Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][C:14]=1[CH3:20])[CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1Cl)[CH:26]=[O:27]>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:30]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][C:23]=2[Cl:22])=[CH:15][C:14]=1[CH3:20])[CH3:8]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An oven-dried 500 mL round-bottomed flask was charged with finely powdered K2CO3 (31.8 g, 230 mmol) and anhydrous DMF (104 mL). Next, a solution of compound 10.3 (26.1 g, 115 mmol) and 3,4-dichlorobenzaldehyde (21.0 g, 120 mmol) in anhydrous DMF (52 mL) was added dropwise at 90° C., and the reaction was vigorously stirred at same temperature for 1 h. The reaction mixture was poured into 468 mL of ice-water and extracted with 3×200 mL of AcOEt. The combined organics were sequentially washed with 2×200 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a yellow oil, which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 10% AcOEt/hexane-20% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (34.9 g). 1H NMR (300 MHz) (CDCl3) δ 9.85 (1H, s); 7.81 (1H, d, J=1.5 Hz); 7.50 (1H, dd, J=1.8, 8.1 Hz); 7.37-7.35 (2H, m); 6.80-6.74 (2H, m); 4.71 (2H, s); 4.30 (2H, q, J=7.2 Hz); 2.32 (3H, s); 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[N:15]=[C:14]([CH2:16][C:17]#[N:18])[O:13][N:12]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[CH:25]=[C:26]([C:31]([CH3:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28])([O-:21])=[O:20].N1CCCCC1>C(O)C>[NH2:18][C:17]1[O:32][C:31]([CH3:33])=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]([C:24]2[CH:34]=[CH:35][CH:36]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:16]=1[C:14]1[O:13][N:12]=[C:11]([CH2:10][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:9])[N:15]=1
Reactant: CN(Cc1ccccc1)Cc1noc(CC#N)n1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)C1=C(C)OC(N)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Yield: 33.4 %

Procedure:
To a stirred mixture of 1.21 g of 3-(N-benzyl-N-methylamino)methyl-5-cyanomethyl-1,2,4-oxadiazole prepared in Example 95 and 1.25 g of methyl 2-(3-nitrobenzylidene)acetoacetate in 10 ml of ethanol was added 0.1 ml of piperidine. The reaction mixture was heated under reflux for 3 hours and then concentrated in vacuo. The residue was triturated with 10 ml of ethyl acetate and the insoluble crystals were collected by filtration. Treatment of a solution of this base in chloroform with etherial hydrogen chloride afforded 820 mg of methyl 2-amino-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-6-methyl-4-(3-nitrophenyl)-4H-pyran-5-carboxylate as pale yellow powder, m.p. 201.5° C. (decomp.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[C:12](=O)[N:13]([C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]=O)=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)=[O:32])=[CH:26][CH:25]=1)C)(C)(C)C>>[CH3:12][NH:13][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: C1COCCN1
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CN3CCOCC3)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from morpholine and (9-{4-[3-(4-formyl-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl)-methyl-carbamic acid tert-butyl ester by the same techniques as in Example 168.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]([Cl:18])=[CH:14][C:15](Cl)=[O:16]>C(#N)C>[Cl:12][C:13]([Cl:18])=[CH:14][C:15]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:8][C:9]([NH2:11])=[O:10])=[O:16]
Reactant: O=C(Cl)C=C(Cl)Cl
Reactant: NC(=O)NNc1ccccc1
Solvent: CC#N
Product: NC(=O)NN(C(=O)C=C(Cl)Cl)c1ccccc1
Yield: 63 %

Procedure:
To a suspension of 7 g of 1-phenylsemicarbazide in 100 ml of acetonitrile, cooled down to 0°-5° C., were added 7.4 g of β,β-dichloroacryloyl chloride, under stirring. The addition having been completed, the reaction mixture was stirred at 5° C. for 30 minutes and then at room temperature for 1 (one) hour. The solid that separated was collected by decanting and by filtration, then was washed with diethylether, thus obtaining 8 g of 1-(β,β-dichloroacryloyl)-1-phenyl-semicarbazide, in accordance with the elemental analysis and the I.R. and N.M.R. spectra.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18]C>CCN(CC)CC.[Cu]I>[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CC#CC(C)(C)C
Reactant: CCCC(=O)Nc1cccc(F)c1Br
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cccc(F)c1C#CC(C)(C)C
Temperature: 80 °C
Yield: 60.1 %

Procedure:
To a solution of N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 7.0 mmol) in Et3N (100 mL) was added 4,4-dimethylpent-2-yne (6.0 g, 60 mmol), CuI (70 mg, 3.8 mmol), and Pd(PPh3)3Cl2 (500 mg) successively at room temperature under N2. The mixture was heated at 80° C. overnight. The cooled mixture was filtered and the filtrate was extracted with EtOAc (40 mL×3). The organic layers were washed with sat. NaCl, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give N-(2-(3,3-dimethylbut-1-ynyl)-3-fluorophenyl)butyramide (1.1 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=7.6, 1H), 7.95 (s, 1H), 7.21 (m, 1H), 6.77 (t, J=7.6 Hz, 1H), 2.39 (t, J=7.6 Hz, 2H), 1.82-1.75 (m, 2H), 1.40 (s, 9H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[Cl:24])=[N:3][CH:4]=1
Reactant: Oc1ccc(F)cc1Cl
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 48 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2-chloro-4-fluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8,12 (1H, br.s), 8.09 (1H, d, J=2.6 Hz), 8.04–7.98 (2H, m), 7.48–7.41 (2H, m), 7.32–7.25 (2H, m), 7.15–7.07 (1H, m), 5.45–5.33 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 463 (M+H)+, 461 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8]C(=O)[C:5]2=[CH:11][C:12]=1[F:13].FC1C=C(C(O)=O)C(=CC=1F)C(O)=O>CN1CCCC1=O.CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]=1[F:13])[C:9]([OH:10])=[O:8]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Agent: O=C(O)c1cc(F)c(F)cc1C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(F)c(F)c1

Procedure:
We have found that 4,5-difluorophthalic anhydride and 4,5-difluorophthalic acid may be decarboxylated in high yield to 3,4-difluorobenzoic acid in N-methyl-2-pyrrolidone or dimethyl acetamide using copper, copper oxide, copper salts, or halides and salts of Zn, Cd, Ag and Ni as a catalyst.
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][S:2]([C:5]3[CH:9]=[CH:8][S:7][C:6]=3[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Product: COC(=O)c1sccc1S(=O)(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared Procedure Q1 and Scheme AC using methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: Anal. Calcd for C24H33N3O5S.HCl: C, 6.00; H, 5.30; N, 7.72. Found: C, 52.9; H, 6.04; N, 7.59; ESMS m/e: 508.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:25])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[CH:32]([C:35]1[NH:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1)([CH3:34])[CH3:33]>>[OH:25][C:12]1([C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=[C:2]([N:36]2[C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=[C:35]2[CH:32]([CH3:34])[CH3:33])[N:10]=3)[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13]1
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(C(=O)OC(C)(C)C)C3)n(C)c2n1

Procedure:
tert-Butyl 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylate (1 g) was reacted with 2-isopropylbenzimidazole via General Procedure I for Buchwald coupling to give 0.65 g of tert-butyl 3-hydroxy-3-(2-(2-isopropyl-1H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)piperidine-1-carboxylate following flash column chromatography.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:3]=1[C:4]#N.C[OH:14].O>[Ni].C(O)(=O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:3]=1[CH:4]=[O:14]
Reactant: N#Cc1c(F)c(F)cc(F)c1F
Reactant: CO
Agent: [Ni]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1c(F)c(F)cc(F)c1F
Temperature: 60 °C

Procedure:
Into a 500 ml-volume glass-made reactor equipped with a condenser tube, 5.00 g of 2,3,5,6-tetrafluorobenzonitrile, 51.00 g of methanol, 52.00 g of water, 45.00 g of acetic acid and 0.50 g of sponge nickel were charged. After purging the vapor phase moiety with hydrogen gas, the mixed solution was stirred at 60° C. under atmospheric pressure while continuously supplying hydrogen. As the time passed, the reaction solution was sampled and analyzed by means of a gas chromatograph. As a result, it was confirmed that 2,3,5,6-tetrafluorobenzyl alcohol was produced together with 2,3,5,6-tetrafluorobenzaldehyde. The yields in the reaction solution are shown in the table below.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]2=[O:23])[CH3:10])[CH2:4][CH2:3]1.[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([N:14]=[CH:13][C:12](=[O:23])[N:11]2[CH:9]([CH3:10])[CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:3][CH2:4]2)=[CH:16][CH:17]=1
Reactant: COc1ccc2ncc(=O)n(C(C)CN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(=O)n(C(C)CN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 43 %

Procedure:
1-[2-(4-aminopiperidin-1-yl)-1-methylethyl]-7-methoxyquinoxalin-2(1H)-one (Intermediate 221) (160 mg crude, 0.51 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (91 mg, 0.51 mmol), and sodium triacetoxy borohydride (320 mg, 1.5 mmol) were reacted as described according to Example 69. Chromatography on silica gel eluting with 5% methanol/dichloromethane containing 0.25% ammonium hydroxide gave 105 mg (63%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13]C)=[O:12].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]ncc2OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cn[nH]c1-c1cc(C(=O)O)ccc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 208.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6, 180 mg, 0.73 mmol) in methanol (4 mL). Sodium hydroxide (117 mg, 2.92 mmol) in water (2 mL) was added and the resulting solution was stirred for 3 h at 60° C., then concentrated under reduced pressure. The pH of the residue was adjusted to 1 with aqueous hydrogen chloride (1 M), then concentrated under reduced pressure. Methanol (5 mL) was added to the residue and the solids were filtered from the solution. The filtrate was concentrated under reduced pressure to obtain the title compound as a limit yellow solid (353 mg, crude).
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)#[N:3].[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([NH:18][NH2:19])=O>CO>[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[N:3]=[C:2]([C:4]2[CH:9]=[N:8][CH:7]=[CH:6][N:5]=2)[NH:19][N:18]=1
Reactant: NNC(=O)c1cnccn1
Reactant: N#Cc1cnccn1
Agent: [Na]
Solvent: CO
Product: c1cnc(-c2n[nH]c(-c3cnccn3)n2)cn1
Reaction time: 1 h

Procedure:
Sodium (50 mg.) is added to 2-cyanopyrazine (1 gram, 0.01 mole) in 20 ml. of methanol. The solution is allowed to stand 1 hour at room temperature and is added to a suspension of pyrazine carboxylic acid hydrazide (1.4 grams, 0.01 mole) in 50 ml. of methanol. The reaction mixture is heated at reflux for 2 hours and then at room temperature for 16 hours. After cooling, the intermediate acylamidrazone is removed by filtration and is then heated at temperatures between 200° to 260° C. over two and one-half hours. After cooling and recrystallization from methanol-water, 0.8 grams of 3,5-dipyrazinyl-1,2,4-triazole, m.p. 269°-270.5° C. is obtained.
Reaction SMILES: [CH:1]([C:4]([CH2:7][OH:8])([F:6])[F:5])([F:3])[F:2].N1C=CC=CC=1.[CH2:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16].Cl.N1C=CC=CC=1>>[CH:1]([C:4]([CH2:7][O:8][S:17]([CH2:15][CH3:16])(=[O:19])=[O:18])([F:6])[F:5])([F:3])[F:2]
Reactant: OCC(F)(F)C(F)F
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)OCC(F)(F)C(F)F

Procedure:
A 10-L four-neck flask was equipped with a refluxing pipe and a dropping funnel to serve as a reactor. To the flask were added HCF2CF2CH2OH (445.35 g; 3.37 mol) and pyridine (306.31 g; 3.88 mol) in an ice bath, and the mixture was stirred. Using the dropping funnel, ethanesulfonyl chloride (411.4 g; 3.20 mol) was dropped, with care for heat generation. The reaction solution changed its color gradually to milky white as pyridine hydrochloride was produced. After the end of the reaction, the reaction solution was washed with a 1 N HCl aqueous solution. The washed solution was separated to collect an organic layer.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[CH2:14][CH2:13][N:12]([C@H:15]3[C@H:19]([OH:20])[CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([C:31]([F:34])([F:33])[F:32])[N:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[CH2:14][CH2:13][N:12]([CH:15]3[CH:19]([OH:20])[CH2:18][N:17]([C:23]4[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([C:31]([F:33])([F:34])[F:32])[N:24]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Cc1nc(C(F)(F)F)nc(Cl)c1C
Reactant: O[C@@H]1CNC[C@H]1N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)nc(N2CC(O)C(N3CCC(O)(c4ccc(Cl)cc4)CC3)C2)c1C

Procedure:
The title compound was prepared following general procedures described above from trans-4-(4-chloro-phenyl)-1-(4-hydroxy-pyrrolidin-3-yl)-piperidin-4-ol hydrochloride and 4-chloro-5,6-dimethyl-2-trifluoromethyl-pyrimidine in the presence of diisopropylethylamine and DMF. 1H-NMR (300 MHz, DMSO): δ 1.58 (2H, m), 1.89 (2H, m), 2.40 (3H, s), 2.60 (3H, m), 2.95 (2H, m), 3.32 (1H, m), 3.44 (1H, m), 3.80 (2H, m), 4.32 (1H, m), 4.90 (1H, s), 5.20 (1H, d), 6.92 (1H, s), 7.42 (4H, dd). Retention Time (LC, method, AA standard): 1.75 min. MS (M+H+): 457
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[O:9][CH2:8][C:5]2=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([CH2:8][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)=[C:4]([CH:3]=1)[C:10]([OH:9])=[O:11]
Reactant: Oc1cccc(Cl)c1
Reactant: O=C1OCc2ncc(Cl)cc21
Product: O=C(O)c1cc(Cl)cnc1COc1cccc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 3-chlorofuro[3,4-b]pyridin-5(7H)-one (Organic letters, 2001, 3, 209.) and 3-chloro phenol:
Reaction SMILES: Br[CH2:2][C:3](=O)[CH3:4].[C:6]([SiH2:10][O:11][C:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+]>COCCOC.S1(CCCC1)(=O)=O>[C:6]([SiH2:10][O:11][C:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[N:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([CH3:4])[N:19]=2)[CH:18]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(=O)CBr
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cnc(N)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O=S1(=O)CCCC1
Product: Cc1cn2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ncc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
Bromoacetone (4.3 g, 31.4 mmol, 2.9 equiv) is added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-pyrazin-2-ylamine (4.0 g, 10.7 mmol) in 1,2-dimethoxyethane (20 ml) and sulfolane (20 ml). The reaction mixture is stirred overnight at 50° C. Then a 10% aqueous solution of NaHCO3 (30 ml) is added, and the mixture is heated to reflux for 1 hour. After cooling, the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (hexane/EtOAc 3:1) affords the title compound (1.7 g, 40%). 1H NMR (400 MHz, d6-DMSO): δ=8.78 (d, J=0.9 Hz, 1H), 8.43 (d, J=1.4 Hz, 1H), 7.92 (s, 1H), 7.63-7.61 (m, 4H); 7.41-7.35 (m, 6H), 4.72 (s, 2H), 2.34 (s, 3H), 1.00 (s, 9H). MS (ES+): 402 (M+H)+.
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([Br:24])[CH:26]=4)[N:30]([CH3:34])[CH:29]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: Cn1ccc2cc(Br)ccc21
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Temperature: 80 °C
Yield: 76.6 %

Procedure:
2,6-Dimethylpyridine (0.75 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from Example 61(c), 1.75 g, 6.43 mmol) and 5-bromo-1-methylindole (from step (a), 1.35 g) in anhydrous dimethylformamide (10 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated to 80° C. for 8 hours. The reaction mixture was partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using 50% dichloromethane and 50% hexane as eluant) to give the subtitle compound as a colourless oil (1.98 g).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[C:23]([O:25]C2CCCCO2)[CH:22]=[CH:21][C:3]=1[C:4](=[O:20])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C2CCCCO2)=[CH:9][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([C:3]2[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:2]=2[OH:1])=[O:20])=[CH:8][CH:9]=1
Reactant: O=C(C=Cc1ccc(OC2CCCCO2)cc1)c1ccc(OC2CCCCO2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of 4,000 g of crude 2'-hydroxy-4,4'-bis(tetrahydropyranyloxy)chalcone (purity: 79.4%), 64 mg of p-toluenesulfonic acid and 12 ml of methanol was agitated at room temperature for 2 hours. The mixture was poured into 120 ml of water, and crystals which formed were filtered and washed with 250 ml of water. The crystals obtained were dried to obtain 1.836 g of 4,2',4'-trihydroxychalcone having purity of 79.4% and yield of 77.4%.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:29][C:30]([NH2:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O.N>ClCCl>[C:33]([N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]3[N:12]=[CH:11][C:10]([CH2:29][C:30]([NH2:32])=[O:31])=[C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)(=[O:35])[CH3:34]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCCNCC3)cc2)cc1NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
25 mg of 4-(benzylamino)-6-{[4-(1,4-diazepan-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 226) was dissolved in 1.5 mL of dichloromethane, to which, under ice cooling, 15.1 mg of acetic anhydride was added, and stirred for 30 minutes. To the reaction mixture 1.5 mL of ammonia water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1), recrystallized from chloroform-methanol-diethylether to obtain 20 mg (73%) of the title compound as light brown needle crystals.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>CO.Cl[Pd]Cl>[CH3:12][C@@H:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=12
Reactant: [H][H]
Reactant: C[C@@H](NC/C=C/c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl[Pd]Cl
Solvent: CO
Product: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Reaction time: 10 h
Yield: 66.3 %

Procedure:
A mixture of compound (VI) (3.0 g), PdCl2 (0.01 g), in methanol (10 mL) was pressurized with 1 bar hydrogen and stirred for 10 hrs at +25° C. The mixture was then filtered through a Celite® pad and concentrated to give Cinacalcet free base, compound (I) (2.0 g).