Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:7][N:8]=1)[CH3:3].[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].C1CCN2C(=NCCC2)CC1>C(#N)C.ClCCl>[CH3:21][O:20][C:18](=[O:19])[CH:17]([CH:2]([C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:7][N:8]=1)[CH3:3])[C:16]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(Cl)c1nnc(-c2cccc(Cl)c2)o1
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(C(=O)OC)C(C)c1nnc(-c2cccc(Cl)c2)o1
Yield: 77.5 %

Procedure:
2-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (331 mg, 1.36 mmol) was mixed with dimethyl malonate (360 mg, 2/76 mmol) and DBU (207 mg, 1.36 mmol) in acetonitrile (3 ml) at 70° C. overnight. The reaction mixture was dilute with dichloromethane and washed with water. The organic layer was dried and concentrated. The residue was purified with 5˜20% ethyl acetate in hexanes to give 357 mg (74.3%) 2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonic acid dimethyl ester as white solid. 1H-NMR(CDCl3) d(ppm): 8.03 (s, 1H), 7.95 (d, 1H), 7.53 (d, 1H), 7.47 (t, 1H), 4.06 (d, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.74 (s, 3H) and 1.51 (d, 3H). Step 2: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid methyl ester: 2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonic acid dimethyl ester (352.8 mg, 1.0 mmol) was mixed with sodium chloride (76.3 mg, 1.3 mmol) and a drop of water in DMSO (1.5 ml) at 175° C. for an h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with water and concentrated. The residue was purified with column chromatography with 10˜20% ethyl acetate in hexanes to give 215 mg (76.8%)3-[5-(3-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid methyl ester as clear oil. 1H-NMR(CDCl3) d(ppm): 8.03 (s, 1H), 7.94 (d, 1H), 7.53 (d, 1H), 7.45 (t, 1H), 3.73 (s, 3H), 3.67 (m, 1H), 3.05 (dd, 1H), 2.73 (dd, 1H) and 1.50 (d, 3H). Step 3: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid hydrazide: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid hydrazide (146 mg, %) was obtained from 3-[5-(3-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid methyl ester (215 mg, 0.766 mmol) reacted with hydrazine hydrate (0.74 ml) in methanol (3 ml) at room temperature for 2.5 h. 1H-NMR(CDCl3) d(ppm): 8.03 (s, 1H), 7.94 (d, 1H), 7.53 (d, 1H), 7.46 (t, 1H), 7.23 (w, 1H), 3.93 (w, 2H), 3.71 (m, 1H), 2.90 (dd, 1H), 2.57 (dd, 1H) and 1.50 (d, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]2[C:5](=[C:6]([CH3:17])[CH:7]=[CH:8][C:9]=2[CH3:16])[N:4]=1)[NH2:2].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[C:10]3[C:5](=[C:6]([CH3:17])[CH:7]=[CH:8][C:9]=3[CH3:16])[N:4]=2)=[O:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: Cc1ccc(C)c2c(C(C)C)cc(NN)nc12
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: Cc1ccc(C)c2c(C(C)C)cc(NNC(=O)Nc3cc(Cl)cc(Cl)c3)nc12

Procedure:
A solution of 2-hydrazinyl-4-isopropyl-5,8-dimethylquinoline (100 mg, 0.44 mmol) and 82 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.74 Hz, 6 H) 2.42 (s, 3 H) 2.74 (s, 3 H) 3.88-4.06 (m, 1 H) 6.89 (s, 1 H) 6.94 (d, J=7.33 Hz, 1 H) 7.07 (t, J=1.90 Hz, 1 H) 7.22 (d, J=7.03 Hz, 1 H) 7.65 (br. s., 2 H) 8.27 (br. s., 1 H) 8.58 (s, 1 H) 9.24 (br. s., 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]2=[O:31])[CH:19]=[C:20]([F:22])[CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[C:20]([F:22])[CH:21]=[C:16]([F:15])[CH:17]=2)[C:24]1=[O:31])=[O:29]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2cc(F)cc(F)c2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2cc(F)cc(F)c2)C1=O
Yield: 26 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.110 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.046 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=[C:37]([OH:41])[CH:36]=2)C(F)=CN=1.CC1OC(C)=CC=1CN>>[CH3:36][C:37]1[O:41][C:23]([CH3:22])=[CH:24][C:25]=1[CH2:20][NH:19][C:14]1[N:13]=[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[C:17]([F:18])=[CH:16][N:15]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Agent: Cc1cc(CN)c(C)o1
Product: Cc1cc(CNc2ncc(F)c(Nc3cccc(O)c3)n2)c(C)o1
Yield: 59 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and (2,5-dimethyl-3-furyl)methylamine (80 mg, 0.63 mmol) gave N2-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 59%). 1H NMR (acetone-d6): δ 2.14 (s, 6H), 4.37 (d, J=4.2 Hz, 2H), 5.96 (s, 1H), 6.77 (d, J=6.6 Hz, 1H), 7.23–7.28 (m, 2H), 7.44 (s, 1H), 8.11 (d J=4.8 Hz, 1H), 9.05 (br, 1H), 9.75 (br, 1H); 19F NMR (282 MHz, acetone-d6): δ −165.77; LCMS: ret. time: 19.23 min.; purity: 94.89%; MS (m/e): 329.08 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11].I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-isoindole-1,3-dione (1 mmol) in anhydrous CH2Cl2 (20 mL), is added iodotrimethylsilane (6 mmol). The mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with brine and is extracted with CH2Cl1). The solvent is removed in vacuo to afford crude (S)-4-amino-2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-isoindole-1,3-dione. The product is purified by recrystallization.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([NH:15][C:16]2[C:17](=[O:33])[N:18]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:25](OC)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13]1.C([Mg]Cl)(C)C.Cl>C1COCC1.O>[CH:1]1([NH:4][C:25](=[O:26])[C:24]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]4([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[OH:5])[CH2:14][CH2:13]4)[C:17]3=[O:33])[CH:23]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To cyclopropylamine (0.60 mL, 8.46 mmol) and Methyl 3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 167c, 0.331 g) in THF (5 mL) at rt was added isopropylmagnesium chloride (0.85 mL of a 2M solution in THF) dropwise. The reaction was stirred for 1 h and then further isopropylmagnesium chloride (0.85 mL of 2M solution in THF) was added and the reaction stirred for 16 h. Water and 2M aqueous HCl were cautiously added and the aqueous layer extracted with dichloromethane (2×). The combined organics were dried (Na2SO4) and the solvent removed in vacuo to give the subtitle product as a yellow solid (0.342 g).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)cc3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.1 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[4-methyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.2 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.075 g, 16%). MS (ISP) 460.1 [(M+H)+]; mp 323° C.
Reaction SMILES: [Na].Cl[CH:3](Cl)[CH2:4][NH:5][C:6](=[O:26])[CH:7]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O>C(O)C.C(Cl)(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH:7]([C:6]1[O:26][CH:3]=[CH:4][N:5]=1)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: O=C(NCC(Cl)Cl)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cccc(OC(c2ccc(Cl)cc2)c2ncco2)c1

Procedure:
Sodium (0.595 g., 0.026 mole) is dissolved in absolute ethanol (20 ml.). N-(β ,β-dichloroethyl) (3-trifluoromethylphenoxy) (4-chlorophenyl)acetamide (4.69 g., 0.011 mole) is then added and the solution refluxed for 20 minutes. A precipitate forms and the solution becomes dark orange and then brown. The reaction mixture is cooled in an ice bath and then diluted with 50 ml. of water. The solution is extracted with 50 ml. of ether and then with 2 × 25 ml. of ether. The ether extracts are combined and washed successively with a sodium hydroxide solution (2 × 25 ml., 1 N), hydrochloric acid (2 × 25 ml., 1 N) and then with water until neutral. The ether solution is then washed with a saturated sodium chloride solution (25 ml.), treated with charcoal and then filtered to remove the charcoal. The ether solution is then dried over anhydrous magnesium sulfate, filtered and the ether removed under vacuum to afford 3.24 g. of an orange oil. The orange oil is dissolved in chloroform and chromatographed on a silica gel column employing as the eluant a mixture of chloroform and ethyl acetate (20:1). One ml. portions are collected and analyzed by thin layer chromatography and IR. The first 32 ml. collected contain no product. The next 18 ml. contain a mixture of starting material and final product. The next 53 ml. contain 2.03 g. of product obtained by evaporation of the solvent. Recrystallization from n-hexane affords 2-[α-(3-trifluoromethylphenoxy) 4-chlorobenzyl]oxazole, m.p. 66°-67°C.
Reaction SMILES: [CH2:1]([N:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[S:6]([C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])(=[O:8])=[O:7])[CH2:2][CH:3]=[CH2:4].O.B(O[O-])=[O:30].[Na+]>C1COCC1>[OH:30][CH2:4][CH2:3][CH2:2][CH2:1][N:5]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[S:6]([C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=1[F:15])(=[O:7])=[O:8]
Reactant: O=BO[O-]
Reactant: C=CCCN(c1ccc(OC)cc1)S(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(CCCCO)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of 1-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene (410 mg, 1.01 mmol) in THF (6.5 mL) at −78° C. was added BH3. THF (1.00 mL of a 1 M solution in THF, 1.00 mmol). After stirring at −78° C. for 1 h and at 0° C. for 1 h, the reaction mixture was treated with H2O (20 ml) and sodium perborate (513 mg, 5.14 mmol). After stirring at rt for 2 h, the mixture was poured onto H2O (20 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with sat. NaCl (20 mL) and dried (MgSO4). Concentration followed by chromatography (2:1/hexanes:EtOAc) afforded 270 mg (64%) of product as a white solid, mp 88–90° C. 1H NMR (CDCl3): d 7.08 (m, 2H), 6.85 (m, 2H), 3.80 (s, 3H), 3.77 (m, 2H), 3.64 (t, J=6.0; 2H), 1.63–1.55 (m, 5H), 1.50 (bs, 1H). Anal. Calcd. for C17H16F5NO4S: C, 48.00; H, 3.79; N, 3.29; S, 7.54. Found: C, 48.08; H, 3.76; N, 3.34; S, 7.46.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15](Cl)=[O:16])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:2]
Reactant: CCOc1nc2c(cnn2CC)nc1C(=O)Cl
Reactant: Nc1nccs1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOc1nc2c(cnn2CC)nc1C(=O)Nc1nccs1

Procedure:
A mixture of 15.3 g. of 6-ethoxy-1-ethyl-1H-pyrazolo-[3,4-b]pyrazine-5-carbonyl chloride (0.06 mol.), 6.6 g. of 2-amino-thiazole (0.66 mol.) and 9.1 ml. of triethylamine (0.66 mol.) in 400 ml. of dry benzene are refluxed for 21/2 hours. After cooling the reaction mixture, the precipitated triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness. The crude 6-ethoxy-1-ethyl -N-2-thiazolyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxamide is recrystallized from ethyl acetate, m.p. 151°-152°, yield 9.9 g. (52 %).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1.O.[SH-:15].[Na+]>C(O)C>[SH:15][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1
Reactant: CCCn1c(Cl)cc(=O)n(C)c1=O
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCn1c(S)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 6-chloro-3-methyl-1-propyl-pyrimidine-2,4(1H,3H)-dione (3.76 g), sodium hydrosulphide hydrate (6.0 g) and ethanol (100 ml) was stirred at room temperature for 48 h then concentrated under reduced pressure. The residue was dissolved in water (500 ml) and washed with ethyl acetate (2×100 ml). The aqueous phase was acidified with dilute hydrochloric acid, then extracted with ethyl acetate (3×100 ml). The combined organic phase was dried (MgSO4) and concentrated in vacuo to give a pale yellow solid which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]2([CH3:25])[NH:11][C:10](=[O:12])[N:9]([C:13]3[CH:18]=[C:17]([NH:19]C(C)=O)[CH:16]=[C:15]([Cl:23])[CH:14]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.[N-]=C=O.COC(=O)[C@@](C)(CC1C=CC(Br)=CC=1)N.N(C1C=C(Cl)C=C(C=1)N)C(C)=O>Cl>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]2([CH3:25])[NH:11][C:10](=[O:12])[N:9]([C:13]3[CH:18]=[C:17]([NH2:19])[CH:16]=[C:15]([Cl:23])[CH:14]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(Cl)cc(N2C(=O)N[C@](C)(Cc3ccc(Br)cc3)C2=O)c1
Agent: CC(=O)Nc1cc(N)cc(Cl)c1
Agent: COC(=O)[C@](C)(N)Cc1ccc(Br)cc1
Agent: Cl
Product: C[C@]1(Cc2ccc(Br)cc2)NC(=O)N(c2cc(N)cc(Cl)c2)C1=O

Procedure:
5-(R)-(4-bromobenzyl)-3-(5-acetamino-3-chlorophenyl)-5-methylimidazoline-2,4-dione (prepared by the process described in Example 1 from the isocyanate derivative of (R)-α-methyl-4-bromophenylalanine methyl ester and 5-acetamino-3-chloroaniline) was hydrolyzed by heating in 2N HCl to give 5-(R)-(4-bromobenzyl)-3-(5-amino-3-chlorophenyl)-5-methylimidazoline-2,4-dione. Sandmeyer reaction with NaNO2, CuCN and KCN provided the title compound as a resin.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:16]O>>[CH3:16][O:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[F:1]
Reactant: COCOc1ccc(C(=O)O)c(F)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(O)cc1F
Yield: 100 %

Procedure:
To a solution of 2-fluoro-4-methoxymethoxybenzoic acid (19.9 g, 100 mmol) in methanol (200 ml) is added conc. hydrochloric acid solution (0.5 ml, catalytic). The solution is heated at reflux overnight. The solution is evaporated in vacuo to give an off-white solid (16.9 g, 100%). δH (300 MHz, CD3OD) 3.83 (3H, s), 6.52 (1H, dd, J=2.3, 12.9 Hz), 6.63 (1H, dd, J=2.1, 8.5 Hz), 7.78 (1H, t, J=8.7 Hz); δC (75 MHz, CD3OD); m/z 170 [(M+), 10%], 139 [(M-OMe)+, 10%]52.34, 104.30, 104.34, 110.78, 112.48, 134.61, 134.96, 163.36, 163.61, 164,93, 165.03, 165.09, 165.19, 166.38, 166.46, 166.79, 167.03, 167.60, 167.65, 205.58.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]2[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:10][CH2:11][C:12]([NH:14][NH2:15])=[N:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:25][CH2:26][C:27](Cl)=O.C([O-])(=O)C.[Na+]>>[Cl:25][CH2:26][C:27]1[N:13]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[C:8]=3[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:10][CH2:11][C:12]2=[N:14][N:15]=1
Reactant: O=C(Cl)CCl
Reactant: NNC1=Nc2cccc(C(F)(F)F)c2C(c2ccccc2F)=NC1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Fc1ccccc1C1=NCc2nnc(CCl)n2-c2cccc(C(F)(F)F)c21

Procedure:
In the manner given in Preparation 10, 6-(trifluoromethyl)-5-(o-fluorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine is reacted with chloroacetyl chloride and after 1.5 hours with sodium acetate, then refluxed to give 1-(chloromethyl)-7-(trifluoromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[OH-].[Na+:12]>O>[C:1]([O-:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[Na+:12]
Reactant: CCCC(CCC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(CCC)C(=O)[O-]
Temperature: 25 °C
Yield: 99.9 %

Procedure:
In a 3-L round-bottomed flask was placed valproic acid (144 g, 1 mole) and 40% NaOH aqueous solution (100 g, 1 mole). The resulting solution was then put on a rotavaper, applied vacuum, and heated up slowly (e.g., water bath temperature from room temperature to 95° C.) to remove the water. Upon completion of the water removal, the reaction mixture was allowed to cool down to room temperature to obtain sodium valproate (166 g, 100%).
Reaction SMILES: N[C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:22]1([CH:32]=O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:7]2[N:6]([CH3:19])[C:5]3[CH:20]=[CH:21][C:2]([CH2:32][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N)ccc21
Reactant: O=Cc1cccc2ccccc12
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(Cc3cccc4ccccc34)ccc21

Procedure:
5-Amino-2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazole (35.5 g, 129.0 mmol) (obtainable according to Example 1, Step c) and 18.2 ml of naphthaline-1-carbaldehyde are reacted by reductive amination according to Example 5, Step a.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[O:12]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[CH:22]=[N+:23]([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[CH3:24][N:23]([CH3:25])[CH:22]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=1
Reactant: Cn1ccc2ccccc21
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: CN(C)C(c1cccc(Oc2ccccc2)c1)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:23](O)(=[O:27])[CH:24]([CH3:26])[CH3:25].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:2]([NH:1][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:4]3)[CH:16]=1
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.096 mmol, 30 mg), isobutyric acid (0.096 mmol, 8.94 μL 8.49 mg), triethylamine (0.193 mmol, 0.027 ml, 19.50 mg) and HOBt (0.096 mmol, 13.02 mg) in DMF (0.8 mL) was added EDCI/WSC (0.096 mmol, 18.47 mg). The whole was stirred at room temperature overnight before the reaction mixture was quenched by the addition of MeOH (100 μL) before being purified by prep HPLC to give a white solid (10.8 mg, 0.028 mmol, 29.4%). MS (ESI): m/z [M+H]+ 382.2