Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=O.C(N[CH:34]([NH2:38])[CH2:35][CH2:36][CH3:37])(OC(C)(C)C)=O.Cl.C([N:42]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.CCN(C(C)C)C(C)C.Cl>ClCCl.CN(C)C=O>[ClH:19].[NH2:42][CH2:37][CH2:36][CH2:35][CH2:34][NH:38][C:23](=[O:25])[CH2:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[CH:5]=2)[N:10]([C:11](=[O:12])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:2]=1[CH3:1]
Reactant: CCCC(N)NC(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(CC(=O)NCCCCN)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 98 %

Procedure:
a Fluorescent Indo-Dansyl Analog: Compound 27z was synthesized by the method outlined in FIG. 4. Briefly, indomethacin was complexed with N—BOC butanediamine for 16 hours at room temperature in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), 1-hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP), N,N′-diisopropylethylamine (DIPEA), and N,N-dimethylformamide (DMF). A yellow solid corresponding to a percent yield of 72% was obtained. This solid was then dissolved in dichloromethane and treated with HCl (gas) for 2 hours at room temperature, producing N-(4-aminobutyl)-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide hydrochloride as a brown solid (98% yield), which was reacted with triethylamine (TEA) in dichloromethane for 5 minutes at room temperature prior to the addition of dansyl chloride. Dansyl chloride was then added, and the reaction was allowed to continue for 16 hours at room temperature, which produced Compound 27z as a yellow solid in a yield of 77%. Compound 27z was characterized by NMR and mass spectroscopy (MS).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C(C)=C(S(O)(=O)=O)C(C)=C(N)C=2C)=[CH:4][C:3]=1S(O)(=O)=O.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1Sc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Example 25 was repeated, provided that the compounds shown in 1st, 2nd and 3rd columns of the following table were used in place of 1-amino-4-(3'-amino-2',4',6'-trimethyl-5'-sulfophenylthio)anthraquinone-2-sulfonic acid, 1-aminobenzene-3-β-sulfatoethylsulfone and 3-aminobenzenesulfonic acid, respectively, thereby obtaining a corresponding anthraquinone compound A color shade on cotton of the compound is as shown in a 4th column of the table.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O.FC(F)(F)C1C=C2C(=CC=1)NC(=O)C=N2>>[Cl:18][C:9]1[CH:8]=[N:7][C:6]2[C:11](=[CH:12][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=c1cnc2ccc(C(F)(F)F)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=c1cnc2cc(C(F)(F)F)ccc2[nH]1
Product: FC(F)(F)c1ccc2ncc(Cl)nc2c1

Procedure:
This 7-trifluoromethylquinoxalin-2-one was allowed to react with phosphorus oxychloride (in the same manner as described above for 6-trifluoromethylquinoxalin-2-one) to yield the intermediate 2-chloro-7-trifluoromethylquinoxaline having a melting point of about 119°-120° C. This compound was allowed to react with ammonia, in the manner described above, to yield the 2-amino-7-trifluoromethylquinoxaline, having a melting point of about 192°-194° C., and identified by IR spectrum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:25]([O:24][CH:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:20]([O:22][CH3:23])=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)OCc1ccccc1

Procedure:
In a similar manner to that described in Reference example 1(c), a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (398 mg), which is obtained in a similar manner to that described in Reference example 39(a), benzylbromide (0.28 ml), hydride (55% suspension in oil, 168 mg) and tetrabutylammonium iodide (43 mg) and the reaction mixture was treated to afford the desired compound (133 mg) as a colorless oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16](O)=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][C:37]1[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=1[NH2:39]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[NH:35][CH2:36][C:37]3[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:39]=2)[N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[CH2:12]1
Reactant: NCc1ccccc1N
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C2=Nc3ccccc3CN2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-(aminomethyl)aniline, the title compound was obtained in 77% purity by HPLC. MS(ESI+): m/z=439.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH3:14][Mg+].[Br-]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([OH:13])[CH3:14])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: C[Mg+]
Reactant: O=Cc1cc(Cl)cc2c1OCCO2
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)c1cc(Cl)cc2c1OCCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
7-Chloro-2,3-dihydrobenzo[b][1,4]dioxine-5-carbaldehyde (0.26 g, 1.32 mmol) was dissolved in 10 mL of diethyl ether and cooled to 0° C. MeMgBr (1.1 mL, 3.31 mmol) was added to the solution and the ice bath was removed. The reaction was allowed to stir at rt for 10 min. and at reflux for 30 min. The reaction was cooled to 0° C. and 10 mL of sat NH4Cl were added to quench the reaction. The diethyl ether layer was separated and washed with water (20 mL×2). The organic layer was dried over Na2SO4 and the solvent was removed by rotary evaporation to collect the desired product (258 mg, 91%). 1H NMR (400 MHz, CDCl3): δ 6.91 (s, 1H), 6.77 (s, 1H), 5.02 (m, 1H), 4.24 (m, 4H), 1.45 (d, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3]C1.C[OH:41]>>[Cl:39][C:36]1[CH:35]=[N:34][C:33]([O:32][CH2:31][CH2:30][O:29][C:11]2[C:10]([C:8]3[CH:7]=[CH:6][C:5]([OH:1])=[C:4]([OH:3])[CH:9]=3)=[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH2:26][OH:41])=[CH:21][N:20]=3)(=[O:17])=[O:18])[N:13]([CH3:28])[N:12]=2)=[N:38][CH:37]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reactant: CO
Product: CC(CO)c1ccc(S(=O)(=O)Nc2c(-c3ccc(O)c(O)c3)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS7-H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron Shaker™ with 1″ throw. 2 mls of this inoculum medium was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-5-isopropyl-2-pyridinesulfonamide (Example 103) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 96 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:34])=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[N:7]=2)[C:17]=1[F:34])(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.100 g, 0.190 mmol) and 2-aminoethyl-methyl-sulfone (0.100 g, 0.812 mmol), the title compound was obtained as an off-white solid (53 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.09 (d, J=5.1 Hz, 1H), 7.62-7.74 (m, 1H), 7.39-7.49 (m, 2H), 7.33-7.39 (m, 1H), 7.20-7.32 (m, 3H), 5.89-6.05 (m, 1H), 3.63 (br. s., 2H), 3.34-3.39 (m, 2H), 3.25-3.31 (m, 1H), 2.99-3.04 (m, 3H), 1.35 (d, J=6.9 Hz, 6H). MS (ESI): 613.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][OH:18]>C(O)CCC>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][CH2:17][OH:18])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NCCO
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO

Procedure:
A mixture of 50 parts of 1-chloro-2-nitro-4-(trifluoromethyl)benzene, 37 parts of 2-aminoethanol and 100 parts of 1-butanol is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. The residue is taken up in a diluted hydrochloric acid solution. The product is extracted with methylbenzene. The layers are separated and the aqueous phase is extracted with methylbenzene. The combined methylbenzene-phases are washed successively with a diluted hydrochloric acid solution and twice with water, dried, filtered and evaporated. The solid residue is crystallized from petroleumether. The product is filtered off and dried, yielding 2-{[2-nitro-4-(trifluoromethyl)phenyl]-amino}-ethanol; mp. 74.9° C.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Cl:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:15]=1[NH2:16].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:16]/[C:15]1[C:17]([Cl:24])=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=1[Cl:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (3.00 g, 18.07 mmol) and 2,6-dichloro-4-nitroaniline (3.74 g, 18.07 mmol) in DCM (60 mL) was cooled to 0° C., under an atmosphere of nitrogen. Triethylamine (7.56 mL, 54.2 mmol) was added, followed by dropwise addition of titanium (IV) chloride solution (1 N in DCM, 10.8 mL, 10.8 mmol). The reaction mixture was stirred at 0° C. for 3 hours, then allowed to reach room temperature over 1 hour. The resultant mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the crude title compound as a yellow/brown solid (5.89 g, 92% yield). LCMS (Method C): RT=4.08 min, m/z: 327 [M+H+−N2].
Reaction SMILES: [CH3:1][C:2](=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[H-].[Na+].C([Li])CCC.[CH3:20][C:21]([CH3:23])=[O:22]>O1CCCC1.CCCCCC.O>[OH:22][C:21]([CH3:23])([CH3:20])[CH2:11][C:10](=[O:12])[CH:4]([C:2]([CH3:3])=[CH2:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(C(C)=O)=C(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=C(C)C(C(=O)CC(C)(C)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.00 g of ethyl 2-(1-methyl-ethylidene)-3-oxo-butanoate [described in Helv. Chim. Act., Vol. 54 (1971), p. 1797] were added dropwise at room temperature to a suspension of 860 mg of sodium hydride as a 50% mineral oil suspension in 50 ml of tetrahydrofuran and the mixture was refluxed for one hour and then cooled to room temperature. 13 ml of a solution of 1.6 M of butyllithium in hexane were added to the mixture at 0° C. and the mixture was stirred at 0° C. for 30 minutes. The mixture was cooled to -10° C. and 1.60 ml of acetone were added thereto. The mixture was poured into water and the mixture was extracted with ether. The ether phase was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate and evaporated to about 100 ml to obtain a solution of ethyl 5-hydroxy-5-methyl-2-(1-methyl-ethenyl)-3-oxo-hexanoate and its isomer, ethyl 5-hydroxy-5-methyl-2-(1-methyl-ethenyl)-3-oxo-hexanoate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[S-:12][C:13]#[N:14].[Na+].[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH2:20]>C(O)C>[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH:20][C:13]1[S:12][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:14]=1
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: COC(=O)CN
Agent: [Na+]
Solvent: CCO
Product: COC(=O)CNc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
14.5 g (66.8 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone and 5.42 g (66.8 mmol) of sodium thiocyanate were stirred in 250 ml of ethanol at 50° C. for 3 h. 5.95 g (66.8 mmol) of aminoacetic acid methyl ester (prepared from its hydrochloride) in 25 ml of ethanol were added, and the reaction mixture was stirred at room temperature for 4 h and allowed to stand overnight. After concentrating, water and ethyl acetate were added to the residue. The organic phase was separated, washed with water, dried and concentrated. Yield: 8.6 g (48%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].F[B-](F)(F)F.[H+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][C:25]([N+]#N)=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1>CS(C)=O.O>[C:1](=[O:4])([S:3][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)=[N:23][C:22]=2[CH:24]=1)[CH3:2]
Reactant: N#[N+]c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reactant: CC([O-])=S
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Sc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 3.4 %

Procedure:
To a stirred solution of potassium thioacetate (130 mg, 1.13 mmol) in DMSO (2.8 mL) at room temperature was added dropwise a solution of 2-(4-chlorophenyl)benzo[d]oxazole-5-diazonium tetrafluoroboric acid salt (370 mg, 1.08 mmol) in DMSO (1.4 mL). After 15 min, the mixture was heated at 70° C. for 1 h. After cooling, the mixture was diluted with water, and then extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 5:95 v/v to ethyl acetate/hexanes 15:85 v/v) and triturated with diethyl ether/hexanes to afford 11.3 mg (3%) of the title compound (LCMS RT=7.89 min, MH+ 304.2)
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][S:10][C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12>ClCCl.[Cl-].[Na+].O>[I:1][C:13]1[N:14]2[C:15]([S:16][CH:17]=[CH:18]2)=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: CSc1ncn2ccsc12
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CSc1nc(I)n2ccsc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.3 %

Procedure:
N-Iodosuccinimide (3.08 g) was added under ice cooling to a solution of 2.28 g of 7-methylthioimidazo[5,1-b]thiazole in dichloromethane. The mixture was stirred at room temperature for 7 hr. Saturated brine was added to the reaction mixture, followed by separation. The organic layer was washed with a dilute aqueous sodium thiosulfate solution and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate:dichloromethane=1:1) to give 3.78 g of 5-iodo-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(=O)[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.S(=O)(=O)(O)O>>[C:14]1(=[O:19])[N:1]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[C:5]([OH:7])=[O:6])[C:17](=[O:18])[CH2:16][CH2:15]1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(N2C(=O)CCC2=O)cc([N+](=O)[O-])c1

Procedure:
3-Succinimido-5-nitrobenzoic Acid [D; Y is CH2CH2, Z is OH] was prepared by heating 3-amino-5-nitrobenzoic acid with succinic anhydride in the presence of sulfuric acid. It had the m.p. 285°-290° C. when recrystallized from aqueous dimethylformamide.
Reaction SMILES: [CH2:1]1[O:21][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[CH:6][CH2:5]2)[O:3][CH2:2]1.C(O)C.C(OCC)(=O)C>[H][H]>[CH2:2]1[O:3][C:4]2([CH2:5][CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[O:21][CH2:1]1
Reactant: [H][H]
Reactant: FC(F)(F)Oc1ccc(C2=CCC3(CC2)OCCO3)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 99.9 %

Procedure:
A mixture of (4-trifluoromethoxyphenyl)cyclohexen-4-one ethyleneketal (43.3 g, 0.144 mol), ethanol (200 ml), ethyl acetate (50 ml) and Pa-C (2 g) was stirred at room temperature for 10 hours in hydrogen atmosphere (at that time, hydrogen (3.59 l) was consumed), filtering off the catalyst from the reaction solution, distilling off the solvent under reduced pressure, to obtain 4-(4-trifluoromethoxyphenyl)cyclohexanone ethyleneketal (43.5 g) (m.p. 41.2° C.), adding thereto formic acid (250 ml), heating the mixture under reflux for 2.5 hours, feeding the reaction substance into water, extracting with a mixed solvent of toluene (400 ml) with ethyl acetate (100 ml), twice washing the resulting orgnaic layer with water, drying over anhydrous MgSO4, filtering off anhydrous MgSO4, distilling off the solvent under reduced pressure and subjecting the resulting residue to column chromatography (silica gel, eluent: toluene), to obtain 4-(4-trifluoromethoxyphenyl)cyclohexanone (20.7 g). Yield: 47%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].O[CH:15](S([O-])(=O)=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+]>C(O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: O=S(=O)([O-])C(O)Cc1ccccc1
Reactant: Nc1cc(Cl)ccc1NCCCO
Agent: [Na+]
Solvent: CCO
Product: OCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21

Procedure:
A mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol, 44.8 parts of sodium α-hydroxybenzeneethanesulfonate and 120 parts of ethanol is stirred and refluxed for 30 minutes. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 5-chloro-2-(phenylmethyl)-1H-benzimidazole-1-propanol as a residue.
Reaction SMILES: Cl[C:2]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[C:5]([C:15]([NH2:17])=[O:16])=[C:4]2[CH2:18][CH2:19][CH2:20][C:3]=12.CCN(C(C)C)C(C)C.CN1C(=O)CCC1.Cl.[CH:38]12[CH2:44][C:43]1([CH2:45][OH:46])[CH2:42][CH2:41][NH:40][CH2:39]2>O>[OH:46][CH2:45][C:43]12[CH2:44][CH:38]1[CH2:39][N:40]([C:2]1[N:10]3[C:6](=[N:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[C:5]([C:15]([NH2:17])=[O:16])=[C:4]3[CH2:18][CH2:19][CH2:20][C:3]=13)[CH2:41][CH2:42]2
Reactant: OCC12CCNCC1C2
Reactant: NC(=O)c1c2c(c(Cl)n3c1nc1ccccc13)CCC2
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c2c(c(N3CCC4(CO)CC4C3)n3c1nc1ccccc13)CCC2
Yield: 74.8 %

Procedure:
11-chloro-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (800 mg) and DIPEA (1.95 ml) were added to an NMP suspension of 3-azabicyclo[4.1.0]hept-6-ylmethanol hydrochloride (1.01 g), and stirring was performed at 220° C. for 60 minutes under microwave irradiation. The reaction liquid was added to water and the precipitate was collected by filtration. The resulting solid was purified by silica gel column chromatography (MeOH/chloroform) to obtain 11-[6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl]-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (788 mg).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].Cl.[NH2:12][CH:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:3]([CH:2]([CH2:6][CH2:7][CH3:8])[C:1]([NH:20][C:18](=[O:19])[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH2:12])=[O:9])[CH2:4][CH3:5]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CC(C)CC(N)C(N)=O
Agent: Cl
Product: CCCC(CCC)C(=O)NC(=O)[C@@H](N)CC(C)C

Procedure:
The title compound was prepared from valproyl chloride (2.0 g, 12.3 mmole) and DL-leucinamide hydrochloride (2.0 g, 12.05 mmole), according to the procedure described in Ex. 1. 2.36 g (9.2 mmole, 76%) of a white crystalline solid, mp 151°-2° C., was thus obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:37]=[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:27]4[CH:36]=[CH:35][C:30]5[O:31][CH2:32][CH2:33][O:34][C:29]=5[CH:28]=4)[N:21]3[N:20]=2)=[CH:14][CH:13]=1)C)(C)(C)C.[CH3:39]C1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[NH2:7][C@@H:8]([CH3:39])[CH2:9][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:37]=[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:27]4[CH:36]=[CH:35][C:30]5[O:31][CH2:32][CH2:33][O:34][C:29]=5[CH:28]=4)[N:21]3[N:20]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)Oc1ccc(Nc2nc3cccc(-c4ccc5c(c4)OCCO5)n3n2)cc1
Solvent: ClCCl
Product: C[C@H](N)COc1ccc(Nc2nc3cccc(-c4ccc5c(c4)OCCO5)n3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
((S)-2-{4-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenoxy}-propyl)-carbamic acid tert-butyl ester (100 mg, 0.196 mmol) was dissolved in dichloromethane (4 ml) and MP-TsOH (1 g, 3.23 mmol) added. The mixture was shaken overnight at room temperature. The resin was collected by filtration and washed with methanol. The product was then cleaved from the resin with 2M ammonia in methanol. The eluant was concentrated in vacuo and the product was purified by prep LCMS.