Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11]1>>[CH:11]1[S:10][CH:14]=[CH:13][C:12]=1[CH2:15][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=Cc1ccsc1
Product: N#Cc1ccc(NCc2ccsc2)cc1
Yield: 38.6 %

Procedure:
The procedure of Example 40 was repeated, except that 1.43 g of 4-aminobenzonitrile was used in place of aniline, and 1.57 g of 3-thiophenecarbaldehyde was used in place of 4-formyl-phenyl sulfamate. The resulting crude product was purified by silica gel column chromatography (using a 2:1 mixture of hexane and ethyl acetate as the eluent) to obtain 1.00 g of 4-[N-(3-thenyl)amino]-benzonitrile.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH3:13])[N:4]=1)#[N:2].[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16])=[C:5]([CH2:12][CH3:13])[N:4]=1)#[N:2]
Reactant: CCCNCCC
Reactant: CCc1nc(C#N)c(C#N)nc1Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCN(CCC)c1nc(C#N)c(C#N)nc1CC
Yield: 49.7 %

Procedure:
2,3-Dicyano-5-chloro-6-ethylpyrazine (1.92 g; 0.01 mole) was dissolved in 30 ml of acetone. The solution was cooled to 0° to 5° C., and with stirring, 2.02 g (0.02 mole) of di-n-propylamine was added dropwise. The mixture was stirred for 30 minutes. The precipitate was separated by filtration. The filtrate was concentrated under reduced pressure to afford a yellow oily product. Water (20 ml) was added to the oily product, and the precipitated white powder was recrystallized from ethanol to afford 1.28 g (yield 50%) of 2,3-dicyano-5-di-n-propylamino-6-ethylpyrazine.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21]1[C:26]2[N:27]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:29][C:25]=2[CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:33]1[CH2:34][CH2:35][N:30]([C:28]2[S:29][C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[C:26]=3[N:27]=2)[CH2:31][CH2:32]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1cccc2sc(N3CCNCC3)nc12
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc2sc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)nc12

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 4-Methoxy-2-piperazin-1-yl-benzothiazole hydrochloride in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]2=[NH:16])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.O=[C:18]([CH3:22])[C:19](=[S:21])[NH2:20]>CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[NH:20][C:19](=[S:21])[C:18]([CH3:22])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N=C1c2cc(Br)ccc2CC12CCOCC2
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCOCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 125.5 %

Procedure:
6-Bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3H)-imine (Example 25 Step 2, 235 mg, 0.84 mmol) and 2-oxopropanethioamide (Intermediate 2, 173 mg, 1.68 mmol) were taken up in anhydrous MeOH (5 mL) and the resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 3 h. When cooled to r.t. the mixture was concentrated and purified on a silica gel column eluted with 0-50% EtOAc in heptane to give 385 mg (95% yield) of the title compound; 1H NMR (500 MHz, DMSO-d6) δ ppm 12.40 (br. s, 1H), 7.53 (dd, 1H), 7.36 (d, 1H), 7.03 (d, 1H), 3.71 (td, 2H), 3.44 (m, 2H), 3.15 (m, 2H), 2.29 (s, 3H), 1.64 (s, 1H), 1.55 (s, 1H), 1.27 (m, 2H); MS (ES+) m/z 365 [M+H]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10]2)=[C:6]([F:8])[CH:7]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[CH2:20]([O:19][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10]2)=[C:6]([F:8])[CH:7]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1ccn(-c2ccc(N)cc2F)c1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(-n2ccc(C#N)c2)c(F)c1
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
5-Amino-2-(3-cyano-1-pyrrolyl)fluorobenzene (4.6 g, 22.9 mmol) was stirred in dry pyridine (50 ml) 0°. Ethyl chloroformate (2.66 g, 24.5 mmol) was added, and stirring continued for 20 minutes at the same temperature before allowing the temperature to rise to ambient over 2 hours. Solvent was evaporated, the residue treated with iced water (50 ml), filtered off, and dried. Crystallisation of the crude product from ethanol (200 ml) gave the title product (4.9 g) mp 188-190°.
Reaction SMILES: [CH3:1][C:2]12[CH2:14][CH2:13][CH:12]3[C:7]([CH3:17])([CH2:8][CH2:9][CH2:10][C:11]3([CH3:16])[CH3:15])[CH:6]1[CH2:5][CH2:4][O:3]2.C[C@@]12[C@H:28]3CC[O:31][C@:27]3(C)[CH2:26][CH2:25][C@H]1C(C)(C)CCC2>>[CH3:17][C@@:7]12[C@@H:6]([CH2:5][CH2:4][C@@:27]([OH:31])([CH:26]=[CH2:25])[CH3:28])[C@@:2]([OH:3])([CH3:1])[CH2:14][CH2:13][C@H:12]1[C:11]([CH3:15])([CH3:16])[CH2:10][CH2:9][CH2:8]2
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CCO[C@]3(C)CC[C@@H]12
Reactant: CC1(C)CCCC2(C)C1CCC1(C)OCCC12
Product: C=C[C@](C)(O)CC[C@@H]1[C@@]2(C)CCCC(C)(C)[C@@H]2CC[C@@]1(C)O

Procedure:
Dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan (occasionally referred to as “Ambroxan (trademark)”) is an aroma chemical with satisfactorily long-lasting properties that is produced via chemical conversion mainly from sclareol extracted from Salvia sclarea. FIG. 1 shows a process for producing dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan from sclareol. As shown in FIG. 1, decahydro-2-hydroxy-2,5,5,8a-tetramethylnaphthaleneethanol and sclareolide (decahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan-2(1H)-one) are known as dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan intermediates. Also, a cyclic ether compound (8α,13-oxido-12,13-dehydro-15,16-dinorlabdane) is known as a dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan intermediate, although it is not shown in FIG. 1.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.Cl[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1>CN(C=O)C>[CH3:1][C:2]([CH3:27])([CH3:26])[CH:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:14]2[CH2:19][CH2:18][N:17]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Clc1ncccn1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(NC(=O)c1nc(-c2ccccc2)n2c1CN(c1ncccn1)CC2)C(C)(C)C
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
Compound 2 (15 mg, 35 umol) was dissolved in DMF (3 mL). DIPEA was added followed by the 2-chloropyrimidine. The reaction was subjected to microwave irradiation and heated at 160° C. for 15 minutes and then for a further 5 minutes under the same conditions to drive to completion. The reaction was quenched by the addition of 2 mL of saturated aqueous NaHCO3 and extracted of DCM (2×1 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and evaporated. The residue was purified by preparative LC/MS using a 10 minute gradient from 70% water/acetonitrile to 10% water/acetonitrile with 0.1% formic acid as a modifier. The desired product, Compound 298, was isolated as a clear oil (11 mg, 68% yield). LCMS (+ESI) m/z 448.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-3-trifluoromethylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H10ClF3N4, 364. Found, 363, 365.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[CH3:15])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](=[O:23])=[O:22].O>C1COCC1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]2[C:5]3[C:6](=[CH:14][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:7]([C:21]([OH:23])=[O:22])[C:8]=2[CH:13]=1
Reactant: O=C=O
Reactant: Cc1cccc2c1-c1c(C)cccc1C2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C(=O)O)c1cc(C)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
A solution of 4,5-dimethylfluorene (5.2 g, 27.0 mmol) in 100 mL of THF at -78° C. was charged with butyl lithium (18.7 mL, 29.0 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5 g, 113.6 mmol) was introduced via cannula over a period of 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred overnight. Water was added (150 mL) and the layers were separated, the water layer was washed with ethyl acetate (5×20 mL), then acidified with conc. HCl. The precipitate was collected, washed with water and dried to give 2,7-dimethyl-9-fluorenecarboxylic acid (4.24 g, 65.9 %).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)N3CCOCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)N3CCOCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-morpholinocarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:2]([CH3:4])[CH3:3])=[CH:8][N:7]=1
Reactant: CC(C)Br
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Br)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2-Bromopropane (701 μl) was added to a suspension of 2-bromo-5-hydroxypyridine (1.0 g) and potassium carbonate (2.38 g) in N,N-dimethylformamide (19 ml), and stirred at 80° C. for four hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (1.05 g) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([OH:15])[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(OC)([C:21]1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([O:15][CH3:21])[C:10]2([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(Cc2ccccc2)CC12CC2
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(Cc2ccccc2)CC12CC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-Benzyl-5-azaspiro[2.4]heptan-7-ol (200 mg) was dissolved into DMF (4 ml) and cooled at 0° C. NaH (120 mg) was added to the reaction and stirred for 10 minutes. To the reaction was added TsOMe (200 mg), the solution was heated at 80° C. for two hours. The reaction was quenched with water and extracted with EtOAc followed by washing with water, then brine and dried over Na2SO4 and evaporated to give the titled product. Mass: (M+1), 158
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([C:6]3[C:7](=[O:13])[CH:8]=[CH:9][C:10](=[O:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([C:6]3[C:7]([OH:13])=[C:8]([S:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:28])=[O:27])[CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C1C=CC(=O)C2=C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)c1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
38 g, of 1,2,3,4,9,9-hexachloro-1,4-dihydro-1,4-methanonaphthalene-5,8-dione, prepared as in Example 3, were dissolved in 200 ml. of ethanol and 18 g. of freshly generated benzenesulfonyl chloride were added. This mixture was refluxed for 5 hours and a white precipitate formed. The white solid was filtered off while hot and was recrystallized from benzene yielding white crystals, m.p. 215°-216° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=O)[C:10](=[C:14](O)[CH3:15])[C:9](=[O:17])[CH2:8]1.O.[NH2:20][NH2:21]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]2[NH:21][N:20]=[C:14]([CH3:15])[C:10]=2[C:9](=[O:17])[CH2:8]1
Reactant: NN
Reactant: CC(O)=C1C(=O)CC(c2cc(Cl)sc2Cl)CC1=O
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Yield: 87.8 %

Procedure:
A solution of 5-(2,5-dichlorothiophen-3-yl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (2.48 g) and hydrazine hydrate (0.508 g) in ethanol (10 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was washed with diisopropylether to give 6-(2,5-dichlorothiophen-3-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (2.15 g) as pale yellow crystals.
Reaction SMILES: C1(C([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22](CBr)=[CH:21][CH:20]=2)(=[O:18])=[O:17])CC2C=CC=CC=2)C=CC=CC=1>C1COCC1.CN(C=O)C>[C:19]1([S:16]([NH2:15])(=[O:18])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(NC(Cc1ccccc1)c1ccccc1)c1ccc(CBr)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccccc1
Yield: 1 %

Procedure:
N-Ethyl-N-(S)-1-isobutyl-2-ethoxyethyl 3-chloro-4-(3H-2-methylimidazo [4,5-c]pyridylmethyl)benzenesulphonamide and (B) N-ethyl-N-(S)-1-isobutyl-2-ethoxyethyl 3-chloro-4-(1 H-2-methylimidazo [4,5-c]pyridylmethyl)benzenesulphonamide were prepared by the method of Example 17 utilizing N-Ethyl-N-(S)-1-isobutyl-2-ethoxyethyl 3-chloro-4-bromo-methylbenzenesulphonamide in lieu of N-1,2-diphenylethyl 4-bromomethylbenzenesulphonamide and 3:1 THF/DMF as solvent.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]3)=[C:19]([O:31]CC3C=CC=CC=3)[CH:18]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O.[Pd]>[C:1]1([S:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]3)=[C:19]([OH:31])[CH:18]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CN(c2ccc(/C=C/C3CCCN3S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C1CN(c2ccc(CCC3CCCN3S(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1
Reaction time: 1 h

Procedure:
To a mixture of 5-{4-[(E)-2-(1-benzenesulfonylpyrrolidin-2-yl)-vinyl]-2-benzyloxyphenyl}-1,1-dioxo-1,2,5-thiadiazolidin-3-one (22 mg) in 4 mL ethanol/water (1:3) is added 5 mg of Degussa Pd/C and the resulting mixture is hydrogenated at 1 atm for 1 h. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by reverse phase Biotage using a gradient of 20-60% EtOH/water as eluent to furnish the title compound: LC retention time=1.10 min (Method A); (M−H)−=464.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[S:12]1[CH:16]=[CH:15][C:14]([Li])=[CH:13]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:14]1[CH:15]=[CH:16][S:12][CH:13]=1)([OH:11])[CH3:10]
Reactant: [Li]c1ccsc1
Reactant: CC(=O)c1cc(Br)ccc1N
Product: CC(O)(c1ccsc1)c1cc(Br)ccc1N

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl)-ethanone and 3-thienyllithium generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 7.43 (dd, J=2.98, 4.98 Hz, 1H), 7.33 (dd, J=1.27, 2.94 Hz, 1H), 7.07 (dd, J=2.37, 8.47 Hz, 1H), 7.04 (d, J=2.33 Hz, 1H), 6.92 (dd, J=1.26, 4.98 Hz, 1H), 6.52 (d, J=8.38 Hz, 1H), 5.99 (bs, 1H), 5.32 (bs, 2H), 1.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O=S(Cl)[Cl:18].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([Cl:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Agent: Cl
Product: O=C(Cl)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
A mixture of 56 g. (0.25 mole) of 5-(p-chlorophenyl)-2-furoic acid and 100 ml. of SOCl2 is refluxed for 31/2 hours so that HCl gas evolves and there is dissolution. The SOCl2 is removed on a rotary evaporator. Benzene is added to the solid residue and is then removed on the rotary evaporator to give 5-(p-chlorophenyl)-2-furoyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[N:10]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])[CH2:16][C@H:15]2[CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:9]1=[O:35])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:12][C:11](=[O:13])[N:10]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH:22]([CH3:23])[CH3:24])[CH3:21])[CH2:16][C@H:15]2[CH2:25][S:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:9]1=[O:35]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2C(=O)C[C@H](NC(=O)OC(C)(C)C)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](N2C(=O)C[C@H](N)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
{(3S)-1-[(1S, 2R, 4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (60 mg), TFA (1 mL), and methylene chloride (3 mL) were mixed and stirred overnight at rt. The mixture was stripped and restripped from methylene chloride (3×) to yield 60 mg of an oil. LCMS detects (M+H)+=374.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl>[OH:15][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)(=[O:4])=[O:3])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1O
Reaction time: 0.5 h

Procedure:
Methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (may be prepared as described in Description 60; 500 mg, 1.995 mmol) was added to a stirred solution of 1-methylpiperazine (200 mg, 2.00 mmol) in dichloromethane (20 ml). The mixture was stirred for 0.5 h, and then concentrated under reduced pressure to yield the title compound as a colourless oil. 430 mg.
Reaction SMILES: C([O:4][CH:5]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[CH:28]=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=[O:7])(=O)C>[OH-].[Na+].CO.O>[OH:4][CH:5]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[CH:28]=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(=O)OC(C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(O)c1ccccc1

Procedure:
A solution of 0.34 g of α-(acetyloxy)-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide in 2 ml of 1N NaOH and 4 ml of methyl alcohol is stirred at room temperature for 30 minutes, diluted with 2 ml of water and evaporated in vacuo. The aqueous suspension is extracted with 30 ml of ethyl acetate and the extract washed with brine, dried with Na2SO4 and filtered through a pad of hydrous magnesium silicate and evaporated in vacuo to a residue. The residue is stirred with ether-hexanes to give 0.26 g of cream colored solid. MS(CI): 438(M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH2:21]O)=[CH:19][N:20]=2)[CH:17]=1.Cl.[OH-].[Na+]>C(O)(=O)C>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH2:21][S:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:19][N:20]=2)[CH:17]=1
Reactant: Cc1ccc2ncc(CO)n2c1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc2ncc(CSc3ccc([N+](=O)[O-])cc3)n2c1
Temperature: 100 °C
Reaction time: 120 h
Yield: 80.9 %

Procedure:
A mixture of 4-nitrothiophenol (2.87 g), 6-methylimidazo[1,2-a]pyridin-3-ylmethanol (3.0 g), concentrated hydrochloric acid (60 ml) and acetic acid (60 ml) was stirred for 5 days at 100° C. The mixture was neutralized with 12N sodium hydroxide at 0° C., and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 2:1→4:1), to give 6-methyl-3-[[(4-nitrophenyl)thio]methyl]imidazo[1,2-a]pyridine (4.48 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH:11]=O.C1(P(=[CH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10]/[CH:11]=[CH:32]/[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: COc1ccc(CC=O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C/C=C/C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of (2-chloro-4-methoxyphenyl)acetaldehyde (1.22 g) in toluene (30.0 mL) was added tert-butyl (triphenylphosphoranylidene)acetate (2.75 g), followed by stirring at 80° C. overnight. The reaction mixture was air-cooled to room temperature, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl (2E)-4-(2-chloro-4-methoxyphenyl)but-2-enoate (1.67 g).