Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl>C(O)C>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH2:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Agent: Cl
Solvent: CCO
Product: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl(3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate (0.814 g, 1.874 mmol) from Step C and HCl (26.2 mL, 52.5 mmol, 2 M in ether) in ethanol (3 mL) were combined. The reaction was stirred at room temperature overnight and then the volatiles were removed. The compound was purified using a 24 g silica gel cartridge with a gradient of 1-10% methanol (2 N ammonia)/dichloromethane over 20 minutes to give (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.37 (s, 1H), 8.21 (d, J=7.9, 1H), 7.93 (d, J=7.9, 1H), 7.75 (t, J=7.9, 1H), 3.41 (dd, J=9.8, 2.8, 1H), 3.13 (dd, J=9.7, 3.1, 1H), 3.03-2.98 (m, 1H), 2.97-2.89 (m, 2H), 2.56-2.45 (m, 1H), 2.14 (tdd, J=8.7, 5.9, 2.9, 1H), 1.5-2.0 (m, 2H) 1.95-1.85 (m, 1H), 1.79-1.69 (m, 1H), 1.32-1.15 (m, 2H); MS (ESI+) m/z 335 (M+H)+.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1>C(O)C.[OH-].[Na+]>[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:20]3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCN1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NN=Cc1ccc(C2=NOC3(CCN(CCCC(=O)O)CC3)C2)cc1

Procedure:
0.28 g (0.685 mmol) of the ethyl ester from Example 7 were hydrolized in a mixture of 4 ml ethanol and 0.9 ml 2 N aqueous sodium hydroxide solution according to the procedure from Example 6. The title acid crystallized from water/ethanol 1:2, and it was filtered and dried in vacuo.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>O1CCCC1>[CH2:12]([NH:16][C:17](=[O:18])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN=C=O
Reactant: COC(=O)c1ccccc1N
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1ccccc1C(=O)OC
Reaction time: 48 h

Procedure:
To a solution of 13.55 gm of methyl anthranilate in 12 ml dry tetrahydrofuran, was added 8.9 ml of n-butyl isocyanate dropwise. The solution was stirred for 51/2 days and filtered. The filtrate was reduced to half of its original volume and further precipitated with hexane and filtered. The two residues were combined to yield the title compound as a white solid, m.p. 84°-85° C.; NMR(delta CDCl3): 0.79, 1.02 (m, 3H, CH3), 1.16-1.76 (m, 4H, CH2CH2), 3.27 (t, 2H, NCH2), 3.87 (s, 3H, OCH3), 4.82 (br, 1H, NH), 6.81-8.59 (m, 4H, ArH), 11.09 (s, 1H, NH). IR: 3305, 3260, 1708, 1642, 1560 cm-1.
Reaction SMILES: [OH:1][C:2](=[C:13]1[C:18](=[O:19])OC(C)(C)OC1=O)[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[F:12].Cl.[F:24][C:25]([F:36])([F:35])[C:26]1[N:30]2[CH2:31][CH2:32][NH:33][CH2:34][C:29]2=[N:28][N:27]=1.C(N(C(C)C)CC)(C)C>C(OC(C)C)(=O)C>[O:19]=[C:18]([N:33]1[CH2:32][CH2:31][N:30]2[C:26]([C:25]([F:36])([F:24])[F:35])=[N:27][N:28]=[C:29]2[CH2:34]1)[CH2:13][C:2](=[O:1])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[F:12]
Reactant: CC1(C)OC(=O)C(=C(O)Cc2cc(F)c(F)cc2F)C(=O)O1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: Cl
Solvent: CC(=O)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 85 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
A mixture of 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)-ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g), 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride (7.2 g), diisopropyl ethylamine (4.5 g), and isopropyl acetate (100 mL) are heated to about 85° C. and stirred for about 4 hours. The reaction mass is then cooled to about 30° C. and quenched with water (90 mL). The organic layer is separated, washed with 5% sodium chloride solution (3×50 mL) and distilled off completely under vacuum to afford 12 g of the title compound. (Yield: 93.3%; purity by HPLC: 95.7%)
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16])=S)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.OO>CO>[CH3:18][N:17]1[C:15](=[O:16])[C:14]2[C:13](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:12]=[C:10]1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1
Agent: N
Agent: OO
Solvent: CO
Product: Cn1c(NC(=O)c2ccccc2)nc2ccccc2c1=O
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a stirred mixture of 9.4 g of the above benzamide, 100 ml of methanolic ammonia and 100 ml of methanol was added dropwise, in increments, 25 ml of 30% hydrogen peroxide. After stirring overnight, the solid was collected, partially dissolved in 500 ml of hot acetonitrile and filtered. The filtrate was chilled, the solid collected and recrystallized from 200 ml of acetonitrile, giving 1.8 g of the desired product as white crystals, mp 185°-187° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.[CH2:34]([S:36]([CH2:39][CH2:40]O)(=[O:38])=[O:37])[CH3:35]>C(#N)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:35][CH2:34][S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: CCS(=O)(=O)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)CCOc1cc(C(=O)O)c(O)c2ccccc12
Temperature: 95 °C
Yield: 53 %

Procedure:
20.4 g (0.1 mol) of 1,4-dihydroxy-2-naphthoic acid and 19 g (0.1 mol) of p-toluenesulfonic acid were added to 200 ml of dehydrated toluene. To the mixture, 27.6 g (0.2 mol) of β-ethylsulfonylethanol was added dropwise for 30 minutes under heating at 95° C. with stirring. After heating with stirring for 7 hours, the mixture was cooled to 20° to 30° C. 100 ml of acetonitrile was added to the mixture, the solid deposited was separated by filtration to obtain 17.2 g (53%) of 1-hydroxy-4-(β-ethylsulfonylethoxy)-2-naphthoic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.[CH3:13][C:14]([OH:19])([CH3:18])[CH2:15][NH:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl>C1COCC1>[OH:19][C:14]([CH3:18])([CH3:13])[CH2:15][N:16]([CH3:17])[C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Reactant: CNCC(C)(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(CC(C)(C)O)C(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 16 h
Yield: 290 %

Procedure:
To a suspension of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (639 mg, 3.7 mmol) and 2-methyl-1-(methylamino)propan-2-ol (500 mg, 4.85 mmol) in THF (15 mL) were added HATU (1.57 g, 4.12 mmol) and N-methylmorpholine (2.13 mL, 19.4 mmol) at ambient temperature. The mixture was heated to 70° C. and stirred for 16 h. After cooling down to ambient temperature, the reaction mixture was poured into 20 mL HCl (2N aqueous solution) and extracted with ethyl acetate (2×100 mL). The organic layers were washed with water, brine and the solvent was evaporated. The aqueous layer was back-extracted with dichloromethane, dried and concentrated in vacuo. Both residues were combined to give 2.75 g of a semi-solid yellow material. The crude material was purified by silica gel chromatography using a methanol/ethyl acetate gradient to yield the product (1.2 g, 90%) as colorless oil.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([Br:18])[CH:12]=2)C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[Br:17][C:15]1[CH:16]=[C:11]([CH:12]=[C:13]([Br:18])[CH:14]=1)[O:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1cc(Br)cc(Br)c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCOc1cc(Br)cc(Br)c1
Temperature: 80 °C
Yield: 78.8 %

Procedure:
1-(4′-Phthalimidobutoxy)3,5-dibromobenzene (1.0 g, 2.20 mmol) was dissolved in ethanol (45 mL) for 5 minutes under nitrogen. Hydrazine monohydrate (610 mg, 12.1 mmol) was added and the reaction was refluxed at 80° C. for 2 hours. To the reaction aqueous 1M HCl (17.7 mL, 17.7 mmol) was added and refluxed at 105° C. for another 2 hours. The aqueous layer was extracted with dichloromethane (2×150 mL). The organic layers were combined, washed with saturated NaHCO3 (3×), water, and brine, then dried over MgSO4, and filtered. Removal of solvent yielded a yellow oil (560 mg, 78%).
Reaction SMILES: C(OC(C1OC(CC(C([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)C)C(OC(C)(C)C)=O)=CC=1)=O)C.[Si:34]([O:41][CH2:42][CH:43]([CH2:47][C:48]1[O:49][C:50]([C:53](=[O:61])[NH:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:52]=1)[CH:44](O)[CH3:45])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][NH:22][CH:44]([CH3:45])[CH:43]([CH2:42][O:41][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH2:47][C:48]1[O:49][C:50]([C:53](=[O:61])[NH:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[CH:51][CH:52]=1
Reactant: CC(O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccc(C(=O)Nc2ccccc2)o1
Reactant: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)NCc2ccc3ccccc3c2)o1
Product: CC(NCc1ccc2ccccc2c1)C(CO[Si](C)(C)C(C)(C)C)Cc1ccc(C(=O)Nc2ccccc2)o1

Procedure:
The title compound was prepared by the same reactions as in Reference Example 1(3) and (4) by using (2RS,3SR)-3-(tert-butyldimethylsilyloxymethyl)-2-hydroxy-4-{5-(phenylcarbamoyl)-2-furyl}butane instead of tert-butyl (2RS,3SR)-2-{5-(ethoxycarbonyl)-2-furylmethyl}-3-hydroxybutanoate used as the starting material in Reference Example 1(3).
Reaction SMILES: C([NH:8][CH2:9][C:10]1[CH:32]=[CH:31][C:13]([C:14]([NH:16][C@@H:17]([CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)[C:18]([OH:20])=[O:19])=[O:15])=[CH:12][CH:11]=1)(OC(C)(C)C)=O.Cl.O1CCOCC1>CO>[NH2:8][CH2:9][C:10]1[CH:32]=[CH:31][C:13]([C:14]([NH:16][C@@H:17]([CH2:21][CH2:22][NH2:23])[C:18]([OH:20])=[O:19])=[O:15])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 189.4 %

Procedure:
The compound obtained in Example 60-2 (49.7 mg) was dissolved in methanol (0.5 ml) and 4 mol/l hydrochloric acid/dioxane solution (0.5 ml) was added. The mixture was stirred for 1.5 hours at room temperature. After the reaction, the solvent was removed by distillation and the residue was dried using a vacuum pump to obtain the title compound (52.4 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[Se:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-])=O.Cl.[Cl-].[NH4+]>O.CO.[Fe]>[NH2:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[Se:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)[se]1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(N)c(C)[se]1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of methyl 5-methyl-4-nitroselenophene-2-carboxylate (2.3 g, 9.28 mmol) in a mixture of water (5 mL) and methanol (40 mL) was added conc. hydrochloric acid (1.0 mL). To the above solution was added iron powder (2.6 g, 46.4 mmol) followed by ammonium chloride (2.5 g, 46.4 mmol) at rt. The reaction mixture was refluxed for 1 h and was then allowed to cool to rt. The solution was filtered and basified with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (4×100 mL) and the combined organic layer was dried over sodium sulfate and filtered. Solvent was evaporated and the residue was chromatographed over silica gel column using hexane-ethyl acetate (80:20) as eluent to give methyl 4-amino-5-methylselenophene-2-carboxylate (1.6 g, 79%), mp 66-68° C. 1H NMR (400 MHz, DMSO-d6): δ 7.57 (1H, s), 4.72 (2H, br s), 3.73 (3H, s), 2.24 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[O:18][N:17]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:18][N:17]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 5) from ethyl 3-(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-1,2,4-oxadiazol-5-yl)propanoate and 1N NaOH.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:84])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C1COCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:84])[C:7]=2[F:8])[CH2:11][CH2:12]1)(=[O:18])[CH3:17]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)N1CCN(Cc2ccnc(Cl)c2F)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccnc(N)c2F)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[(4-acetylpiperazin-1-yl)methyl]-2-chloro-3-fluoropyridine (14-3, 85 mg, 0.31 mmole) in dry toluene (2 mL) was added NaOtBu (42 mg, 0.44 mmole), racemic BINAP (29 mg, 0.05 mmole), Pd2(dba)3 (14 mg, 0.02 mmole), and benzophenone imine (0.06 mL, 0.38 mmole) then the mixture was heated to 80 ° C. After 18 hr the mixture was cooled to RT. A solution of 1N HCl:THF (1:1, 10 mL) was added and the mixture stirred for 1 hr. The mixture was washed with EtOAc (2×). The aqueous layer was made basic with saturated NaHCO3 then extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered, and concentrated. Flash column chromatography (gradient, 0-5% MeOH/CH2Cl2) gave the titled compound as a light yellow solid: 1H-NMR (500 MHz, CDCl3) δ7.81 (d, 1H, J=5.12 Hz), 6.71 (t, 1H, J=4.88 Hz), 4.56 (bs, 2H), 3.63 (t, 2H, J=5.13 Hz), 3.56 (s, 2H), 3.10 (t, 2H, J=5.13 Hz), 2.46 (m, 2H), 2.08 (s, 3H); MS (ES) (M+H)+253.
Reaction SMILES: [Cl:1][C:2]([Cl:19])([Cl:18])[C:3]([NH:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[O:4].[Br:20]Br>C(O)(=O)C>[Br:20][C:11]1[S:10][C:9]([NH:8][C:6]([NH:5][C:3](=[O:4])[C:2]([Cl:1])([Cl:18])[Cl:19])=[O:7])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=1
Reactant: COC(=O)c1ccsc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)sc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate (1 eq) in glacial acetic acid (20 mL) was added a solution of bromine (1.3 eq) in glacial acetic acid (5 mL) slowly over a period of 5 min. After the addition was complete, the resulting dark solution was stirred for 30 mins at RT. The solvent was evaporated under vaccum and the residue was triturated with H2O. The title compound was obtained by filtration (99%) as an off-white solid. The product was used in the next step without any further purification after drying for 2 days under P2O5. LC/MS (ES, M+H=425).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][NH:14][C:15]([O:17]CC)=O)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl.O1CCOCC1>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:12])[NH:13][NH:14][C:15]2=[O:17])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)NNC(=O)Nc1ccc(C(C)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To ethyl 2-(4-acetylphenylcarbamoyl)hydrazinecarboxylate (I-4a: 354 mg, 1.335 mmol) in MeOH (10 mL) was added K2CO3 (553 mg, 4.00 mmol). The mixture was stirred at 55° C. for 2 hours, cooled to room temperature, and then HCl 4N in dioxane (1.668 mL, 6.67 mmol) was added. The precipitate was filtered, and the filtrate was concentrated in vacuo. The resulting solid was triturated in CH2Cl2, filtered and dried giving 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (I-4b: 125 mg, 43%) as a light yellow solid. LC-MS (M+1) 220.2, t=0.78 minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3 H) 7.68 (d, J=8.84 Hz, 2 H) 8.05 (d, J=8.59 Hz, 2 H) 10.65 (s, 2 H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:17])(=O)=O.CS(C1C=CC(N2C=NN=N2)=CC=1)=O.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:17][CH2:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(-n2cnnn2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: CS(=O)c1ccc(-n2cnnn2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCSc1ccc(-n2cnnn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4.8 g. of 1-[p-(methylthio)phenyl]-1H-tetrazole in 80 ml. of methylene chloride was treated with 2.2 ml. of sulfuryl chloride in 10 ml. of methylene chloride. The solution was stirred at room temperature for 1 hour, evaporated to dryness on a steam bath, washed with hexane and recrystallized from methylene chloride to give white crystals, m.p. 115°-117° C. This product was also obtained by a similar reaction of 0.5 g. of 1-[p-(methylsulfinyl)phenyl]-1H-tetrazole and 0.18 ml. of thionyl chloride in methylene chloride.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.[N+:26]([O-])([OH:28])=[O:27]>>[F:1][C:2]([F:17])([F:18])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][C:10]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 24 h

Procedure:
To 58.1 g. (0.212 mole) of 1,4-bis(2,2,2-trifluoroethoxy)benzene in 400 ml. of trifluoroacetic acid is added dropwise with stirring 13.7 ml. of concentrated nitric acid over 3.5 hours at 25± 2° C. Stirring is continued for 24 hours, then the mixture is concentrated to one-third the original volume. The concentrate is poured into 600 ml. of water, and the resulting solution is extracted twice with diethyl ether. The ether solution is washed thrice with saturated sodium chloride solution, then with dilute sodium hydroxide solution until the washings are basic. The solution is washed again with saturated sodium chloride solution, dried and evaporated. The liquid residue is distilled to provide 2,5-bis(2,2,2-trifluoroethoxy)nitrobenzene as a clear, pale yellow liquid, b.p. 116°-119° C/0.35 mm Hg.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=[O:9])[CH2:4][CH2:3]1.Cl>[OH-].[NH4+]>[F:1][C:2]1([F:13])[CH2:3][CH2:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=C(O)C1CCC(F)(F)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of ethyl 4,4-difluorocyclohexanecarboxylate (2500 mg, 13 mmol) in ammonium hydroxide (28%, 50 ml) was stirred at 60° C. overnight. After removal of solvent, the residue was washed with water. The precipitate was obtained as product (white solid, 800 mg). 1H NMR (300 MHz, CDCl3): δ 5.31-5.45 (br, 2H), 2.02-2.27 (m, 3H), 1.92-2.02 (m, 2H), 1.72-1.87 (m, 4H). The mother liquor was acidified with 1N HCl to pH<1. The compound was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate, filtered, condensed. 4,4-difluorocyclohexanecarboxylic acid was obtained as a 1200 mg of white solid which was further converted to 4,4-difluorocyclohexanecarboxamide by following procedure.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[N:18]2)=[CH:13][CH:12]=1.[Br:30]Br>C(O)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:30][C:12]1[CH:13]=[C:14]([N:17]2[CH:21]=[C:20]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[CH:19]=[N:18]2)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1]
Reactant: BrBr
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N3CCOCC3)cn2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N3CCOCC3)cn2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 4-{[1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl]carbonyl}morpholine obtained in Example 6 (0.500 g) in acetic acid (8.0 ml), bromine (0.200 g) was added dropwise and stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous sodium thiosulfate and concentrated under reduced pressure. The resulting residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1) to give the titled compound (0.175 g) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(C(NCCc2c[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.5 %

Procedure:
2.0 g of tryptamine (12.5 mmol) were dissolved in DCM (50 mL) and treated in one portion with triethylamine (1.74 mL. 12.5 mmol, 1 eq) and trityl chloride (3.44 g, 12.3 mmol). The resulting solution was stirred for 24 h at room temperature while protected from light. Volatiles were evaporated and the residue treated with aqueous HCl (1 N). The solid formed was filtered and washed with small portions of ether then dissolved in aqueous sodium hydrogen-carbonate and extracted into DCM. The organic layer was dried and evaporated to give 4.48 g (89% ) of 3-(N-trityl-(2-aminoethyl))-indole, which was used without further purification.