Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][C:20]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=2)([OH:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To a suspension of magnesium (7.8 g, 325 mmol) in THF (120 mL) at room temperature under a nitrogen atmosphere was added a solution of 3-bromoanisole (37.5 mL, 296 mmol) in THF (60 mL) over 10 min. The resulting mixture was stirred at 50° C. for 4 hours and was cooled to room temperature. To the mixture was added a solution an N-benzyl-3-piperidinone (30.0 g, 159 mmol) in THF (50 mL). The reaction was stirred at room for 10 hours. The mixture was poured slowly over ice-water (100 mL) and the aqueous layer was washed with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with hexanes/EtOAc (3:1) to afford 38.4 g of 1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol 1HNMR (400 MHz, CDCl3) δ 7.31-7.20 (comp, 6H), 7.09 (s, 1H), 7.01 (d, 1H), 6.79 (d, 1H), 4.01-3.96 (br, 1H), 3.79 (s, 3H), 3.58 (s, 2H), 2.91 (d, 1H), 2.74 (d, 1H), 2.32 (d, 1H), 2.09-1.82 (comp, 2H), 1.81-1.61 (comp, 3H); MS (M+1) 298.2.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16].CCN(CC)CC>C1(C)C=CC=CC=1>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:10])[N:9]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reaction time: 0.25 h

Procedure:
A solution of o-tolyl-hydrazine hydrochloride (0.3 mmol) in 0.5 mL of toluene with 4,4-dimethyl-3-oxopentanenitrile (375 mg, 3 mmol, 10 equiv) and Et3N (84 μL, 0.6 mmol, 2 equiv) is stirred at 110° C. overnight. The solvent is evaporated and the residue taken up in EtOAC and washed with saturated NaHCO3 and brine. The organic layer is then concentrated and the residue diluted in 1 mL of ethanol and 1 mL of 1M HCl. The mixture was left at rt for 15 min and then it was concentrated. 5-tert-Butyl-2-o-tolyl-2H-pyrazol-3-ylamine is used crude in the preparation of Example 34.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[O:10][CH3:11].Cl.Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=2[O:10][CH3:11])[CH2:22][CH2:21]1
Reactant: COc1ccc(Br)cc1CCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)cc1CN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 235 %

Procedure:
A mixture of 1.1 g of 2-(chloromethyl)-4-bromoanisole, 1 g of 1-(2-pyrimidyl)piperazine dihydrochloride and 2.0 mL N,N-diisopropylethylamine in 10 mL chloroform was heated at reflux temperature for 2 hr, cooled to room temperature, washed with 1 N NaOH and water. The solvent was removed by evaporation under reduced pressure to yield 3.6 g of 2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-4-bromoanisole as a white solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@H:25]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)[CH2:27][CH2:26]1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@@H:28]2[CH2:27][CH2:26][C@H:25]([N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:30][CH2:29]2)=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N(CC#N)[C@H]1CC[C@@H](Nc2nc(Cl)ncc2Cl)CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CC[C@@H](N(CC#N)S(C)(=O)=O)CC4)n3)cc2CC1

Procedure:
cis-N-(4-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and cis-N-cyanomethyl-N-[4-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a pale yellow foam (52 mg, 54%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.33 (s, 1H), 7.28 (d, 1H, J=8.0 Hz), 7.02 (d, 1H, J=8.0 Hz), 6.95 (s, 1H), 5.25 (d, 1H, J=6.0 Hz), 4.33-4.27 (m, 1H), 4.25 (s, 2H), 3.91-3.79 (m, 1H), 3.56 (t, 2H, J=5.6 Hz), 3.39 (s, 3H), 3.09 (s, 3H), 2.95-2.86 (m, 4H), 2.80-2.67 (m, 6H), 2.29-2.20 (m, 2H), 1.97-1.73 (m, 6H).
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([CH:23]=O)=[CH:16][C:15]=1[CH2:25][CH2:26][CH3:27])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[Si:6]([O:13][C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([CH:23]=[CH2:1])=[CH:16][C:15]=1[CH2:25][CH2:26][CH3:27])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CCCc1cc(C=O)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=Cc1cc(CCC)c(O[Si](C)(C)C(C)(C)C)c(CCC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a solution of 1.0 g (2.80 mmol) of methyl triphenylphosphonium bromide in 5.0 mL of ether at 0° C. was added 1.12 mL (2.5M, 2.80 mmol) of butyllithium. The reaction mixture was stirred for 30 minutes at 0° C. and then 756 mg (2.33 mmol) of the title compound from Example 14 (Step A) was added. After stirring for 1 h at room temperature, the reaction mixture was poured into ethyl acetate and washed with water and then saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromotography (silica gel, hexane/ethyl acetate 97:3) gave 411 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[C:3]=1[C:13]#[N:14].[OH-:15].[K+].O>CC(O)(C)C>[NH2:14][C:13]([C:3]1[C:4]2[O:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]=2[CH:11]=[CH:12][C:2]=1[Cl:1])=[O:15]
Reactant: CC1(C)Cc2ccc(Cl)c(C#N)c2O1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1(C)Cc2ccc(Cl)c(C(N)=O)c2O1
Yield: 75.7 %

Procedure:
A stirred solution of 10.0 grams (0.048 mole) of 6-chloro-7-cyano-2,3-dihydro-2,2-dimethylbenzofuran in 200 mL of 2-methyl-2-propanol is warmed to reflux, and 9.5 grams (0.17 mole) of 85% potassium hydroxide is added in one portion. Upon completion of addition, the reaction mixture is heated at reflux for about 75 minutes. The reaction mixture is then cooled and poured into 400 mL of water that is cooled in an ice bath. The resultant solid is collected by filtration and dried under vacuum, yielding 8.2 grams of 7-aminocarbonyl-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:24][C:21]([F:22])([F:23])[O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[C:9]([C:10]([F:13])([F:11])[F:12])[CH:8]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1cnc(-c2ccc(OC(F)(F)F)cc2)cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described in example 16 c], 6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid methyl ester was treated with lithium aluminium hydride in tetrahydrofuran under reflux conditions for 12 h to give the title compound as yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:33]=[CH:32][C:14]([O:15][CH2:16][CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:27])=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:34][CH2:35][C:36]([F:39])([F:38])[F:37])[C:12]=1[OH:40])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:8]([C:11]1[CH:33]=[CH:32][C:14]([O:15][CH2:16][CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[C:13]([CH2:34][CH2:35][C:36]([F:38])([F:37])[F:39])[C:12]=1[OH:40])(=[O:10])[CH3:9]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(=O)OC(COc1ccc(C)c(N)c1)COc1ccc(C(C)=O)c(O)c1CCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1cc(OCC(COc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)OC(C)=O)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.9 ml of methyl chlorooxalate in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 8.3 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propoxy}-6-methyl-aniline and 2.9 ml of triethylamine in 70 ml of methylene chloride in the course of about 5 minutes and the mixture is then stirred at room temperature for a further 2 hours. The reaction mixture is poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. Methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propoxy}-6-methyl-phenyl}}-oxamate is thus obtained as an oil with an Rf value=0.13 (silica gel; toluene/ethyl acetate=6:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[OH:10][CH:11]([CH3:15])[C:12](O)=O.Cl.N>CO>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:12]([CH:11]([OH:10])[CH3:15])[NH:9][C:5]2=[CH:4][CH:3]=1
Reactant: CC(O)C(=O)O
Reactant: Nc1ccc(Cl)nc1N
Agent: Cl
Agent: N
Solvent: CO
Product: CC(O)c1nc2nc(Cl)ccc2[nH]1

Procedure:
6-Chloropyridine-2,3-diamine (150 mg, 1.05 mmol) and 2-hydroxypropanoic acid (277 mg, 2.61 mmol) were heated to 110° C. for 4 hours. To the cooled mixture was then added 1 N hydrochloric acid, followed by 7N ammonia in methanol to neutralize the acid. The aqueous solution was then evaporated under reduced pressure and the resulting oil was purified via flash chromatography (silica, 0-3% methanol/ethyl acetate) to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.CCN(CC)CC>CCO.[Pd]>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([F:17])([F:15])[F:16])[CH:3]=[CH:2]2
Reactant: COc1cccc2c(Cl)cc(C(F)(F)F)nc12
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc2ccc(C(F)(F)F)nc12
Reaction time: 0.75 h

Procedure:
To a solution of 4-chloro-8-methoxy-2-trifluoromethylquinoline (0.57 g) in 5 mL absolute EtOH is added 10% Pd/C (125 mg) and NEt3 (0.3 mL). The reaction is hydrogenated under atmospheric pressure for 0.75 h. The reaction is then filtered over Celite and the filtrate is evaporated. The residue is taken up in Et2O and the triethylamine hydrochloride salt is filtered. The desired product is obtained as a light yellow solid by evaporation of the Et2O filtrate (0.38 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][C@@:11]([NH:34]C(=O)OC(C)(C)C)([CH2:14][C:15]#[C:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)[CH:20]=[CH:19][N:18]=2)[C:10]1=[O:42].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:34][C@@:11]1([CH2:14][C:15]#[C:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:13][N:9]([CH3:8])[C:10]1=[O:42]
Reactant: CN1CC[C@](CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)(NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC[C@@](N)(CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)C1=O
Yield: 111.7 %

Procedure:
Trifluoroacetic acid (10 mL, 134.63 mmol) was added to a solution of the tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 106) (5.38 g, 10.99 mmol) in DCM (50 mL) at 20° C. and the reaction was stirred until complete. Solid K2CO3 was added to quench the TFA present and the mixture was diluted with water. The phases were separated and the aqueous layer was washed with dichloromethane (×2). The combined organic layers were dried (MgSO4) and the solvent was evaporated to give the (3S)-3-amino-1-methyl-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-2-one (D107) (4.78 g, 12.276 mmol, 111.7% yield) as an amber oil containing some Ph3PO;
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].[Br:10]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:10][C:8]1[S:7][C:6]([NH2:9])=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(N)n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(N)sc1Br
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 4-isopropyl-thiazol-2-ylamine (2.0 g, 14 mmol) in 30 mL CHCl3 was added dropwise to a stirring solution of bromine ((2.697 g, 17 mmol) in 15 mL CHCl3. The reaction mixture was stirred for 60 hours at room temperature. The reaction mixture was poured into saturated aqueous NaHCO3, and extracted wtih methylene chloride. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 2.05 g of 5-bromo-4-isopropyl-thiazol-2-ylamine as an oil.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][C@@H:8]([O:10][CH2:11][CH2:12][CH3:13])[CH3:9])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:17])=O>>[CH3:1][C@H:2]([CH2:6][CH2:7][C@@H:8]([O:10][CH2:11][CH2:12][CH3:13])[CH3:9])[C:3]([Cl:17])=[O:4]
Reactant: CCCO[C@@H](C)CC[C@H](C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CCCO[C@@H](C)CC[C@@H](C)C(=O)Cl

Procedure:
The (2S,5S)-2-methyl-5-propoxyhexanoic acid prepared above was reacted with oxalyl chloride to obtain (2R,5S)-2-methyl-5-propoxyhexanoic acid chloride. The title compound was prepared in the same manner as in Example 9 from the acid chloride obtained above and the corresponding core-compound, 4-octyloxyphenyl 4'-hydroxy-4-biphenylcarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1.[OH-].[Na+]>C(O)C>[CH:37]1([CH2:36][O:30][C:28]2[CH:27]=[CH:26][C:25]([CH3:31])=[C:24]([C:22]([N:19]3[CH2:20][CH2:21][CH:16]([N:14]4[C:13](=[O:32])[C:12]([CH3:34])([CH3:33])[C:11]([C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:15]4)[CH2:17][CH2:18]3)=[O:23])[CH:29]=2)[CH2:39][CH2:38]1
Reactant: BrCC1CC1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCC5CC5)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 0.35 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.11 ml (bromomethyl)cyclopropane in 8 ml ethanol is treated with 0.11 ml 10n aqueous sodium hydroxide solution and stirred under a blanket of nitrogen for about 16 h at 80° C. until the reaction is completed largely according to TLC analysis. The solvent is evaporated under reduced pressure, and the resulting crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[CH3:19][O:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](Cl)=[O:25]>O1CCCC1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:21]([O:20][CH3:19])=[O:27])=[N:7][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(=O)CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: COC(=O)CCC(=O)Nc1ccc(C#N)cn1
Yield: 71 %

Procedure:
The 6-amino-3-pyridinecarbonitrile (commercially available, 0.470 g, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL) then N,N-dimethylaniline (0.5 mL, 1.0 eq.) and methyl-4-chloro-4-oxo-butanoate (0.54 mL, 1.1 eq.) were successively added. The mixture was reflux for 12 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give methyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A1 (71%). M.p.=161-164° C. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.20 (m, 2H), 3.58 (s, 3H), 2.74 (t, 2H), 2.61 (t, 2H) ppm. LC-MS (Method B): RT 1.19, 234 (M+H+) The following compounds from table A or B were prepared by the same method using commercial or described starting aminopyridine:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1Cl)=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>O1CCOCC1>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)c(C(=O)c3ccccc3)cnc12
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)c3ccccc3)cnc12

Procedure:
3-Benzoyl-4-chloro-8-methoxyquinoline (3.0 g, 0.01 mol) was heated under reflux in 1,4-dioxan (100 ml) with o-toluidine (5.0 ml) for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane, and washed with dilute hydrochloric acid, sodium hydrogen carbonate solution, water and brine. The organic solution was dried and evaporated to an oil which was chromatographed (silic gel, 1% methanolic ammonia in dichloromethane). 3-Benzoyl-4-(2-methylphenylamino)-8-methoxyquinoline was isolated as crystals (0.95 g, 25.8%) from ether/hexane, m.p. 128-130.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1.O=[C:25]([CH3:39])[CH2:26][CH2:27][N:28]1C(=O)C2C(=CC=CC=2)C1=O>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][N:21]([CH:25]([CH3:39])[CH2:26][CH2:27][NH2:28])[CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CSc1ccc(C2(C3CCN(C(C)CCN)CC3)Oc3ccccc3O2)cc1

Procedure:
Using general procedure B with the above amine (65 mg, 0.20 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (86 mg, 0.40 mmol) and then using general procedure D afforded 3-{4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (42 mg, 53% over 2 steps).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].[ClH:22].Cl.O>C(O)C>[ClH:22].[NH:20]([N:21]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:8]1)[C:17]([NH2:19])=[NH:18]
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1cccs1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1coc2c1C(=NNC(=N)N)CC(c1cccs1)C2
Yield: 85.8 %

Procedure:
A mixture of 3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.065 ml), water (0.065 ml) and ethanol (30 ml) was refluxed for 2.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 48) (0.36 g) as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16](CC#N)[CH:17]=[CH:18][CH:19]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2].[OH-].[Na+].Cl.[C:26]([O:29]CC)(=[O:28])[CH3:27]>C(O)C.O>[CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16]([CH2:27][C:26]([OH:29])=[O:28])[CH:17]=[CH:18][CH:19]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:10])([CH3:11])[CH3:12])[CH3:2]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CC#N)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CC(=O)O)c1

Procedure:
195 mg of the resulting nitrile compound was dissolved in 6 ml of ethanol, and a 3N aqueous solution (2ml) of sodium hydroxide was added. The mixture was refluxed for 3 hours, and then acidified with 1N hydrochloric acid. Ethyl acetate and water were added, and the organic layer separated was worked up in a customary manner. The product was purified by silica gel column chromatography [ethyl acetate / methanol=20/1] to give 176 mg of the captioned compound as a colorless oil.