:95][CH:94]=4)=[O:90])[C@H:83]([C:81]([N:78]4[CH2:79][CH2:80][C@H:76]([NH:75][C:73](=[O:74])[CH2:72][N:42]([CH3:41])[C:43]([NH:58][C:59]([O:61][CH2:62][C:63]5[CH:64]=[CH:65][C:66]([N+:69]([O-:71])=[O:70])=[CH:67][CH:68]=5)=[O:60])=[N:44][C:45]([O:47][CH2:48][C:49]5[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=5)=[O:46])[CH2:77]4)=[O:82])[CH2:87]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CN(CC(=O)N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=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)N4CC[C@H](NC(=O)CN(C)C(=NC(=O)OCc5ccc([N+](=O)[O-])cc5)NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 53.5 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-diphenylphosphoryloxy-1-carbapen-2-em-3-carboxylate (936 mg) and (2S,4S)-2-[(3S)-3-[2-[1-methyl-2,3-di(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidin-1-ylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.30 g), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[(3S)-3-[2-[1-methyl-2,3-di(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (972 mg) was obtained as an amorphous substance.
Reaction SMILES: [N:1]1([CH:10]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([P:21](=[O:32])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([F:20])[F:19])=[CH:14][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Li]CCCC.[CH:44]([O:47][C:48]1[CH:60]=[C:59]([C:61]2[CH:66]=[CH:65][C:64]([CH2:67]Br)=[CH:63][CH:62]=2)[CH:58]=[CH:57][C:49]=1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])([CH3:46])[CH3:45]>CCCCCC.C1COCC1>[N:1]1([C:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([P:21]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:32])([F:19])[F:20])=[CH:16][CH:17]=2)[CH2:67][C:64]2[CH:63]=[CH:62][C:61]([C:59]3[CH:58]=[CH:57][C:49]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])=[C:48]([O:47][CH:44]([CH3:46])[CH3:45])[CH:60]=3)=[CH:66][CH:65]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(C)Oc1cc(-c2ccc(CBr)cc2)ccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(c2ccccc2)n2nnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Oc1cc(-c2ccc(CC(Cc3ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)ccc1C(=O)OC(C)(C)C

Procedure:
To a solution of di(tert-butyl) {4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-phenylethyl]phenyl}(difluoro)methylphosphonate (0.060 g, 0.110 mmol) in TRF (1.0 mL) were added n-BuLi 1.6 M in hexane (0.086 mL) and the bromide of Example 11, Step 1 (0.045 g, 0.111 mmol) in THF (1.0 mL). Then using the same protocol as described for Example 14 Step 1 the title compound was obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]([NH2:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21]>>[C:23]1([C:20]([NH:29][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)([CH3:22])[CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: CC(C)(N)c1ccccc1
Product: CC(C)(Nc1nccc(-n2cnc3ccccc32)n1)c1ccccc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with cumylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 330.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.37 (d, J=4.8 Hz, 1H); 8.05 (br s, 1H); 7.77 (d, J=7.6 Hz; 1H); 7.54 (d, J=7.8 Hz, 2H); 7.41 (m, 2H); 6.75 (d, J=5.5 Hz; 1H); 5.91 (br s, 1H); 1.81 (s, 6H).
Reaction SMILES: NC1C=C(OCCOC)C(OC)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[C:48]2[CH:49]=[C:50]([O:58][CH3:59])[C:51]([O:53][CH2:54][CH2:55][O:56][CH3:57])=[CH:52][C:47]=2[N:46]=[C:45]2[N:60](CC=C)[NH:61][C:62]([CH3:63])=[C:44]2[N:43]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[C:48]2[CH:49]=[C:50]([O:58][CH3:59])[C:51]([O:53][CH2:54][CH2:55][O:56][CH3:57])=[CH:52][C:47]=2[N:46]=[C:45]2[NH:60][NH:61][C:62]([CH3:63])=[C:44]2[N:43]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(OC)c(OCCOC)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COCCOc1cc(N)c(C(=O)c2ccccc2Cl)cc1OC
Product: COCCOc1cc2c(cc1OC)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-8-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVgg) was prepared by reacting 0.0023 moles of (2-amino-5-methoxy-4-(2-methoxyethoxy)phenyl)-(2-chlorophenyl)-methanone (Xgg) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-8-methoxyethoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVgg) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=413.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[C:19]([S:21]([CH3:23])=O)[N:18]=[C:17]([NH2:24])[N:16]=2)=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3.SC[CH2:27][CH2:28][OH:29].C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O.O>[NH2:24][C:17]1[N:18]=[C:19]([S:21][CH2:23][CH2:27][CH2:28][OH:29])[CH:20]=[C:15]([C:3]2[C:2]([Cl:1])=[CH:14][C:6]3[CH2:7][O:8][CH2:9][C:10]4[C:5]=3[C:4]=2[CH:13]=[CH:12][CH:11]=4)[N:16]=1
Reactant: OCCCS
Reactant: CS(=O)c1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SCCCO)cc(-c2c(Cl)cc3c4c(cccc24)COC3)n1
Temperature: 80 °C
Yield: 42.7 %

Procedure:
Partially purified 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine (29.1 mg) obtained in Step 5 of Example 314 was dissolved in N,N-dimethylformamide (1 mL), 3-mercapto-1-propanol (17 μL, 0.197 mmol) and N,N-diisopropylethylamine (55 μL, 0.316 mmol) were added, and this was stirred at 80° C. Four hours later, 3-mercapto-1-propanol (8 μL, 0.093 mmol) and N,N-diisopropylethylamine (23 μL, 0.132 mmol) were added, and this was stirred at 80° C. for another eleven hours. The reaction solution was cooled to room temperature, water (10 mL) and 1 N hydrochloric acid (1 mL) were added, and this was extracted with ethyl acetate (15 mL, 10 mL). The organic layers were combined, and then washed with 0.01 N hydrochloric acid (8 mL), water (8 mL), and brine (8 mL), then dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; methylene chloride:methanol=20:1), and thus, 3-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-propan-1-ol (compound 326) (13.4 mg) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:19](Cl)(=[O:21])[CH3:20]>ClC(Cl)C>[CH2:5]([C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCCCCCCCc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (22.6 g) is suspended in dichloroethane (500 ml) and octylbenzene (16) (21.5 g) is added at room temperature. To the mixture is added acetyl chloride (8.87 g) under ice-cooling. The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water and extracted with ether. The organic layer is washed with brine and dried over sodium sulfate. The solvent is evaporated to give 4′-octylacetophenone (18′) as a colorless oil.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:21](=[O:23])[CH3:22])[CH:15]=2)=[C:11]([C:33]#[N:34])[C:10]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=1[Cl:42])C=C.C(O)(=O)C.C(Cl)Cl.C1([SiH3])C=CC=CC=1>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.CCOC(C)=O.C(Cl)Cl>[C:33]([C:11]1[C:10]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[C:9]([C:5]2[NH:6][CH:7]=[CH:8][N:4]=2)[S:13][C:12]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:21](=[O:23])[CH3:22])[CH:15]=1)#[N:34]
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(N(Cc3ccc(OC)cc3)C(C)=O)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CN(C(C)=O)c2cc(-c3sc(-c4ncc[nH]4)c(-c4ccc(Cl)cc4Cl)c3C#N)ccn2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To the solution of N-{4-[5-(1-allyl-1H-imidazol-2-yl)-3-cyano-4-(2,4-dichlorophenyl)-2-thienyl]pyridin-2-yl}-N-(4-methoxybenzyl)acetamide (1.32 g, 1.61 mmol) and Tetrakis(triphenylphosphine)palladium(0) (93.1 mg, 0.0805 mmol) in Acetic acid (15 mL, 260 mmol) and Methylene chloride (30 mL, 500 mmol) under N2 atmosphere was added dropwise PHENYLSILANE (1.10 mL, 8.92 mmol). The mixture was stirred at 40° C. for 2 hours. The solvent was removed in rotavapor then the residue was dried in high vacuum to give a residue. The residue was chromatographed in silica column using 7N NH3-MeOH/DCM (1/99, ˜1 L), then EtOAc/DCM (30/70 to 60/40) to give an impure product. The second chromatograph using EtOAc/DCM (30/70 to 80/20) gave a pure product (0.469 g, yield 50.7%). LCMS: (AA) ES+, 574, 576; ES−, 572, 574. 1H NMR (400 MHz, d1-chloroform) δ: 8.60-8.62 (d, J=5.27 Hz, 1H), 7.71 (d, J=2.00 Hz, 1H), 7.63 (s, br, 1H), 7.55-7.57 (dd, J=5.27, 1.76 Hz, 1H), 7.50-7.52 (dd, J=8.28, 2.01 Hz, 1H), 7.40-7.42 (d, J=8.28 Hz, 1H), 7.18-7.20 (d, J=8.78 Hz, 2H), 7.07 (m, 2H), 6.80-6.82 (d, J=8.78 Hz, 2H), 5.14 (s, 2H), 3.76 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([C:12]2[C:13]([CH3:18])=[N:14][NH:15][C:16]=2[NH2:17])[CH:3]=1.[Cl:19][C:20]1[C:21]([OH:29])=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[CH:25]=O>C(O)(C(F)(F)F)=O>[Cl:19][C:20]1[CH:27]=[C:24]([C:25]2[C:3]3[C:2]([F:1])=[C:7]4[O:8][CH2:9][CH2:10][O:11][C:6]4=[CH:5][C:4]=3[C:12]3[C:13]([CH3:18])=[N:14][NH:15][C:16]=3[N:17]=2)[C:23]([F:28])=[CH:22][C:21]=1[OH:29]
Reactant: Cc1n[nH]c(N)c1-c1cc(F)c2c(c1)OCCO2
Reactant: O=Cc1cc(Cl)c(O)cc1F
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nc(-c3cc(Cl)c(O)cc3F)c3c(F)c4c(cc3c12)OCCO4
Yield: 11.1 %

Procedure:
A solution of 4-(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-methyl-1H-pyrazol-5-amine (100 mg, 0.40 mmol) and 5-chloro-2-fluoro-4-hydroxybenzaldehyde (70 mg, 0.40 mmol) in TFA (2 mL) was stirred at 90° C. for 16 h. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give 2-chloro-5-fluoro-4-(6-fluoro-1-methyl-8,9-dihydro-3H-[1,4]dioxino[2,3-g]pyrazolo[3,4-c]isoquinolin-5-yl)phenol (18 mg, 11% yield) as a yellow solid after lyophillization of the pure fractions. 1H NMR (400 MHz, d6-DMSO) δ 10.98 (s, 1H), 7.55 (m, 2H), 6.86 (dd, 1H), 4.44 (m, 4H), 2.74 (s, 3H); MS (EI) for C19H12ClF2N3O3: 404 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][C:14]31[CH:12]([CH2:13]3)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[C].[Pd].CO>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:17][NH:16][CH2:15][C:14]31[CH:12]([CH2:13]3)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC12CCC3CC31CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCC3CC31CNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 10% palladium-carbon catalyst (47.6 mg, 50 wt %) was added to a solution of 6-tert-butoxycarbonylamino-8-benzyloxycarbonyl-8-azatricyclo[4.3.0.01,3]nonane (derived from optical isomer A) (95.2 mg, 0.255 mmol) in methanol (2.55 mL) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred at room temperature for one hour. A 10% palladium-carbon catalyst (28.6 mg, 30 wt %) was added. After the atmosphere was replaced with hydrogen, the mixture was stirred at room temperature for one hour. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give 56.0 mg of the title compound as a black oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:58])([CH3:59])[CH3:60])=[CH:54][CH:55]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41])=[O:14]
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Reactant: CC(C)(C)C(F)(F)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(F)(F)c1ccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 5-chloronaphthalene-1-carboxylic acid (238 mg, 1.15 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol) and 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol (0.40 g, 1.09 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 5-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-1-naphthamide (252 mg, 42%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].CCOC(C)=O>CO.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of compound 54a (15 g, 51 mmol) in MeOH (100 mL) was added saturated NH4Cl solution (100 mL) followed by Fe(s) (9.1 g, 160 mmol). The resulting mixture was stirred for 5 h at 80° C. and then 200 mL of EtOAc was added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:5 v/v)) to obtain compound 54b as a black solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H20N2O2: 249.2 (M+H). Found 249.0.
Reaction SMILES: O1CCCC1.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C@@H:16]2[NH:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]2=O)=[CH:7]1.[OH-].[Na+]>O>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C@@H:16]2[NH:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17]2)=[CH:7]1
Reactant: O=C1[C@H](Cc2c[nH]c3ccccc23)NCCN1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CCN2CCN[C@@H](Cc3c[nH]c4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Combine lithiium aluminumhydride (100 mmol) and tetrahydrofuran (75 ml). Add (S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine (25 mmol) portionwise. Heat to reflux. After 24 hours, cool to ambient temperature. Carefully add water (3.8 mL), 15% aqueous sodium hydroxide solution (3.8 mL), and water (10.5 mL). Stir vigourously for 1 hour. Filter, rinse the filter cake repeatedly with tetrahydrofuran. Concentrate the filtrate in vacuo to obtain a residue. Chromatograph the residue to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1
Reactant: COC(=O)N=C(Nc1ccc(C(=O)c2ccccc2)cc1N)SC
Reactant: COc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccc(OC)cc2)C1=N)SC
Reaction time: 3 h

Procedure:
To a mixture of 3-amino-4-(3-carbomethoxy-S-methylisothioureido)benzophenone (3.43 g.; 0.01 mol) in benzene (100 ml.) there is added p-methoxybenzaldehyde (1.36 g.; 0.01 mol) and p-toluenesulfonic acid monohydrate (0.1 g.). The mixture is refluxed and stirred for 3 hours. The water reaction is removed by a Dean-Stark distillation receiver. The mixture is poured into an excess of hexane and the suspension formed is filtered. The filter cake is dried to afford 3-imino-(4-methoxyphenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.