Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:16]=[CH:15][C:14]=1[C:25]([NH:27][CH2:28][C:29]([CH2:35][NH2:36])([OH:34])[C:30]([F:33])([F:32])[F:31])=[O:26].C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[NH2:12][C:13]1[N:17]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[N:16]=[CH:15][C:14]=1[C:25]([NH:27][CH2:28][C:29]([CH2:35][NH:36][C:4]([C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:5])([OH:34])[C:30]([F:33])([F:32])[F:31])=[O:26]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(F)cccc2Cl)C(F)(F)F)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
A solution of 2-chloro-6-fluorobenzoyl chloride (0.169 g) in dry tetrahydrofuran (1 ml) was added to a stirred mixture of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.289 g) and diisopropylethylamine (0.21 ml) in a mixture of dichloromethane (4 ml) and tetrahydrofuran (3 ml) cooled to <5° C. After the addition, the cooling bath was removed and the reaction mixture stirred at room temperature for 20 minutes. Water (10 ml) and dichloromethane (10 ml) were added to the reaction mixture and the resultant mixture stirred vigorously. The phases were separated using a hydrophobic frit and the aqueous phase washed with additional dichloromethane (10 ml). The organic phase was evaporated and the residue purified by chromatography on silica (20 g cartridge) eluting with 0-100% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated to give the title compound (0.409 g).
Reaction SMILES: [CH2:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:5](=[O:17])[CH2:4]1)[CH3:2].[C:18](=[O:28])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:19].CC(C)([O-])C.[Li+].O1CCCC1.O>O1CCCC1.C(OCC)(=O)C>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:9]=[CH:8][C:7]([NH:6][C@H:3]([CH2:1][CH3:2])[CH2:4][C:5]([NH:19][C:18](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:17])=[CH:12][CH:11]=1
Reactant: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Reactant: NC(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 86 %

Procedure:
80.0 mg (0.33 mmol) of (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone produced in Example 6and 74.8 mg (0.50 mmol) of benzyl carbamate were dissolved in tetrahydrofuran (3 mL) and further mixed with a lithium tert-butoxide/tetrahydrofuran solution (1 mol/L, 0.50 mL, 0.50 mmol) at room temperature. After stirring at the same temperature for 1.5 hours, water (5.0 mL) was further added to the reaction solution and extraction with ethyl acetate (5 mL) was repeated three times. The residue obtained by concentrating the separated organic layer dried with anhydrous magnesium sulfate was purified on silica gel column chromatography to obtain benzyl (R)-{3-[4-(trifluoromethyl)phenylamino]-pentanoyl}carbamate as a white solid (112 mg, isolated yield: 86%). 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.98 (3H, t), 1.5-1.8 (2H, m), 2.9-3.2 (2H, m), 3.8-3.9 (1H, m), 4.2-4.3 (1H, br), 5.17 (2H, s), 6.60 (2H, d), 7.3-7.4 (7H, m), 7.5-7.6 (1H, br)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][N+:14]#[C-:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1([C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.[OH2:33]>CS(C)=O>[CH2:29]([O:28][C:26]([C:21]1([CH2:20][CH2:19][CH2:18][CH2:17][C:13]([N+:14]#[C-:15])([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2([C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:33])[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOC(=O)C1(CCCCBr)CCCC1
Reactant: O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [C-]#[N+]C(CCCCC1(C(=O)OCCCC)CCCC1)(CCCCC1(C(=O)OCCCC)CCCC1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
Under a N2 atmosphere, NaH (60% (w/w) in mineral oil, 3.20 g, 80.0 mmol) was added portion wise to a solution of TosMIC (6.58 g, 33.0 mmol) and BU4NI (1.31 g, 3.55 mmol) in dry DMSO (100 mL) while stirring vigorously and cooling with a water bath. After 30 min, butyl 1-(4-bromo-butyl)-cyclopentanecarboxylate (21.59 g, 67.2 mmol) was added drop wise to the mixture in 20 min and after 1 h of stirring, another portion of NaH (60% (w/w) in mineral oil, 0.56 g, 14 mmol) was added. After 20 min, H2O (250 mL, ice-cold) was added drop wise while cooling with a water bath and the resulting mixture was extracted with Et2O (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried (Na2SO4) and filtered through a layer of silica. The residue was washed with Et2O (200 mL) and the combined filtrate and washings were evaporated in vacuo. The remaining oil was purified by column chromatography (silica, heptane/EtOAc=8:1) to give butyl 1-{9-[1-(butoxycarbonyl)cyclopentyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl}-1-cyclopentanecarboxylate as a yellow oil (13.38 g). This oil (13.38 g) was dissolved in CH2Cl2 (250 mL), and conc aqueous HCl (75 mL) was added. After stirring vigorously for 18 h, H2O (300 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×100 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 (2×250 mL) and brine (250 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was suspended in heptane (100 mL) and filtered. The filtrate was evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane/EtOAc=6:1) to give butyl 1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate (9.05 g, 56%) as a slightly yellow liquid. 1H NMR (CDCl3): δ=4.05 (t, J=6.5 Hz, 4H), 2.36 (t, J=7.5 Hz 4H), 2.14–2.05 (m, 4H), 1.65–1.32 (m, 28H), 1.24–1.16 (m, 4H), 0.96 (t, J=7.2 Hz, 6H). 13C NMR (CDCl3): δ=210.8, 177.8 (2×), 64.1 (2×), 54.0 (2×), 42.6 (2×), 39.0 (2×), 36.0 (4×), 30.7 (2×), 25.6 (2×), 24.9 (4×), 24.1 (2×), 19.1 (2×), 13.6 (2×). HRMS calcd for C29H50O5 (M+): 478.3658, found 478.3663.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8]>CN(C)C=O>[OH:4][CH2:3][CH:2]([NH:1][CH:8]=[CH:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH3:5]
Reactant: C#CC(=O)OCC
Reactant: CC(N)CO
Solvent: CN(C)C=O
Product: CCOC(=O)C=CNC(C)CO
Reaction time: 6 h

Procedure:
3.76 g (50 mmol) of 2-amino-1-propanol (III: R=methyl) was added to 100 ml of dimethylformamide and cooled. To this, 4.91 g (50 mmol) of ethyl propiolate (II, R1 =ethyl) was slowly added dropwise. The reactant mixture was stirred at not more than 5° C. for 6 hours and further stirred at room temperature for 2 hour.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Si:39]([O:46][C:47]1[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])=[CH:53][C:52]([Br:63])=[CH:51][C:48]=1[CH:49]=O)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>O1CCCC1.CCCCCC.C(OC)(C)(C)C>[Br:63][C:52]1[CH:51]=[C:48](/[CH:49]=[CH:7]\[C:6]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:4]([O:3][CH3:2])[CH:5]=2)[C:47]([O:46][Si:39]([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:41])[CH3:40])=[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:57])[CH3:58])[CH:53]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(C=O)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(/C=C\c2cc(Br)cc(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
A suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (1.69 g, 3.23 mmol) in tetrahydrofuran (30 mL) was cooled to 0° C. and butyllithium (2 mL of a 1.6 N solution in hexane, 3.23 mmol) was added dropwise. The brick red solution was stirred at 0° C. for 20 min, then a solution of 19 (0.96 g, ca 2.2 mmol) in tetrahydrofuran (12 mL) was added dropwise. The temperature was allowed to rise to room temperature overnight, than the reaction was diluted with tert-butylmethyl ether (ca 100 mL) and washed with water (ca 50 mL, containing 1 mL 2N HCl) then brine (30 mL). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give a crude which was purified by column (elution with cyclohexane:AcOEt 10:1) to give 0.75 g of 20 still impure with 20% of the E isomer.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Br[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:10][CH:11]=1)([O-:17])=[O:16]
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Nc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of pyridin-2-amine, 9, (0.5 g; 2.5 mmol), 2-bromo-5-nitropyridine, 10, (0.28 g; 2.9 mmol), 1,3-Bis(diphenylphosphino)propane (0.04 g; 0.08 mmol) in toluene was added to a mixture of sodium tert butoxide (0.33 g; 3.5 mmol) and Pd(dba)3 (0.05 g; 0.05 mmol) in toluene and allowed to stir at ambient temperature for 18 hours. The mixture was filtered through a bed of celite and the solvent removed under reduced pressure. The crude mixture was purified on a flash silica gel column (hexane/ethyl acetate) to afford 5-nitro-N-(pyridin-2-yl)pyridin-2-amine, 11, (0.25 g; 47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:8]O)[CH:7]=1.P(Br)(Br)[Br:12].C(Cl)Cl.C([O-])(O)=O.[Na+]>CCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:8][Br:12])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(Br)ccc1I
Agent: CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: BrCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a stirred mixture of (5-Bromo-2-iodo-phenyl)-m-ethanol (9.14 g, 29.2 mmol) in CH3Cl (150 mL) under argon was added 1M PBr3 in CH2Cl2 (35.0 mL, 35.0 mmol). The reaction mixture was stirred at room temperature for 20 min and then poured into a mixture of ice and saturated NaHCO3 solution (300 mL). The pH was adjusted to basic by addition of solid NaHCO3. This aqueous layer was extracted with EtOAc (1×600 mL, 2×400 mL). The combined EtOAc extracts were washed with brine (1×100 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 4-bromo-2-bromomethyl-1-iodo-benzene (5.69 g, 52%). 1H NMR (CDCl3): δ 7.68 (d, 1H, J=8.80 Hz), 7.59 (s, 1H), 7.18 (d, 1H, J=8.80 Hz), 4.51 (s, 2H). HPLC: Rt=3.87 min.
Reaction SMILES: N[C:2]1[C:3]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C=O.[C:18]([BH3-])#[N:19].[Na+].[C:22](=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[Cl:15][C:14]1[C:3]2[C:2]([N:19]([CH3:18])[CH3:22])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[S:5][C:4]=2[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1sc2cccc(Cl)c2c1N
Reactant: O=C([O-])[O-]
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1sc2cccc(Cl)c2c1N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3-amino-4-chlorobenzo[b]thiophene-2-carboxylate (1.7 g, 7.0 mmol) [Beck J. R., supra] and paraformaldehyde (2.0 g, 67 mmol) in 45 mL of acetic acid is treated in portions with sodium cyanoborohydride (2.0 g, 32 mmol). The mixture is stirred at room temperature for 24 hours, then diluted cautiously with 250 g of ice and water. Solid sodium carbonate is added until the mixture is slightly basic. After extraction with ethyl acetate, the combined organic layers are washed with brine, then dried (anhydrous sodium sulfate), and evaporated to provide methyl 4-chloro-3-(dimethylamino)benzo[b]thiophene-2-carboxylate as an oil.
Reaction SMILES: [CH3:1][C:2](=[CH2:14])[C:3]#[C:4][C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13].[CH:15](OCC)([O:19][CH2:20]C)[O:16][CH2:17]C.[C:25](=O)([O-])[O-:26].[Na+].[Na+]>>[CH3:14][C:2]([O:26][CH3:25])([CH2:1][CH:15]([O:19][CH3:20])[O:16][CH3:17])[C:3]#[C:4][C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13]
Reactant: C=C(C)C#CC1=C(C)CCCC1(C)C
Reactant: CCOC(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: COC(CC(C)(C#CC1=C(C)CCCC1(C)C)OC)OC
Temperature: 20 °C
Reaction time: 16 h

Procedure:
88.5 g (0.47 mole) of 1-[3-methyl-but-3-en-1-yn-1-yl]-2,6,6-trimethyl-cyclohex-1-ene were added in the course of 60 minutes, at 0° C., to a mixture of 148 g (1 mole) of triethyl orthoformate and 5 g (0.032 mole) of FeCl3 and the reaction mixture was then stirred for 16 hours at 20° C. Thereafter it was rendered alkaline with 70 ml of saturated sodium carbonate solution, the aqueous phase was separated off and the organic phase was dried. The NMR spectrum shows the presence of a mixture of starting material and product.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([NH:41][S:47]([CH3:46])(=[O:49])=[O:48])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(N)c4)oc3C)c(OC)c2)cs1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(NS(C)(=O)=O)c4)oc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}amine (100 mg), methanesulfonyl chloride (0.013 mL), triethylamine (0.024 mL) and tetrahydrofuran (1 mL) was stirred at room temperature for 1 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The eluate was subjected to reversed phase HPLC and eluted with acetonitrile-water (10:90-100:0, v/v). The obtained fraction was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give N-{3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}methanesulfonamide (37 mg, yield 33%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 113-115° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][C@@H:12]([CH2:14][OH:15])[C@H:11]([OH:16])[C@@H:10]2[OH:17])[C:5]([N:18]=[N:19]C2C=CC(Cl)=CC=2)=[C:4]([Cl:27])[N:3]=1.[Cl:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1N>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][C@@H:12]([CH2:14][OH:15])[C@H:11]([OH:16])[C@@H:10]2[OH:17])[C:5]([N:18]=[N:19][C:30]2[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=2[Cl:28])=[C:4]([Cl:27])[N:3]=1
Reactant: Nc1nc(Cl)c(N=Nc2ccc(Cl)cc2)c(N[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)n1
Reactant: Nc1ccccc1Cl
Product: Nc1nc(Cl)c(N=Nc2ccccc2Cl)c(N[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)n1

Procedure:
Compound 9, (1S,2R,3S,5S)-3-[[2-amino-6-chloro-5-[(2-chlorophenyl)azo]-4-pyrimidinyl]amino]-5-(hydroxymethyl)-1,2-cyclopentanediol was prepared by the same method used for Compound 11, using a stoichiometric amount of 2-chloroaniline instead of 4-chloroaniline.
Reaction SMILES: Cl[CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[NH2:14][C:12]1[S:13][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([CH2:8][CH3:9])[N:11]=1
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: NC(N)=S
Solvent: CCO
Product: CCc1nc(N)sc1C(=O)OC
Yield: 94.7 %

Procedure:
Methyl 2-chloro-3-oxo-pentanoate obtained in Example (22a) (1.91 g, 11.57 mmol) was dissolved in ethanol (50 mL). Thiourea (0.77 g, 10.09 mmol) was added, and the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was washed with hexane/ethyl acetate: 5/1 to obtain 1.78 g of the title compound as a pale yellow solid (95%).
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[C:22]1([NH:28][C:29]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:16]=[C:15]([NH2:17])[C:14]4[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=4)[N:8]=3)[CH2:2][CH2:3]2)=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=S)Nc4ccccc4)CC3)nc(N)c2cc1OC
Reaction time: 8 h
Yield: 69.9 %

Procedure:
In 20 ml of dioxane, there was dissolved 0.87 g. (3 mmole) of 2-piperazino-4-amino-6,7-dimethoxyquinazoline. To the resultant solution was added dropwise a solution of 0.41 g. (3 mmole) of phenylisothiocyanate dissolved in 10 ml of dioxane at room temperature. The mixture was further stirred overnight. After evaporation of the solvent, the residue was chromatographed on silica gel and eluted with 20% dioxane-chloroform to obtain 0.89 g. of the desired product.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[CH:9]=[CH:8][C@@H:7](O)[CH2:6]1)=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:30][C:31]1[C:36]2[N:37]=[CH:38][NH:39][C:35]=2[C:34]([F:40])=[CH:33][N:32]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:2]([O:4][C@@H:5]1[CH2:6][C@@H:7]([N:39]2[C:35]3[C:34]([F:40])=[CH:33][N:32]=[C:31]([F:30])[C:36]=3[N:37]=[CH:38]2)[CH:8]=[CH:9]1)(=[O:3])[CH3:1].[C:2]([O:4][C@@H:5]1[CH2:6][C@@H:7]([N:37]2[C:36]3[C:31]([F:30])=[N:32][CH:33]=[C:34]([F:40])[C:35]=3[N:39]=[CH:38]2)[CH:8]=[CH:9]1)(=[O:3])[CH3:1]
Reactant: Fc1ncc(F)c2[nH]cnc12
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C=C[C@H](n2cnc3c(F)cnc(F)c32)C1
Product: CC(=O)O[C@H]1C=C[C@H](n2cnc3c(F)ncc(F)c32)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(1R,3S)-(+)-cis-4-cyclopentene-1,3-diol 1-acetate (3-1) (500 mg, 3.5 mmol, 1.0 equiv) was dissolved in dry THF (17.6 mL). Triphenylphosphine (1.4 g, 5.3 mmol, 1.5 equiv) was added, followed by 4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-4) (655 mg, 4.2 mmol, 1.2 equiv). The mixture was cooled to 0° C. and DIAD (1 mL, 5.3 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred at ambient temperature for 1 hour. Upon disappearance of starting material, the solvent was removed at reduced pressure and the yellow residue was purified via flash chromatography on a 120 g silica gel column (gradient elution 0 to 100% ethyl acetate in hexanes) to yield (1R,4R)-4-(4,7-difluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-enyl acetate (4-1) and (1R,4R)-4-(4,7-difluoro-3H-imidazo[4,5-c]pyridin-3-yl)cyclopent-2-enyl acetate (4-2) as a 2:3 regioisomeric mixture. 1H NMR (4-1) (500 MHz, CDCl3): δ 7.907 (s, 1H); 7.83 (t, J=2.5 Hz, 1H); 6.44 (m, 1H); 6.31 (m, 1H); 5.93-5.99 (m, 2H); 2.67 (m, 1H); 2.43 (m, 1H); 2.10 (s, 3H). LRMS m/z (M+H) 279.9 found, 280.1 required. 1H NMR (4-2) (500 MHz, CDCl3): δ 7.98 (s, 1H); 7.81 (t, J=2 Hz, 1H); 6.44 (m, 1H); 6.31 (m, 1H); 5.93-5.99 (m, 2H); 2.67 (m, 1H); 2.43 (m, 1H); 2.10 (s, 3H). LRMS m/z (M+H) 279.9 found, 280.1 required.
Reaction SMILES: [CH2:1]([C:5]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].CN(C)[CH:23]=[O:24].[CH3:26][C:27]([CH3:30])([O-])[CH3:28].[K+].CI>C(OCC)C.O>[CH3:23][O:24][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:5]([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)([CH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4])[C:6]([O:7][C:27]([CH3:30])([CH3:28])[CH3:26])=[O:14]
Reactant: CC(C)(C)[O-]
Reactant: CN(C)C=O
Reactant: CCCCC1(Cn2cncn2)C(=O)Oc2ccccc21
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CCOCC
Product: CCCC(c1ccccc1)C(Cn1cncn1)(C(=O)OC(C)(C)C)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a clear solution of 3-butyl-3-[(1,2,4-triazol-1-yl)methyl]-2(3H)-benzofuranone (5.0 g, 0.0184 mole) and dimethyl formamide (20 mL) in a 300 mL round bottom flask, potassium t-butoxide (6.2 g, 0.0553 mole) was added and the reaction mixture stirred at room temperature for 5 minutes before adding methyl iodide (3.2 g, 0.0221 m). The reaction mixture was stirred with heating at 40° C. for 1 hour and 1.0 g of water was added. The stirring was continued for an additional 2 hours at 40° C., before adding 100 mL of water and 100 mL of ethyl ether for work up. The organic phase was isolated and dried over magnesium sulfate, evaporated by rotary evaporator to afford 4.0 g of oily concentrate (yield 61%), Example 69 of Table 1.
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C.[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47](CCC(O)=O)=[CH:46]1>>[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:46]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2c[nH]c3ccccc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(1H-indol-3-yl)-propionic acid (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.