Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]CC)=O.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([NH:14][C:3](=[O:5])[CH2:2][SH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)CS
Solvent: CCO
Product: O=C(CS)NC1CCCCC1
Reaction time: 72 h

Procedure:
A solution of ethyl 2-mercaptoacetate (12 g) and cyclohexylamine (29.7 g) in ethanol (50 ml) was allowed to stand at ambient temperature for 72 hours, and was then refluxed for 6 hours. The solvent was evaporated and the residue dissolved in ethyl acetate (200 ml). The solution was washed sequentially with 2M HCl (3×50 ml), water (2×50 ml) and brine (50 ml) and the solvent removed in vacuo. The crude product was purified by chromatography on silica (eluting with dichloromethane/methanol 99:1 v/v) to give N-cyclohexyl-2-mercaptoacetamide as low-melting tan crystals; NMR: 1.0-2.0(complex, 11H, cyclohexyl-CH2 and SH), 3.2(d, 2H, CH2), 3.6-3.9(m, 1H, cyclohexyl-CH), 6.4-6.9(broad d, 1H, NH); m/e 174 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[H-].[Na+].[CH3:18][C:19]([CH3:21])=O>C(COC)OC.O>[CH2:2]([O:3][C:4](=[O:5])[C:6]([F:7])=[C:19]([CH3:21])[CH3:18])[CH3:1]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(F)=C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
Triethyl 2-fluoro-2-phosphonoacetate (20 g, 82.6 mmol) (Aldrich) was added dropwise to a stirred solution of sodium hydride (3.6 g, 90.8 mmol) in dimethoxyethane (100 mL) at 0° C. After stirring at room temperature for 20 min, acetone (4.78 g, 82.6 mmol) was added and the reaction mixture was refluxed for overnight. The two phase mixture was cooled, diluted with water and extracted with ether. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified with chromatography (Hexanes) to give 2-fluoro-3-methyl-but-2-enoic acid ethyl ester as colorless oil (Yield: 9.0 g, 61.6%).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)=O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH2:21]([O:20][C:14](/[CH:15]=[CH:1]/[C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCOC(=O)c1[nH]c(C=O)cc1C
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)/C=C/c1cc(C)c(C(=O)OCC)[nH]1
Temperature: 100 °C
Reaction time: 38 h
Yield: 47.7 %

Procedure:
Ethyl 5-formyl-3-methyl-1H-pyrrole-2-carboxylate 470 mg, monoethyl malonate 378 mg, piperidine 0.05 mL and pyridine 6 mL were mixed and stirred at 100° C. for 38 hours. Ice water was added to the reaction liquid and the precipitate was recovered by filtration. The precipitate was washed with water and dried in flowing air under heating to provide 311 mg of the title compound.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20]S)=[CH:11]1.C1C=CC2NC=C(CCO)C=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]1([CH3:5])[C:11]2[NH:10][C:18]3[C:13]([C:12]=2[CH2:19][CH2:20][O:4]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: SCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Reaction time: 0.17 h

Procedure:
Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for 30 minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 21/2 hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid ethyl ester, as an oil, νmaxCHCl3 1715 cm-1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1Cl>CN(C=O)C.O>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: COC(=O)c1cccnc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 100 °C

Procedure:
A mixture of 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared according to Preparation 5 above) (3.2 g, 15.4 mmol) and 2-chloro-nicotinic acid methyl ester (1.78 g, 10.4 mmol) was dissolved in DMF (10 mL) and heated to 100° C. for 2 h. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo to afford the product as yellow solid.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].C[O-].[Na+].[CH:9]12[O:14][CH:10]1[CH2:11][CH2:12][CH2:13]2>CO>[OH:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: C1CC2OC2C1
Reactant: O=C(O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CS[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Mercaptoacetic acid (22.5 g 0.244 mole) was added to a cold (+5° C.) solution of sodium methoxide [prepared from sodium (11.2 g, 0.488 mole)] in methanol (125 ml). After stirring for 20 minutes, cyclopentene oxide (19.5 g, 0.23 mole) was added dropwise over 20 minutes to the cold solution. The ice bath was removed and the reaction was refluxed for 45 minutes. The reaction was cooled to room temperature and made acidic by the addition of 4 N hydrochloric acid. Water (100 ml) was added and the mixture was extracted twice with 150 ml of diethyl ether. The combined diethyl ether extracts were washed with water (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:1]([C@H:4]1[N:9]([C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1nccc(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 150 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A mixture of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (0.9 g, 2.56 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (1.0 g, 5.1 mmol, 2 eq.) and DIEA (1.0 g, 7.7 mmol, 3 eq.) in i-PrOH (6 mL) was stirred in a microwave oven at 150° C. for 2 h. TLC showed the starting material was consumed completely (PE:EtOAc=3:1). The solvent was removed in vacuo at 40° C., and the residue was purified by column chromatography on silica gel eluting with PE/EtOAc=6/1 to give (R)-methyl 1-isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (1.0 g, 78% yield) as a white solid. LC-MS m/z 498.1 [M+H]+. 1H NMR (CDCl3 300 MHz): δ 8.52 (d, J=4.8 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 6.83 (d, J=4.8 Hz, 1H), 6.06 (d, J=7.8 Hz, 1H), 5.39-5.28 (m, 1H), 4.33-4.24 (m, 1H), 4.20-4.12 (m, 1H), 3.93 (s, 3H), 3.77-3.65 (m, 1H), 3.39 (s, 3H), 2.52-2.38 (m, 1H), 1.25 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.6 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:11][NH2:12]>C(O)CCC>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[NH:12][N:11]=1
Reactant: NN
Reactant: N#Cc1ccccc1F
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
2-Fluorobenzonitrile (605 mg, 5 mmol) and 85% aqueous hydrazine hydrate (352 mg, 6 mmol) were mixed with 1-butanol (3 mL). The mixture was heated at reflux with stirring for 5 h then cooled to room temperature. The resulting precipitate was collected by filtration and washed with dichloromethane and the filter cake was dried in vacuo to give 3-amino benzpyrazole (293 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([OH:11])[CH3:10].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1c(F)cccc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(O[Si](C)(C)C(C)(C)C)c1c(F)cccc1Cl
Yield: 94.6 %

Procedure:
1-(2-Chloro-6-fluorophenyl)ethanol (8.5 g), imidazole (8.1 g) and t-butyldimethylsilylchloride (8.71 g) were stirred in DMF for 24 hours. The mixture was diluted with ether and washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 1-(2-chloro-6-fluorophenyl)ethyl (t-butyldimethylsilyl)ether (13.3 g) as a clear oil, NMR (CDCl3) -0.1(s,3H), 0.05(s,3H), 0.85(s,9H), 1.5(d,3H), 5.4(q,1H), 6.9(m,1H), 7.05(m,2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[C:18]([NH:37]CCO)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:19]1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[NH2:37][CH2:18][CH2:19][N:11]1[C:10](=[O:15])/[C:9](=[CH:8]/[C:7]2[CH:16]=[CH:17][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)/[S:13][C:12]1=[O:14]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 182.5 %

Procedure:
Compound 2 (1.26 g, 5.08 mmol), 2-(tritylamino)ethanol (2.00 g, 6.60 mmol) and triphenylphosphine (1.80 g, 6.86 mmol) were dissolved in 51 mL of anhydrous THF, and stirred at room temperature for 5 min. DIAD (1.3 mL, 6.60 mmol) was added to the reaction mixture and then stirred overnight at 45° C. The reaction mixture was diluted with ethyl acetate and washed with sat'd NH4Cl aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (30% ethyl acetate in hexanes) to afford 3 (75.0%, 2.71 g) as a white solid.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:15][N:16]([CH:18]=O)C>>[C:2]1([C:1]2[NH:8][CH:4]=[C:3]([C:2]3[CH:7]=[CH:18][N:16]=[CH:15][CH:1]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: N=C(N)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(-c2nc(-c3ccncc3)c[nH]2)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
2-Bromo-1-(pyrindin-4-yl)ethanone hydrobromide (6.4 g, 23 mmol) was added portionwise to a solution of benzamidine (11.2 g, 93 mmol) in dry DMF (50 mL) at 0° C., maintaining an internal temperature of <5° C. The stirred reaction was allowed to warm to rt over 2 h and then heated to 40° C. for 16 h. The crude reaction was poured into saturated aqueous NaHCO3 solution (600 mL), and partition and extracted with EtOAc (3×300 mL). The combined organic layers were dried (Na2SO4) and evaporated. The resulting crude residue was purified by flash chromatography (SiO2, 100:0-90:10 DCM-MeOH) to give 3.68 g (72%) of 4-(2-phenyl-1H-imidazol-4-yl)pyridine: 1H NMR (CDCl3) δ 9.73 (broad s, 1H), 8.61 (d, J=6.0, 1.2 Hz, 2H), 7.91 (d, J=8.0, 1.6 Hz, 2H), 7.77 (d, J=6.0, 1.2 Hz, 2H), 7.57 (s, 1H), 7.48 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:23][CH:22]=1.[CH3:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[C:36]([OH:43])[CH:37]=[CH:38][CH:39]=2)[N:34]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:8][O:43][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[N:34]=[C:33]([CH3:32])[CH:42]=[CH:41]3)=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:23][CH:22]=1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CCl)c2Cl)cc1
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(2,4-dichloro-3-chloromethylphenyl)-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (50 mg), 2-methyl-8-hydroxyquinoline (17 mg) and potassium carbonate (44 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 1 day. The mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography on silica gel to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[4-(methylcarbamoyl)-cinnamoylaminomethyl]pyrrole (40 ml) as an amorphous powder.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[CH:36]=[CH:37][C:38]([O:45][CH3:46])=[C:39]([CH2:41][C:42]([OH:44])=[O:43])[CH:40]=1>>[CH3:46][O:45][C:38]1[CH:37]=[CH:36][C:35]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:22])([F:24])[F:23])=[CH:20][C:15]=2[CH2:14][N:3]2[C@@H:2]([CH3:1])[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[CH:40][C:39]=1[CH2:41][C:42]([OH:44])=[O:43]
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(Br)cc1CC(=O)O
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)cc1CC(=O)O

Procedure:
Prepared according to the procedure described in Example 7, Step 2, using the following starting materials: (4S,5R)-4-methyl-5-phenyl-3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-oxazolidin-2-one and 5-bromo-2-methoxyphenylacetic acid. M+H is 500.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH:8]([Cl:12])[C:9](Cl)=[O:10].C(N(CC)CC)C>C(OCC)C>[Cl:7][C:8]1([Cl:12])[CH:1]2[CH:2]([CH2:3][CH2:4][CH:5]=[CH:6]2)[C:9]1=[O:10]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C1=CCCC=C1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1C2CCC=CC2C1(Cl)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
A mixture of 238 g of cyclohexadiene and 245 g of dichloroacetyl chloride in 2 litres of diethyl ether under nitrogen was refluxed while adding 220 g of triethylamine dropwise over a period of 3 hours. The mixture was then stirred at room temperature for 20 hours and filtered. The filtrate was washed with brine, 1 N hydrochloric acid, saturated sodium bicarbonate and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue distilled to give 224 g of 8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one, the compound of formula (4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:24])[C@:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:6]=1.C(N(CC)CC)C.[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36]Br)[CH3:33]>CN(C)C=O>[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36][NH:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:24])[C@:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:6]=1)[CH3:33]
Reactant: C[C@@H](n1cc(N)cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOC(CBr)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(CNc1cnn([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
(2R,3R)-3-(4-amino-1H-pyrazol-1-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol obtained in Step 2 (0.12 g, 0.35 mmol) was dissolved in N,N-dimethylformamide (2 mL) and triethylamine (0.058 g, 0.42 mmol) was slowly added thereto. The mixture was stirred at room temperature for 30 minutes, and bromoacetaldehyde diethyl acetal (0.065 mL, 0.42 mmol) was added thereto, followed by stirring at 80° C. for 4 hours. The reaction was terminated by adding ice water (0.1 mL) thereto. The resulting residue was extracted with ethyl acetate (20 mL), and the extract was washed successively with saturated ammonium chloride (20 mL) and brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (0.071 g, yield 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[Li].O>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(CNc2nccc(NCCc3ccc(OC)c(OC)c3)n2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCNc2ccnc(NCc3ccc(C(=O)O)cc3)n2)cc1OC
Reaction time: 24 h
Yield: 92.5 %

Procedure:
To a stirred solution of compound 8 (670 mg, 1.59 mmol) in THF (15 mL) at room temperature was added a solution of LiOH.H2O (166 mg, 3.97 mmol) in water (5 mL). After 24 h, the reaction mixture was concentrated, diluted with water and acidified with 2N HCl (pH at 5-6). A precipitate formed, which was separated by filtration, rinsed with water and dried to afford the title compound 9 (600 mg, 1.47 mmol, 93% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): AB system (δA=7.87, δB=7.41, J=8.2 Hz, 4H), 7.68-7.58 (m, 1H), 7.12-6.56 (m, 5H), 5.75 (d, J=5.5 Hz, 1H), 4.53 (d, J=6.3 Hz, 2H), 3.74 and 3.72 (2s, 6H), 3.48-3.30 (m, 2H), 2.80-2.60 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:3]=1.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][OH:20])#[N:15]>>[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:20][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:3]=1)#[N:15]
Reactant: N#Cc1cccc(CO)c1
Reactant: Clc1cncc(N2CCNCC2)n1
Product: N#Cc1cccc(COc2cncc(N3CCNCC3)n2)c1

Procedure:
Starting materials, 2-chloro-6-(1-piperazinyl)pyrazine and 3-cyanobenzyl alcohol. Fragmenting mass analysis supports the stated structure. Purity 90% (HPLC). HRMS m/z calcd for C16H17N5O (M)+ 295.1433, found 295.1431.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2.CO.[OH-].[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20]([OH:22])=[O:21])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
To a mixed solution of ethyl 5-fluoro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.24 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.20 g), and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and aqueous citric acid solution was added to the obtained residue. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (205 mg, yield 93%) as pale-pink crystals. MS:341 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:3]1=[O:14]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1OC[C@@H](c2ccccc2)NC1=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@H](C)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (2S,5R)-2-methyl-5-phenylmorpholin-3-one from Step E (90 mg, 0.47 mmol) in DMF (2 mL) at 0° C. was added NaH (20 mg of a 60% dispersion in oil, 0.50 mmol). After 10 min, ethyl bromoacetate (79 mg, 0.47 mmol) was added and the mixture was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (3 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-90:10 to 60:40, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].C([O-])([O-])=O.[Na+].[Na+].[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O.O1CCOCC1>[CH2:17]([O:16][C:14]([NH:3][C:2]([CH3:4])([C:5]([OH:7])=[O:6])[CH3:1])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-methylalanine (50 g, 0.49 mmol) and Na2CO3 (156 g, 1.47 mol) in water (1 L) was added a solution of CbzCl (91 g, 0.54 mmol) in dioxane (500 mL) at 0° C. over 15 minutes. The resulting solution was stirred at room temperature for 18 hours. The reaction was extracted with Et2O (2×500 mL), and the aqueous layer collected, acidified to pH=1 with cHCl and extracted with EtOAc (2×500 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford a white solid as the title compound that was used directly in the next step (111 g, 97%).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].C1(S(O)(=O)=O)C=CC=CC=1.[Cl:16][CH2:17][CH2:18][C:19]#[N:20]>C(Cl)Cl.CC(C)=O>[S:1]([NH:5][C:19](=[NH:20])[CH2:18][CH2:17][Cl:16])(=[O:3])(=[O:2])[NH2:4]
Reactant: NS(N)(=O)=O
Reactant: N#CCCCl
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a suspension of benzenesulfonic acid (31.6 g, 0.2 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the heating period, the mixture was cooled to room temperature, diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml), and the suspension filtered and the product dried.