Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:16][N:15]([NH2:17])[CH2:14][CH2:13][N:12]1[C:18](=[O:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl>[C:18]([N:12]1[CH2:13][CH2:14][N:15]([NH:17][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:16][CH:11]1[C:9](=[O:10])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCN(N)CC1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(NC(=O)c2ccc(F)cc2)CC1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of rac-N-benzyl-1-acetyl-4-aminopiperazine-2-carboxamide (274 mg) and triethylamine (0.28 ml) in dichloromethane (5 ml) was added 4-fluorobenzoyl chloride (0.13 ml) at 0° C. The mixture was stirred at ambient temperature for 1 hour, washed with water and brine. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and chloroform (1:9) to give crystals. Recrystallization of methanol, ethyl acetate and n-hexane gave rac-N-[4-acetyl-3-(N-benzylcarbamoyl)-1-piperazinyl]-4-fluorobenzamide (104 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.12 g, 4.66 mol) in dichloromethane (10 ml), triethylamine (3.88 ml) and acetic anhydride (1.32 ml, 14 mmol) are added at 0° C. The reaction mixture is stirred for overnight, quenched with ice-water and extracted with dichloromethane. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give crude 8-acetyl-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.34 g).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]1[NH2:10].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:22][N:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:26][C:25]([C:36](Cl)=[O:37])=[N:24]1>C(Cl)Cl>[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]1[NH:10][C:36]([C:25]1[CH:26]=[C:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[N:23]([CH2:22][C:21]2[CH:39]=[CH:40][C:41]([CH3:42])=[C:19]([Cl:18])[CH:20]=2)[N:24]=1)=[O:37]
Reactant: Cc1ccc(Cn2nc(C(=O)Cl)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Reactant: CC1CCCC(C)C1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cn2nc(C(=O)NC3C(C)CCCC3C)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Yield: 32.8 %

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 36 from 0.605 g of 2,6-dimethylcyclohexylamine hydrochloride, 1 ml of triethylamine in 15 ml of DCM and 1.5 g of the compound obtained in step A of EXAMPLE 36 in 15 ml of DCM. 0.6 g of the expected product is obtained; m.p.=59.9° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18]I)[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[NH2:24][C:23]1[CH:22]=[CH:21][C:27]([CH3:28])=[C:26]([CH2:18][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:25]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CI)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(N)cc1I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: Cc1ccc(N)cc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 61 %

Procedure:
Following the General Procedure of Description 15 (Part B), The zinc insertion product of (6c) was used in situ to cross couple with commercial 3-iodo-4-methyl-aniline (1.21 g, 5.2 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (119 mg, 0.13 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (158 mg, 0.52 mmol, 10 mol-%) in anhydrous degassed DMF (6 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography with an ethyl acetate (EtOAc)/hexane mixture (EtOAc/hexane=7:3, v/v) furnished 1.15 g (61% yield) of the title compound (6d) as a yellow viscous oil. Rf˜0.28 (EtOAc/hexane=1:1, v/v). 1H NMR (300 MHz, CDCl3): δ 6.91 (d, J=8.1 Hz, 1H), 6.50-6.46 (m, 2H), 5.20-5.10 (br. m, 1H), 4.18-4.00 (m, 1H), 3.24 (br. s, 2H), 2.88-2.78 (br. dd, 1H), 2.70 (dd, 1H), 2.44 (dd, J=15.4 Hz, 5.4 Hz, 1H), 2.36 (dd, J=15.4 Hz, 5.4 Hz, 1H), 2.22 (s, 3H), 1.45 (s, 9H), 1.40 (s, 9H) ppm. LC/MS: Rt=1.433 min; ESI (pos.) m/z=365.20 (M+H+)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH3:19])=[O:17].ClCCl>O>[CH3:19][O:18][C:16]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:17]
Reactant: COC(=O)Cl
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)N1CCC(CO)CC1
Temperature: 5 °C
Yield: 90 %

Procedure:
4-Hydroxymethylpiperidine (47.6 g, 1.0 eq) and water (300 mL) were charged to a flask. The resulting mixture was cooled to 0-10° C. Potassium carbonate (85.7 g, 1.5 eq) dissolved in water (150 mL) and methyl chloroformate (38.4 mL, 1.1 eq) were added while maintaining the temperature at below 10° C. When the addition was complete, the reaction mixture was warmed up to 20-30° C. for 1 hour. After the reaction was complete, dichloromethane (500 mL) was added to the reaction mixture. The organic layer was collected and washed with 1 M phosphoric acid solution (200 mL), saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL). The organic layer was dried over sodium sulfate (50 g, 1 w/w eq) and then distilled under vacuum to produce the title intermediate. (67.0 g, 90% yield)
Reaction SMILES: [CH:1]1[C:11]2[C:10](=S)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(Cl)Cl>C(OCCO)C>[CH:1]1[C:11]2[C:10]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: S=C1Nc2ccccc2Nc2ccccc21
Reactant: NCc1cccnc1
Solvent: ClCCl
Solvent: CCOCCO
Product: c1cncc(CNC2=Nc3ccccc3Nc3ccccc32)c1
Yield: 56.6 %

Procedure:
A solution of 0.6 g (2.7 mmol) of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione [German Patent, DE-2,306,762, C.A. 79:126533a (1973)] in 10 mL 2-ethoxyethanol was treated with 0.6 mL (5.4 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (95/5) gave the product. On adding CH2Cl2, the product crystallized. There was obtained 459 mg (58.1% yield) of the pure product as a yellow solid, mp 150-152° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =301.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([C:13]2[C:18]([CH2:19][CH3:20])=[CH:17][C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:15][C:14]=2[CH2:28][CH3:29])O)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([C:14]1[CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:18]([CH2:19][CH3:20])[C:13]=1[CH2:11][C:9]1[N:8]=[CH:7][NH:6][CH:10]=1)[CH3:29]
Reactant: CCc1cc(Oc2ccccc2)cc(CC)c1C(O)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(Oc2ccccc2)cc(CC)c1Cc1c[nH]cn1

Procedure:
Prepared in analogy to Example 57(e) from rac-2-(tert-butyl-dimethyl-silanyl)-4-[(2,6-diethyl-4-phenoxy-phenyl)-hydroxy-methyl]-imidazole-1-sulfonic acid dimethylamide, triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 100° C. for 16 h. White crystalline solid. MS (ISP): 307.3 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:42]1([CH:48]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:49][CH2:50][O:51][NH2:52])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:52][O:51][CH2:50][CH2:49][CH:48]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NOCCC(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NOCCC(c1ccccc1)c1ccccc1
Yield: 26.1 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (85 mg, 0.15 mmol) and 3,3-diphenylpropoxyamine hydrochloride (48 mg, 0.18 mmol) according to Method C with HPLC purification to give the title compound (29 mg). 7.75 (s, 1H), 7.33 (d, J=9.5 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 4.71 (s, 2H), 4.39 (dd, 1H), 4.25 (m, 1H), 4.11 (t, J=8.0 Hz, 1H), 3.57 (m, 2H), 3.01 (m, 2H), 2.93 (m, 1H), 2.75 (m, 1H), 2.24 (m, 2H), 1.35 (s, 9H); IR (KBr) 3274, 2978, 1684 1651 cm−1; HRMS m/z 739.3126 (calc. of monoisotopic mass for C41H45N3O10 gives 739.3105).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)#[N:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:40]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:33]#[N:34])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 39 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (39%).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](I)[CH3:19].O>CN(C)C=O>[CH3:1][CH:2]([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([O:6][CH2:18][CH3:19])=[O:5]
Reactant: CCI
Reactant: CC(=O)CCC(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)CCC(C)=O
Reaction time: 2 h

Procedure:
3-Methyl-6-oxoheptanoic acid (2.45 g) was stirred in dry dimethylformamide (60 ml) at 20° C. and anhydrous sodium carbonate (1.64 g) was added. Ethyl iodide (5.4 ml) was added dropwise and the mixture was refluxed with stirring for 2 hours. The mixture was cooled, poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with saturated aqueous sodium thiosulphate solution, water, and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was purified by chromatography on silica, eluting with 1:4 diethyl ether: hexane. Ethyl 3-methyl-6-oxoheptanoate was obtained as an orange oil (2.0 g) Mass spectrum (Chemical Ionisation) M+1 187
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Br[C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]4[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc3nccc(-c4ccncc4)c3c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (250 mg, 0.75 mmol), 5-bromopyridine-3-sulfonamide (213 mg, 0.9 mmol), tetrakistriphenylphosphine palladium (0) (95 mg, 0.08 mmol), and saturated aqueous NaHCO3 (2.5 mL), and dioxane (5 mL)) was heated at 120° C. for 1 h and cooled to room temperature. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure. The crude product was purified by Gilson reverse phase HPLC (8-25% 6 min gradient 0.1% TFA in H2O/CH3CN) followed by neutralization with saturated aqueous NaHCO3 and extracted into EtOAc. Evaporation provided the title compound as an off white solid. (85 mg, 31%). ESMS [M+H]+=363.1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:38]=[CH:39][C:32]([S:31][CH3:30])=[CH:33][CH:34]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: CSc1ccc(CBr)cc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(SC)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-methylsulfanyl-benzyl bromide following a procedure analogous to that described for Intermediate 7.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Brc1cnc2ccc(NCc3cccnc3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and pyridin-3-ylmethanamine according to general procedure 1 providing the intermediate (88 mg, 45%) as a white solid: Rf=0.66 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.70 (d, J=1.9 Hz, 1H), 7.99-7.97 (m, 1H), 7.85-7.82 (m, 1H), 7.59 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.73 (d, J=9.7 Hz, 1H), 4.57 (s, 2H); ES-MS: (M+H)=304, 306 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.CON(C)[C:15](=[O:17])[CH3:16]>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:15](=[O:17])[CH3:16]
Reactant: CON(C)C(C)=O
Reactant: Clc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1sccc1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
To a solution of 3-chlorothiophene (4.80 g, 40.48 mmol) in THF (50 mL) was added BuLi (2.5N in hexane, 17.9 mL) at −30° C. After addition, the mixture was stirred for 30 min at −10° C., and then cooled to −45° C. N-methoxy-N-methyl acetamide (55.0 g, 48.8 mmol) was added and allowed to warm to room temperature during 40 min and maintained for an additional 20 min. Brine (80 mL) was added to quench the reaction, extracted with EA (60 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated to afford 24-1 (˜80% pure) as a yellow oil (6.80 g) which used for the next step directly.
Reaction SMILES: Cl[CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4].[SH-:18].[Na+].Cl>>[SH:18][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: [SH-]
Reactant: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1
Agent: Cl
Agent: [Na+]
Product: COc1ccc2cc(C(S)C(=O)O)ccc2c1
Reaction time: 15 h

Procedure:
A mixture of 0.05 moles of α-chloro-6-methoxy-2-naphthylacetic acid and 5 g. of sodium hydrosulfide in 100 ml. of absolute ehtanol and under a nitrogen atmosphere is stirred for 15 hours. The mixture is then acidified with 6 N hydrochloric acid. The solvent is removed in vacuo and the residue is extracted into ether, washed with water, saturated sodium chloride solution, dried and evaporated to dryness to obtain α-mercapto-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2)([O-:16])=[O:15].C(N(CC)CC)C>C(#N)C>[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[N:21]=[CH:20]2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2ncc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
In 100 ml of acetonitrile were dissolved 10 g of 4-nitrophenylsulfonyl chloride and 8.8 g of 5-nitroindazole and the solution was cooled to 0° C. Then, 6.8 g of triethylamine was gradually added dropwise to the solution and the mixture was allowed to stand overnight to precipitate crystals. Then, 50 ml of water was added dropwise to the system and the crystals formed were collected by filtration, washed with water and then ethyl acetate, and dried to provide 12.1 g of the desired product having a melting point of from 196° C. to 197° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]([CH3:19])[CH3:18])[CH:13]([OH:16])[C:14]#[N:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:17]([CH3:19])[CH3:18])[CH:13]([O:16][C:26](=[O:28])[CH3:27])[C:14]#[N:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(O)C#N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C#N)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 90.6 %

Procedure:
To a solution containing 3-[(benzyloxycarbonyl)amino]-2-hydroxy-4-methylpentanenitrile (32.0 g, 0.12 mol) and pyridine (59 mL) was added acetic anhydride (73.6 g, 68 mL, 0.72 mol) dropwise at RT. After 3 h the reaction was diluted with ethyl acetate and washed with water. The organic layer was separated, dried (anhydrous magnesium sulfate) and evaporated. The residue was purified by column chromatography (silica gel, 1:1 hexane:ethyl acetate) to give 33.08 g (94.0%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-acetoxy-4-methylpentanenitrile as a viscous yellow oil; TLC Rf =0.70 (silica gel, 1:1 hexane:ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][CH2:13][OH:14])[N:8]=1)[CH3:6].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[C:31]([O:14][CH2:13][CH2:12][C:9]1[N:8]=[C:7]([CH:5]([CH3:6])[C:4]2[CH:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:2]([F:1])[CH:3]=2)[O:11][N:10]=1)(=[O:33])[CH3:32]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCO)no1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a solution of 1.56 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-hydroxyethyl)-1,2,4-oxadiazole in 40 ml of dry THF were successively added dropwise 0.56 g of triethylamine and 0.43 g of acetyl chloride with ice-cooling. After stirring for 4 hours at room temperature, the reaction mixture was poured into ice-water and extracted with benzene. The organic phase was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel using chloroform to give 1.57 g of 3-(2-acetoxyethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as a colorless oil, nD23 1.5564.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][C:30]([CH2:43][CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:43]([C:30]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:44]
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(CC)(CCCBr)c1ccccc1
Product: CCOC(=O)CC(CC)(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1

Procedure:
Prepared from 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-ylamide and ethyl 5-bromo-2-ethyl-2-phenyl-pentanecarboxylate.