Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[Cl:14][C:15]1[S:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=1>O1CCOCC1>[Cl:14][C:15]1[S:16][C:17]([CH2:20][N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:18][CH:19]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1C(=O)N(Cc2ccc(Cl)s2)c2ccccc21
Reaction time: 0.08 h
Yield: 22.4 %

Procedure:
A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0° C. under argon. The mixture was allowed to stir for 5 minutes and then 2-chloro-5-(chloromethyl)thiophene (0.12 mL, 1.02 mmol) in dioxane (10 mL) was added dropwise to the resulting mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified by preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22%). 1H NMR (400 MHz): δ 7.62 (d, J=7.4, 1H), 7.56 (t, J=7.8, 1H), 7.14 (t, J=7.7, 1H), 6.94 (d, J=8.0, 1H), 6.90 (d, J=3.2, 1H), 6.78 (d, J=3.7, 1H), 4.90 (s, 2H).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CS(C)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][OH:30]>C(Cl)Cl>[N:1]1([C:10]2[N:18]=[C:17]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH2:29][OH:30])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: OC[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: ClCCl
Product: OC[C@@H]1CCCN1c1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 110 °C
Yield: 64.6 %

Procedure:
250 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 470 mg of (S)-(+)-2-pyrrolidinemethanol. The mixture is then heated at 110° C. for approximately 16 hours. The mixture is allowed to return to ambient temperature. A paste is formed in CH2Cl2 (methylene chloride). Drying is carried out under vacuum. 200 mg of expected product are obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:4]([S:7][CH2:8][C:9]([OH:11])=O)=[N:5][N:6]=1.[OH-:25].[Na+].[NH2:27]O.O>C1COCC1.CO>[Br:1][C:2]1[N:3]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:4]([S:7][CH2:8][C:9]([NH:27][OH:25])=[O:11])=[N:5][N:6]=1
Reactant: [OH-]
Reactant: NO
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (1.0 mmol) in THF (2 mL) and methanol (2 mL) is added to a solution of sodium hydroxide (5 mmol) and 50% aqueous hydroxylamine (2 mL). After stirring for 1 hr at room temperature, water (4 mL) is added and the volatile solvents removed in vacuo. The solution is then neutralized to pH 7-8 by addition of HCl (1N), and the resulting precipitate isolated by filtration to provide 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)-N-hydroxyacetamide.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][NH:23][CH2:22][CH2:21][NH:20]3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([F:38])=[C:34](F)[CH:35]=2)[C:30](=[O:39])[C:29]([C:40]([OH:42])=[O:41])=[CH:28]1)[CH3:26]>N1C=CC=CC=1>[CH2:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([F:38])=[C:34]([N:23]3[CH2:22][CH2:21][NH:20][CH:19]([C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:10]([S:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)(=[O:9])=[O:8])[CH:11]=4)[CH2:24]3)[CH:35]=2)[C:30](=[O:39])[C:29]([C:40]([OH:42])=[O:41])=[CH:28]1)[CH3:26]
Reactant: O=S(=O)(c1ccccc1)n1cc(C2CNCCN2)c2ccccc21
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cn(S(=O)(=O)c5ccccc5)c5ccccc45)C3)cc21
Temperature: 95 °C
Yield: 84.5 %

Procedure:
30 A mixture of 4.092 g of 1-{phenylsulfonyl)-3-(2-piperazinyl)-1H-indole and 1.012 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 5 ml of pyridine was heated at 95° C. for 3 hours, then cooled and the solid collected, washed with methanol and ether, giving 1.94 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-indol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid.
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH4+].[OH-].[CH3:23][C:24]([CH3:26])=O>>[NH2:18][C:17]1[NH:16][C:14](=[O:15])[C:13]2[N:12]=[CH:11][N:10]([CH:1]3[CH:2]4[CH:4]([O:5][C:24]([CH3:26])([CH3:23])[O:3]4)[CH:6]([CH2:7][OH:8])[O:9]3)[C:20]=2[N:19]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CC(C)=O
Agent: [NH4+]
Agent: [OH-]
Product: CC1(C)OC2C(CO)OC(n3cnc4c(=O)[nH]c(N)nc43)C2O1
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 92 %

Procedure:
To a slurry of guanosine (0.25 g, 1.0 eq) (10) and acetone (15 mL) at room temperature was added 70% HClO4 (0.103 mL, 1.35 eq). The reaction was stirred for approximately 70 minutes, at which time it was clear and colorless. The reaction was then cooled to 0° C. in an ice/water bath and concentrated NH4OH (0.167 mL, 1.41 eq) was added causing the formation of a milky white, gelatinous precipitate. The precipitate was collected on filter paper, resulting in a white papery solid that was dried at reduced pressure and ambient temperature for approximately 1 hour yielding 11 (0.262 g, 92%).
Reaction SMILES: [OH:1][P:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:4][CH2:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([O:12]C(C)(C)C)=[O:11])=[O:7])=[O:3].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[OH:3][P:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:4][CH2:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])=[O:1]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCP(=O)(O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)[C@@H]1CCCN1C(=O)CCP(=O)(O)c1ccccc1

Procedure:
1-[3-(Hydroxyphenylphosphinyl)-1-oxopropyl]-L-proline, 1,1-dimethylethyl ester (1.40 gm., 0.0038 mol.) is dissolved in 20 ml. trifluoroacetic acid and 5ml. anisole and stirred 1 hour. The acid is removed in vacuo and the residue triturated several times with ether/hexane. The residue is taken up in water and the solution washed with ether, millipore filtered and lyophilized. The resulting foam is crystallized from ethyl acetate to give 1-[3-(hydroxyphenylphosphinyl)-1-oxopropyl]-L-proline m.p., 125°-128°, total 300 mg. (25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:26](Cl)(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:26]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C(Cl)C=Cc1ccccc1
Product: COc1cc(-c2cc(CN3CCN(C(=O)C=Cc4ccccc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and cinnamoyl chloride (65 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:38])=[O:5])(=[O:13])=[O:14])=[C:16]([O:25][CH2:26][CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[CH:17]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ccccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ccccc23)c1

Procedure:
A solution of 3-[4-acetylamino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (110 mg) in methylene chloride (6 mL) and trifluoroacetic acid (3 mL) was stirred at room temperature for 4 hours. The solvent was evaporated. The residue was triturated with ether and the resulting amorphous solid (58 mg) was collected by filtration.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:16][CH2:15][CH2:14][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccc(Br)cc1F
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1COCCOCc1ccccc1
Yield: 50.5 %

Procedure:
To a stirred solution of (4-bromo-2-fluorophenyl)methanol (5 g, 24.509 mmol) in DMF (50 mL) at 0° C. NaH (60% suspension in mineral oil, 1.96 g, 49.018 mmol) was added in portions. To the resulting suspension ((2-bromoethoxy)methyl)benzene (6.32 g, 29.41 mmol) was added at 0° C., and the reaction mixture was allowed to stir at RT for 16 h until complete consumption of (4-bromo-2-fluorophenyl)methanol, as evidenced by TLC analysis. The reaction mixture was quenched with MeOH (5 mL), diluted with ice cold water (50 mL) and was extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water (50 mL), brine (50 mL), dried over anhydrous NaSO4, filtered and concentrated. The obtained crude compound was purified by CC using 5% EtOAc in PE as eluent to afford 1-((2-(benzyloxy)ethoxy)methyl)-4-bromo-2-fluorobenzene (4.2 g, 51%) as yellow liquid (TLC solvent system: 30% EtOAc in PE; Rf: 0.6).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:14]1([C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=O)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:24]([C:23]3[CH:27]=[CH:28][C:20]([CH:14]4[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]4)=[CH:21][CH:22]=3)[O:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Reactant: CC(C)N1CCC(C(=N)NO)CC1
Product: CC(C)N1CCC(c2noc(-c3ccc(C4CCCCC4)cc3)n2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1-isopropyl-N-hydroxypiperidine-4-carboxamidine and 4-cyclohexylbenzoyl chloride.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][NH2:10])=[CH:4][CH:3]=1.[C:11](O)(=[O:18])/[C:12](=[C:14](\[CH:16]=O)/[Br:15])/[Br:13].Cl>C(O)C>[Br:13][C:12]1[C:11](=[O:18])[N:9]([CH2:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[N:10]=[CH:16][C:14]=1[Br:15]
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: NNCc1ccncc1
Agent: Cl
Solvent: CCO
Product: O=c1c(Br)c(Br)cnn1Cc1ccncc1
Yield: 59 %

Procedure:
4-Picolylhydrazine hydrochloride (500 mg, 3.13 mmol), mucobromic acid (807 mg, 3.13 mmol) and concentrated hydrochloric acid (500 μL) in ethanol (5 mL) were stirred at 90° C. for 1 day. After completion of the reaction, the resulting crystals were collected by filtration, washed with methanol and dried to give the desired product (59% yield).
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][S:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH3:11][O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14]>ClCCl>[F:17][C:16]([F:19])([F:18])[S:13]([O-:15])(=[O:14])=[O:12].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][S+:8]([CH3:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CCSCC1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)SC1CC[S+](C)CC1
Product: O=S(=O)([O-])C(F)(F)F
Yield: 103.8 %

Procedure:
To a cooled (5° C.) solution of 4-acetylmercaptotetrahydrothiopyran (1.91 g, 10.9 mmol) in dichloromethane (20 mL) was added methyltrifluoromethanesulfonate (1.3 mL, 11.5 mmol) dropwise over 30 minutes. The solvent was removed in vacuo to give 3.85 g (>100%) of the title compound as an oil which was used as such: 1Hmr (D2O) δ: 2.14-3.79 (m, 8H, ring protons), 2.39 (s, 3H, COCH3), 2.93 (s, 3H, SCH3) and 5.46 ppm (s, 1H, CHS).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].I.C(=O)(O)[O-].[Na+].[CH3:17][C:18]([CH3:20])=O>>[CH3:17][C:18]1([CH3:20])[O:4][C@@H:3]2[C@@H:5]([C@@H:7]([CH2:9][OH:10])[O:8][CH:2]2[OH:1])[O:6]1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-ribose and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 60° C. for 6 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. After completion of the reaction, a small amount of aqueous sodium bicarbonate was added. The acetone was then distilled off under reduced pressure, and the residue was dissolved in benzene, washed with aqueous sodium bicarbonate and water and dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure and the residue was further distilled under reduced pressure, whereby 3.84 g (30%) of 2,3-O-isopropylidene-D-ribofuranose was obtained as a fraction boiling at 108°-111° C./0.04 mmHg.
Reaction SMILES: CO[C:3](=[O:18])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH2:5].[CH3:19][N:20]=[C:21]=[S:22]>>[C:14]([O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:21](=[S:22])[N:20]([CH3:19])[C:3]1=[O:18])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CN=C=S
Product: CN1C(=O)C(CCCCNC(=O)OC(C)(C)C)NC1=S

Procedure:
Using an analogous procedure to Example 1 Nε-t-butyloxycarbonyl-L-lysine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=4[N:13]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[C:37]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([N:8]3[C@@H:1]4[C@@H:6]([CH2:5][CH2:4][N:3]([C:39]([C:38]5[CH:42]=[CH:43][CH:44]=[C:36]([F:35])[C:37]=5[N:45]5[N:49]=[CH:48][CH:47]=[N:46]5)=[O:40])[CH2:2]4)[CH2:7]3)=[N:13][C:12]=2[CH:14]=1
Reactant: Clc1ccc2oc(N3C[C@@H]4CCNC[C@@H]43)nc2c1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1cccc(F)c1-n1nccn1)N1CC[C@H]2CN(c3nc4cc(Cl)ccc4o3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 2-((1R,6S)-3,8-diazabicyclo[4.2.0]octan-8-yl)-5-chlorobenzo[d]oxazole (Intermediate 32) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 50) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C22H18ClFN6O2, 452.88; m/z found 453.1 [M+H]+. 1H NMR (CD3OD): 8.01-7.35 (m, 5H), 7.25-6.81 (m, 3H), 4.75-4.24 (m, 2H), 4.12-3.03 (m, 6H), 2.25-1.81 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])=[C:6]([Cl:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1Cl
Yield: 96 %

Procedure:
A mixture of 100.0 g of 3-chloro-4-(hydroxy)benzoic acid methyl ester, 148.6 g of 1-bromotetradecane, 170.4 g of potassium carbonate and 1 L of acetone is heated at reflux temperature for 40.5 hours. The cooled reaction is filtered, concentrated in vacuo and purified by column chromatography (silica gel:0-2% ethyl acetate/hexane) to give 197.1 g of the desired product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][O:22][CH:23]([CH3:27])[C:24](O)=[O:25]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:24](=[O:25])[CH:23]([O:22][CH3:21])[CH3:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: COC(C)C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Solvent: CO
Product: COC(C)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-methoxy-propanoic acid (CAN 4324-37-2) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 10% ethanol/n-heptane); (+) enantiomer isolated; LC-MS (UV peak area/ESI) 100%, 389.0874 (M+H)+; αD20 (MeOH)=+37.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31]1([CH3:43])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39](Cl)(=[O:41])=[O:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)[S:39]([C:32]2[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=2[CH3:43])(=[O:41])=[O:40])=[CH:7][CH:8]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COc1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(Cc2ccc(OC3CCCCO3)cc2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-methoxy-phenyl)-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.100 g, 0.319 mmol) and triethylamine (0.133 mL, 0.957 mmol) in 2 mL methylene chloride was added 2-mesitylenesulfonyl chloride (0.139 g, 0.638 mmol). The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with 2 mL methylene chloride and the combined organic layers were evaporated to afford the title compound of Step A which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12](Cl)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([N:25]4[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1nc(Nc2cc(C3CC3)[nH]n2)c2ccccc2n1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1CCN(c2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of (5-cyclopropyl-1H-pyrazol-3-yl)-(2-chloro-quinazolin-4-yl)-amine (118 mg, 0.41 mmol) in tert-butanol (3.0 mL) was added 4-methylpiperidine (0.49 mL, 4.1 mmol) and the reaction mixture heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in a mixture EtOH:water (1:3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (×2), and rinsed with Et2O (×2) to afford III-111 as a white solid (123 mg, 85%): mp 190° C.; 1H NMR (DMSO) δ 0.66 (2H, s), 0.93 (5H, br s), 1.07 (2H, d), 1.66 (3H, s), 1.91 (1H, s), 2.85 (2H, t), 4.72 (2H, d), 6.33 (1H, s), 7.06 (1H, t), 7.29 (1H, d), 7.52 (1H, t), 8.31 (1H, d), 9.95 (1H, s), 12.18 (1H, br s); IR (solid) 2925, 2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435, 1394; MS 349.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[CH3:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=1
Reactant: Cc1nc(Cl)cc(-c2ccccc2)n1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2ccccc2)nc(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 313 mg of 4-chloro-2-methyl-6-phenylpyrimidine and 118 mg of 2-butyn-1-ol, to which 67 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 260 mg of 2-methyl-4-phenyl-6-(2-butynyloxy)pyrimidine (the present compound (78)).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][C:6]([CH3:8])=O.[CH2:9]([C:11]([CH3:13])=[O:12])[CH3:10]>C(C(CC)=O)C>[C:1]([OH:4])(=[O:3])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:6][CH:5]=1.[C:11]([C:13]1[CH:2]=[CH:1][CH:8]=[CH:6][CH:5]=1)(=[O:12])[CH2:9][CH3:10]
Reactant: CCC(C)=O
Reactant: CC(C)=O
Reactant: CC(=O)O
Solvent: CCC(=O)CC
Product: CCC(=O)c1ccccc1
Product: O=C(O)c1ccccc1

Procedure:
Further examples of ketones produced from ketones and carboxylic acids include: acetone and benzoic acid to obtain acetophenone; acetone and propionic acid to obtain methyl ethyl ketone and diethyl ketone; acetone and phenylacetic acid to obtain phenylacetone; diethyl ketone and acetic acid to obtain acetone and methyl ethyl ketone; diethyl ketone and benzoic acid to obtain propiophenone; benzophenone and acetic acid to obtain acetophenone; and benzoic acid and methyl ethyl ketone to obtain acetophenone and propiophenone.