Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].CCN(CC)CC>CC#N>[CH2:11]([NH:14][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[C:12]#[CH:13]
Reactant: Clc1nc2ccccc2o1
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-chlorobenzoxazole (1.53 g, 10 mmol) in CH3CN (5 mL) was added dropwise to a mixture of propargyl amine (550 mg, 9.9 mmol) and Et3N (2.09 mmol, 15 mmol) and CH3CN (10 mL) under N2, and the resulting mixture was heated to reflux for 4 h, then stirred overnight at rt. The mixture was filtered, and the filtrate was partitioned between EtOAc (100 mL) and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4) and concentrated to dryness. The crude solid was diluted with heptane (20 mL) and Et2O (50 mL) and the mixture was heated to boiling and filtered hot. The filtrate was concentrated to dryness, then taken up in boiling Et2O (50 mL) and the solution was cooled and filtered. The filtrate was diluted with hexane (125 mL) and cooled to −20° C. for 4 h, and the crystallized product was collected by filtration (1.1 g, 64%). MS (APCI(+)) m/e 173.0 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=O)[CH3:19])[CH:2]=1.Cl.[NH2:22][OH:23].Cl>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[N:22][OH:23])[CH3:19])[CH:2]=1
Reactant: NO
Reactant: CC(=O)c1ccccc1Oc1cnc2ccccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccccc1Oc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.1 %

Procedure:
0.46 g of 1-[2-(quinolin-3-yloxy)-phenyl]-ethanone and 0.15 g of hydroxylamine hydrochloride were dissolved in 3 ml of pyridine and then the mixture was stirred for 24 hours at room temperature. After the reaction mixture was treated with dilute hydrochloric acid and separated with ethyl acetate, the organic layer was concentrated to obtain 0.54 g of 1-[2-(quinolin-3-yloxy)-phenyl]-ethanone oxime (Compound Number 23).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:19](C(OCC)=O)[C:20]([O:22]CC)=[O:21].Cl>CC(=O)CC>[CH3:8][O:7][C:6]1[C:4]2[O:5][C:19]([C:20]([OH:22])=[O:21])=[CH:2][C:3]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: COc1cccc(C=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cccc2cc(C(=O)O)oc12
Yield: 37.4 %

Procedure:
To a suspension of o-vanillin (25.0 g) and potassium carbonate (28.4 g) in 2-butanone (10 ml) was added diethyl bromomalonate (49.1 g), and the mixture was refluxed under nitrogen atmosphere for 7 hours and cooled. To the mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the resulting red oil was suspended in a solution of potassium hydroxide (17.5 g) in ethanol (175 ml). The suspension was refluxed for 2 hours and cooled, and to the mixture was added water. The mixture was made acidic with 1N hydrochloric acid and extracted with ethyl acetate (twice). The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give yellow solid of 7-methoxybenzofuran-2-carboxylic acid (11.8 g).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.BrBr.[C:15]1([C:23]([CH2:25][C:26]2[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[CH:28][CH:27]=2)=[S:24])[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1>ClC1C=CC=CC=1>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:23]2[S:24][C:33]3[CH:32]=[C:29]([O:30][CH3:31])[CH:28]=[CH:27][C:26]=3[CH:25]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CC(=S)c2ccc(OC)cc2)cc1
Agent: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Temperature: 25 °C
Yield: 2.5 %

Procedure:
The p-toluene sulfonic acid mono hydrate (310 mg, 1.6 mmol) in 25 ml of chlorobenzene is placed in a 25 ml, 3-neck round bottom flask fitted with a thermometer, nitrogen gas inlet, 10 ml addition funnel, reflux condenser, Dean-Stark trap with drying tube, magnetic stirrer, and heating mantle. 10 ml of solvent is distilled off and bromine (0.08 ml, 1.55 mmol) is added followed by thiodesoxyanisoin (700 mg, 1.6 mmol) in 10 ml of chlorobenzene over 5 minutes. After stirring at reflux for 15 minutes the reaction is allowed to cool to room temperature. A precipitate forms and is filtered off. The filter cake is washed with 50 ml of chlorobenzene. The filtrate is washed with water (2×50 ml), 5% sodium bicarbonate, 50 ml water, and 50 ml of 10% aqueous sodium chloride. The organics are dried over sodium sulfate and concentrated. The crude product is purified by silica gel chromatography then triturated with chlorobenzene. The side product solid is filtered off and the filtrate concentrated. The residue is triturated with ethyl acetate and filtered to give 10.8 mg of pure product. (0.25%). 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C@H:12]([C:23]([OH:25])=[O:24])[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([C@H:13]2[C@H:12]([C:23]([O:25][CH3:26])=[O:24])[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of (6R,7R)-4-(tert-butoxycarbonyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-7-carboxylic acid (3.11 g) in DMF (10 mL) were added potassium carbonate (1.32 g) and methyl iodide (0.748 mL). The mixture was stirred at room temperature for 2 hr under nitrogen purging, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (2.86 g) as a colorless oil.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:25]2[CH2:26][CH2:27][NH:28][CH2:29][C:24]2=[N:23][N:22]=1.[Cl:30][C:31]1[C:32]([C:40]#[N:41])=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35]>ClCCl.CN(C)C=O>[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:33]([C:34]([N:28]2[CH2:27][CH2:26][N:25]3[C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=4)=[N:22][N:23]=[C:24]3[CH2:29]2)=[O:35])[C:32]=1[C:40]#[N:41]
Reactant: c1ccc(-c2nnc3n2CCNC3)nc1
Reactant: N#Cc1c(Cl)cccc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1c(Cl)cccc1C(=O)N1CCn2c(nnc2-c2ccccn2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
EDC (174 mg, 0.909 mmol) followed by HOBT (127 mg, 0.826 mmol) was added to a suspension of 3-(2-pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I101) (166 mg, 0.826 mmol) and 3-chloro-2-cyanobenzoic acid (I125) (150 mg, 0.826 mmol) in Dichloromethane (DCM) (4 mL) and N,N-dimethylformamide (DMF) (1 mL) and the reaction was stirred at room temperature for 18 h. LCMS indicated that the major peak was the desired product. The solvent was evaporated and the residue partitioned between EtOAc and sat. NaHCO3 and the organic layer was collected. This was dried (Na2SO4) and the solvent evaporated to afford an orange oil. This was purified by MDAP to afford a pale yellow oil which solidified on standing to afford 174 mg of desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:21][C:20]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Yield: 109.7 %

Procedure:
A mixture of ethyl 3-(2,4-difluorophenylthio)-4-nitrobenzoate (1.1 g), iron powder (1.1 g) and ammonium chloride (0.11 g) in ethanol (10 ml) and water (5 ml) was stirred and refluxed for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated to give crystals of ethyl 4-amino-3-(2,4-difluorophenylthio)benzoate (1.1 g).
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH2:30])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCI
Reactant: CCOC(=O)CN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CC(=O)OCC)C(C)=O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 1.7 h
Yield: 28 %

Procedure:
1.20 g (2.76 mmol) of 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 44 was dissolved in 20 ml of dimethylformamide under argon atmosphere, 111 mg of sodium hydride (60% oil dispersion) and 0.82 ml of 1-iodohexane were added under ice-cooling and the mixture was stirred at room temperature for 1.7 hours. 33 mg of sodium hydride was added and the mixture was stirred for additional 40 minutes. A 10% aqueous solution of citric acid was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetonitrile=10:1) to give 433 mg (28%) of 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-6,8-difluoro-5-hexylamino-4H-1-benzopyran-4-one.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]2.[CH3:46][N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:50]5[CH2:51][CH2:52][CH2:53][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN1CCCNCC1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCCN(C)CC1
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
A mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.25 g, 0.402 mmole), 1-methyl-1,4-diazepane (0.23 g, 0.25 mL, 2.00 mmoles) in DMSO was stirred at 85° C. for 2.5 h. The suspension was poured onto ice-water, filtered and re-dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH— with 0.1% NH4OH) to give tert-butyl 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate which taken on directly to the next step. HPLC retention time 5.96 mins.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]=[C:21]([CH3:29])[N:22]([CH2:24][C:25]([O:27]C)=[O:26])[CH:23]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]=[C:21]([CH3:29])[N:22]([CH2:24][C:25]([OH:27])=[O:26])[CH:23]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cn1CC(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
A mixture of methyl (4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-2-methyl-1H-imidazol-1-yl)acetate (Example 204, 0.18 g, 0.44 mmol) and 1 M LiOH solution (5 mL, 5.0 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. for 3 h. The reaction mixture was acidified with 1 M HCl solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.14 g, 85%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:35]([O:37][CH2:38][C:39](Cl)=O)[CH3:36]>ClCCl>[CH2:35]([O:37][CH2:38][C:39]1[N:12]([CH2:13][C:14]2([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:36]
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNc2c(N)cnc3ccccc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-{[(3-aminoquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate (50.3 mmol, prepared as described above) in dichloromethane (330 mL) at 0° C. was added triethylamine (8 mL, 57.4 mmol) followed by dropwise addition of ethoxyacetyl chloride (88%, 6.59 g, 50.3 mmol). After 3 h at rt, more triethylamine (4 mL) and acid chloride (1.70 g) were added. The solution was stirred 1 h, then concentrated in vacuo to a foam and ethanol (400 mL) and triethylamine (24 mL) were added. The resulting solution was heated at reflux for 20 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (600 mL) and washed with water (2×200 mL) and brine (2×250 mL). The organic layer was dried twice over MgSO4, filtered, and concentrated to an oil. The oil was purified twice by flash chromatography (silica gel, gradient elution with 3-5% methanol/dichloromethane) to provide tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate as a yellow foam containing dichloromethane (13.13 g). Based on 1H NMR integration, the calculated amount of product was 12.59 g (57%).
Reaction SMILES: [N:1]1([NH:14]C(=O)OC(C)(C)C)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.Cl>C(O)C.C(OCC)C>[N:1]1([NH2:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)Nn1cnc2cnc3ccccc3c21
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Nn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A solution of tert-butyl N-(1H-imidazo[4,5-c]quinolin-1-yl)carbamate (6.74 g, 23.7 mmol) in 40 mL of ethanol was treated with 40 mL of HCl (40 mL, 119 mmol, 3 M in ethanol) and heated to reflux. After 1 h, the reaction mixture was cooled to ambient temperature, diluted with 80 mL of diethyl ether, and cooled in an ice water bath which precipitated a tan solid. The HCl salt of the product was collected by vacuum filtration and rinsed with diethyl ether until the filtrate ran clear. The dried HCl salt was dissolved in 75 mL of water and made basic by addition of 50% NaOH solution until the pH of the water was 12–13. The free base of the product precipitated out and was triturated in the basic water for 30 min while being cooled in an ice water bath. The solid was collected by vacuum filtration and dried under vacuum to give 2.86 g of 1H-imidazo[4,5-c]quinolin-1-amine as a tan granular solid.
Reaction SMILES: Br.[Br:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](=O)([O-])[O-:11].[K+].[K+]>O.C(OC)=O>[CH:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][Br:2])[CH2:5][CH2:6]1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: BrCC1CCNCC1
Agent: Br
Agent: [K+]
Solvent: COC=O
Solvent: O
Product: O=CN1CCC(CBr)CC1
Reaction time: 20 h

Procedure:
To a solution of 4-bromomethylpiperidin hydrobromide (12.8 g, 0.05 mole) in water (5 ml), methyl formate (25 ml) and potassium carbonate (10 g) were added and the mixture stirred for 20 hours. The solvent was decanted, and the residue was extracted with two 25 ml portions of ether. The combined organic phases were washed with water, dried and evaporated to give (A) as a colourless oil. The IR spectrum (chloroform) showed a strong band at 1650 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C.[Cu]I>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[N:9]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COc1ccc2c(c1)N(c1ccccc1)C(=O)C2
Temperature: 120 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a mixture of 6-methoxy-1,3-dihydroindol-2-one (500 mg, 3.06 mmol), copper(I) iodide (58.3 mg, 306 μmol), N,N′-dimethylethylenediamine (65.3 μl, 613 μmol) and potassium carbonate (932 mg, 6.74 mmol) in ACN (6.5 ml) was added iodobenzene (411 μl, 3.68 mmol). The reaction mixture was stirred for 1 h at 120° C. in a microwave reactor. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:5). 550 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C(=O)C)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O

Procedure:
Using 3.7 g of N-(trans-4-methylcyclohexyl)-4-acetoxy-3-methoxycinnamamide (Example 130), 100 ml of methanol, and 5 g of potassium carbonate, a reaction similar to that conducted in Example 105 was carried out. As a result, 2.75 g of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C@@H:2]([NH:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.BrC1C=C(C(F)(F)F)C=CC=1.C1([C@H](NCC=C)C)C2C(=CC=CC=2)C=CC=1.C(N)C=C>>[C:3]1([C@H:2]([NH:13][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)[CH3:1])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: C=CCN[C@H](C)c1cccc2ccccc12
Agent: FC(F)(F)c1cccc(Br)c1
Solvent: C=CCN
Product: C[C@@H](NC/C=C/c1cccc(C(F)(F)F)c1)c1cccc2ccccc12

Procedure:
U.S. Pat. No. 7,393,967 discloses a process for preparing Cinacalcet via coupling of 3-bromotrifluorotoluene with allylamine (R)—N-(1-(naphthalen-1-yl)ethyl)prop-2-en-1-amine in the presence of a catalyst and at least one base to obtain (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine (CNC-ene) and reducing the unsaturated Cinacalcet to obtain Cinacalcet, as depicted in the following Scheme 6:
Reaction SMILES: [C:1]([NH:9][CH:10]([C:14](=[O:16])[CH3:15])[CH2:11][C:12]#[CH:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O>[CH3:15][C:14]1[O:16][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH2:11][C:12]#[CH:13]
Reactant: C#CCC(NC(=O)c1ccccc1)C(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C#CCc1nc(-c2ccccc2)oc1C
Yield: 101.4 %

Procedure:
A solution of 4-benzoylamino-1-hexyn-5-one (30 g, 0.14 mol) in trifluoroacetic anhydride (100 ml) and trifluoroacetic acid (200 ml) was heated to 35°-40° C. for 6 hours. The solution was concentrated and the residue taken up in ethyl acetate (400 ml). To this solution was added saturated sodium bicarbonate solution (400 ml) followed by solid sodium bicarbonate until the water layer became neutral. The layers were separated, the organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a brown oil (28 g) which was used as such.