Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3ccc(C)cc3nc2OC)CC1
Yield: 90 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.09-3.18 (m, 4H), 3.77-3.82 (m, 4H), 3.88 (s, 3H), 4.13 (s, 3H), 6.87-7.80 (m, 8H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH2:17]([O:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1cccc2c(O)ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOc1ccnc2c([N+](=O)[O-])cccc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
To a solution of 4-hydroxy-8-nitroquinoline (200 mg) and allyl bromide (140 mg) in dimethylformamide (2 ml) was added potassium carbonate (290 mg) at 0° C., and the mixture was stirred for 6 hours at 50° C. The mixture was diluted with dichloromethane and washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved into hot ethyl acetate (2 ml), and the solution was stirred at ambient temperature. The resulting precipitate was collected by filtration to give 4-allyloxy-8-nitroquinoline (120 mg).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH2:20][CH:19]1[CH2:21]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[O:18]1[CH2:20][CH:19]1[CH2:21][N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Product: c1ccc(-c2nsc(N3CCN(CC4CO4)CC3)n2)cc1
Yield: 60 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from 1-(3-phenyl-1,2,4-thiadiazol-5-yl)-piperazine and 3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after Biotage chromatography the title compound as a white powder in a 60% yield.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[S:27][C:21]3[C:20](=[O:35])[N:19]([C:16]4[CH:15]=[N:14][C:13]([N:10]5[CH2:11][CH2:12][C@@H:8]([NH:7][CH3:6])[CH2:9]5)=[CH:18][CH:17]=4)[CH2:24][CH2:23][C:22]=3[CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN[C@@H]1CCN(c2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
Dissolve ((R)-1-{5-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (0.367 g, 0.70 mmol) in DMF (10 mL). Treat the mixture with 60% NaH (33.7 mg, 0.84 mmol). Stir the resulting suspension at room temperature for 1 h. Add iodomethane (66 μL, 1.05 mmol) and stir at room temperature for 3 h. Quench the mixture with water (35 mL) and extract with EtOAc (3×40 mL). Wash the combined organic layers with water (3×30 mL), dry with Na2SO4, filter, and concentrate. Dissolve the resulting crude material in CH2Cl2 (5 mL), treat with TFA (3 mL) and stir at room temperature for 1 h. Remove the excess reagent in vacuo. Dilute the residue with CHCl3 (40 mL) and wash with 2.0 M NaOH (30 mL). Treat the cloudy organic layer with CH3OH (1.0 mL), dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 10% CH3OH (with 2M NH3)/CHCl3 to give 0.222 g (72%) of 2-(4-chloro-phenyl)-6-[6-((R)-3-methylamino-pyrrolidin-1-yl)-pyridin-3-yl]-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]3)=[CH:2]1.Cl.Cl.Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]2)[CH2:30][CH2:29]1>>[OH:42][CH:39]1[CH2:38][CH2:37][N:36]([CH2:35][CH2:34][N:31]2[CH2:30][CH2:29][CH:28]([NH:27][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:3]3[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][CH:2]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:33][CH2:32]2)[CH2:41][CH2:40]1
Reactant: O=C(O)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1

Procedure:
This compound is synthesized analogously to example 1 from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 105 (see example 50) and amine 21.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6](=[O:10])[C:7]([NH2:9])=[S:8])[CH3:4].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.CC(=O)OCC>C1(C)C=CC=CC=1>[CH2:3]([O:5][C:6]([C:7]1[S:8][CH:15]=[C:13]([CH2:12][Cl:11])[N:9]=1)=[O:10])[CH3:4]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CCl)CCl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(CCl)cs1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of amino-thioxo-acetic acid ethyl ester (7.29 g. 54.74 mmol) in toluene (58 mL) was treated with 1,3-dichloroacetone (8.41 g, 62.95 mmol). The resulting mixture was stirred at reflux for 2 h. EA (60 mL) was added and the org. layer was washed with sat. aq. NaHCO3, brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (70:30 hept-EA) gave the title compound as an orange oil. TLC:rf (4:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.89 min; [M+H]+=206.45.
Reaction SMILES: ClCCl.[CH3:4][C@@:5]1([OH:32])[C@H:10]([O:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[O:13])[C@@H:9]([CH2:21][O:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[O:24])[O:8][CH:6]1O.CS(Cl)(=O)=O>C(N(CC)CC)C>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([C:23]([O:22][C@@H:21]2[C@@H:9]([CH2:10][O:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[O:8][C@@H:6]3[O:32][C@:5]23[CH3:4])=[O:24])=[CH:26][CH:27]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2OC(O)[C@](C)(O)[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H]3O[C@]3(C)[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a 72 L vessel was charged dry dichloromethane (32 L), triethylamine (3.0 L), and diol 2-2 (3.44 kg, 90 wt % pure). The mixture was warmed to 30° C., then methanesulfonyl chloride (0.79 L) was added over 40 min. After 1 h, the batch was partitioned between pH 7 buffer (20 L) and methyl tert-butyl ether (44 L). The organic phase was washed with 1M aqueous NaCl (38 L) then switched to toluene by vacuum distillation followed by concentration to about 9 L. The resulting solution of epoxide was used directly in Step B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4.C(N(CC)CC)C.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>C1C=CC=CC=1>[CH:29]1([C:33]([N:19]2[CH2:18][CH2:17][C@@:14]34[C:15]5[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(O)CCC(=O)C3
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@]13CCN(C(=O)C4CCC4)[C@H](C2)[C@]1(O)CCC(=O)C3

Procedure:
In an anhydrous system 32 g of 3-methoxy-14-hydroxy-6-ketomorphinan, 16 ml triethylamine and 300 ml of benzene are stirred together and, over a 30 minute period, a solution of 13 g of cyclobutylcarbonylchloride in 100 ml of benzene is added. The internal temperature is kept below 25° by means of an ice bath, after which stirring is continued for four more hours at room temperature. In the isolation, triethylaminehydrochloride is removed by filtration, the solvent evaporated, and the residue solidified by stirring in 200 ml of petroleum ether to give crude N-cyclobutylcarbonyl-3-methoxy-14-hydroxy-6-ketomorphinan.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:14])([F:13])[CH2:11][CH3:12])[O:5][CH:6]=1.[C:17]([CH2:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])=[O:21])#[N:18].CCCCCCC=CCCC>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[C:20](=[O:21])[C:19]([C:17]#[N:18])=[C:9]([C:10]([F:14])([F:13])[CH2:11][CH3:12])[CH:8]=2)[O:5][CH:6]=1
Reactant: N#CCC(=O)NCc1ccc(F)cc1F
Reactant: CCC(F)(F)C(=O)CC(=O)c1cc(Br)co1
Agent: CCCC=CCCCCCC
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCC(F)(F)c1cc(-c2cc(Br)co2)n(Cc2ccc(F)cc2F)c(=O)c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.4 %

Procedure:
To a solution of 1-(4-bromo-furan-2-yl)-4,4-difluoro-hexane-1,3-dione (220 mg, 0.75 mmol), and 2-cyano-N-(2,4-difluoro-benzyl)-acetamide (300 mg, 1.4 mmol) in benzene (4 mL) was added 1,8-diaza-bicycle-[5.4.0]-undec-7-ene (60 μL, 0.4 mmol). The red reaction mixture was then heated to reflux. After 3 hours, heating was discontinued and the reaction was allowed to cool to ambient temperature. After stirring at ambient temperature for 16 hours the reaction mixture was diluted with CH2Cl2 and purified by adsorbing the material onto silica gel, loading the resulting solid onto the column and eluting with a gradient from 0% to 30% ethyl acetate/hexane to afford 6-(4-bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (188 mg, 54% yield) as a yellow oil. 1H-NMR (400 MHz, CDCl3): δ 7.62 (1H, s), 7.1-7.03 (1H, m), 6.86-6.78 (2H, m), 6.76 (1H, s), 6.64 (1H, s), 5.46 (2H, s), 2.31 (2H, t of q, JH-H=7.6 Hz, JH-F=16.9 Hz), 1.11 (3H, t, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]=[O:11])=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5].[BH4-].[Na+].CC(C)=O>CO>[F:1][C:2]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(I)ccc(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: N#Cc1c(I)ccc(CO)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of Example 220A (5.0 g, 18 mmol) in MeOH (100 mL) at 0° C. was treated with NaBH4 (822 mg, 22 mmol) and the mixture was stirred for 1 h at 0° C. Acetone was added and the mixture was stirred for 5 min, then concentrated to dryness. The residue was partitioned between H2O and EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 3:2 hexanes/EtOAc to give the desired product (3.14 g). Rf=0.38 (3:2 hexane:EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I-].[K+].[CH2:28]([CH:31]=[CH:32][CH2:33][NH2:34])[CH2:29][CH3:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:34][CH2:33][CH2:32][CH2:31][CH2:28][CH:29]=[CH2:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Reactant: CCCC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Preparation 39, 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine, potassium iodide and propylallylamine in tetrahydrofuran are reacted to give 8-chloro-1-[(allylpropylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 45 8-Nitro-1-[(allylpropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(C(=O)O)cc2OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methyl 3-benzyloxy-4-(4-ethylbenzyl)benzoate (1.6 g) was dissolved in a mixture of tetrahydrofuran (5 mL) and ethanol (5 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 80° C. for 1 hour. After cooling to room temperature, the resulting solution was acidified with 2 mol/L hydrochloric acid. The mixture was stirred under ice-cooling for 3 minutes, and the precipitates were collected by filtration, washed with water and dried to give 3-benzyloxy-4-(4-ethylbenzyl)benzoic acid (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([N:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].O>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([N:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH2:10][CH2:11][CH2:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)CCCC(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(O)CCCC(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 16 h

Procedure:
A solution of the product of Example 53 (2 g) in propan-2-ol (50 ml) and sodium borohydride (1 g) were heated under reflux for 2 hours. The mixture was allowed to stand for 16 hours at ambient temperature and was poured into water (500 ml). The resulting mixture was extracted with ether and the ether extracts were dried and evaporated to give 6-[1-(3,4-dichlorophenyl)cyclobutyl]-6-dimethylaminohexan-2-ol as an oil the boiling point of which was not determined.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[C:22]([CH3:24])[CH:21]=[N:20]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[C:22]([CH3:24])[CH:21]=[N:20]2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 439 [M+1]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([CH3:16])[CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH:8]([OH:15])[CH2:7]1.N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][C:3]([O:15][CH:8]1[CH:9]([CH:12]([CH3:13])[CH3:14])[CH2:10][CH2:11][CH:6]([CH3:16])[CH2:7]1)=[O:4]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC1CCC(C(C)C)C(OC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of chloroacetyl chloride (6.4 mL, 80 mmol) in 40 mL anhydrous diethyl ether was added dropwise within 2 h to a solution of (−)-menthol (3a) (12.5 g, 80 mmol) and pyridine (6.5 mL, 80 mmol) in anhydrous diethyl ether (160 mL) at 0° C. After warming to RT, the white suspension was stirred for 2 h and the resulting mixture was then filtered. The filtrate was washed with HCl (60 mL, 2 N), saturated. NaHCO3 (60 mL), brine and dried with Na2SO4. Removal of the solvent and drying under vacuum afford (−)-menthyl chloroacetate (4a) (17.64 g, 94%), which was used without further purification. U.S. Pat. No. 4,456,611; Helv. Chim. Acta 1988, 71, 1553.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)[S:18][C:11]=12.C([O-])([O-])=O.[K+].[K+]>>[F:6][C:7]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH2:20][CH2:21][N:22]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:23][CH:24]=3)[S:18][C:11]=12
Reactant: C=CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
Acryloyl chloride (131.3 mL, 1.62 mmol) was added to a suspension of 7-(2-fluoro-4-nitrophenoxy)-2-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridine (85) [US 2007/0004675 A1](150 mg, 0.40 mmol) and K2CO3 (223.4 1.62 mmol) and the mixture was stirred overnight at room temperature. It was then filtered and concentrated under reduced pressure affording title compound 98 (172 mg, 100% yield) that was used in the next step without further purification. MS (m/z): 426.1 (M+1)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[S:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([NH:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[S:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:17])[CH3:16]
Reactant: CSc1c(N)cnc2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CSc1c(NC(C)=O)cnc2ccccc12
Yield: 90 %

Procedure:
22.67 g (0.1 mole) of 3-amino-4-methylthio-quinoline-hydrochloride [or 19.02 g (0.1 mole) of the corresponding base] are dissolved in 125 ml of pyridine, whereupon 10.7 g (0.105 mole) of acetic anhydride are added at 10°-15° C. When the yellow colour of the solution has disappeared, the reaction mixture is poured into 1000 ml of water. The precipitated white crystals are filtered. Thus 20.9 g of 3-acetylamino-4-methylthio-quinoline are obtained, yield 90%, m.p.: 137°-138° C. (after crystallization from ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]1[CH:51]=[CH:52][C:53]([NH2:56])=[N:54][CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:49][C:50]1[CH:51]=[CH:52][C:53]([NH:56][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:14][C:15]=23)=[O:24])=[N:54][CH:55]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cn1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Temperature: 70 °C
Yield: 78.1 %

Procedure:
To a DMF (0.25 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 25 mg, 0.076 mmol) and HATU (35 mg, 0.092 mmol) was added 5-fluoropyridin-2-amine (10 mg, 0.092 mmol), followed by drop-wise addition of DIEA (0.040 mL, 0.23 mmol) at ambient temperature. The reaction was heated at 70° C. overnight, cooled, and directly purified by reverse-phase chromatography (5 to 66% acetonitrile/water) to yield the final product as white solid (25 mg, 78%). LCMS (apci) m/z=422.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br.C(OCC)C>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)COc1ccc(C(=O)CBr)cc1
Reaction time: 48 h
Yield: 46 %

Procedure:
2-(4-acetylphenoxy)acetic acid (2.81 g, 14.5 mmol) was dissolved in acetic acid (100 mL) and treated with bromine (740 μL, 14.5 mmol) and stirred 48 hours. Bromine (370 mL, 7.25 mmol) was added and solution was stirred for an additional 16 hours. Volatiles were removed under reduced pressure to provide a brown solid which was titrated with diethyl ether to provide 2-(4-(2-bromoacetyl)phenoxy)acetic acid (1.82 g) as a light brown solid.
Reaction SMILES: [I:1][C:2]1[S:19][C:5]2[NH:6][N:7]=[C:8]([C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=3)[C:4]=2[CH:3]=1.N1C2SC(C#N)=CC=2C=N1.[H-].[Na+].[C:32](Cl)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.O>[I:1][C:2]1[S:19][C:5]2[N:6]([C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:7]=[C:8]([C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=3)[C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1cc2c(-c3ccc4ccccc4c3)n[nH]c2s1
Agent: N#Cc1cc2cn[nH]c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Ic1cc2c(-c3ccc4ccccc4c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2s1
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a solution of 75 mg of 5-iodo-3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole in 1 m L of N,N-dimethylformamide 1 was added 12 mg of sodium hydride at room temperature, stirred for 15 minutes, then added with 56 mg of trityl chloride, and stirred at this temperature for a day. The solution was added with water and diluted with ethyl acetate, and the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:30), to afford 93 mg of the title compound as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH3:8].[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C)C=O.O>[C:12]([C:11](=[C:15]([OH:17])[CH3:16])[C:10]([O:9][CH2:7][CH3:8])=[O:14])#[N:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)=C(C)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcyanoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3×100 ml). Combined organic layer was washed with saturated sodium carbonate solution (3×100 ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3×100 ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).