Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:30][CH:29]([NH2:31])[CH2:28]2)=[CH:22][CH:21]=1>ClCCl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:28][CH:29]([NH:31][S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:30]2)=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
0.214 g of 4-fluorophenylsulfonyl chloride and 0.28 cm3 of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 0.307 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 10 cm3 of dichloromethane. After stirring for 16 hours at room temperature, the reaction mixture is washed with 10 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluant: dichloromethane/ethyl acetate (100/0 to 95/5 by volume) gradient]. 0.18 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-fluorophenylsulfonamide is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.74 (broad t, J=7.5 Hz: 2H); 2.39 (broad t, J=7.5 Hz: 2H); 3.98 (mt: 1H); 4.20 (s: 1H); 4.79 (d, J=9 Hz: 1H); from 7.10 to 7.35 (mt: 10H); 7.86 (mt: 2H)].
Reaction SMILES: Cl[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[NH4+:12]>>[NH2:12][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(Cl)cc(Cl)c1=O
Reactant: [NH4+]
Agent: [OH-]
Product: Cn1nc(Cl)cc(N)c1=O
Temperature: 150 °C
Yield: 86.5 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyridazin-3(2H)-one (5.0 g, 27.9 mmol) and ammonium hydroxide (55 mL, 1412 mmol) was heated at 150° C. for 2 hours and then cooled to room temperature. The solvent was removed, and the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography (silica gel, eluted with 40% ethyl acetate in hexanes to afford 3.85 g (87%) of the title compound.
Reaction SMILES: [ClH:1].CC(C)(C)C(O[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[C:11]=2[S:10][CH2:9]1)=O>O1CCOCC1>[ClH:1].[NH2:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[C:11]=2[S:10][CH2:9]1
Reactant: CC(C)(C)C(=O)ON[C@H]1CSc2c(cccc2-c2cccc(C#N)c2)NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2cccc3c2SC[C@H](N)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.6 mL of a solution of hydrogen chloride in dioxane (4 M) are added to a 25 mL round-bottomed flask containing 139 mg of 45 (0.352 mmol). The mixture is stirred for 4 hours at room temperature under argon. A white precipitate forms, which is filtered off by suction and washed with 3 mL of dioxane and then 5 mL of isopropyl ether. 72 mg of amine 46 (white solid) are thus obtained in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1>C(#N)C>[CH2:1]([C:4]1[N:5]([CH2:26][C:27]2[N:28]=[CH:29][S:30][CH:31]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: BrCc1cscn1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cscn1
Yield: 82.3 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.150 g, 0.595 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (1.90 g, 0.0595 mmol) and 4-(bromomethyl)-1,3-thiazole (0.159 g, 0.893 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.171 g, 82% yield): 1H NMR (400 MHz, CDCl3) δ 8.81-8.80 (d, J=4.0 Hz, 1H), 7.78 (m, 2H), 6.68 (d, J=4.0 Hz, 1H), 6.63 (s, 1H), 5.51 (s, 2H), 2.80-2.76 (t, J=8.0 Hz, 2H), 1.82-1.76 (q, J=8.0 Hz, 2H), 1.06-1.02 (t, J=8.0 Hz, 3H).
Reaction SMILES: [P:1]([CH:5]([S:13]([OH:16])(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)([OH:4])([OH:3])=[O:2]>[Pd].O>[P:1]([CH:5]([S:13]([OH:16])(=[O:14])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]1)([OH:4])([OH:3])=[O:2]
Reactant: O=P(O)(O)C(Cc1ccccn1)S(=O)(=O)O
Agent: [Pd]
Solvent: O
Product: O=P(O)(O)C(CC1CCCCN1)S(=O)(=O)O
Reaction time: 48 h

Procedure:
A mixture of 1 g of 1-phosphono-2-(2-pyridinyl)ethanesulfonic acid and 0.5 g of palladium on charcoal catalyst in 50 ml of distilled water is hydrogenated on a Parr apparatus at 40 PSI for about 2 days. The catalyst is removed by filtration, and the filtrate is concentrated to a few mls. Ethanol is added slowly to precipitate a solid, which is recrystallized from water/ethanol to afford 1-phosphono-2-(2-piperidinyl)ethanesulfonic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O>[C:22]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1cccc(C#CCCOCCCCCCBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCCCCOCCC#Cc1cccc([N+](=O)[O-])c1
Temperature: 75 °C
Yield: 75.6 %

Procedure:
A mixture of 1-{4-[(6-bromohexyl)oxy]but-1-ynyl}-3-nitrobenzene (4.18 g), sodium acetate (9.68 g), tetrabutylammonium bromide (384 mg) in DMF (15 ml) and water (10 ml) was heated to 75° C. for 6 h. The mixture was then allowed to cool to 20° C. and then extracted with Et2O. The organic solution was concentrated and purified by chromatography on a Biotage (40 g) eluting with Et2O-petroleum ether(1:19 increasing to 1:1) to give the title compound (2.973 g). LCMS RT=3.84 min.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](Cl)=[O:16])[O:7][CH2:6]1)[CH2:2][CH3:3].[CH2:21](N(CCC)C1CC2C(=CC=CC=2C(OC)=O)OC1)CC.[Li]C.O>O1CCCC1.[Cu]I>[CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](=[O:16])[CH3:21])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Reactant: CCCN(CCC)C1COc2cccc(C(=O)Cl)c2C1
Agent: [Cu]I
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Dipropylamino-5-chloroformylchroman*HCl (4.42 g, 13.4 mmol), prepared from 3-dipropylamino-5-methyloxycarbonylchroman (Example 2) analogous to the procedure used in Example 3, in dry tetrahydrofuran (20 ml), was added to a pre-formed solution of lithium dimethylcuprate; prepared from MeLi and CuI, in 200 mL tetrahydrofuran at -78° C. The solution was stirred for 15 minutes at -78° C. and was then allowed to reach room temperature during 10 minutes. Then, 30 mL H2O was slowly added. The organic phase was decanted, dried with Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8. The title compound was crystallized as salt from ethyl acetate. Mp 106°-108° C. (oxalate).
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[S:4][CH:3]=1)[NH:10][C:9]1[CH2:14][CH2:15][NH:16][CH2:17][C:8]3=1.[H-].[Na+].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl>CN(C)C=O>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][N:10]1[C:11]2[C:7](=[C:6]3[C:2]([CH3:1])=[CH:3][S:4][C:5]3=[CH:13][CH:12]=2)[C:8]2[CH2:17][NH:16][CH2:15][CH2:14][C:9]1=2
Reactant: CN(C)CCCCl
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CNCC4
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc2ccc3c(c4c(n3CCCN(C)C)CCNC4)c12

Procedure:
The compound is formed analogously to that described in Example 31, from 4.8 g of 1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole, 1.0 g of a dispersion of NaH and 2.4 ml of 3-dimethylaminopropyl chloride in dimethylformamide. Melting point: 92° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCc1cccc(CNCc2ccc(Oc3ccccc3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(Oc3ccccc3)cc2)S(C)(=O)=O)c1

Procedure:
The title compound of Step B was prepared following the method described in Step A of Example 1 from 3-{3-[(4-phenoxy-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step A and methanesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamin. 1H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 7.14 (m, 4H), 6.97 (m, 4H), 4.31 (s, 2H), 4.30 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.78 (s, 3H), 2.61 (t, 2H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.N([O-])=[O:18].[Na+]>S(=O)(=O)(O)O.O>[OH:18][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 54.7 %

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone (O4.050; 3.00 g) was dissolved in 35% aqueous sulfuric acid (25 ml) while heating. The solution was cooled to −5° C. and a solution of sodium nitrite (780 mg) in 15 ml of water was added dropwise within 10 min. After 40 min at −5° C., the cooling bath was removed and the mixture was heated to 100° C. for 2 h. After cooling, the mixture was extracted twice with EA. The combined EA phases were washed with saturated sodium hydrogencarbonate solution, dried, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/MtB ether gradient of 0-100% within 40 min). 1.62 g of the title compound were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:9]=[CH:8][NH:7][N:6]=1.[CH3:10][NH:11][CH3:12]>CO>[CH3:10][N:11]([CH3:12])[CH2:2][CH2:3][NH:4][C:5]1[CH:9]=[CH:8][NH:7][N:6]=1
Reactant: CNC
Reactant: ClCCNc1cc[nH]n1
Solvent: CO
Product: CN(C)CCNc1cc[nH]n1
Temperature: 100 °C

Procedure:
In a sealable flask, the N-(2-chloroethyl)-1H-pyrazol-3-amine (0.214 g, 1.47 mmol) were combined with 1.5 mL of dimethylamine (40% in H2O). The mixture flask was sealed, and the mixture was heated to 100° C. fir 16 h. The mixture was cooled to rt, and transferred to a rb flask with MeOH. The solvent was removed under reduced pressure to give the N1,N1-dimethyl-N2-(1H-pyrazol-3-yl)ethane-1,2-diamine in quantitative yield. LCMS: m/e 155.3 (M+H)+, ret time 0.96 min (method 3).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[N:4]=[CH:5][N:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.17) (178 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a brown solid (112 mg, 41%). MS (ISN) 545.0 [(M−H)−]; mp 247° C.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[CH3:18][N:19]([CH3:30])[C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH:26]=O)=[CH:22][CH:21]=1>O1CCCC1>[CH3:18][N:19]([CH3:30])[C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH:26]=[CH:14][C:15]([OH:17])=[O:16])=[CH:22][CH:21]=1
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: CN(C)c1ccc(C=CC=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)c1ccc(C=CC=CC(=O)O)cc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
Butyllithium (24 mL of 2.5 N solution) was added to 120 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (5.5 g) in 45 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. over a period of one hour. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of p-dimethylaminocinnamaldehyde (5.0 g) in 80 mL of anhydrous THF was added to the reaction at −65° C. over a period of 30 minutes. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. The reaction was then quenched with 400 mL of water and extracted with 300 mL of ethyl acetate three times. The aqueous layer was acidified with 5% hydrochloric acid (11 mL) to a pH of 6.1. The solid formed was filtered, washed with 75 mL of water and dried to yield 3.83 g of the desired 5-(p-dimethylaminophenyl)-2,4-pentadienoic acid. 1H NMR (DMSO-d6, 300 MHz), δ(ppm) 7.34 (m, 3H), 6.82 (m, 2H), 6.70 (d, 2H), 5.84 (d, 1H), 2.94 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=O)[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].[NH2:24][NH:25][C:26]([NH2:28])=[S:27].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=[N:24][NH:25][C:26]([NH2:28])=[S:27])[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: NNC(N)=S
Reactant: COc1cc(-c2nc(C)c(C(C)=O)s2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(-c2nc(C)c(C(C)=NNC(N)=S)s2)cc(OC)c1OC
Yield: 65 %

Procedure:
2-(3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole prepared in Example 1 (1.0 g corresponding to its 0.0033 mol) was dissolved in 30 ml of ethanol, and to the solution, 8.6 ml of an aqueous 2% solution of sodium hydroxide (0.0045 mol) and 0.4 g (0.0044 mol) of thiosemicarbazide were added, and the mixture was heated for 3 hours under a reflux condenser. After cooling the reaction mixture, it was introduced into 300 ml of iced water, and the precipitate which separated was collected by filtration. After washing the precipitate with water, it was recrystallized from ethanol to obtain the object consisting of yellow needle-like crystals amounting to 0.82 g at a yield of 65%, which decomposed at 209° to 212° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:41]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=2)(=[O:43])=[O:42])=[CH:4][CH:5]=1)[CH3:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNc1ccc(CNS(=O)(=O)c2ccc(OC)cc2)c2sc3ccccc3c(=O)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of 1.40 g (3.94 mmol) of 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) in 30 mL of chloroform containing 1.5 mL of triethylamine was cooled to 0° C. and treated with p-methoxybenzenesulfonyl chloride (0.83 g, 4.02 mmol). After 10 min at 0° C. the reaction mixture was stirred at room temperature for 2 h. Chloroform was removed in vacuo, the residue dissolved in 100 mL of methylene chloride containing 1 mL of triethylamine and treated with additional p-methoxybenzenesulfonyl chloride (0.85 g) with stirring at room temperature. The mixture was concentrated in vacuo, the residue was purified by passing through a pad of silica gel (1% triethylamine/chloroform) affording 1.57 g of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-p-methoxy-benzenesulfonamide. The sulfonamide was treated with methanesulfonic acid (0.3 g) in isopropanol/isopropyl acetate/methanol to afford 1.07 g of the methanesulfonate salt, m.p. 133°-137° C.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]1[CH:21]2[CH:12]([CH2:13][C:14]3[C:19]([CH:20]2[N:22]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25](N)[N:24]=[CH:23]2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]1.O>CN(C)C=O>[CH2:8]1[CH:21]2[CH:12]([CH2:13][C:14]3[C:19]([CH:20]2[N:22]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=[CH:23]2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1c(N)ncn1C1c2ccccc2CC2CCCCC21
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2CC2CCCCC21
Yield: 38 %

Procedure:
4.3 Parts of 1,1-dimethylethyl nitrite were dissolved in 40 ml N,N-dimethylformamide and heated to +60° C. A solution of 8 parts of methyl 1-(1,2,3,4,4a,9,9a,10-octahydroanthracen-9-yl)-4-amino-1H-imidazole-5-carboxylate in 50 ml N,N-dimethylformamide was dropwise added at +60° C. After 1.5 hour the solution was poured into water and extracted with ethyl acetate. The organic phase was dried with Na2SO4, filtered and concentrated. The resulting 8.5 parts of crude material were chromatographed on a silica gel column with an ethyl acetate/hexane mixture (1:1). 2.9 Parts (38%) of methyl 1-(1,2,3,4,4a,9,9a,10-octahydroanthracen-9-yl)-imidazole-5-carboxylate, mp. 151°-152° C. (compound 2.2), were obtained. According to 1H-NMR the product consists of an epimeric mixture of 2 isomers.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[O:15]1CCOCC1>>[CH:1]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)=[O:15]
Reactant: CCOC(=O)c1cnc(SC)nc1C
Reactant: C1COCCO1
Product: CCOC(=O)c1cnc(SC)nc1C=O

Procedure:
A solution of ethyl 4-methyl-2-(methylthio)pyrimidine-5-carboxylate in dioxane (330 mg, 1.56 mmol) was treated with SeO2 (220 mg, 2.0 mmol) at 100° C. for 3 days. After cooling, the reaction mixture was concentrated and the residue was purified by flash chromatography (20% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 227 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[CH3:14][S:15]([NH2:18])(=[O:17])=[O:16].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([NH:18][S:15]([CH3:14])(=[O:17])=[O:16])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of isophthalic acid monomethyl ester (500.0 mg, 2.8 mmol), methanesulfonamide (340 mg, 3.6 mmol) and DMAP (440 mg, 3.6 mmol) in anhydrous dichloromethane (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (690 mg, 3.6 mmol). The mixture was allowed to stir for 12 hours at room temperature and then concentrated under reduced pressure. The residue was chromatographed on a Biotage 40M eluting with 2% methanol/98% dichloromethane to provide the titled compound. MS (ESI) m/e 259 (M+H)+, 257 (M−H)−; 1H NMR (300 MHz, CD3OD) δ ppm 3.36 (s, 3H) 3.95 (s, 3H) 7.64 (t, J=7.80 Hz, 1H) 8.13 (dd, J=7.80, 1.36 Hz, 1H) 8.25 (m, 1H) 8.55 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(C)c1

Procedure:
To a suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 46.5 mmol) in methanol (125 mL) was added concentrated sulfuric acid (1 mL). The reaction was heated at reflux overnight with a homogeneous solution obtained after several minutes of heating. After cooling, the methanol was removed in vacuo and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 10.2 g of title compound as a brown solid, m.p. 41–43° C.