Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Cl.[Na+].[I-:12]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][I:12]
Reactant: [I-]
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccc(CI)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dichloro-1-(chloromethyl)benzene (0.8 mmoles) in acetone (2 mL) was treated with NaI (0.48 g) and stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue extracted with DMF to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:5]([Cl:8])=[N:6][CH:7]=1.C(Cl)Cl.O1CCCC1.[Br:28]Br>C(O)(=O)C>[Br:28][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[Cl:18])[C:9]([C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:19]
Reactant: O=C(Cc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(c1cc(Br)cnc1Cl)C(Br)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a stirred solution of 1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethanone (1.01 g, 2.66 mmol) in 1:1 methylene chloride/tetrahydrofuran (26 mL) was added bromine (136 μL, 2.66 mmol) and 3 mL acetic acid. The reaction mixture was stirred at room temperature overnight, at which point the orange color had dissipated. Concentration gave 2-bromo-1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethanone as an orange oil (1.1 g, 95%), which was used in the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(O)cc1
Temperature: 105 °C
Yield: 80.1 %

Procedure:
To 20 g of p-hydroxybenzaldehyde and 32.5 g of monoethyl malonate were added 6 ml of pyridine and 0.2 ml of piperidine, then the mixture thus obtained was heated at 100 to 110° C. for 10 hours under stirring. The reaction mixture was then cooled, extracted with chloroform, and the chloroform layer was washed with a saturated aqueous solution of potassium hydrogen sulfite and water in this order, the chloroform extract was dried with magnesium sulfate. The solvent was removed by evaporation and the residue thus obtained was crystallized from isopropyl ether-n-hexane to yield 25.2 g of ethyl 4-hydroxycinnamate. Light yellow indefinite form crystals. Melting point: 70°-71° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:22])[CH2:12][C:13]1[N:18]=[C:17]([O:19]C)[CH:16]=[C:15]([Cl:21])[N:14]=1.C(#N)C.C[Si](C)(C)Cl>C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:22])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15]([Cl:21])[N:14]=1
Reactant: COc1cc(Cl)nc(CC(=O)N2CCc3c(F)cccc32)n1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21

Procedure:
2 g of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-chloropyrimidin-2-yl)ethanone are added to a microwave tube with 30 ml of acetonitrile. 3.1 g of KI and 2.4 ml of trimethylchlorosilane are added. After microwave irradiation for one hour at a temperature of 100° C., the reaction medium is diluted with 100 ml of ethyl acetate and 20 ml of water. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 95/05 dichloromethane/methanol, so as to give 1.13 of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one in the form of a white solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[N:8][CH:7]=1)CCC.I[C:21]1[CH:22]=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[CH:24]=[CH:25][C:26]=1[OH:27].[F-].[Cs+]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:9]1[CH:10]=[CH:11][C:6]([C:21]2[CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[CH:24]=[CH:25][C:26]=2[OH:27])=[CH:7][N:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1I
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1-c1ccnnc1
Temperature: 45 °C
Yield: 37.2 %

Procedure:
To a solution of 4-(tributylstannyl)pyridazine (1.71 g, 4.64 mmol) and 3-iodo-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 2, 1.30 g, 3.57 mmol) in N,N-dimethylformamide (20 mL) was added caesium fluoride (1.10 g, 7.14 mmol). The mixture was degassed before the addition of tetrakis(triphenylphosphine) palladium (0) (412 mg, 0.357 mmol), then heated to 45° C. for 4 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography (0%-20% methanol in dichloromethane gradient elution). The residue was triturated with acetonitrile and filtered to afford the title compound (420 mg, 37%) as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:16][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][C:12]=1[F:15])[N:5]([CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20][CH2:19]1)[C:6](=[O:17])[CH2:7][CH2:8]2
Reactant: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Reactant: CC(C)(C)C(=O)OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCC1CCN(CCCN2C(=O)CCc3cc(F)c(F)cc32)CC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
A 4 ml vial was charged with 1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (52 mg, 0.20 mmol), 2,2-dimethylpropionic acid piperidin-4-ylmethyl ester (45 mg, 0.21 mmol) (40 mg, 0.20 mmol), and Cs2CO3 (200 mg, 0.60 mmol) in dry DMF (1 ml). The reaction was shaken at 80° C. for 3 days and the reaction was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography to yield the title product as an oil (26 mg, 62 μmol, 31%). 1H NMR (CDCl3) d 7.07 (dd, J=1.8, 3.1 Hz, 1H), 6.98-6.91 (m, 1H), 3.94-3.87 (m, 4H), 2.94-2.86 (m, 2H), 2.82 (br t, J=6.8 Hz, 2H), 2.02 (dd, J=5.2, 7.6 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.94 (dt, J=2.0, 11.6 Hz, 2H), 1.74-1.58 (m, 3H), 1.42-1.28 (m, 2H), 1.91 (s, 9H); 13C NMR (CDCl3) d178.7, 169.7, 149.3 (dd, J=13, 230 Hz), 145.6 (dd, J=243, 13 Hz), 136.7 (br), 122.7 (br), 116.6 (d, J=18 Hz), 105.3 (d, J=22 Hz), 68.8, 55.8, 53.7, 42.3, 39.1, 35.7, 31.1, 29.1, 25.2, 24.9; HPLC-MS (ammonium acetate) [M+H]+=423.20.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13])#[N:2].Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[C:1]([CH2:3][C:4]1[C:12]2[C:7]([N:8]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=[CH:10][CH:11]=2)=[N:6][C:5]=1[CH3:13])#[N:2]
Reactant: Cc1[nH]c2ncccc2c1CC#N
Reactant: BrCCc1ccccc1
Solvent: CC#N
Product: Cc1nc2n(CCc3ccccc3)cccc-2c1CC#N
Yield: 25.3 %

Procedure:
A solution of 130 mg (0.76 mmol) of 3-cyanomethyl-2-methyl-pyrrolo[2,3-b]pyridine and 150 mg (0.81 mmol) of 2-bromoethyl-benzene in 2 ml of acetonitrile was refluxed for 40 h. The solvent was evaporated and the crude product was chromatographed on silica gel with ethyl acetate: methanol: water 100:12:4. Recrystallization from a small amount of ether: petroleumether 1:1 gave 53 mg (25%) of 3-cyanomethyl-2-methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][CH3:11])(=[O:9])[CH:7]=[CH2:8]>C(#N)C>[N:1]1([CH2:8][CH2:7][C:6]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: C=CC(=O)OC
Solvent: CC#N
Product: COC(=O)CCn1ccnc1
Yield: 98.1 %

Procedure:
5.0 g(73.4 mmol) of imidazole and 12.6 g(148.6 mmol) of methyl acrylate were dissolved in 100 ml of acetonitrile, and then refluxed for 8 hours. Acetonitrile and the excess methyl acrylate was removed under reduced pressure. Then, 200 ml of ethyl acetate was added to the residue and the solution thus obtained was washed with saturated sodium chloride solution. Removal of ethyl acetate under reduced pressure provided 11.1 g(Yield: 90%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]([CH3:7])=[CH2:6].[CH3:8][CH:9]([CH2:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:10]>>[CH:9]([CH:11]([CH2:2][CH:3]=[CH:4][C:5]([CH3:7])=[CH2:6])[C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])([CH3:10])[CH3:8]
Reactant: CC(C)CC(=O)CC(C)C
Reactant: C=C(C)C=CCCl
Product: C=C(C)C=CCC(C(=O)CC(C)C)C(C)C

Procedure:
According to the procedure described in Example 1, from 1-chloro-4-methyl-2,4-pentadiene and 2,6-dimethyl-heptan-4-one there is obtained the above ketone; b.p.=72° C./0.3 mm Hg; nD20 =1.4728. Odour: linalool-like with a musk note, very natural.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[O:3]1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:25]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:3]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(O)O2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Reaction time: 1 h

Procedure:
To a stirring solution of (±)2-hydroxy-5-(p-toluenesulfonyloxymethyl)-tetrahydrofuran (example 58) (4.20 g, 15.44 mmol), pyridine (2.75 mL, 33.97 mmol) and DMAP (catalytic) in methylene chloride (100 mL) at rt was added acetic anhydride (2.91 mL, 30.88 mmol). After stirring the solution for 1 h, it was washed with water (50 mL), 1N HCl (50 mL), saturated NaHCO3 (50 mL), dried (MgSO4) and concentrated to give the title compound as a 1:1 mixture of cis and trans isomers (4.85 g, 100%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](Cl)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:38]([N:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]([N:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:16][CH:17]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N(Cc1ccccc1)c1ccccc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
A mixture of 75 mg (0.166 mmole) of N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl chloride (from Step B), 46 mg (0.25 mmole) of N-phenylbenzylamine, 58 μL (43 mg, 0.33 mmole) of N,N-diisopropylethylamine, and 1 mL of dry toluene was stirred under N2 at 110° C. for 48 hours. The cooled reaction mixture was concentrated by rotary evaporation. Flash chromatography of the residual oil on silica gel (elution with 4:1 and then 3:1 hexane-EtOAc) gave 91 mg (92%) of the title compound as a tacky foam, homogeneous by TLC in 3:1 hexane-EtOAc; FAB-MS m/e 599 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](OC(OCC)OCC)(=O)C>C1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[N:9][N:8]=2)[CH:7]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: NNc1ccc(F)cn1
Solvent: C1CCCCC1
Product: Fc1ccc2nncn2c1
Yield: 70 %

Procedure:
(5-Fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol) in diethoxymethyl acetate (5 mL) was stirred at RT for 2 h. The resulting precipitate was diluted with cyclohexane (5 ml) and filtered to give the title compound (379 mg, 70%). 1H NMR (400 MHz, CDCl3): 7.25 (1H, m), 7.84 (1H, m), 8.09 (1H, t), 8.84 (1H, s).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-:20].[K+]>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:20])([OH:17])=[O:16]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ccc(C)cc2)c1C#N
Agent: [K+]
Solvent: O
Product: Cc1ccc(-n2ncc(C(=O)O)c2C(N)=O)cc1
Reaction time: 72 h

Procedure:
To 10 g. of ethyl 5-cyano-1-(4-methylphenyl)-4-pyrazolecarboxylate was added 5.6 g. of potassium hydroxide and 200 ml. of water followed by enough water to cause solution. The mixture was stirred under reflux for 8hours and allowed to stand for 3 days. It was then poured over ice, made acid and filtered. The solids from the filtration were heated in 100 ml. of ethyl acetate, and the undissolved solid was separated, dried and identified as 4.25 g. of the desired product, m.p. 260° dec. The product was identified by nuclear magnetic resonance analysis in DMSOd6. δ2.36 (s, 3), methyl; 7.32 (d, 2), aromatic; 7.45 (d, 2), aromatic; 8.01 (s, 1), pyrazole; 7.91 (s, 1), carboxamide; 8.33 (s, 1), carboxamide.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[CH:12]2[O:13][CH2:14][C@@H:15]([O:16][C:17](=[O:45])[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25](=[O:44])[C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:43])[CH:41]=[CH2:42])=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[CH:11]2[O:10][CH2:9]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.COC1C=CC(O)=CC=1>C(O)C>[OH:7][C@@H:8]1[CH:12]2[O:13][CH2:14][C@@H:15]([O:16][C:17](=[O:45])[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25](=[O:44])[C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:43])[CH:41]=[CH2:42])=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[CH:11]2[O:10][CH2:9]1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O[C@@H]3COC4C3OC[C@@H]4OC3CCCCO3)cc2)cc1
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O[C@@H]3COC4C3OC[C@@H]4O)cc2)cc1
Temperature: 55 °C
Yield: 82.2 %

Procedure:
A mixture of 28.1 g of 4-(4-(6-acryloyloxy-hexyloxy)benzoyloxy)-benzoic acid 6-(S)-(tetrahydropyran-2-yloxy)-hexahydrofuro[3,2-b]furan-3-(R)-yl ester (5) (45 mmole), 0.85 g (3.38 mmole) of pyridinium 4-toluenesulfonate and 100 mg of 4-methoxyphenol in 150 ml of ethanol was heated for 7 hours at 55° C. under a nitrogen atmosphere. After cooling to 0° C. a precipitate appeared, which was collected on a filter and dried in a desiccator. 20 g (81%) of a solid were obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH2:15].C(O)(=O)C>C(O)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2)CC1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
1-Boc-piperazine (30 g, 285 mmol), 4-vinylpyridine (40 g, 216 mmol) and acetic acid (12.9 g, 215 mmol) were mixed in ethanol (400 mL) and heated to reflux for 18 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in water and ethyl acetate and neutralized with satd NaHCO3. The layers were separated. The water layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography to provide 1-Boc-4-[2-(4-pyridinyl)ethyl]piperazine (55.9 g, 87%) as an off white solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[C:14]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:29]([O:36][C:37](ON1C(=O)CCC1=O)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC#N>[CH2:29]([O:36][C:37]([NH:1][CH:2]([CH2:8][C:9]1[C:14]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=[C:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)C(N)Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C
Solvent: CC#N
Product: CCOC(=O)C(Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To a solution of 1K (1.14 g, 2.96 mmol) in CH3CN (15 mL) was added N-(benzyloxy carbonyloxy)succinimide (819 mg, 3.25 mmol). The reaction was stirred at RT for 16 h. After this time, no starting material was detected by LC-MS. The reaction was concentrated under reduced pressure. The resulting residue was purified by silica gel (110 g) column chromatography eluting with a gradient of EtOAc (0-50%) in hexane to give the title compound as an white foam (1.50 g, 97%). LC/MS (method A): retention time=3.63 min, (M+H)+=526.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]=1[NH:11][CH2:12][C:13]([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][C@H:16]1[CH3:30])=[O:14].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:10][C:8]1[CH:7]=[N:6][C:5]([NH:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])=[C:4]([CH:9]=1)[C:3]([OH:31])=[O:2]
Reactant: COC(=O)c1cc(Cl)cnc1NCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNc1ncc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethylamino}-nicotinic acid methyl ester (0.16 g, 0.36 mmol) in tetrahydrofuran (3 mL), methanol (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.075 g, 1.78 mmol). The reaction was stirred at ambient temperature overnight, concentrated in vacuo, diluted with dichloromethane and passed through a glass frit. The filtrate was treated with diethyl ether saturated with hydrogen chloride gas, and the white precipitate thus formed was collected by filtration to give the title compound as its hydrochloride salt (0.13 g).
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][C:2]=1[C:17](OCC)=O.[Cl-].NC(=[NH2+])C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:17]=1
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Agent: CC(N)=[NH2+]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)nc(C(=O)OCC)n1
Temperature: 100 °C

Procedure:
To a stirred solution of triethyl 1,3,5-triazine-2,4,6-tricarboxylate (J. Org. Chem. 59, 4950, 1994) (2.02 g, 6.80 mmol.) in DMF (15 mL) is added 1-aminoethaniminium chloride (1.29 g, 13.60 mmol). After the addition, the mixture is heated at 100° C. for 18 hours then the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate=3:1) to give diethyl 6-aminopyrimidine-2,4-dicarboxylate; HPLC Retention time 0.89 minutes (condition C); MS 240.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(C(F)(F)F)cn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-5-trifluoromethyl-pyridine following a procedure analogous to that described for Intermediate 12. LC (method 5): tR=1.22 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[N:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[N:20]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)n1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)c(C)n1
Yield: 82.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyrazin-2-yl)piperazin-1-yl]methanone (611 mg) described in Preparation Example 105 and (R)-4-methyloxazolidin-2-one (212 mg) described in Preparation Example 25, the title compound (528 mg) was obtained.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:28])([F:27])[CH2:14][N:15]=[C:16]([NH2:26])[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1>C(O)C>[F:28][C:13]([F:12])([F:27])[CH2:14][N:15]=[C:16]([NH2:26])[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24]([CH3:25])=[O:9])[N:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Product: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
3-Chloroperbenzoic acid (0.8 g.) was added to a solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylthiopyrimidine (0.5 g.) in ethanol (50 ml.) and the solution left at room temperature for 18 hours and then evaporated to dryness. The residue was dissolved in ethyl acetate, the solution washed with aqueous potassium carbonate solution and then dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (0.5 g.) which was used without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12]>C(O)C.O>[CH3:12][C:11]1([CH3:13])[S:14][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:9][CH:10]1[C:15]([OH:17])=[O:16]
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC1(C)SC(c2ccccc2)NC1C(=O)O
Reaction time: 0.25 h

Procedure:
One mole of benzaldehyde was dissolved in 100 cc of 90% ethanol with continuous stirring. One mole of penicillamine was dissolved in water with continuous stirring. The two solutions were then mixed together while stirring was continued. The solution was left to stand at room temperature. Within 15 minutes, a white precipitate occurred. The white precipitate was washed with distilled water through sintered glass. The washed precipitate was then dryed at 100° C. to obtain crystals.