Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH3:26])[CH2:7][CH2:6][N:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([O:11][C@H](C2C=CC=CC=2)C)=[O:10])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1([CH3:26])[CH2:3][CH2:4][N:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1)N1CCC(C)(O)CC1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CCN([C@@H](C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of (S)-1-phenylethyl(R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate (0.185 g, 0.52 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 2 hours. The volatiles were subsequently removed in vacuo and the residue was purified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm; CH3CN—H2O-0.1% TFA) to give the title compound (as TFA salt) as a pale bluish solid (0.128 g, 98%). LCMS: Anal. Calcd. for C14H19NO3: 249. found: 250 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]([N:18]3[C:23](=[O:24])[CH:22]=[CH:21][C:20]([NH:25]C(=O)OC(C)(C)C)=[CH:19]3)([CH3:17])[CH3:16])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][C:20]1[CH:21]=[CH:22][C:23](=[O:24])[N:18]([C:15]([CH3:16])([CH3:17])[CH2:14][O:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[CH:19]=1
Reactant: COc1ccc2c(OCC(C)(C)n3cc(NC(=O)OC(C)(C)C)ccc3=O)ccnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(OCC(C)(C)n3cc(N)ccc3=O)ccnc2c1
Reaction time: 1.5 h

Procedure:
To a stirred solution of tert-butyl 1-(1-(7-methoxyquinolin-4-yloxy)-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridin-3-ylcarbamate (55 mg, 125 μmol) in CH2Cl2 (1 mL) was added TFA (3 mL). After 90 min at 23° C., the solvents were removed under reduced pressure. The residue was partitioned between CH2Cl2 and NaOH (1 M). The organic was dried over MgSO4, reduced to a brown solid under reduced pressure. MS (ESI pos. ion) m/z (MH+): 340. Calc'd exact mass for C19H21N3O3: 339. 1H NMR (400 MHz, Chloroform-d) 8 ppm 1.65 (s, 6 H) 2.35 (s, 2 H) 3.94 (s, 3 H) 3.99 (s, 2 H) 6.30 (d, J=5.52 Hz, 1 H) 6.64 (d, J=9.03 Hz, 1 H) 7.09-7.20 (m, 4 H) 7.29-7.36 (m, 2 H) 7.64 (s, 1 H) 7.82 (d, J=9.03 Hz, 1 H) 8.31-8.39 (m, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O>[N+:21]([C:18]1[CH:19]=[CH:20][C:12]2[N:11]=[C:9]([C:8]3[CH:24]=[CH:25][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=3)[O:16][C:14](=[O:15])[C:13]=2[CH:17]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)o2)cc1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a suspension of 2-(4-tert-butylbenzoylamino)-5-nitrobenzoic acid (37.1g, 108 mmol) and N,N-dimethylformamide (0.4 mL, 5.4 mmol) in methylene chloride (200 mL) was added oxalyl chloride (10.4 mL, 119 mmol) in a dropwise manner. After stirring for 2 h, the mixture was filtered and the small amount of black solid was discarded. The filtrate was concentrated in vacuo to give 32.9 g (94%) of the title compound as a light brown solid; mp 159-61° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([OH:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.5 h

Procedure:
To a solution of 0.25 g (0.82 mmol) (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2 ml N,N-dimethylformamide, 40 mg (0.90 mmol) sodium hydride (55–65% dispersion in oil) was added. After 30 min, 0.10 ml (0.23 g, 1.64 mmol) methyl iodide was added. After 1 h the reaction mixture was poured onto water and extracted three times with ethyl acetate. The organic layers were washed twice with water, then brine and were dried over magnesium sulfate. After filtration and evaporation of the solvent the product was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:5) as eluant.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11]>>[C:11]1([CH2:10][CH2:9][C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:12])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Oc1ccccc1
Reactant: CCCCO
Product: O=C(CCc1ccccc1)Oc1ccccc1
Yield: 93 %

Procedure:
When 1-butanol is replaced by equimolar amounts of phenol in the first reaction in this example, phenyl 3-phenylpropionate is obtained in a 93% yield if the reaction is performed in the presence of pTSA and in a 39% yield if the reaction is carried out in the presence of pTSA. M. p. of phenyl 3-phenylpropionate after distillation at reduced pressure and recrystallization from light petroleum: 15°-16° C. (lit. (13), 16°-17° C.).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3cccc(F)c3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2cccc(F)c2)cc1
Yield: 87.5 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((3-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0325 g, 0.056 mmol) and LiOH (0.013 g, 0.564 mmol) in 9:1 EtOH/H2O (2 mL0 was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((3-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0269 g, 0.049 mmol, 87% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.39 (dt, J=5.8, 7.9 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.16-7.23 (m, 2H), 7.01-7.10 (m, 4H), 5.95 (br. s., 1H), 5.12-5.19 (m, 2H), 3.62 (br. s., 1H), 2.88 (br. s., 1H), 2.65 (s, 3H), 2.23 (s, 3H), 1.24 (s, 9H), 0.87 (br.s., 3H), 0.67 (br. s., 3H). 6H of piperidine were not resolved. LCMS (M+H)=549.4.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:18]([C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(Cl)cc1
Product: CN(c1ccc(Cl)cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (60 mg, 0.302 mmol) and 4-chloro-N-methylaniline (50 mg, 0.332 mmol) by a procedure similar to example 1b and was isolated as white powder (30 mg, 50%). 1H NMR (CDCl3): 8.66 (d, J=8.4 Hz, 1H), 7.78 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.19 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[CH:4]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[O:21]1[CH2:2][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[CH:4]=1
Reactant: C=Cc1ccc2c(c1)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2cc(C3CO3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Ethenyl-2-benzofuran-1(3H)-one (28.4 g, 177 mmol) was dissolved in DCM (400 mL) then mCPBA (47.7 g, 213 mmol) was added. The mixture was stirred at room temperature overnight. Some starting olefin remained. Another 25 g of mCPBA was added and the mixture was stirred overnight. The mixture was poured into ice cold Na2SO3 solution (saturated). The layers were separated and the organic layer was washed with 5% NaOH solution, brine, then was dried (MgSO4). The crude product was purified by MPLC (330 g column, eluting with 40% EtOAc/hexane, 2 L, then with 45% EtOAc/hexane, 2 L, to afford 5-(oxiran-2-yl)-2-benzofuran-1(3H)-one. LC-MS: M+1=177.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[C:20]([NH:1][C:2](=[S:10])[NH:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:21])[C:19]1[CH:18]=[CH:22][CH:11]=[CH:3][CH:4]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2
Product: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2)sc2c1CCOC2
Temperature: 50 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
tert-Butyl 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.099 g, 0.39 mmol, 1 equiv.) and PhCONCS (0.06 mL, 0.4 mmol, 1 equiv.) were dissolved in THF (2 mL) and stirred at 50° C. for 16 h. The solvent was removed and the product was purified by preparatory HPLC (0-30% EtOAC:hexanes). The product was isolated as a white solid (0.131 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 14.75 (s, 1H), 9.21 (s, 1H), 7.92 (dd, J=5.2, 3.3 Hz, 2H), 7.64-7.57 (m, 1H), 7.54-7.46 (m, 2H), 4.71 (s, 2H), 3.94 (t, J=5.6 Hz, 2H), 2.90 (t, J=5.6 Hz, 2H), 1.63 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 173.72, 165.23, 164.54, 147.15, 133.48, 131.81, 129.36, 129.04, 127.77, 125.77, 117.76, 82.36, 65.20, 64.71, 28.51, 27.38.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=1.[H][H]>CO.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: O=C(O)CCCC#Cc1cccc(OCc2ccc3ccccc3c2)c1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCCCCc1cccc(OCc2ccc3ccccc3c2)c1
Reaction time: 8 h

Procedure:
To a solution of 6-[3-(naphthalen-2-ylmethoxy)-phenyl]-hex-5-ynoic acid (0.54 g, 1.4 mmol) in methanol (15 mL) is added 10% Pd/C (0.10 g) and this mixture is placed on a Parr apparatus and pressurized to 43 psi with hydrogen. This reaction is allowed to shake overnight. The reaction is filtered and the solvent removed in vacuo. The residue is purified by flash chromatography (silica, 5% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.83-7.89 (m, 4H), 7.46-7.56 (m, 3H), 7.17-7.22 (m, 1H), 6.77-6.85 (m, 3H), 5.21 (s, 2H), 2.59 (t, 2H), 2.31 (t, 2H), 1.58-1.70 (m, 6H); MS (EI) 348 (M)+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:3]1[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][C:2]=1[C:32]1[C:26]2[S:25][C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:28]=3[C:27]=2[CH:29]=[CH:30][CH:31]=1
Reactant: Brc1ccc2c3ccccc3c3ccccc3c2c1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)sc1c(-c3ccc4c5ccccc5c5ccccc5c4c3)cccc12
Yield: 85.1 %

Procedure:
4.4 g (14.6 mmol) of 2-bromotriphenylene, 4.0 g (17.5 mmol) of 4-dibenzothiopheneboronic acid, 0.51 g (0.44 mmol) of tetrakistriphenylphosphinepalladium, and 4.0 g (43.4 mmol) of potassium carbonate were charged in a 250 mL round bottom flask with solvent 90 mL of toluene and 10 mL of water. The reaction mixture was purged with nitrogen for 30 min and then was heated up to reflux for overnight under nitrogen with stirring. The reaction mixture was cooled and the organic extracts were purified by column chromatography and recrystallization with toluene. 5.1 g (86%) of white solid was obtained as the product which was confirmed by proton NMR.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].O[C@:6]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][C@@H:10]([CH:12]=[CH2:13])[C@H:9]([OH:14])[C@H:8]([OH:15])[CH2:7]1.C(N(CC)CC)C>ClCCl>[CH:12]([C@H:10]1[C@@H:9]2[O:14][S:1](=[O:2])[O:15][C@@H:8]2[CH:7]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1)=[CH2:13]
Reactant: C=C[C@@H]1C[C@](O)(C(=O)OC)C[C@@H](O)[C@H]1O
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C[C@@H]1CC(C(=O)OC)=C[C@H]2OS(=O)O[C@@H]12
Reaction time: 0.5 h

Procedure:
Thionyl chloride can be added dropwise to a 0° C. solution of Example 17F and triethylamine in dichloromethane. After stirring for 30 minutes, the reaction mixture can be washed with saturated NaHCO3 solution, and brine, dried (MgSO4) filtered and concentrated to afford the crude desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([OH:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]1=[O:16].[H-].[Na+].[CH2:19](Br)[CH3:20].O>CN(C)C=O>[CH3:1][N:2]1[CH2:6][CH:5]([O:7][CH2:19][CH3:20])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]1=[O:16]
Reactant: CCBr
Reactant: CN1CC(O)N(c2ccc(Cl)c(Cl)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1CN(C)C(=O)N1c1ccc(Cl)c(Cl)c1
Temperature: 10 °C
Yield: 82.1 %

Procedure:
Dissolved in 100 ml of dimethylformamide was 10.4 g (0.04 mole) of 1-methyl-3-(3,4-dichlorophenyl)-4-hydroxyimidazolidine-2-one. The solution was cooled to 10° C. and 2 g (0.04 mole) of sodium hydride was added to the solution with stirring. After the addition, the mixture was stirred for 30 minutes and 4.4 g of ethyl bromide was added dropwise. The mixture was stirred at room temperature for 2 hours and water was added to the reaction mixture. The mixture was extracted with chloroform and the chloroform extract was concentrated, giving 9.5 g of an oil in 82.1% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][Br:24])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Yield: 100.9 %

Procedure:
N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (126 mg, 0.72 mmol, 2.1 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength A=310 nm for 4 hours at ambient temperature (about 20° C.). Then, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4. Solvent was removed under the reduced pressure to give 138.6 mg of crude N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (II), which contained 93% of N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (II) as determined by 1H-NMR integral. This product can be further purified by crystallization from MTBE/hexane mixture to afford pure material.
Reaction SMILES: [Br:1]CC1C=CC(S(C)(=O)=O)=C(F)C=1.[F:14][C:15]([F:28])([F:27])[S:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17]>>[Br:1][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([S:16]([C:15]([F:28])([F:27])[F:14])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1F
Product: O=S(=O)(c1ccc(CBr)cc1)C(F)(F)F

Procedure:
The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3-fluoro-4-methanesulfonyl-benzaldehyde with 4-trifluoromethanesulfonyl-benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2[O:19][CH3:20])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2[O:19][CH3:20])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(F)c(F)c2OC)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc(F)c(F)c1F

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(3,4,5-trifluoro-2-methoxy-phenyl)-methanone (Example 196) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C18H21N5O4SF3 [(M+H)+] 460.1261, observed 460.1267.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+].CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(C3CCN(CCc4ccccc4)CC3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35.3 %

Procedure:
A mixture of 5.0 g of 6-fluoro-3-(4-piperidinyl)-1H-indazole, 4.6 g of (2-bromoethyl)benzene, 4.2 g of sodium bicarbonate and 50 ml of dimethylformamide was stirred at 60° for 3 hr and at ambient temperature for 14 hr. The reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was recrystallized twice from 2-propanol (one charcoal treatment) to yield 2.6 g (35%) of product, mp 163°-165° C.
Reaction SMILES: ClC([O:4][CH3:5])Cl.[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:13]>>[CH3:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[O:4]
Reactant: COC(Cl)Cl
Reactant: Cc1ccccc1C
Product: Cc1ccc(C=O)cc1C

Procedure:
The above reaction of Example 21A is repeated except that o-xylene and dichloromethyl methylether are the starting materials. Using the same reaction conditions and techniques, there is obtained 3,4-dimethylbenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]3[CH:9]([OH:18])[N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.S(=O)(=O)(O)O.[CH3:31]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]3[CH:9]([O:18][CH3:31])[N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1
Reactant: CO
Reactant: NC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2O
Agent: O=S(=O)(O)O
Product: COC1N=C(c2ccccc2)c2cc(Cl)ccc2-n2nc(C(N)=O)nc21

Procedure:
To a solution of 8-chloro-4-hydroxy-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide (3/2 hydrate) in methanol is added a small amount of concentrated sulfuric acid, and the mixture is treated in the same manner as that of Example 3 to give 8-chloro-4-methoxy-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide as crystals (1/3 hydrate). This product is identical with the product in Example 3 with respect to melting point and infrared absorption spectrum.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(=O)([O-])O.[Na+]>ClCCl>[S:26]([O:13][CH2:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:15][CH:14]=1)(=[O:28])(=[O:27])[CH3:25]
Reactant: OCCc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(N2CCOCC2)cc1
Reaction time: 4 h

Procedure:
4-Morpholinophenethyl alcohol (2.35 g, 11.3 mmol) was dissolved in dichloromethane (20 ml). Diisopropylethylamine (2.60 ml, 14.8 mmol) and methanesulfonyl chloride (1.11 ml, 14.8 mmol) were added to the obtained solution at 0° C., and they were stirred for 4 hours. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1) and then with them (1:1) as the eluents, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 4-morpholinophenethyl mesylate in the form of a white solid (2.60 g, 81%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:11][C:12]([O:14]C)=O)[NH2:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:16][N:17]=[C:18]=[O:19]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:11][C:12](=[O:14])[N:17]([CH3:16])[C:18](=[O:19])[NH:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CN(N)c1cccc(C#N)c1
Reactant: CN=C=O
Solvent: CC#N
Product: CN1C(=O)CN(c2cccc(C#N)c2)NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl [1-(3-cyanophenyl)hydrazino]acetate (700 mg) was dissolved in dry acetonitrile (10 ml) under nitrogen. Methyl isocyanate (0.7 ml) was added to the reaction mixture which was then heated at reflux for 1.5 h. The solvent was removed in vacuo and the oily residue was dissolved in methanol (10 ml) under nitrogen. Sodium methoxide (2.17M solution in methanol; 3.9 ml) was added and the solution was stirred at room temperature for 2 h. The reaction was poured into pH 6.5 phosphate buffer (100 ml) and extracted with ethyl acetate (3×80 ml). The combined, dried organic extracts were concentrated at reduced pressure to give a solid which was triturated with ether (3×20 ml) to give the title compound (640 mg), m.p. 174°-178°. N.m.r. indicated 0.084 mol ethyl acetate.