Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)[CH2:45][C:46]([F:49])([F:48])[F:47])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cccc(CN(CC(F)(F)F)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (92 mg) in DMF (0.89 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (77 μL) and potassium carbonate (74 mg) at 0° C., and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was cooled to 0° C., potassium carbonate (246 mg) was added, and the mixture was stirred at 80° C. for 2 days. The reaction mixture was cooled to 0° C., 2,2,2-trifluoroethyl trifluoromethanesulfonate (256 μL) was added, and the mixture was further stirred at 80° C. for 3 days. The mixture was cooled to room temperature, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was directly used for the next reaction.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([NH:30][CH3:29])=[O:23])[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)O)c3)nc2N1C1CCCC1
Agent: Cl
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)NC)c3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 39, with (R)-1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-imidazole-4-carboxylic acid (Example 37) instead of (R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44), and with methylamine hydrochloride instead of dimethylamine hydrochloride. 1H NMR (CDCl3) δ: 8.52 (s, 1H), 8.34 (s, 1H), 7.76 (s, 1H), 4.30-4.41 (m, 2H), 3.46 (s, 3H), 3.30 (s, 3H), 3.01 (s, 3H), 1.73-2.16 (m, 10H), and 0.87 ppm (t, J=7.7 Hz, 3H); LCMS: 398.1 m/z (M+H)+; ret. Time: 3.367 min (Analytical Method A).
Reaction SMILES: O=C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:17][C:18](=[O:40])[NH:19][C@H:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:22][C:23]([O:25]CC1C=CC=CC=1)=[O:24])OCC1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:17][C:18](=[O:40])[NH:19][C@H:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 142 %

Procedure:
A suspension of (9S,13S)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate (4.30 g, 6.64 mmol), 10% Pd/C (1.0 g) and ammonium formate (4.0 g) in EtOH (70 mL) under a empty balloon was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite and washed with EtOAc. The solvent was evaporated to give (S)-4-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (4.07 g, 70%) which was used without further purification. ESMS m/z: 432.3 (M/2+H)+.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9]Br)[C:3]([O:5][CH3:6])=[O:4].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][C@H:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH3:6][O:5][C:3](=[O:4])[CH:2]1[CH2:7][CH2:8][CH2:9][N:32]1[C@@H:25]([CH3:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(Br)CCCBr
Reactant: C[C@H](N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCCN1[C@@H](C)c1ccccc1
Reaction time: 9.5 h
Yield: 78.1 %

Procedure:
Methyl (RS)-2,5-dibromovalerate (24.5 g) and toluene (19.8 g) were added to a 49% aqueous potassium carbonate solution (53.3 g), and heated to 80° C. (S)-α-methylbenzylamine (12.0 g) was added dropwise to the mixture obtained above at that temperature, and was stirred at that temperature for 9.5 hours. Water (33.9 g) was added to the reaction mixture, and then the organic layer was separated from the resulting mixture. Separated organic layer was washed with water, a 1% aqueous hydrochloric acid solution and water in this order, and concentrated under reduced pressure. Thus, N-[(S)-α-methylbenzyl]-(RS)-proline methyl ester (16.3 g) was obtained in a yield of 77.8%.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[NH:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH2:10][O:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>C(#N)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[N:14]([S:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])(=[O:31])=[O:30])[CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH2:10][O:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(CC2COCc3ccccc3CN2)cc1
Reactant: COc1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COc1ccccc1S(=O)(=O)N1Cc2ccccc2COCC1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a mixture of compound 3l (900 mg, 2.7 mmol) and TEA (546 mg, 5.4 mmol) in acetonitrile (30 mL) was added 2-methoxybenzene sulfonyl chloride (559 mg, 2.7 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at rt overnight. The solvent was evaporated in vacuo and purified by CC to give 3 as a white solid (510 mg, 38% yield).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:18]([C@H:26]1[CH2:35][C@H:34](O)[C@H:33]2[C:28]([CH:29]=[CH:30][C@H:31]([CH3:54])[C@@H:32]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH2:40]2)=[CH:27]1)[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:18][C@H:26]1[CH2:35][C@H:34]([O:12][C:11](=[O:13])[CH:10]([O:9][C:8]2[CH:16]=[CH:17][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[CH2:14][CH3:15])[C@H:33]2[C:28]([CH:29]=[CH:30][C@H:31]([CH3:54])[C@@H:32]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:48])[CH3:49])[CH2:40]2)=[CH:27]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccc(C(C)(C)C)cc1)C(=O)O
Product: CCC(Oc1ccc(C(C)(C)C)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 101 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 803 mg of (2RS)-2-(4-t-butylphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsiloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.41g of the title compound as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>C(NCC)C.C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][OH:15])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: c1ccccc1
Product: OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 50.2 %

Procedure:
In 50 ml of diethylamine were dissolved 5.0 g (22 mmol) of 4-bromo-α, α,α-trifluorotoluene and 1.25 g (22 mmol) of propargyl alcohol, and 80 mg (0.11 mmol) of bis(triphenylphosphine)palladium (II) chloride and 40 mg (0.22 mmol) of copper (I) iodide were added to the solution, followed by stirring of the resulting mixture at 50° C. for 35 minutes. To the mixture were added 40 mg (0.06 mmol) of bis(triphenylphosphine)palladium (II) chloride, and the resulting mixture was stirred for a further 35 minutes. After the mixture was cooled to room temperature, it was diluted with benzene and filtered, and then the filtrate was washed with water. After the mixture was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 50 g of silica gel and eluted with a mixed solvent of ethyl acetate-hexane (3:17) to obtain 2.21 g (yield: 50%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][C@H:10]2[CH2:11][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-tert-butyl-3-hydroxycyclobutylcarbamate (440 mg), p-toluenesulfonyl chloride (498 mg) and pyridine (0.74 mL) are dissolved in dichloromethane (7 mL) and a catalytic amount of 4-(dimethylamino)pyridine is added. The reaction mixture is stirred at ambient temperature overnight, concentrated, partitioned between ethyl acetate and water. The organic phase is washed with a 20% aqueous solution of citric acid, dried (MgSO4) and concentrated to give the title compound. Yield: 806 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[ClH:19]>C(O)C.C(OCC)(=O)C>[ClH:19].[ClH:19].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(N2CCC(C(=O)O)CC2)cc1
Reaction time: 8 h

Procedure:
In a 75-mL Parr bottle, 1-(4-nitrophenyl)piperidine-4-carboxylic acid (0.13 g, 0.52 mmol) is dissolved in ethanol/ethyl acetate (1:1, 30 mL). Concentrated hydrochloric acid (0.5 mL) is added. After degassing the mixture with dry ice, palladium on carbon (10%, 30 mg) is added. The reaction mixture is shaken overnight under 50 psi hydrogen, then filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 1-(4-aminophenyl)piperidine-4-carboxylic acid dihydrochloride.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:11][O:12][NH:13][CH3:14].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:13]([O:12][CH3:11])[CH3:14])=[O:6]
Reactant: CNOC
Reactant: O=C(Cl)CCC(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)CCC(F)(F)F
Temperature: 0 °C
Yield: 270.9 %

Procedure:
4,4,4-Trifluorobutyric acid chloride (6.4 g from above) in CH2Cl2 (80 ml) was treated with O,N-dimethylhydroxylamine hydrochloride (60.0 mmol, 5.85 g). The mixture was cooled to 0° C., then treated with pyridine (160.0 mmol, 12.9 ml), then allowed to warm to room temperature overnight. The mixture was diluted with CH2Cl2 (200 ml), then washed with brine(2×50 ml). Solvent was removed from the volatile product by simple distillation at atmospheric pressure to provide 20 g of 4,4,4-trifluoro-N-methoxy-N-methyl butyramide, which may be used without further purification. 1H NMR (CDCl3) δ3.70 (3H, s), 3.19 (3H, s), 2.78-2.65 (2H, m), 2.57-2.40 (2H, m).
Reaction SMILES: [CH3:1][O:2][O:3][CH2:4][C:5]1[N:25]=[C:8]2[N:9]([CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([O:23][CH3:24])[CH:15]=3)[CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1.[CH:26]1([NH-:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:13][CH:14]1[CH2:22][CH2:21][CH:17]([N:31]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:13][N:9]3[CH:10]=[CH:11][CH:12]=[C:7]4[N:6]=[C:5]([CH2:4][O:3][O:2][CH3:1])[N:25]=[C:8]34)=[CH:15][C:16]=2[O:23][CH3:24])[CH2:16][CH2:15]1
Reactant: COOCc1nc2cccn(Cc3ccc(C(=O)O)c(OC)c3)c-2n1
Reactant: [NH-]C1CCCC1
Product: COOCc1nc2cccn(Cc3ccc(C(=O)N(C4CCCC4)C4CCC(C)CC4)c(OC)c3)c-2n1

Procedure:
4-[(2-(methoxyoxymethyl)-4H-imidazo[4,5-b]pyridin-4-yl)methyl]-2-methoxybenzoic acid, N-2-methylcyclohexyl, N-cyclopentyl amide;
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:18][C:19]([O:21][CH3:22])=[O:20].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[Br:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:31])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Nc1nc2ccc(Sc3ccccc3)cn2c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)Nc1nc2ccc(S(=O)c3ccccc3)cn2c1Br
Reaction time: 1 h

Procedure:
Alternatively, one may treat a suspension of 3-bromo-2(methoxycarbonylamino)-6(phenylthio) imidazo [1,2-a] pyridine (1.0 gm. 2.64 mmoles) in 100 ml. of dichloromethane with 85% metachloroperbenzoic acid (464 mg., 2.64 mmoles). After 1 hour at room temperature, the solution is washed with aqueous saturated sodium bicarbonate solution, and with water. After drying the solvent is removed in vacuo and the residue is chromatographed over silica gel to yield 3-bromo-2-(methoxycarbonylamino)-6-phenylsulfinyl imidazo [1,2-a] pyridine m.p. 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:4]([N+:26]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[NH2:26][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)Oc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1Cl
Temperature: 45 °C
Yield: 82.7 %

Procedure:
A solution of 1,1-dimethylethyl 4-({4-chloro-5-[(1-methylethyl)oxy]-2-nitrophenyl}amino)-1-piperidinecarboxylate (D84, 260 mg, 0.63 mmol) in ethanol (40 ml) was treated with Raney Nickel followed by dropwise addition over 10 minutes of a solution of hydrazine hydrate (0.315 ml, 6.3 mmol) in ethanol. The mixture was heated at 45° C. for 1 hr, then the Raney Nickel was filtered off washing with ethanol and the filtrate concentrated under vacuum to afford the title compound as a purple coloured oil (200 mg, 83%).
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][C:7]3([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:8][CH:9]([CH2:11][C:5](O)([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[BrH:20]>C(O)(=O)C.O>[Br:20][C:5]12[CH2:6][C:7]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:8][CH:9]([CH2:10][C:3]([CH2:1][CH3:2])([CH2:12]3)[CH2:4]1)[CH2:11]2
Reactant: Br
Reactant: CCC12CC3CC(O)(C1)CC(c1ccccc1)(C3)C2
Solvent: O
Solvent: CC(=O)O
Product: CCC12CC3CC(Br)(C1)CC(c1ccccc1)(C3)C2
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Stir 0.03 mol of 1-ethyl-3-hydroxy-5-phenyl adamantane (III) with 100 ml of 40% HBr in glacial acetic acid for 20 min at 60° C. and for 30 min at room temperature. Subsequently dilute the reaction mixture with water and extract with ether. Wash the combined organic extracts with sodium chloride solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH3:13])[CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14].[CH2:19]([Li])CCC.CCCCCC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]([CH3:17])[CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH3:19])[CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14]
Reactant: [Li]CCCC
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-bromo-6-isopropyl-4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-quinoline (Intermediate 5, 6.81 g, 24.9 mmol), and 150 ml of anhydrous THF under argon at −78° C. was slowly added 1.6 M solution of n-butyl lithium and hexane (33 ml, 52.4 mmol). The reaction mixture was stirred at −78° C. for 10 minutes and thereafter N,N-cirmethylformamide (8.0 ml, 100 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 15 minutes and then quenched with saturated NH4Cl. The product was extracted with diethyl ether. The organic layer was washed with water and brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (silica, using 5% ethyl acetate in hexane) to give the title compound as a yellow oil.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]([O:18]C)=O)[CH:9]=[C:10]([CH:15]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:20]([O:23][CH3:24])(=[O:22])[CH3:21].C[O-].[Na+].Cl>CN(C)C=O.O>[CH3:14][O:13][C:11]([C:10]1[CH:9]=[C:8]([C:16](=[O:18])[CH2:21][C:20]([O:23][CH3:24])=[O:22])[CH:7]=[C:6]([N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[CH:15]=1)=[O:12]
Reactant: COC(C)=O
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Temperature: 55 °C
Yield: 8.9 %

Procedure:
A mixture of dimethyl 5-(pyrrol-1-yl)isophthalate (3.0 g), methyl acetate (0.86 g) and sodium methoxide (0.81 g) in N,N-dimethylformamide (21 ml) was heated at 55° C. for 3 hours. After being cooled to room temperature, the reaction mixture was poured into water (100 ml) and the whole was adjusted to pH 3 with 10% hydrochloric acid. The resulting precipitate was collected and washed with water. This crude product was purified by column chromatography on silica gel (150 ml) with benzene-ethyl acetate (30:1) as an eluent. The fractions containing the object product were collected and evaporated in vacuo. The residue was recrystallized from methanol to afford methyl 3-[3-methoxycarbonyl-5-(pyrrol-1-yl)phenyl]-3-oxopropionate (0.31 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:11]=1)=O)C.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:11]=1)=[O:3]
Reactant: CCOC(=O)c1ccc2c(-c3ccc(F)cc3)c(-c3cccc(C)n3)nn2c1
Reactant: CN(C)CCN
Product: Cc1cccc(-c2nn3cc(C(=O)NCCN(C)C)ccc3c2-c2ccc(F)cc2)n1
Yield: 10 %

Procedure:
Heat 3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-6-carboxylic acid ethyl ester (75 mg, 0.2 mmol) in 2 ml of N,N-dimethylethylenediamine at 90° C. for 6 hr in a sealed glass tube with stirring. Extract reaction solution once with water/methylene chloride and concentrate the organic layer in vacuo. Purify using preparative TLC (Silica Gel, 90:10 methylene chloride/methanol) to give 12 mg (10%) of the title compound MS ES+ m/e 418.2 (M+1).
Reaction SMILES: [K].[S:2]([NH2:6])([NH2:5])(=[O:4])=[O:3].[C:7](OCC)(=[O:13])[C:8](OCC)=[O:9]>C(O)(C)C.CO>[OH:9][C:8]1[C:7]([OH:13])=[N:6][S:2](=[O:4])(=[O:3])[N:5]=1
Reactant: NS(N)(=O)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: CO
Solvent: CC(C)O
Product: O=S1(=O)N=C(O)C(O)=N1
Yield: 145 %

Procedure:
The compound was prepared according to Carmack et al. (J. Org. Chem. 1975, 40, 2743) as follows. Potassium metal (10.0 g, 0.26 mol) was dissolved in cool isopropanol (50 mL) which was then diluted with methanol (50 mL). A methanolic solution (100 mL) of sulfamide (12.32 g, 0.13 mol) was added dropwise with vigorous stirring, followed by dropwise diethyl oxalate (17.4 mL, 0.13 mol). The resulting mixture was heated at reflux for 18 hours. The mixture was cooled, filtered, and the solid was washed with methanol and dried to give 28.3 g of 3,4-dihydroxy-[1,2,5]thiadiazole-1,1-dioxide as the di-potassium salt. This was stirred with PCl5 (90.0 g, 0.43 mol) at 150° C. for 10 minutes. When enough POCl3 was generated to maintain stirring, the mixture was cooled to 60° C. and stirred for 18 hours. The reaction was cooled, diluted with diethyl ether, filtered, and washed with additional diethyl ether. The ether filtrate was added dropwise to ethanol (500 mL) at 0° C. The resulting solution was heated to reflux for 1.5 hours, cooled, and concentrated to 1/4 volume. The diethoxy derivative was collected as a white solid (4.80 g). The mother liquor afforded an additional 1.80 g. (Total yield: 26%): mp 171°-172° C. (Th. 178°-179° C.); 1H NMR (CDCl3): δ 4.59 (q, 4H), 1.50 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:14][O:15]C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][S:12][CH:13]=2)=[CH:5][C:4]=1[CH:14]=[O:15]
Reactant: COc1ccc(-c2csnn2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2csnn2)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.99 grams (5.15 mmol) of 4-(4-methoxyphenyl)-1,2,3-thiadiazole (Maybridge Chemical Co.) in 23 mL of anhydrous methylene chloride (CH2Cl2) cooled to 0° C., was treated with 2.3 mL (21.9 mmol) of titanium tetrachloride and stirred for 30 min. The red solution was treated with 0.97 mL (10.7 mmol) of α,α-dichloromethyl methyl ether and allowed to warm to room temperature overnight. The reaction mixture was then poured over 100 mL of saturated aqueous sodium bicarbonate (NaHCO3), the pH was adjusted to 7-8 with solid NaHCO3 and the solution was then extracted with CH2Cl2. The organic layer was dried with magnesium sulfate (MgSO4) and concentrated to a yellow solid. Chromatography on silica gel (20% EtOAc: 80% Hexane) gave the pure title compound as a light yellow solid, 0.35 g (31%).