Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(NC(C)C)(C)C.[Li].[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[Cl:22][C:23]1[C:24]([C:25]([NH:1][C:2]2[C:3]([Cl:13])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=2[C:8]([F:9])([F:11])[F:10])=[O:26])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: Cc1cc(C(F)(F)F)c(N)c(Cl)n1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(C(F)(F)F)c(NC(=O)c2cccnc2Cl)c(Cl)n1
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
To a cooled (-78° C.) solution of 2.1 g of the 3-amino-2-chloro-6-methyl-4-(trifluoromethyl)pyridine in 10 ml of THF was added dropwise over 3 min. 7 ml of lithium diisopropylamine (LDA, 1.5 M in cyclohexane). The mixture was stirred 5 min., and 0.9 g of 2-chloronicotinoyl chloride in 3 ml of THF was added over 1 min. After 5 min. an additional 3 ml of LDA solution was added followed by an additional 0.5 g of the acid chloride in 1 ml of THF. The resulting mixture was stirred 10 min. and then quenched with 100 ml of water. After partitioning with 30 ml of ethyl acetate, the organic phase was extracted with water and the combined aqueous phases extracted with methylene chloride, dried (magnesium sulfate), filtered and evaporated to give the crude product. This was washed with a small amount of ethyl acetate and dried to give 1.3 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[C:11](Cl)([Cl:13])=[O:12]>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[C:11]([Cl:13])=[O:12]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: CC1(C)CCCC(C)(C)N1C(=O)Cl

Procedure:
A solution of 29.7 g (0.21 mol) of redistilled 2,2,6,6-tetramethylpiperidine in 50 ml of xylene is added dropwise in the course of 1.5 hours, at -40°, to 40.2 g of a 25.7% solution of phosgene in xylene (0.105 mol), with stirring and under an inert gas atmosphere. After adding the amine, the mixture is stirred for a further 4 hours at -10° and for 18 hours at -5° to 0°. The 2,2,6,6-tetramethylpiperidinocarboxylic acid chloride which is thus obtained is not isolated but is now treated with a solution of 19.73 g (0.05 mol) of N,N'-bis-(2,2,6,6-tetramethyl-piperid-4-yl)-hexamethylenediamine and 20.4 ml (0.12 mol) of diisopropyl-ethylamine in 50 ml of xylene, this solution being added in the course of 2 hours, at -10°. After stirring for a further 18 hours at room temperature and for 6 hours at 50° C., the reaction mixture is cooled to room temperature, diluted with 300 ml of hexane and extracted four times with 150 ml of water, the organic phase is dried over sodium sulfate and the solvents are distilled off completely under a waterpump vacuum. The residue, which solidifies as crystals after a short time, is recrystallised from acetonitrile, and by this means pure N,N'-bis(2,2,6,6-tetramethylpiperid-4-yl)-N,N'-bis-(2,2,6,6-tetramethylpiperidinocarbonyl)-hexamethylenediamine is obtained as a colourless compound with a melting point of 137°-139°. ##STR40##
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:35][C:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 2-amino-2-phenylpropane (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with a 3:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 67 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]([S:4][C:5]([S:28]C(=O)C)=[C:6]([N:18]1[CH:21]([S:22](CC=C)=O)[CH2:20][C:19]1=[O:27])[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:1]([S:4][C:5]1[S:28][S:22][CH:21]2[N:18]([C:19](=[O:27])[CH2:20]2)[C:6]=1[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])(=[O:3])[CH3:2]
Reactant: C=CCS(=O)C1CC(=O)N1C(C(=O)OCOC(=O)C(C)(C)C)=C(SC(C)=O)SC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)SC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)CC2SS1
Yield: 53.6 %

Procedure:
A solution of 82 mg of pivaloyloxymethyl 3,3-di(acetylthio)-2-(4-allylsulphinylazetidin-2-on-1-yl)propenoate and 32 mg of 4-toluenesulphonic acid hydrate in 10 ml of dioxane was heated rapidly to reflux and maintained under reflux for 1 hour. The solvent was removed by evaporation and the residue chromatographed on silica gel using ethyl acetate/hexane mixtures as eluant. The product (35 mg, 54%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)O)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])=[O:41])=[CH:36][CH:35]=1>>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:41])=[CH:38][CH:39]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1cn(-c2ccc(OC(F)(F)F)cc2)nc1OCc1ccccc1)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccc(OC(F)(F)F)cc3)nc2OCc2ccccc2)C2CCCCC2)cc1
Yield: 55.7 %

Procedure:
Using {3-(benzyloxy)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}(cyclohexyl)methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.26 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.39 g, 56%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.O>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:14]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:11]2=[O:13]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(O)cc2C(=O)N1c1ccc(O)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A suspension of 4-hydroxyphthalic acid (3.00 g) and 4-aminophenol (1.98 g) in glacial acetic acid (15 mL) was heated under nitrogen at 120° C. for 1.5 h. The brown reaction solution was cooled to room temperature, poured into water (200 mL) and allowed to sit undisturbed for 30 min. The precipitate was collected by filtration and washed with water (2×60 mL). The solid was dried under high vacuum at 50° C. for 18 h yielding the title compound (3.14 g) as a tan solid. 1H NMR (DMSO-d6): 10.99 (s, 1H), 9.72 (s, 1H), 7.76 (d, 1H, J=7.8 Hz), 7.18 (m, 4M), 6.86 (m, 2H); MS: 256 (MH+).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10].C(#N)C.[OH-].[Na+]>O>[CH2:2]([O:4][C:5]([CH2:6][NH:7][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[CH:24][C:23]=2[Cl:33])[CH:19]=[CH:20][C:12]=1[N+:9]([O-:11])=[O:10])=[O:8])[CH3:3]
Reactant: O=C(Cl)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CN
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CNC(=O)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 95.7 %

Procedure:
7 g of aminoacetic acid ethyl ester chloride, 20.7 g of 2-nitro-5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-benzoic acid chloride and 180 ml of acetonitrile were initially introduced into the reaction vessel. 4 g of sodium hydroxide, dissolved in 10 ml of water, were added dropwise at -10° to -5° C. The reaction mixture was then poured onto water and adjusted to pH 10 and the crystalline product was filtered off. 23 g (95% of theory) of 5-(2,6-dichoro-4-trifluoromethyl-phenoxy)-2-nitro-benzoic acid (ethoxycarbonylmethyl)-amide with a melting point of 146° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:42]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:42])[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (82.5 mg, 0.13 mmol) in 1,4-dioxane (1 mL) was added trimethylboroxine (39 mg, 0.31 mmol), Pd(PPh3)4 (15 mg, 10 mol %) and potassium carbonate (35 mg, 0.25 mmol). The resulting reaction mixture was purged with nitrogen and sealed in a microwave vessel. The vessel was subject to microwave irradiation at 130° C. for 15 min. The crude mixture was diluted with brine and extracted with EtOAc. The combined organic extracts were dried over Na2SO4. The titled compound was obtained as a glassy material after two preparative TLC plates developed respectively by 20% EtOAc in hexanes and dichloromethane. LC-MS: 584.08 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.84 (s, 1H), 7.65-7.70 (m, 2H), 7.29 (s, 0.5), 7.18-7.22 (m, 1.5H), 7.10-7.15 (m, 1H), 7.01 (d, J=8.0 Hz, 0.5H), 6.98 (d, J=8.5 Hz, 0.5H), 6.66 (d, J=5.0 Hz, 0.5H), 6.64 (d, J=5.5 Hz, 0.5H), 5.54 (d, J=8.5 Hz, 0.5H), 5.31 (d, J=8.0 Hz, 0.5H), 4.82 (d, J=15.5 Hz, 1H), 4.02 (d, J=15 Hz, 0.5H), 3.71-3.82 (m, 5H), 3.15-3.24 (m, 1H), 2.42 (s, 1.5H), 2.41 (s, 1.5H), 1.13-1.27 (m, 6H), 0.48 (d, J=6.5 Hz, 1.5H), 0.31 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]3[O:15]C(C)(C)[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>C(=O)(O)[O-].[Na+]>[C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:17])[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CNc1ncnc2c1ncn2[C@@H]1O[C@H](c2nc(C(C)(C)C)no2)[C@@H]2OC(C)(C)O[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1ncnc2c1ncn2[C@@H]1O[C@H](c2nc(C(C)(C)C)no2)[C@@H](O)[C@H]1O
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution of 9-{(3aR,4R,6S,6aR)-6-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-N-isobutyl-9H-purin-6-amine (14 mg) in a cold mixture of trifluoroacetic acid:water (9:1; 1 ml) was kept at 4° C. for 18 h. The resulting solution was basified in an ice bath with saturated aqueous sodium bicarbonate (20 ml), extracted with ethyl acetate (2×20 ml), the extracts dried (MgSO4) and evaporated to dryness in vacuo to afford the title compound (7.66 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C.[ClH:18]>O1CCOCC1>[ClH:18].[ClH:18].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH2:10]
Reactant: CC(C)(C)OC(=O)NCCOc1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1ccccn1
Yield: 96.8 %

Procedure:
tert-Butyl 2-(pyridin-2-yloxy)ethylcarbamate (0.353 g) was treated with 4M of hydrogen chloride in 1,4-dioxane (0.6 mL) at RT for 1 h. The solvent was evaporated under reduced pressure. The residue was washed with ether, and dried to give the desired product (0.30 g, 96.8%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1CCC1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 120 %

Procedure:
To a −78° C. solution of 2.8 mL (20.0 mmol) of diisopropylamine in 40 mL of dry tetrahydrofuran was added 13.75 mL (22 mmol) of 1.6 M n-butyllithium in hexanes. The reaction was let warm to 0° C. and then cooled to −78° C. A solution of 2.7 mL (20 mmol) of ethyl cyclobutanecarboxylate in 10 mL of tetrahydrofuran was added dropwise and the reaction let warm to 0° C. The reaction was stirred for 15 min before being cooled to −78° C. To the solution was added 3.1 mL (26 mmol) of benzyl bromide dropwise and the reaction stirred for 15 min before being let warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated ammonium chloride, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 5.24 g of crude ethyl 1-benzylcyclobutanecarboxylate. The crude product was dissolved in 100 mL of tetrahydrofuran and cooled to 0° C. To this solution was added dropwise 14.1 mL (14.1 mmol) of 1M lithium aluminum hydride in tetrahydrofuran. The reaction was stirred for 1 h before being carefully quenched with brine. The mixture was filtered through a celite plug and the filter cake washed with ethyl acetate. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 1.6 g (45%) of ethyl (1-benzylcyclobutyl)methanol. 1H NMR (300 MHz, DMSO-d6) δ 7.18-7.34 (m, 5H), 4.63 (t, J=5 Hz, 1H), 3.24-3.25 (d, J=5H, 2H), 2.71 (s, 2H), 1.66-1.79 (m, 6H).
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)[C:3]([OH:5])=O.[CH:12]1([NH:19][C:20]([NH2:22])=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:19][C:20]2[S:21][CH:2]([CH2:6][C:7]3[N:8]=[CH:9][NH:10][CH:11]=3)[C:3](=[O:5])[N:22]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: O=C1N=C(NC2CCCCCC2)SC1Cc1c[nH]cn1

Procedure:
Synthesis was performed from (2S)-2-amino-3-(1H-imidazol-4-yl)propanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Brc1cc(C2OCCO2)ccn1
Yield: 80.9 %

Procedure:
60 g of 2-bromo-4-pyridinecarboxaldehyde was dissolved in 600 ml of benzene, and 40 g of ethylene glycol and 6 g of p-toluenesulfonic acid were put in the solution. The mixture was heated under reflux for 18 hours while water was removed by using a Dean-Stark trap. After the reaction, the reaction mixture was made basic by adding ice and a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with water and dried. The solvent was evaporated. The residue was distilled to give 60 g (yield 82%) of 2-bromo-4-(1,3-dioxolan-2-yl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]2[CH:14]([O:15][CH3:16])[CH2:13][NH:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH3:17][CH:18]1[C:23]2[S:24][C:25]([C:27](O)=[O:28])=[N:26][C:22]=2[CH2:21][CH2:20][N:19]1[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:16][O:15][CH:14]1[CH2:13][N:12]([C:27]([C:25]2[S:24][C:23]3[CH:18]([CH3:17])[N:19]([CH3:30])[CH2:20][CH2:21][C:22]=3[N:26]=2)=[O:28])[CH2:11][CH:10]1[NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8]
Reactant: CC1c2sc(C(=O)O)nc2CCN1C
Reactant: COC1CNCC1NC(=O)c1ccc(Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC1CN(C(=O)c2nc3c(s2)C(C)N(C)CC3)CC1NC(=O)c1ccc(Cl)s1

Procedure:
Prepared analogously to Example 1b from (3SR,4SR)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidine and (RS)-4,5-dimethyl-4,5,6,7-tetrahydro-thiazolo[5.4-c]pyridine-2-carboxylic acid (prepared analogously to WO2004058728) with HATU as coupling reagent.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33]I)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:36](Cl)[CH3:37]>N1C=CC=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][C:37]2[CH:36]=[CH:3][CH:2]=[CH:1][N:20]=2)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Cl)Cl
Reactant: O=C(O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: c1ccncc1
Product: O=C(O)C(=NOCCc1ccccn1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 60 °C
Reaction time: 56 h

Procedure:
A mixture of 5 g of syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-iodoethoxyimino)-acetic acid solvated with dichloroethane (=4.27 g of pure product) and 30 ml of pyridine was heated at 60° C. for 24 hours and then stood at room temperature for 56 hours. The mixture was vacuum filtered and the recovered product was rinsed with pyridine and then ether and dried to obtain 1.66 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-pyridylethoxyimino)-acetic acid (pyridinium internal salt) melting at 250° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:12])=[C:9]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:8]=2[CH:18]=1)([O-])=O.[H][H]>[Pt].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:12])=[C:9]([CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])[C:8]=2[CH:18]=1
Reactant: [H][H]
Reactant: Cc1oc2ccc([N+](=O)[O-])cc2c1CCN(C)C
Agent: [Pt]
Solvent: C1CCOC1
Product: Cc1oc2ccc(N)cc2c1CCN(C)C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
A mixture of 2.1 gm (8.6 mMol) 5-nitro-2-methyl-3-(N,N-dimethyl-2-aminoethyl)benzofuran and 0.5 gm platinum on carbon in tetrahydrofuran was hydrogenated at an initial hydrogen pressure of 60 p.s.i. at room temperature for 15 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residual oil was subjected to flash silica gel chromatography, eluting with dichloromethane containing 10% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 1.42 gm (76%) 5-amino-2-methyl-3-(N,N-dimethyl-2-aminoethyl)benzofuran. The dihydrochloride salt was prepared and recovered as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>CN(C=O)C.COC(OC)(C)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:10][O:11][C:13]([CH3:18])([CH3:14])[O:12]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(O)Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Solvent: CN(C)C=O
Product: CC1(C)OCC(Cc2ccc(Br)cc2)O1
Yield: 1994.1 %

Procedure:
A solution of 3-(4-bromo-phenyl)-propane-1,2-diol (1.41 g, 6.10 mmol) and p-toluenesulfonic acid (50 mg) in DMF (10 mL), 2,2-dimethoxypropane (10 mL) is stirred at rt for 2 h. The reaction mixture is diluted with sat. aq. NaHCO3 (150 mL) and extracted with diethyl ether (2×200 mL). The organic extracts are washed with water (200 mL), dried over MgSO4 and evaporated to give 4-(4-bromo-benzyl)-2,2-dimethyl-[1,3]dioxolane (1.57 g) as a pale brownish oil; LC-MS: tR=1.00 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[C:11]=2[CH3:27])[CH2:4][O:3]1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[O:3][CH2:4][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:18]3[NH:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[O:37])[C:11]=2[CH3:27])[CH2:6][O:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC2COC(C)(C)OC2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OCC2COC(C)(C)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
To a toluene (45 ml)-methanol (5 ml) solution of the 2-(((4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (766 mg, 1.92 mmol) obtained in the step (12c), a toluene (0.5 ml)-methanol (0.5 ml) solution of 3-chloroperbenzoic acid (459 mg, 1.73 mmol as the content was regarded as 65%) was added dropwise at −65° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred in the same conditions for one hour and 20 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added. The aqueous layer was extracted with ethyl acetate and chloroform (three times). Organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 30 g, elution solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing the title compound were collected, concentrated to obtain the title compound (688 mg, yield: 86.2%) as a light brown foam.