Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[O:15][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Br)cc2)CC1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(Oc2ccccc2)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.7 %

Procedure:
To a solution of 4-[(4-bromophenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (370 mg, 1.00 mmol), phenol (141 mg, 1.50 mmol) and Ph3P (393 mg, 1.50 mmol) in THF (6 mL) at room temperature was added DIAD (0.295 mL, 1.50 mmol) dropwise. The mixture was stirred at room temperature for 2.5 hours. Aqueous work-up and purification gave 4-[(4-bromophenyl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (213 mg, 48%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C@@:8]3([C:21]4([CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]4)[N:20]4[C@@H:15]([C:16](=[O:41])[O:17][C@@H](C5C=CC=CC=5)[C@H]4C4C=CC=CC=4)[C@@H:14]3[C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=3[F:49])[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.Cl.[N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([C@@H:14]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=4[F:49])[C@H:15]([C:16]([OH:41])=[O:17])[NH:20][C:21]43[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]4)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1cccc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: O
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)O)[C@H](c1cccc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
1N sodium hydroxide solution (50 ml, 50 mmol) was added to a methanol (250 ml) solution of the compound (15.7 g, 23.4 mmol) obtained in Step 1 of Example 1 and the resulting mixture was heated to reflux overnight. After cooling, methanol (500 ml) and water (200 ml) were added to the reaction mixture and then the resulting mixture was neutralized by addition of 1N hydrochloric acid (50 ml) under ice cooling. Cerium (IV) diammonium nitrate (26.9 g, 49.1 mmol) was added under ice cooling, the resulting mixture was stirred for 20 minutes, then potassium carbonate (13.6 g, 98.3 mmol) was added and the resulting mixture was further stirred for 30 minutes. Insoluble matter was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was diluted with water, followed by extraction with ethyl acetate. The aqueous layer was further subjected to extraction with chloroform:methanol [5:1 (v/v)], the organic layers were combined and dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure and the residue was dried to give 6.54 g (57%) of the title compound as a pale yellow solid.
Reaction SMILES: C(OC([N:8](C)[C@@H:9]([CH2:13][C:14](C)(C)C)[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[NH2:8][C@@H:9]([CH2:13][CH3:14])[C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:11]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CC[C@H](N)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-N-(tert-butoxycarbonyl)-2-aminobutyric acid for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.33 (d, J=7.1, 1H), 7.57 (d, J=8.7, 2H), 6.61 (d, J=8.7, 2H), 4.38-4.30 (m, 1H), 3.52 (ddd, J=12.9, 8.7, 4.2, 2H), 3.32 (dd, J=10.1, 7.9, 1H), 3.21 (dd, J=9.7, 8.1, 1H), 3.00 (dd, J=9.9, 4.1, 1H), 2.75-2.61 (m, 2H), 2.34-2.10 (m, 2H), 2.11-1.96 (m, 2H), 1.92 (dtd, J=13.1, 7.9, 5.1, 1H), 1.81-1.71 (m, 1H), 1.62 (dq, J=12.7, 7.9, 1H), 1.40-1.30 (m, 1H), 1.03 (t, J=7.4, 3H); MS (ESI+) m/z 356 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[O:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][C:26](O)=[O:27]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:26](=[O:27])[CH2:25][CH:21]3[CH2:22][CH2:23][CH2:24][O:20]3)[N:11]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Reactant: O=C(O)CC1CCCO1
Product: O=C(CC1CCCO1)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O

Procedure:
The product from Example 29B and 2-(tetrahydrofuran-2-yl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.46-11.62 (m, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.40-8.43 (m, 1H), 7.93-8.06 (m, 2H), 7.75-7.79 (m, 2H), 7.69 (dd, J=5.0, 1.5 Hz, 1H), 4.16 (p, J=6.7 Hz, 1H), 3.79 (td, J=7.7, 6.1 Hz, 1H), 3.63 (td, J=7.8, 6.4 Hz, 1H), 2.57 (dd, J=14.2, 6.9 Hz, 1H), 2.44-2.52 (m, 1H), 1.99-2.07 (m, 1H), 1.78-1.95 (m, 2H), 1.57-1.66 (m, 1H); MS (APCI+) M/Z 385 (M+H)+.
Reaction SMILES: [CH:1]([N:14]([CH3:34])[CH2:15][CH2:16][N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1C(=O)C2C(=CC=CC=2)C1=O)([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.NN.O>C(O)C>[CH:1]([N:14]([CH3:34])[CH2:15][CH2:16][N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCCN1C(=O)c2ccccc2C1=O)CCN(C)C(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(CCCCN)CCN(C)C(c1ccccc1)c1ccccc1

Procedure:
Batch size: 20.8 g (45.6 mmol) 2-(4-{[2-(benzhydryl-methyl-amino)-ethyl]-methylamino}-butyl)-isoindol-1,3-dione and 4.6 g (91.9 mmol) hydrazine.hydrate in 200 ml ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.O.[OH-].[Na+].[I:18]I>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([I:18])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Nc1nc(O)cc(-c2ccccc2)n1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(O)c(I)c(-c2ccccc2)n1
Yield: 78 %

Procedure:
Following the procedure of Example 16 but substituting 21.4 g. (0.113M) of 2-amino-6-phenyl-4-pyrimidinol, 200 ml. water, 500 ml. chloroform, 5.6 g. sodium hydroxide and 28.8 g. I2, a yield of 29.0 g. (78%) of 2-amino-5-iodo-6-phenyl-4-pyrimidinol is obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH:9]2[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]([CH:13]=1)[CH2:11][CH2:10]2)(=O)=O.C([O-])(O)=O.[Na+].[F:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[N:37]1[C:41]([C:42]2[C:43]([NH2:57])=[N:44][CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=2)=[N:40][N:39]=[N:38]1>COCCOC.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]>[NH2:57][C:43]1[N:44]=[CH:45][C:46]([C:7]2[CH2:8][CH:9]3[N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:12]([CH:13]=2)[CH2:11][CH2:10]3)=[CH:47][C:42]=1[C:41]1[N:37]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=2[F:29])[N:38]=[N:39][N:40]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nnnn3-c3cccc(F)c3F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1C2C=C(c3cnc(N)c(-c4nnnn4-c4cccc(F)c4F)c3)CC1CC2
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
A solution of tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (50 mg, 140 μmol, 1.0 eq.) in DME (2 mL) was degassed with nitrogen for 15 minutes. NaHCO3 (1.2 mM solution, 350 μL, 420 μmol, 3 eq.) and 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (56 mg, 140 μmol, 1.0 eq.) were added and degassing was continued for an additional 30 minutes. PdCl2(dppf)2 (10 mg, 14 μmol, 0.1 eq.) was added and degassing was continued for an additional 15 minutes. The reaction was sealed and microwaved at 90° C. for 15 minutes. After cooling, the organic layer was concentrated, NaHCO3 was added, and the product was extracted with EtOAc. Silica gel chromatography (EtOAc/hexanes) provided tert-butyl 3-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (34 mg, 51% yield); 1H NMR (300 MHz, CDCl3): 8.25 (m, 1H); 7.6-7.25 (m, 3H); 7.07 (s, 1H); 6.4 (br s, 2H); 6.0 (m, 1H); 4.38 (m, 2H); 2.65 (m, 1H); 2.15 (m, 1H); 2.14-1.5 (m, 4H); 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3](C(O)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][C:3]1[C:2]([F:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: BrBr
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(C(F)(F)F)cnc1Br
Reaction time: 16 h
Yield: 28.7 %

Procedure:
The 3-fluoro-5-(trifluoromethyl)-picolinic acid (7.35 g, 0.035 mole) staring material was put into 150 ml of dry carbon tetrachloride and then red mercuric oxide (9.1 g, 0.042 mole) was added and the mixture was stirred and refluxed 1 hour and 25 minutes. A solution of bromine (6.7 g, 0.042 mole) in 20 ml of dry carbon tetrachloride was added slowly with the mixture at reflux over the next 2-1/3 hours. Light from a UV lamp was directed on the reaction mixture during the addition and the reaction mixture was refluxed for another hour. 25 Ml more of dry carbon tetrachloride was added and the refluxing was continued for about 16 hours more while UV radiation was applied. The reaction was then filtered through CELITE diatomaceous earth to remove the mercury salt. The carbon tetrachloride was removed on a still and the product was distilled over to yield 2.45 g of a yellow oil with analysis of, in percent by weight:
Reaction SMILES: [CH3:1][C:2]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)([CH3:5])[C:3]#[CH:4]>ClC1C=CC=CC=1Cl>[CH3:5][C:2]1([CH3:1])[O:6][C:7]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:4]=[CH:3]1
Reactant: C#CC(C)(C)Oc1ccc2ncccc2c1
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=Cc2c(ccc3ncccc23)O1

Procedure:
A solution of 6-[(1,1-dimethyl-2-propynyl)oxy]quinoline (16.7 mmol) in 1,2-dichlorobenzene (10 mL) was stirred at 180° C. for 1 hour. Upon the completion of the reaction, the solvent was distilled off, and the residue was recrystallized from hexane-ethyl acetate to obtain the aimed compound (2-steps, quant.).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Product: CS(=O)(=O)Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 7 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and N-(cis-2,3,4,4a,9,9a-Hexahydro-1H-indeno[2,1-b]pyridin-7-yl)-methanesulfonamide following a procedure analogous to that described in Example 1. Yield: 7% of theory; LC (method 1): tR=2.07 min; Mass spectrum (ESI+): m/z=411 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)=[CH:11][CH:10]=2)O1.I[C:38]1[O:39][CH:40]=[CH:41][N:42]=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>[O:39]1[CH:40]=[CH:41][N:42]=[C:38]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:31][C:32]([F:33])([F:34])[F:35])[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC1(C)OB(c2ccc(OCCN(CC(F)(F)F)c3ccc(C#N)c(C(F)(F)F)c3)cc2)OC1(C)C
Reactant: Ic1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc(N(CCOc2ccc(-c3ncco3)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 40B from 4-[(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}ethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 40A) and 2-iodo-1,3-oxazole (step A above), with the following exceptions: additional 2-iodo-1,3-oxazole (0.3 equiv) was added after 2 h of heating, additional Pd(PPh3)4 (0.005 g) was added after 4 h of heating, and heating was maintained for only 6 h: MS (ESI) m/z 456 (M+1).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([Cl:23])=[N:18][N:17]=[C:16]2Cl.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:30][NH2:31].CN1CCCC1=O>O>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([Cl:23])=[N:18][N:17]=[C:16]2[NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:27]([Cl:26])[CH:28]=1
Reactant: Clc1nnc(Cl)c2cc(Br)ccc12
Reactant: COc1ccc(CN)cc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1ccc(CNc2nnc(Cl)c3ccc(Br)cc23)cc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
5.2 ml DBU was added to a mixture of 3.8 g 6-bromo-1,4-dichlorophthalazine, 3.5 g 3-chloro-4-methoxybenzylamine hydrochloride and 30 ml 1-methyl-2-pyrrolidinone, and the mixture was stirred at 100° C. for 3 hr. After cooling, water was added to the reaction solution which was then extracted with ethylacetate. The extract was washed with brine. It was dried over anhydrous magnesium sulfate and filtered, and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography to give 1.8 g of the title compound as a less polar compound.
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:5])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH3:12][C:11]1[C:6]([CH:4]([NH2:1])[CH3:5])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccnc1C(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccnc1C(C)N
Yield: 76.4 %

Procedure:
A solution of the above azide (254 mg, 1.57 mmol) and PPh3 (828 mg, 3.16 mmol) in 10% aqueous THF (10 mL) was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica (CH2Cl2/MeOH, 9:1), giving 1-(3-methyl-pyridin-2-yl)-ethylamine as a yellow liquid (163 mg, 1.20 mmol, 76%). 1H NMR (CDCl3) δ 1.35 (d, 3H, J=6.6 Hz), 2.00 (s, 2H), 2.33 (s, 3H), 4.30 (q, 1H, J=6.6 Hz), 7.05 (dd, 1H, J=7.5, 4.8 Hz), 7.40 (d, 1H, J=7.5 Hz), 8.41 (d, 1H, J=4.2 Hz).
Reaction SMILES: C[O-].[Na+].[CH:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1.[C:12]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:14])[CH3:13]>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5](/[CH:4]=[CH:13]/[C:12]([C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)=[O:14])[CH:6]=1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: O=Cc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/c1cccnc1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
A 28% solution of sodium methoxide in MeOH (0.9 g) was added to a mixture of nicotinaldehyde (6.71 g) and 6-acetyltetraline (10.83 g) in MeOH (50 ml) and the mixture was stirred at room temperature for 12 hours. After removal of the solvent, the residue was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate =1:1) followed by recrystallization from hexane-ethyl acetate to give the titled compound (9.30 g).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:19]3[C:27](O)=[CH:26][C:22]4[CH2:23][CH2:24][O:25][C:21]=4[CH:20]=3)([CH2:17][OH:18])[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:17][O:18][C:27]4=[CH:26][C:22]5[CH2:23][CH2:24][O:25][C:21]=5[CH:20]=[C:19]34)[C:9]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1cc2c(cc1O)CCO2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCC3

Procedure:
Following the procedure described in EXAMPLE 1, and making non-critical variations using 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (43%): MS (ES+) m/z 446.4 (M+1).
Reaction SMILES: OC(CCC[CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13](N2)=O)CS1)=O.C1(=O)N([N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]2[S:28][S:29]CCC([O-])=O)C(=O)CC1>[Cl-].[Na+].C(O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28][S:29][C:13]1[CH:7]=[CH:8][CH:16]=[CH:11][N:12]=1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C([O-])CCSSC1C=CC=CN1N1C(=O)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(SSc2ccccn2)nc1
Reaction time: 0.5 h

Procedure:
RA-NAH prepared in the item (1) above was weighed in an amount of 10.4 mg, and dissolved in 2 ml of 0.1 M sodium chloride-0.1 M phosphate buffer (pH 7.5). 80 μl of a solution of 5 mM N-succinimidyl-3-(2-pyridyldithio)propionate (hereinafter, referred to as “SPDP”, Sigma-Aldrich Co.) dissolved in ethanol was added thereto, and the PDP reaction was carried out at room temperature for 30 minutes. The solution was dialyzed against distilled water to remove excessive SPDP, followed by freeze-drying, to thereby yield 9.5 mg of a freeze-dried product of PDP-NAH.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.Cl[C:14]1C=CC(C(O)=O)=N[CH:19]=1.BrC(CC)C>>[CH:11]([C:4]1[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH2:14][CH3:19])[CH3:12]
Reactant: CCc1cc(Cl)cnc1C(=O)O
Reactant: O=C(O)c1ccc(Cl)cn1
Solvent: CCC(C)Br
Product: CCC(C)c1cc(Cl)cnc1C(=O)O

Procedure:
The (RS)-3-sec-butyl-5-chloro-pyridine-2-carboxylic acid was prepared in analogy to the preparation of 5-chloro-3-ethyl-pyridine-2-carboxylic acid by treatment of 5-chloropyridine-2-carboxylic acid with 2-bromo-butane. The (RS)-3-sec-butyl-5-chloro-pyridine-2-carboxylic acid was obtained as a white solid (yield: 6% of theory). Mass (calculated) C10H12ClNO2 [213.66]; (found) [M+H]+=213, [M+2-H]+=215.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@@H:17]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18]1)[CH2:9][CH2:10]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CC#N.C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:18]2[C:19](=[O:22])[CH2:20][CH2:21][C@H:17]2[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCN(Cc1ccccc1)C[C@@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C1CC[C@H]2CN(Cc3ccccc3)CCN12
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Methanesulfonic acid 2-[benzyl-((S)-5-oxo-pyrrolidin-2-ylmethyl)-amino]-ethyl ester (2.9 g, 8.89 mmol) was dissolved in a mixture of CH3CN/THF (1/1, 40 ml) and then 60% NaH (462 mg, 11.56 mmol) was added portionwise at room temperature, under a nitrogen atmosphere. After stirring for 16 hours, the solvent was removed under vacuum and the residue was taken up with water and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4) and evaporated under vacuum. The residue was purified by flash chromatography (DCM/abs EtOH/Petroleum Ether/33% NH4OH/Et2O 300/180/900/9.9/360 respectively) to afford the title compound as a yellow oil (2 g, 97% yield).
Reaction SMILES: C1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])C=CC=CC=1.[C:25]1([CH2:31]S(Cl)(=O)=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH2:31][S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:8])=[O:9])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Product: CCOC(=O)c1c(NS(=O)(=O)Cc2ccccc2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxlyate and phenylmethanesulphonyl chloride.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([C:47]1[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:40])[CH3:39].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:40][C:38]([C:41]1[CH:46]=[CH:45][C:44]([O:1][CH2:2][C@@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])=[CH:43][CH:42]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH3:39]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)c1ccc(OC[C@@H]2CCC[C@@H]2N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.8 %

Procedure:
To an ice cold solution of (±) cis-1-hydroxymethyl-2-phthalimidocyclopentane (1.0 g, 4.08 mmol), triphenylphosphine (1.28 g, 4.9 mmol) and 4-cumylphenol (1.04 g, 4.9 mmol) in dry tetrahydrofuran (40 ml) was added diethyl azodicarboxylate (0.77 ml, 4.9 mmol). The mixture was allowed to warm to room temperature and stirred for 48 h. The reaction was poured into ice water (200 ml) and extracted into diethyl ether (3×100 ml). The combined extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by chromatography on a silica gel column eluting with 10-40% diethyl ether in petroleum ether 40-60. Pooling of pure fractions afforded the title compound as a colourless oil (0.48 g). Additional fractions afforded a further 0.76 g of product which was slightly contaminated with 4-cumylphenol.