Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-:3])=[O:2].[CH:15](=O)[CH2:16][CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([NH:14][CH2:15][CH2:16][CH3:17])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCNc1cc([N+](=O)[O-])ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.8 %

Procedure:
To a stirred suspension of methyl 4-nitroanthranilate (prepared from 4-nitroanthranilic acid, 14.2 g) in methanol (600 ml) was added propionaldehyde (5.04 g) followed by glacial acetic acid (7.2 ml). Sodium cyanoborohydride (4.56 g) was added and the reaction mixture stirred at room temperature for 16 hours. Further propionaldehyde (5.04 g) and sodium cyanoborohydride (4.56 g) were added and the mixture stirred for a further 24 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and 10% potassium carbonate solution. The organic layer was separated and the aqueous re-extracted with ethyl acetate (2×100 ml). The combined organics were washed with saturated sodium chloride solution then dried (sodium sulphate) and evaporated to give the crude product, which was purified by column chromatography on silica using 10% diethyl ether/petroleum ether (60-80) to afford the required product (3.42 g, 20%). 1H NMR (250 MHz, DMSO-d6) δ0.98 (3H, t), 1.66 (2H, sextet), 3.26 (2H, dq), 3.86 (3H, s), 7.33 (1H, dd), 7.46 (1H, d), 7.88 (1H, t), 8.04 (1H, d).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Br.Br.[NH:16]1[CH2:22][CH:21]([OH:23])[CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:16]2[CH2:22][CH:21]([OH:23])[CH2:20][NH:19][CH2:18][CH2:17]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Reactant: OC1CNCCNC1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cnn(CC(F)F)c1N1CCNCC(O)C1
Temperature: 130 °C
Yield: 90.8 %

Procedure:
A mixture of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (800 mg, 3.78 mmol), 1,4-diazepan-6-ol dihydrobromide (1.58 g, 5.67 mmol) and DIPEA (2.5 mL, 14.35 mmol) in EtOH (6 mL) was heated at 130° C. in a microwave for 3 hr. The solvent was removed under reduced pressure and the residue was passed through an SCX column washing with DCM and 1:1 MeOH:DCM and MeOH and eluting with 1N ammonia in MeOH to give 1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-6-ol as a pale yellow gum (1.0 g). This gum (1.0 g, 3.44 mmol) was dissolved in DCM (100 mL) and treated with di-tert-butyl dicarbonate (2.25 g, 10.31 mmol) and DIPEA (2.4 mL, 13.75 mmol). The reaction mixture was stirred at room temperature for 1.5 hr and washed with saturated aqueous NaHCO3 solution (100 mL). The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100%) EtOAc/isohexane gave tert-butyl 4-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as a pale green gum (46% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 6.18 (tdd, J=55.6, 5.6, 3.2 Hz, 1H), 4.49-4.31 (m, 2H), 4.19-2.95 (m, 10H), 1.60-1.40 (m, 9H).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.C([N:12](CC)CC)C.[CH:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]1[CH2:29][CH:28]([CH2:30]O)[CH2:27][CH2:26][N:21]12>ClCCl>[NH2:12][CH2:30][CH:28]1[CH2:27][CH2:26][N:21]2[C:22]3[C:18]([CH:19]=[C:20]2[CH2:29]1)=[CH:17][CH:25]=[CH:24][CH:23]=3
Reactant: OCC1CCn2c(cc3ccccc32)C1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: NCC1CCn2c(cc3ccccc32)C1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2.4 g of methanesulfonic anhydride and 2 ml of triethylamine were added to a stirred solution of 2.01 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol in 40 ml of dichloromethane under a nitrogen atmosphere. After 18 hours, the mixture was washed with saturated sodium bicarbonate solution, dried and evaporated to an oil. Then, 1.8 g of this oil were dissolved in 10 ml of isopropanol and 5 ml of 33% aqueous ammonia and the mixture was heated to 80° C. for 10 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was dried and evaporated to give 1.3 g of 8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole of melting point 85°-90° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1CCCCC1.[C:31](=[O:33])=[O:32]>C1COCC1>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[C:31]([OH:33])=[O:32])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A solution of (4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (2.31 g, 8.33 mMol) in anhydrous THF (50 mL) at −78° C. was treated with a 1.4 M solution of sec-butyllithium in cyclohexane (13 mL, 18.33 mMol), at a rate which did not allow the internal temperature to exceed −60° C. The solution was stirred at −78° C. for 15 minutes, then allowed to warm to −40° C. and stirred for 2.5 hours. The reaction was treated with gaseous CO2, stirred 30 minutes while warming to −20° C., then quenched with saturated ammonium chloride. The mixture was warmed to room temperature, and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated in-vacuo. The residue was triturated with hot heptane to yield 1.9 g of white powder as product. NMR (500 MHz, DMSO) δ 12.89 (s, 1H), 8.24 (d, 1H, J=9 Hz), 7.84 (s, 1H), 7.21 (d, 1H, J=7 Hz), 1.51 (s, 9 Hz). Yield=72%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[O:21][C:20]([F:19])([F:31])[F:32])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3ccccc3OC(F)(F)F)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2-Trifluoromethoxybenzoyl chloride (1.64 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 2 days.
Reaction SMILES: N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:19]([N:21]([CH2:25][CH:26]=[CH2:27])[CH2:22][CH:23]=[CH2:24])=[O:20].[SH2:28]>CO>[CH:19]([N:21]1[CH2:25][CH:26]([CH3:27])[S:28][CH:23]([CH3:24])[CH2:22]1)=[O:20]
Reactant: S
Reactant: C=CCN(C=O)CC=C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CO
Product: CC1CN(C=O)CC(C)S1
Reaction time: 48 h

Procedure:
Piperidine (10 ml) and 10 ml of a 40% solution of benzyltrimethylammoniumhydroxide in methanol were added to a solution of N-formyl-diallylamine (55 g) in methanol (200 ml). Hydrogen sulfide (50 g) was introduced into the resulting solution, and unreacted hydrogen sulfide was kept at reflux for 7 hours by means of "cold finger". The mixture was left at room temperature for 48 hours, flushed with nitrogen, diluted with ether, and washed with water. The organic phase was dried, and the solvent evaporated in vacuo. Distillation of the residue gave the title compound with boiling point 145° C./15 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH2:14]C#N)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17].Cl.[C:23](=[O:26])([O-])[OH:24].[Na+]>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH2:14][C:23]([OH:24])=[O:26])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17]
Reactant: Cc1nc2ccc(CC#N)cc2n1Cc1ccccc1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2ccc(CC(=O)O)cc2n1Cc1ccccc1Cl

Procedure:
To 0.500 g of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetonitrile was added 10% hydrochloric acid, and the mixture was heat-refluxed for 15 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and was extracted with chloroform. The organic layer was concentrated, and was purified through silica-gel column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 9:1 to 4:1) to give 0.170 g of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic acid (160).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:10]2[C:15]([C:16]=1[NH2:17])=[C:14]([CH3:18])[C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[N:9]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:10]2[C:15]([C:16]=1[N:17]=[C:29]=[O:31])=[C:14]([CH3:18])[C:13]([C:19]([F:21])([F:20])[F:22])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(F)(F)F)ccc2c1c(N)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1c(C(F)(F)F)ccc2c1c(N=C=O)c(C(=O)OC(C)(C)C)n2-c1ccsc1

Procedure:
To a solution of 3-amino-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1E (1.74 g, 4.39 mmol) in anhydrous toluene (50 mL) was added triphosgene (0.44 g, 1.48 mmol) and triethylamine (0.89 g, 8.81 mmol). The reaction mixture was heated at reflux for 3 hours. Toluene (50 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 3-isocyanato-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1F which was used in the next step without further purification.
Reaction SMILES: [C:1](OCC)(=[O:7])[C:2](OCC)=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1.CC[O-].[Na+].C(O)(=O)C>O>[OH:3][C:2]1[C:1]([OH:7])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CN(CC(=O)OCC)c1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Diethyl oxalate (83 ml, 0.61 mol) was added dropwise to a stirred solution of diethyl 2,2′4-(4-methoxyphenyl)azanediyl)diacetate (4) (180 g, 0.61 mol) in NaOEt (21% by wt in EtOH) (506 ml, 1.3 mol), the mixture was stirred at 100° C. for 1 h. The reaction was quenched with acetic acid (210 ml, 3.7 mol) and the resulting suspension was poured into iced water (1 L), the resulting off-white solid collected by vacuum filtration. The crude product was recrystallised from hot EtOH (3.5 L) to give diethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-001) (152 g, 71%) as a white solid: m/z 350 (M+H)+ (ES+); 348 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 7.13-7.01 (m, 2H), 6.92-6.81 (m, 2H), 3.99 (q, J=7.1 Hz, 4H), 3.78 (s, 3H), 0.99 (t, J=7.1 Hz, 6H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C:45](=[NH:62])[NH:46][CH2:47][CH2:48][CH2:49][C@@H:50]([C:59]([OH:61])=O)[NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.[NH2:64][CH2:65][CH2:66][NH:67][C:68](=[O:77])[O:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>CN(C=O)C>[CH2:70]([O:69][C:68](=[O:77])[NH:67][CH2:66][CH2:65][NH:64][C:59](=[O:61])[C@H:50]([CH2:49][CH2:48][CH2:47][NH:46][C:45]([NH:44][C:42]([O:41][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:43])=[NH:62])[NH:51][C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)NC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
419.3 mg (1.1 mmol) of HATU and 258.5 mg (2 mmol) of N,N-diisopropylethylamine are added to a solution of 408.4 mg (1 mmol) of N5-[{[(benzyloxy)carbonyl]amino}(imino)methyl]-N2-(tert-butoxycarbonyl)-L-ornithine in 15 ml of anhydrous DMF. After stirring at RT for 15 min, 253.76 mg (1.1 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:23][OH:24])=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:21])([CH3:20])[CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:21])([CH3:19])[CH3:20])[CH:14]=3)[C:9]2=[O:22])[C:3]=1[CH2:23][O:24][C:25](=[O:27])[CH3:26]
Reactant: CC(C)(O)c1ccc2c(c1)CCN(c1cccc(Br)c1CO)C2=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1c(Br)cccc1N1CCc2cc(C(C)(C)O)ccc2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Intermediate 43 (238 mg, 0.610 mmol) in DCM (6 ml) were added TEA (0.085 ml, 0.610 mmol), DMAP (7.5 mg, 0.061 mmol), and acetic anhydride (62 mg, 0.610 mmol). The resulting mixture was stirred for 24 hrs at r.t. The solvents were removed in vacuo and the crude product was purified by flash chromatography (silica gel, cyclohexane/EtOAC gradient) to yield Intermediate 44.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[C:9]([CH2:11][C:12]([O:14][CH:15]([CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:37]([OH:49])[CH:36]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:20]([OH:32])[CH:19]=1)=[O:13])#[N:10].[CH3:50][C:51]([CH3:53])=O>>[C:9]([C:11](=[C:51]([CH3:53])[CH3:50])[C:12]([O:14][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:20]([OH:32])[CH:19]=1)[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[C:37]([OH:49])[CH:36]=1)=[O:13])#[N:10]
Reactant: N#CCC(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CC(C)=O
Agent: O=S(=O)(O)C(F)(F)F
Product: CC(C)=C(C#N)C(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 56 °C
Yield: 86 %

Procedure:
1 g of trifluoromethanesulfonic acid was added to a solution of 55.2 g (0.1 mole) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl cyanoacetate in 300 ml of acetone, and the solution was heated for 3 hours at a temperature of 56° C. After cooling to room temperature, the resulting crystalline precipitate was filtered off with suction and recrystallized from acetone. After drying, 51 g (86 percent of theory) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl 2-cyano-3,3-dimethylacrylate were obtained in the form of colorless crystals having a melting point of 145° to 147° C. and a purity of 99 percent (HPLC). The structure of the compound obtained was confirmed by UV, IR and NMR spectra.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=2[N:17]=1.C(N(CC)C(C)C)(C)C>CC#N>[Cl:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: Clc1cccnc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1ccc2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1
Reaction time: 0.33 h

Procedure:
A mixture of the hydrochloride salt from step (b) above (0.564 g, 2.4 mmol), 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.27 g, 1.22 mmol, Example 1c) and N,N-diisopropylethylamine (0.84 mL, 4.8 mmol, Aldrich) in MeCN (1 mL) was subjected to microwave irradiation at 180° C. with stirring for 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexane, to give the title compound as a white solid. M.p. 208-210° C. MS (ESI, pos. ion) m/z: 382 (M+1).
Reaction SMILES: Br[CH:2](C)[C:3]([C:8]1[CH:9]=[CH:10][C:11]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH2:14][C:15]([O:17]C)=[O:16])[CH:13]=1)(OC)OC.[C:27](=O)([O-:29])[O-:28].[K+].[K+].CO>O>[C:27]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([S:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[CH:13]=1)[CH3:2])([OH:29])=[O:28]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1cc(C(OC)(OC)C(C)Br)ccc1Sc1ccccc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A mixture of 4.39 g (10 mmol.) of methyl 5-(2-bromo-1,1-dimethoxypropyl)-2-phenylthiophenylacetate obtained in Example 1-(2), 3.45 g (10 mmol.) of anhydrous potassium carbonate, 26 ml of methanol and 13 ml of water was heated under reflux and stirring for 2 hours. The reaction mixture was distilled to remove distillates having boiling points of below 100° C. To the residue was added 10 ml of water, and the mixture was heated under reflux and stirring for 12 hrs. The reaction mixture was treated in the same manner as in Example 6-(1) to obtain 2.46 g of the desired product as white crystals (yield 78%), m.p. 145°-146° C.
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].[CH2:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11]S1.C(O)C>O>[CH2:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][S:1]1(=[O:6])=[O:2]
Reactant: O=S(=O)([O-])O[O-]
Reactant: c1ccc2c(c1)CSC2
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=S1(=O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Potassium peroxymonosulphate (110 g) was added portionwise to a mixture of 1,3-dihydrobenzo[c]thiophene (23 g; J. Amer. Chem. Soc., 81, 4266), ethanol (400 ml) and water (300 ml) and the mixture was stirred at ambient temperature for 18 hours. Water (400 ml) was added and the mixture was extracted with chloroform (3×100 ml). The combined organic extracts were washed with water, dried (MgSO4) and evaporated. The residue was recrystallised from ethyl acetate to give 1,3-dihydrobenzo[c]thiophene-2,2-dioxide (17 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[C:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH2:21])([CH3:20])[CH3:19])(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C>ClCCl>[C:12]([C:15]1[CH:16]=[C:17]([C:18]([NH:21][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)([CH3:20])[CH3:19])[CH:22]=[CH:23][CH:24]=1)(=[O:14])[CH3:13]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(C(C)(C)N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(C(C)(C)NC(=O)Oc2ccc(Cl)cc2)c1
Reaction time: 2 h
Yield: 81 %

Procedure:
4-Chlorophenyl chloroformate (317 μL, 2.24 mmol) in dichloromethane (2 mL) was added to a mixture of 3-acetyl-α, α-dimethylbenzylamine 24 and diisopropylethylamine (390 μL, 2.24 mmol). The reaction mixture was stirred for 2 h. It was then diluted with dichloromethane, washed with 1 N HCl, and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate as eluent to give 25 (594 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.73 (s, 6H), 2.60 (s, 3H), 5.65 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 7.25 (d, J=6 Hz, 2H), 7.44 (t, J=8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 8.07 (1H, s); 13C NMR (DMSO-d, 100 MHz) δ 27.45, 29.79, 55.50, 124.23, 124.55, 127.31, 129.28, 129.55, 129.79, 130.39, 137.30, 148.70, 150.32, 152.97, 198.64; ESI-HRMS for C18H19NO3Cl (M+H)+ calcd. 332.1053. found 332.1059.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>C(O)C>[CH2:12]([NH:14][C:15]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[S:16])[CH3:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)NCCSCc1[nH]cnc1C
Yield: 86.4 %

Procedure:
i. A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (6.9 g.) and ethyl isothiocyanate (3.84 g.) in ethanol was heated under reflux for 2 hours. Concentration followed by recrystallisation of the residue from aqueous ethanol gave N-ethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (9.0 g.), m.p. 140°-141°. (Found: C, 46.5; H, 7.1; N, 21.7; S, 25.1. C10H18N4S2 requires: C, 46.5; H, 7.0; N, 21.7; S, 24.8).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:12]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:17][C:15]1[CH:14]=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: COc1cc(CO)ccc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.24 g (7.6 mmol) of NBS (N-bromosuccinimide) is added in small portions to a solution of (2-methoxy-biphenyl-4-yl)-methanol (1.35 g, 6.3 mmol) and triphenyl phosphine (2.0 g, 7.0 mmol) in 15 mL of CH2Cl2 at 0° C. The cooling bath is removed and the reaction mixture is stirred at room temperature overnight. The reaction mixture is then concentrated in vacuo, and the residue is purified by chromatography on silica gel (10% EtOAc/hexane) to furnish 4-bromomethyl-2-methoxy-biphenyl as a clear, colorless oil. 1H NMR (250 MHz, CDCl3) δ 7.45-7.55 (m, 2H), 7.20-7.45 (m, 4H), 7.05 (dd, 2H), 7.0 (d, 1H), 4.50 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH2:12](S)[CH3:13]>C(OCC)C>[CH2:12]([O:6][C:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)=[O:7])[CH3:13]
Reactant: CCS
Reactant: CC1(C(=O)O)CC1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
100 gm of 1-methylcyclopropanoic acid was added to 150 ml of diethyl ether. The system was cooled to 0°-5° C. and 119 gm of thionyl chloride was added dropwise over a period of time. After addition, the system was heated at reflux for 8 hours. The system was then cooled to 0°-5° C. and 62 gm of ethanethiol was added dropwise. The system was heated at reflux for 6 hours and then stirred at room temperature for 72 hours. The diethyl ether was removed by stripping to give the 1-methylcyclopropanoic acid ethyl ester.