Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[CH2:26]([NH2:28])[CH3:27].C1COCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[CH2:26]([NH:28][C:23](=[O:24])[CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([N:15]2[C:7]3=[C:8]4[S:14][CH:13]=[CH:12][C:9]4=[N:10][CH:11]=[C:6]3[N:5]=[C:4]2[C@H:2]([OH:1])[CH3:3])[CH2:17][CH2:18]1)[CH3:27]
Reactant: CCN
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCNC(=O)C[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetic acid (11 mg, 0.031 mmol), 2.0 M ethylamine in THF (23 μL, 0.046 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (23 mg, 0.052 mmol) in N,N-dimethylformamide (0.4 mL) was added N,N-diisopropylethylamine (0.016 mL, 0.092 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with MeOH and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.8 mg, 15%). LCMS calculated for C20H27N4O2S (M+H)+: m/z=387.2. Found: 387.1.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[CH:35]=1)=[O:30]>>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[CH:35]=[C:31]1[C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[C:4]2[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:14])=[O:15])=[CH:17][CH:18]=1)=[O:30]
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Reactant: O=C(NCCCO)c1cc2ccccc2s1
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCNC(=O)c2cc3ccccc3s2)cc1
Yield: 19 %

Procedure:
The product of Example 2 (0.5 g, 1.58 mmol) was coupled to N-(3-hydroxypropyl)-1-benzothiophene-2-carboxamide (1.26 g, 5.37 mmol) using the procedure of Example 3 to provide 0.16 g (19% yield) of an off white solid. Electrospray Mass Spec: m/z 539.3 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[Cl:9][CH2:10][C:11](=O)[CH2:12]Cl>CCOC(C)=O>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:12]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cccs1
Solvent: CCOC(C)=O
Product: ClCc1coc(-c2cccs2)n1
Yield: 62.9 %

Procedure:
Thiophene-2-carboxamide (0.8 g, 6.29 mmol) and 1,3-dichloropropan-2-one (0.96 g, 7.55 mmol) were heated at 150° C. for 2.5 hours. The dark solid was dissolved in EtOAc and washed with aqueous NaHCO3, then the organic phase was dried over Na2SO4, filtered and evaporated to dryness. The dark brown oil was purified by flash chromatography (Petroleum ether/EtOAc=9/1) to obtain 4-(chloromethyl)-2-(thiophen-2-yl)oxazole (790 mg, 63% yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35]CC4C=CC=CC=4)=[C:31]([C@@H:43]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH2:44][CH2:45][N:46]([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH:30]=3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[NH:67][CH:68]=[O:69])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[Si:60]([O:59][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:67][CH:68]=[O:69])[CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([C@@H:43]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:44][CH2:45][N:46]([CH:47]([CH3:49])[CH3:48])[CH:50]([CH3:52])[CH3:51])[CH:30]=2)=[CH:22][CH:21]=1)([C:63]([CH3:66])([CH3:64])[CH3:65])([CH3:62])[CH3:61]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(NC=O)c3)cc2)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NC=O)c3)cc2)ccc1O)C(C)C
Temperature: 90 °C

Procedure:
N-{2-(benzyloxy)-5-[(1R)-2-({2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}ethoxy)phenyl]ethyl}amino)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]phenyl}formamide (Preparation 45, 174 mg, 0.18 mmol) was dissolved in methanol (20 ml) and ammonium formate (230 mg, 3.7 mmol) and 20% palladium hydroxide on carbon (26 mg) added. The stirred reaction was then heated at 90° C. for 2 hours. After cooling to room temperature, the mixture was filtered and solvent removed in vacuo. The residue was then taken up in ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organics were separated, washed with brine then dried (magnesium sulphate) and the solvent removed in vacuo to yield the title compound as a yellow glass, 180 mg.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([N:16]([CH2:31][CH2:32][S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[C:17](=[O:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=1)[CH3:15].[C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)#[N:39].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[C:38]([C:40]1[CH:45]=[CH:44][C:43]([C:2]2[C:7](=[O:8])[N:6]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH:14]([N:16]([CH2:31][CH2:32][S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH3:15])=[CH:42][CH:41]=1)#[N:39]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCS(=O)(=O)CCN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)C(C)c1nc2ccc(F)cn2c(=O)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCS(=O)(=O)CCN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)C(C)c1nc2ccc(F)cn2c(=O)c1-c1ccc(C#N)cc1
Yield: 54.6 %

Procedure:
E5 (66.8 mg, 0.11 mmol), 4-cyanophenyl boronic acid (20 mg, 0.13 mmol), and Pd(dppf)2Cl2 (9 mg, 0.01 mmol) was added into a 10 mL CEM microwave tube, followed by THF (1.1 mL) and sodium carbonate (0.55 mL, 2M). The mixture was reacted by microwave at 150° C. for 10 min and then partitioned between water and ethyl acetate. Column chromatography with gradient dichloromethane:ethyl acetate (4:1 to 3:1 to 2:1) afforded 38 mg 7.01 as a yellow foamy solid in a racemic mixture. Additional amounts of 7.01 were prepared and combined.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](Cl)=[O:24]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:23](=[O:24])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:8]2
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCCN[C@H]1CCc2cccc(OC)c2C1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCN(C(=O)Cc1cccs1)[C@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A4-1 when using 310 mg (1.4 mmol) enantiomerical pure (S)—N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R═OMe) and 0.35 mL (2.8 mmol) 2-thienyl acetic acid chloride. Flash chromatography was done with hexane/ethyl acetate 20/1.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:43])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@@H:25]([C:27]([O:29]CC3C=CC=CC=3)=[O:28])[CH3:26])[N:21]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:43])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@@H:25]([C:27]([OH:29])=[O:28])[CH3:26])[N:21]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 2.1 g 4-(2-{[5-((R)-1-Benzyloxycarbonyl-ethoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-acetyl)-piperazine-1-carboxylic acid butyl ester in 60 ml ethyl acetate were added 0.4 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite, washed with ethyl acetate and concentrated to give the crude product which was used in the subsequent reaction. Yield: 1.8 g
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=4)[CH:16]=[CH:17][C:11]=3[C:10](=[O:29])[NH:9][C:8]=2[CH:30]=1.[Cl:31][C:32]1[N:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CO.CS(C)=O>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[NH:13][C:12]4[CH:14]=[C:15]([C:18]5[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=5)[CH:16]=[CH:17][C:11]=4[C:10](=[O:29])[NH:9][C:8]=3[CH:30]=2)=[CH:34][CH:33]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCO)cc2NC3=O)ccc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(Cl)nc4)cc2NC3=O)ccc1[N+](=O)[O-]

Procedure:
A mixture of Example 239 (41 mg, 0.1 mmol), 6-chloro-pyridin-3-ol (19 mg, 0.15 mmol), PPh3 (39 mg, 0.15 mmol), and di-tert-butyl azodicarboxylate (35 mg, 0.15 mmol) in THF (2 ml) was stirred at room temperature for 16 hours. The reaction mixture was diluted with MeOH/DMSO (1:1), and purified by preparative HPLC to provide the desired product. MS (ESI) m/e 517 (M+H)+; 1H NMR (499 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.11 (d, J=3.12 Hz, 1H), 8.01 (d, J=8.42 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J=8.11 Hz, 1H), 7.52 (s, 1H), 7.47 (m, 1H), 7.40 (d, J=8.73 Hz, 1H), 7.34 (m, 2H), 7.30 (dd, J=8.11, 1.56 Hz, 2H), 6.95 (m, 2H), 4.21 (t, J=6.55 Hz, 2H), 4.03 (s, 3H), 2.92 (t, J=6.55 Hz, 2H).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40]([NH:46][CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 33 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 33% yield: mp 177-179° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.50 (d, J=3.9 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.29-7.21 (m, 3H), 7.04-6.97 (m, 2H), 6.26 (t, J=5.7 Hz, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.42 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 162.6, 160.8, 157.3, 155.3, 153.6, 148.5, 136.0, 134.1, 131.3, 129.9, 123.7, 116.9, 115.9, 115.6, 47.2, 42.0, 41.6, 41.3, 17.2; MS (ES+) m/z 475.0 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccnn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccnn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (391 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (263 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([CH:5]1[C:9](=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:20])[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[OH:21]O.[H-].[Na+].[Cl-].[NH4+]>CO>[O:21]1[C:6]2[CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:9](=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:20])[C:7]1=2
Reactant: CCCCC1C=CC(=O)C1=CCCCCCC(=O)OC
Reactant: OO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CO
Product: CCCCC1C(=CCCCCCC(=O)OC)C(=O)C2=C1O2
Yield: 72 %

Procedure:
660 mg (2.37 mmol) of 4-butyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone was dissolved in 10 ml of methanol. With ice cooling and stirring, 1.2 ml of 30% aqueous hydrogen peroxide and then 0.23 ml of 1N sodium hydride were added to the solution and the mixture was stirred at 0° C. for 20 minutes. Saturated aqueous ammonium chloride was added thereto and was extracted with hexane. The organic layer was washed with a saturated saline solution, dried over sodium sulfate anhydride, filtered, concentrated, and chromatographed on a column of silica gel (silica gel, 30 g; eluent, hexane:ethyl acetate=10:1) to obtain 500 mg (yield 72%) of 2,3-epoxy-4-butyl-5-(6-methoxycarbonylhexylidene)cyclopentenone.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@@H:51]([O:52][C:53](=[O:60])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C@H:50]([O:61][C:62](=[O:69])[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C@@H:49]([CH2:70][O:71][C:72](=[O:79])[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[O:48][CH:46]1[OH:47])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:80][C:81]([Cl:85])([Cl:84])[C:82]#[N:83].CCCCCC.CCOC(C)=O>C(Cl)Cl.C1CCN2C(=NCCC2)CC1>[Cl:80][C:81]([Cl:85])([Cl:84])[C:82](=[NH:83])[O:47][CH:46]1[O:48][C@H:49]([CH2:70][O:71][C:72](=[O:79])[C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)[C@@H:50]([O:61][C:62](=[O:69])[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C@H:51]([O:52][C:53](=[O:60])[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C@@H:45]1[O:44][C@H:11]1[O:12][C@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:10]1[O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: O=C(OC[C@H]1O[C@H](O[C@@H]2C(O)O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N=C(OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1O[C@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
To a pre-cooled (0° C.) solution of 29 (609 mg, 0.569 mmol) in anhydrous DCM (2.8 mL, 0.2 M) was added trichloroacetonitrile (114 μL, 1.138 mmol, 2 eq). A solution of DBU (4.3 μL, 0.05 eq, 0.0285 mmol) in anhydrous DCM (0.3 mL) was added. The mixture was stirred at 0° C. for 4 h and TLC (hexane-EtOAc=65:35) indicated complete conversion. The crude mixture was evaporated onto silica gel and purified by silica column chromatography (2.5×14 cm, gradient elution with hexane-EtOAc-Et3N 210:20:0.5, 200:50:0.5, 180:60:0.5, 150:70:0.5). The product fractions were combined, evaporated and dried in a vacuum desiccator over P2O5 o/n to give the trichloroacetimidate 30 as white foam (530 mg, 77%), used without further purification in the next step.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]([C:8]1[C:9]([NH:13][NH2:14])=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].C[O:16][C:17](=O)[N:18]=[C:19](SC)[C:20]([C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[C:35]=1[F:46])=[N:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[N:13]1[C:17](=[O:16])[NH:18][C:19]([CH:20]([C:34]2[CH:43]=[C:42]([O:44][CH3:45])[C:37]3[O:38][CH2:39][CH2:40][O:41][C:36]=3[C:35]=2[F:46])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]=[C:31]([CH3:33])[O:30][N:29]=3)=[CH:24][CH:23]=2)=[N:14]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c[nH]nc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)OCCO2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A solution of 62 mg of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)), 106 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 41d) and 88 μl of triethylamine in 5 ml of DMF was heated at 85° C. for 15 hours under a nitrogen atmosphere with stirring. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in 8 ml of methanol, and then 133 mg of sodium cyanotrihydroborate, 49 μl of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (68 mg) as a light green solid.
Reaction SMILES: [OH:1][CH:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[S:10][C:11](=S)[S:12][C:4]=2[C:3]1=[O:14].[OH2:15]>CC(C)=O.C(O)(=O)C.[Hg](OC(C)=O)OC(C)=O>[OH:1][CH:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[S:10][C:11](=[O:15])[S:12][C:4]=2[C:3]1=[O:14]
Reactant: O
Reactant: CC1(C)OC(O)C(=O)c2sc(=S)sc21
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC1(C)OC(O)C(=O)c2sc(=O)sc21
Reaction time: 0.17 h

Procedure:
13 mg (0.05 mmol) of 6-hydroxy-4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-7(6H)-one 6 was dissolved in acetone (5 mL) and added to a solution of Hg(OAc)2 (50 mg, 0.15 mmol) in 1 ml of acetic acid. The color of the reaction mixture changed very fast from yellow to white. The solution was stirred for 10 minutes and then 20 mL of water was added. The resulting mixture was extracted with CH2Cl2 (3×5 mL). The organic layer was separated and then was washed with saturated aqueous NaHCO3 (10 mL). The organic layer was separated again and the aqueous layer was re-extracted again with CH2Cl2 (2×5 mL). The organic layers were combined and evaporated to get 6-hydroxy-4,4-dimethyl-4H-[1,3]dithiolo[4,5-c]pyran-2,7(6H)-dione 8 as a pale beige oil. Yield: 7 mg (0.03 mmol, 57%). 1H NMR in CDCl3 (δ, ppm): 5.51 (1H, s, hemiacetal), 1.74 (3H, s, CH3), 1.68 (3H, s, CH3). 13C NMR in CDCl3 (δ, ppm): 187.09, 181.81, 159.93, 124.38, 91.15, 76.16, 31.47, 28.27. IR (neat, cm−1): 3419, 2978, 2929, 2864, 1670, 1625, 1548.
Reaction SMILES: [N:1]([C:4]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([CH3:21])[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8]2[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>CCO.O.[Zn]>[CH3:20][N:17]1[CH2:18][CH2:19][C:7]2[N:6]([CH2:5][C:4]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([NH2:1])[CH3:21])[C:14]3[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=3[C:8]=2[CH2:16]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(N=[N+]=[N-])c2cccnc2)CCN(C)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(C)(N)c2cccnc2)CCN(C)C1
Temperature: 80 °C
Yield: 0.4 %

Procedure:
5-(2-Azido-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Crude) (500 mg, 1.4 mmol) was dissolved in EtOH (4 mL) and water (1 mL). Ammonium chloride (243 mg, 4.5 mmol) followed by zinc dust (293 mg, 4.5 mmol) were added to the reaction mixture and heated at 80° C. for 1 h. The reaction mixture was concentrated to dryness, basified with aqueous ammonia solution and extracted with EtOAc (150 mL). The organic layer was dried over sodium sulfate, evaporated in vacuo and purified by reverse phase HPLC to afford 2 mg of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-amine. 1H NMR (CD3OD, freebase): δ (ppm): 8.39 s (1H), 8.3 d (1H), 7.72 d (1H), 7.32 t (1H), 7.11 (1H), 6.91 d (1H), 6.8 d (1H), 4.18 dd (2H), 3.61 dd (2H), 2.7 m (2H), 2.46 s (3H), 2.35 s (3H), 2.26 m (2H). Chiral HPLC provided enantiomers 149a and 149b.