Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]2[N:14]=[C:15](N)[N:16]=[C:4]2[N:3]=1.N([O-])=O.[Na+].C(OCC)(=O)C.O.[BrH:29]>C(O)(=O)C.C(Cl)Cl.C(OCC)(=O)C.C(Cl)Cl>[Br:29][C:15]1[N:16]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]2[N:14]=1
Reactant: Cc1cc(-c2ccccc2)n2nc(N)nc2n1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2)n2nc(Br)nc2n1
Temperature: 25 °C

Procedure:
To 2.0 g (8.9 mmol) of 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidin-2-amine stirring in a mixture of 20 ml of 48% hydrobromic acid and 10 ml of glacial acetic acid, 2.0 g (29.0 mmol) of sodium nitrite was slowly added portionwise with good stirring at ambient temperature. The thick suspension was stirred at about 60° C. for 15 minutes followed by stirring another 10 minutes without heat. Ethyl acetate (150 ml) and excess water were added. The ethyl acetate layer was separated whereby a certain amount of insoluble material present was ignored and the extract washed with water (2X), saturated sodium bicarbonate, brine, dried over magnesium sulfate, and evaporated in vacuo to give a solid residue. Silica gel column chromatography (methylene chloride followed by 10:1 methylene chloride/ethyl acetate) afforded the title compound, 15 m.p. 178°-180° C.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C:36]1([O:39]C(=O)C)[CH2:38][CH2:37]1)=[O:35]>>[OH:39][C:36]1([C:34]([N:2]2[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3]2)=[O:35])[CH2:38][CH2:37]1
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Agent: Cl
Product: O=C(N[C@@H]1CCN(C(=O)C2(O)CC2)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[C:20]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[N:19]=2)[CH2:14][CH2:13]1>>[CH3:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:23]([NH:24][C:8]([C:6]3[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:10])=[CH:22][CH:21]=[C:20]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[N:19]=2)[CH2:16][CH2:17]1
Reactant: CC1CCN(c2nc(N3CCN(C)CC3)ccc2N)CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Product: CC1CCN(c2nc(N3CCN(C)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1

Procedure:
The title compound was prepared according to the procedure from Example 4, step (c) using 2-cyano-5-furancarboxylic acid (as prepared in Example 1) and 4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine (as prepared in the previous step). Purification of the resulting residue by silica gel preparative TLC eluting with 10% methanol in dichloromethane afforded the title compound in 50% as a yellow glass. 1H-NMR (400 MHz, CDCl3): δ 8.76 (br s, 1H), 8.410 (d, 1H, J=8.8 Hz), 7.24 (d, 1H, J=3.7 Hz), 7.21 (d, 1H, J=3.7 Hz), 6.37 (d, 1H, J=8.8 Hz), 3.53 (m, 4H), 3.21-3.18 (m, 2H), 2.85 (m, 2H), 2.52 (m, 4H), 2.34 (s, 3H), 1.82-1.79 (m, 2H), 1.57 (m, 1H), 1.47-1.37 (m, 2H) 1.05 (d, 3H, J=6.5 Hz). NOE 1H-NMR experiments confirmed the correct regiochemical assignment. LC-MS (ESI, m/z): Calcd. for C22H29N6O2, 409.2 (M+H); found: 409.2.
Reaction SMILES: [CH3:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([CH3:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH2:45])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27].CC(C)N=C=NC(C)C>>[CH3:1][C:2]1[C:15]([NH:16][C:17]2[NH:20][C:21]3[C:22]([N:45]=2)=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([C:26](=[O:27])[NH:28][C@H:29]2[CH2:30][CH2:31][C@H:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]2)[CH:39]=3)=[C:14]([CH3:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N=C=S
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Agent: CC(C)N=C=NC(C)C
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1Nc1nc2nc(OCC(F)F)c(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)cc2[nH]1

Procedure:
The title compound is prepared from N-(2,4-dimethyl-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (65 mg, 0.24 mmol) and 5,6 diamino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (90 mg, 0.24 mmol) with DIC in analogy to examples 8a/8b.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:10].BrBr>C(O)(=O)C>[BrH:10].[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccncc1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccncc1
Reaction time: 2 h
Yield: 129.8 %

Procedure:
To a stirred solution of 4-acetyl pyridine (3.62 g, 29.88 mmol) in acetic acid (30 mL) is added a 48% aqueous solution of hydrogen bromide (5.3 mL, 47.16 mmol). Bromine is added (1.6 mL, 31.14 mmol) drop wise in 4 equal portions. The reaction is stirred for about 2 hours and a solid precipitated. Bromine (1.6 mL, 31.14 mmol) is added and the reaction is stirred overnight. The resulting precipitate is collected, washed with diethyl ether, and dried under vacuum to give the title compound (8.6 g, 102%). 1H NMR (d6-DMSO) δ 9.02 (d, 2H), 8.17 (d, 2H), 5.08 (2H)
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[C:13]([O:17][C:18](=[O:36])[NH:19][C:20]([N:29]1[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]1)=[N:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:24]([O:23][C:22](=[O:28])[NH:21][C:20]([N:29]1[CH2:34][CH2:33][CH:32]([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:31][CH2:30]1)=[N:19][C:18](=[O:36])[O:17][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:25])([CH3:26])[CH3:27]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a mixture of N-hydroxyphthalimide (1.89 g, 11.62 mmol), di-tert-butyl[(4-hydroxypiperidin-1-yl)methylylidene]biscarbamate 63 (2.00 g, 5.81 mmol, US 2004/209921 A1) and triphenylphosphine (3.05 g, 11.62 mmol) in THF (100 mL) was added diisopropyl azodicarboxylate (2.47 mL, 12.78 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 64 (0.9 g) as a white solid.
Reaction SMILES: [OH-].[Na+:2].[CH:3]([N:5]1[CH:14]([C:15]([NH:17][C:18]2([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:19]2=[O:32])=[O:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]>C(O)C>[CH:3]([N:5]1[CH:14]([C:15]([NH:17][C:18]2([CH2:33][CH2:34][C:35]([O-:37])=[O:36])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:19]2=[O:32])=[O:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[Na+:2]
Reactant: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)C2Cc3ccccc3CN2C=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCN1C(=O)C(CCC(=O)[O-])(NC(=O)C2Cc3ccccc3CN2C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.79 ml of 1N sodium hydroxide was added to 30 ml of an ethanol solution of 1.70 g of ethyl 3-[3-(2-formyl-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonylamino-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl]propionate. The mixture was stirred at room temperature for 4 hours. After removal of solvent, the residue was dissolved in water, washed with water with diethyl ether, made acidic with 10% hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was further extracted with a sodium hydrogen carbonate aqueous solution. The extract was adsorbed by a nonionic adsorption resin (trade name: HP-20, produced by Mitsubishi Kasei Corporation) and eluted with water and a water-methanol (1:1) mixed solution. The eluate was lyophilized to afford 1.24 g of sodium 3-[3-(2-formyl-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonylamino-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl]propionate as a pale yellow powder. IR (Nujol) (cm-1): 3680 to 2400 (br) , 1710, 1660, 1610, FAB-MS (m/z): 522 (MNa+), 500 (MH+, base).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]ncc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 39 %

Procedure:
The title compound is prepared from 1H-indazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 39% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=332 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:17].BrBr>C(Cl)(Cl)Cl>[NH:22]1[CH:21]=[CH:20][N:19]=[C:18]1[C:16]1[S:17][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[N:15]=1
Reactant: COc1ccc(-c2ccccc2)cc1NC(=S)c1ncc[nH]1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccccc2)c2sc(-c3ncc[nH]3)nc12
Yield: 32.5 %

Procedure:
0.049 g of 1H-Imidazole-2-carbothioic acid (4-methoxy-biphenyl-3-yl)-amide (0.16 mmol) was taken up in chloroform and treated with 8.1 μl of Br2 (0.16 mmol) for 4 h at reflux. Then the reaction was quenched with sodium thiosulfate (38%) and extracted with chloroform. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography (silica gel, methylene chloride/methanol 40:1) to yield 0.016 g of 2-(1H-imidazol-2-yl)-4-methoxy-7-phenyl-benzothiazole (33%) as a colorless solid; M.p.: 205–206° C.
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]1[O:8][N:7]=[C:6]([C:9]2[CH:27]=[CH:26][C:12]([O:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([CH3:25])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5]1.Cl>C1COCC1>[CH3:25][C:17]1[CH:16]=[C:15]([CH2:14][O:13][C:12]2[CH:26]=[CH:27][C:9]([C:6]3[CH2:5][CH:4]([CH:3]=[O:2])[O:8][N:7]=3)=[CH:10][CH:11]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: COC(OC)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(C3=NOC(C=O)C3)cc2)c2ccccc2n1
Yield: 28.9 %

Procedure:
The product from step 10a (0.4 g, 1.0 mmol) was dissolved in THF (5 mL) and 6 N HCl (5 mL) and heated to 60° C. for 2.5 h. The reaction was cooled and concentrated, and the aqueous layer was neutralized with NaOH and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The oil was purified with FCC eluting ethyl acetate:methylene chloride (80:20) to give 3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazole-5-carbaldehyde (0.1 g, 72%) as an oil. MS found: (M+H)+=347.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:22][CH:4]1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[CH:9][CH:8]=1.[CH3:23]I.O>CN(C)C=O>[O:3]1[CH2:22][CH:4]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH3:23])[CH:15]=[C:16]([C:18]([F:20])([F:19])[F:21])[N:17]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 g of sodium hydride dispersion (55% in oil) are added, while cooling in an ice bath, to a solution of 12 g of 2-[4-(2,3-epoxypropoxy)-phenyl]-4-(trifluoromethyl)-imidazole (J. med. Chem. 20, 1024 (1977)) in 90 ml of dimethylformamide and the yellow suspension is stirred for 11/2 hours at room temperature. After the addition of 8 ml of methyl iodide, stirring is continued for a further 12 hours at room temperature, the reaction mixture is subsequently poured into water and extracted several times with ethyl acetate. After separating off the organic phase and removing the solvent, the residue is dissolved in chloroform and filtered over silica gel. The filtrate is again concentrated by evaporation and the residue is recrystallized from ether/hexane, yielding 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-4-(trifluoromethyl)-imidazole having a melting point of 65°-68°.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:30][NH:29][C:21]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[O:28])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)c1ccncc1
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccncc1

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and isonicotinic acid hydrazide (580.1 mg, commercially available), the title compound was afforded (quantitative).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>CO>[N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCCC1
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCN1CCCC1
Yield: 59.7 %

Procedure:
N-[3-(1-Pyrrolidinyl) propyl] phthalimide (729 mg) and hydrazine monohydrate (284 mg) were dissolved in methanol (9 ml) and the resulting solution was refluxed with heating for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure followed by addition of a 4N sodium hydroxide aqueous solution to the resulting residue and extraction thereof with chloroform. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (Reference Compound 2-1, 216 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1.C([O-])(=O)C.[Cs+]>CS(C)=O.O.[Cu]>[C:11]([O:10][C:9](=[O:15])[NH:8][C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:3][CH2:4]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: Cc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To a round bottomed flask was added cis tert-butyl 4-aminocyclohexylcarbamate (0.5020 g, 2.342 mmol, Matrix Scientific), 2-bromo-5-methylpyridine (0.484 g, 2.81 mmol, Acros Organics), copper (0.012 g, 0.187 mmol, Fisher Scientific), and cesium acetate (2.79 g, 14.52 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (2.93 ml) to stir at 100° C. for 17 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic extract was washed with ammonium hydroxide, water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (279.5 mg, 0.915 mmol, 39.1% yield). LCMS showed product peak at 1.56 min (m+1=306.0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[C:21]([CH3:25])[C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]nc(N)c1C#N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Product: Cc1nn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc2c1C#N
Yield: 65.9 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg) 1.0 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (222 mg, 66%). MS (ISP) 337.1 [(M+H)+]; mp 238° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=O.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(C1C=CC=CC=1)(=O)C>O.C(O)C>[I:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]=[CH:3][C:18]([C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)=[O:19])=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(I)cc1)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 50 %

Procedure:
Sodium hydroxide (5.5 g, 138 mmol) and 4-iodoacetophenone (25.0 g, 102 mmol) were dissolved in water (50 mL) and ethanol (80 mL). 4-Bromo benzaldehyde (18.8 g, 102 mmol) dissolved in ethanol (40 mL) was added dropwise to the acetophenone solution. A slurry quickly formed, which was allowed to stir overnight. The slurry was filtered, was with water until the filtrate was neutral to pH paper, and dried at 100° C. for 12 hours. A light tan solid was obtained (21.1 g, 50% yield).
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[CH2:9]([N:11]1[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[C:12]1S)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:9]([N:11]1[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[CH:12]1)[CH3:10]
Reactant: CCn1c(CO)cnc1S
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCn1cncc1CO
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To 5.0M nitric acid (102 ml) was added sodium nitrite (314 mg), and 1-ethyl-5-hydroxymethyl-2-mercaptoimidazole (18.0 g) was added by portions to the mixture at 0° C. The mixture was allowed to be at room temperature and the mixture was stirred for 2 hours, and water (100 ml) was added to the mixture. The mixture was neutralized with potassium carbonate at 0° C., and the solvent was distilled off under reduced pressure. Ethanol was added to the mixture, and the insolubles were filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue was added methanol-ethyl acetate, and basic silica gel was added to the mixture. This mixture was purified by basic silica gel column chromatography (methanol-ethyl acetate=1:8) to obtain solid, which was recrystallized from diisopropyl ether-ethyl acetate, to give 1-ethyl-5-hydroxymethylimidazole (10.0 g) as brown crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:25]([C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCN1C(=O)C2(COc3cc(Nc4ccccc4)ccc32)c2ccccc21
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.08 g, 0.19 mmol) in anhydrous toluene (4.00 mL) was added aniline (0.03 g, 0.29 mmol), xanthphos (0.02 g, 0.03 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.02 g, 0.02 mmol). The reaction mixture was refluxed for 16 h, cooled down to ambient temperature and concentrated in vacuo to dryness. The black residue was subjected to column chromatography (ethyl acetate/hexane, 1/7) to give the title compound (0.05 g, 62%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 6H), 7.18 (d, 1H), 7.12-7.05 (m, 3H), 6.98-6.90 (m, 2H), 6.71 (d, 1H), 6.57 (d, 1H), 6.48 (dd, 1H), 4.93 (d, 1H), 4.67 (d, 1H), 3.88-3.64 (m, 2H), 1.80-1.65 (m, 2H), 1.45-1.30 (m, 4H), 0.92 (t, 3H); MS (ES+) m/z 399.5 (M+1).
Reaction SMILES: [NH2:1][C:2](=[N:11][O:12][C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])=O)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>C1(C)C=CC=CC=1>[C:7]([O:6][C:4]([CH2:3][C:2]1[N:1]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])[O:12][N:11]=1)=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)CC(N)=NOC(=O)c1cnccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1noc(-c2cnccc2C(F)(F)F)n1
Yield: 54.2 %

Procedure:
28 g of tert-butyl 3-amino-3-(4-trifluoromethyl-3-pyridinecarbonyloxy-imino)propionate are dissolved in 380 ml of toluene and heated under reflux for 17 hours. Concentration and chromatographic purification of the residue over silica gel gives 14.4 g of the product as a pale brown oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:14]1[CH:37]=[CH:36][CH:35]=[CH:34][C:15]=1[O:16][C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@@H:18]1[NH:26][C:27](OC(C)(C)C)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:38]>O1CCCC1>[ClH:38].[CH2:7]([C:14]1[CH:37]=[CH:36][CH:35]=[CH:34][C:15]=1[O:16][C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@@H:18]1[NH:26][CH3:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1

Procedure:
To a solution of LiAlH4 (436 mg, 12 mmol) in dry tetrahydrofuran (30 ml) under nitrogen was added dropwise a solution of (±)cis-1-(2-benzylphenoxy)-2-tert-butoxycarbonylaminoindane (500 mg, 1.2 mmol) in dry tetrahydrofuran (10 ml). The reaction was heated at reflux for 2 h then cooled with an ice/water bath and quenched with the minimum of water. The reaction was filtered and dried over Na2 SO4. Solvents were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 5% ethanol in chloroform to afford a colourless oil (356 mg,) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. 191°-193° C. (from acetonediethyl ether).