Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:8]S(C(C)(C)C)=O)[CH2:7][CH2:6][O:5][CH2:4]1)#[N:2].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:27][C:28]1[CH:29]=[C:30]([C:35]2[C:43]([C:44]([NH2:46])=[O:45])=[C:38]3[CH2:39][NH:40][CH2:41][CH2:42][N:37]3[N:36]=2)[CH:31]=[CH:32][C:33]=1[F:34]>C1COCC1.O>[Cl:27][C:28]1[CH:29]=[C:30]([C:35]2[C:43]([C:44]([NH2:46])=[O:45])=[C:38]3[CH2:39][N:40]([C:16]([NH:8][C:3]4([C:1]#[N:2])[CH2:7][CH2:6][O:5][CH2:4]4)=[O:18])[CH2:41][CH2:42][N:37]3[N:36]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNCC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)S(=O)NC1(C#N)CCOC1
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(NC(=O)N2CCn3nc(-c4ccc(F)c(Cl)c4)c(C(N)=O)c3C2)CCOC1
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of Intermediate 334B (30.3 mg, 0.204 mmol) and TEA (0.142 mL, 1.018 mmol) in THF (8 mL) was added triphosgene (54.4 mg, 0.183 mmol) at 0° C. and the reaction mixture was stirred for 30 min at the same temperature. A solution of Intermediate 185B (60 mg, 0.204 mmol) in THF (1 mL) was added and the reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC to afford Compound 334 as an off-white solid (20.6 mg, 23%). HPLC retention time 7.12 and 7.33 min (Methods B and C respectively). MS(ES): m/z=433 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (dd, J=7.28, 2.26 Hz, 1H), 7.65-7.72 (m, 2H), 7.44-7.51 (m, 1H), 7.17-7.41 (m, 2H), 4.79 (s, 2H), 4.16-4.23 (m, 3H), 3.81-3.96 (m, 5H), 2.40-2.49 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13]([NH:15][C:16]([N:18]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])=[N:12][CH:11]=1)(C)(C)C.Cl>C(Cl)Cl.C(OCC)C>[CH:25]1([N:18]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16](=[O:17])[NH:15][C:13]2[S:14][C:10]([CH2:9][NH:8][CH2:7][C:6]([OH:31])=[O:5])=[CH:11][N:12]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)CNCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)CNCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 76 %

Procedure:
{[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-amino}-acetic acid tert-butyl ester (14 mg, 0.03 mmol) was dissolved in methylene chloride. Hydrogen chloride (100 μL, 4N in dioxane) was added and the reaction was stirred at ambient temperature until no ester could be detected. The reaction was diluted with diethyl ether and concentrated. The resulting residue was dissolved in a minimum amount of methylene chloride, precipitated with diethyl ether and decanted. This was repeated to afford 9 mg (69%) of the desired compound. HPLC-MS: m/z 395 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCCC1.[H-].[Na+].Cl[C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30]>C(OCC)C>[CH2:32]([O:31][C:29]([O:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20])=[O:30])[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)COC(=O)Cl
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC1C(OC(=O)OCC(C)C)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Yield: 26.7 %

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (6.0 mg, 60% oil dispersion) in one portion at 5° C. The mixture was stirred for half an hour at the same temperature and then isobutyl chloroformate (7 mg) was added thereto. The reaction mixture was stirred for 2 hours at ambient temperature and then diluted with diethyl ether. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (elution by diethyl ether/n-hexane=1/3) to yield 6-isobutoxycarbonyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (5.1 mg) as an oil.
Reaction SMILES: [OH2:1].[C:2]1([OH:10])[CH:9]=[C:7](C)[CH:6]=[C:4](O)[CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12]>C(OCC)C.C([O-])(O)=O.[Na+].O>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([O:10][C:2]1[CH:3]=[CH:4][CH:6]=[CH:7][C:9]=1[OH:1])(=[O:22])=[O:21])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: O
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Oc1ccccc1O
Temperature: 25 °C
Reaction time: 36 h
Yield: 64 %

Procedure:
A mixture of orcinol monohydrate (4.32 g, 30.2 mmol) and 2-nitrobenzenesulfonyl chloride (6.65 g, 30.0 mmol) in diethyl ether (100 mL) and saturated NaHCO3 (100 mL) was stirred at ambient temperature for 36 h. The reaction mixture was diluted with water (100 mL) and extracted into 10% tetrahydrofuran/ethyl acetate, dried (MgSO4), and concentrated. The residue was diluted with diethyl ether (150 mL) and the resulting disulfonated product (1.6 g) removed by filtration. The filtrate was concentrated and purified by flash chromatography (3:97 to 10:90 diethyl ether/dichloromethane) to give 5.67 g (61%) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3) δ7.99 (dd, 1H, J=7, 2 Hz), 7.79-7.86 (m, 2H), 7.65-7.73 (m, 1H), 6.60-6.61 (m, 1H), 6.58-6.59 (m, 1H), 6.50-6.51 (m, 1H), 5.32 (s, 1H), 2.25 (s, 3H).
Reaction SMILES: [Li]CCCC.C[Si](C)(C)N[Si](C)(C)C.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH:26][C:27](=[O:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)=[C:20]([CH:25]=1)[C:21]([O:23]C)=O.Cl>C1COCC1>[Br:15][C:16]1[CH:25]=[C:20]2[C:19](=[CH:18][CH:17]=1)[NH:26][C:27](=[O:36])[C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[C:21]2[OH:23]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1cccc(Cl)c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
n-BuLi (1.6 M in hexane, 79 mL, 126 mmol) was added dropwise to a mixture of hexamethyldisilazane (26.7 mL, 126 mmol) in THF (150 mL) at −78° C. under nitrogen. The mixture was stirred for 1 hour, then was warmed to −40° C. A solution of methyl 5-bromo-2-(2-(3-chlorophenyl)acetamido)benzoate (21.1 g, 55 mmol, Intermediate 60, step a) in THF (150 mL) was added. The mixture was allowed to warm to room temperature and ice was added. The aqueous phase was acidified with 6 N aqueous HCl. The precipitate was collected by filtration, washed with DCM, and air-dried to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[CH:10]=1.CCN(CC)CC.ClC(Cl)(Cl)[C:33](Cl)=[O:34].Cl.Cl.[CH:40]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)([CH3:42])[CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[N:7]=[C:8]([C:33](=[O:34])[NH:49][CH:46]2[CH2:47][CH2:48][N:43]([CH:40]([CH3:42])[CH3:41])[CH2:44][CH2:45]2)[N:9]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[CH:10]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COC(=O)CCc1cn(Cc2cc(-c3ccc(Cl)s3)on2)cn1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cn(Cc2cc(-c3ccc(Cl)s3)on2)c(C(=O)NC2CCN(C(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-imidazol-4-yl}-propionic acid methyl ester (140 mg) and NEt3 (70 μL) in DCM (5 mL) was added a solution of trichloroacetyl chloride (50 μL) in DCM (1 mL) dropwise at 0° C. The mixture was stirred for 5 min at 0° C. and for 30 min at RT. More NEt3 (280 μL) and 1-isopropyl-piperidin-4-ylamine dihydrochloride (88 mg) were added and stirring was continued for 2 h at RT. The mixture was concentrated and the residue was purified by preparative HPLC. The fractions containing the product were evaporated to provide 47 mg of the title compound as its trifluoroacetate salt. MS (ESI+): m/e=520, chloro pattern.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Cl:29][C:30]1[C:31]([CH3:58])=[C:32]([NH:38][C@H:39]([C:54]([OH:57])([CH3:56])[CH3:55])[C:40]([NH:42][NH:43][C:44](=[O:53])[C:45]2[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=2)=O)[CH:33]=[CH:34][C:35]=1[C:36]#[N:37]>C(Cl)Cl.C1COCC1>[Cl:29][C:30]1[C:31]([CH3:58])=[C:32]([NH:38][C@@H:39]([C:40]2[O:53][C:44]([C:45]3[CH:46]=[CH:47][C:48]([C:51]#[N:52])=[CH:49][CH:50]=3)=[N:43][N:42]=2)[C:54]([OH:57])([CH3:55])[CH3:56])[CH:33]=[CH:34][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)C(C)(C)O)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of triphenylphosphine (1.70 g, 6.48 mmol) in DCM (50 mL) was added I2 (1.63 g, 6.42 mmol) at 0° C. After all the Iodine was dissolved completely, Et3N (1.8 mL, 12.9 mmol) was added, followed by a solution of (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-cyanobenzohydrazide (1.37 g, 3.22 mmol) in DCM (10 mL) and THF (10 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 30 min. The reaction was quenched with saturated aq. sodium thiosulfate (10 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (R)-2-chloro-4-(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methylbenzonitrile (1.18 g, 90%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.19 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.71 (d, J=9.0 Hz, 1H), 5.14 (d, J=9.0 Hz, 1H), 4.67 (s, 1H), 2.39 (s, 3H), 1.53 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:9][CH2:10][CH2:11][CH2:12][N:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8]
Reactant: O=C1COCC(=O)N1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1COCC(=O)N1CCCBr

Procedure:
A pale yellow suspension of morpholine-3,5-dione (1.2 g, 10 mmol), of 1,3-dibromopropane (3.4 ml, 33 mmol), and potassium carbonate (2.7 g, 19 mmol) in 23 ml of 2-butanone is refluxed under an argon athmosphere for 22 hours. After cooling, the suspension is concentrated on a rotary evaporator, poured into ice/water, and extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous sodium sulphate, and evaporated. The residual yellow oil (2.06 g) is purified by chromatography (Biotage 40Mi, I=15 cm, cyclohexane/ethyl acetate 3:1).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([O:13]CC)=[O:12])[O:9][C:8]([CH:28]([Br:30])[CH3:29])([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)[O:7]1)=[O:5])C.[OH-].[Na+].C(COC)OC>O>[Br:30][CH:28]([C:8]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)[O:7][C@@H:6]([C:4]([OH:5])=[O:3])[C@H:10]([C:11]([OH:13])=[O:12])[O:9]1)[CH3:29]
Reactant: CCOC(=O)[C@@H]1OC(c2ccc3cc(OC)ccc3c2)(C(C)Br)O[C@H]1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2cc(C3(C(C)Br)O[C@@H](C(=O)O)[C@H](C(=O)O)O3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A mixture of the two diastereoisomers of 2-(1-bromoethyl)-2(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid diethyl ester 3 and 4 (prepared in a similar manner as described in Example 1) (21.18 g, 0.044 mol, ratio 3:4=1:1), sodium hydroxide (3.52 g, 0.088 mol), dimethoxyethane (35 ml) and of water (35 ml) was kept, under stirring, at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with diethylether. The aqueous phase was acidified with concentrated hydrochloric acid to pH 1 and extracted with diethylether. The organic phase was washed with water and dried over sodium sulphate. Evaporation of the solvent under reduced pressure gave the two diastereoisomers of 2-(1-bromoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 5 and 6 (16 g, 0.0367 mol; yield 85.5%) in ratio 5:6=1:1 (determined by 1H-NMR 200 MHz).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][C:26]([CH2:35][CH3:36])([C:30]([O:32]CC)=[O:31])[O:27]4)=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1.[OH-].[Na+]>C(O)(C)C>[F:38][C:2]([F:1])([F:37])[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][C:26]([CH2:35][CH3:36])([C:30]([OH:32])=[O:31])[O:27]4)=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1
Reactant: CCCc1c(OCCCOc2ccc3c(c2)OC(CC)(C(=O)OCC)CC3)ccc2c(C(F)(F)F)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCc1c(OCCCOc2ccc3c(c2)OC(CC)(C(=O)O)CC3)ccc2c(C(F)(F)F)noc12
Yield: 100.7 %

Procedure:
Ethyl 7-(3-(3-trifluoromethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propoxy)-2-ethylchromane-2-carboxylate (49 mg, 0.092 mmol) was dissolved in isopropanol 2 ml and 2N NaOH aq. 1 ml and was stirred at 70° C. overnight. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and 2N HCl aq. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound 47 mg as a pale yellow oil (quant.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[CH2:21][CH:20]3[CH2:22][CH:17]2[CH2:18][N:19]3C(=O)C)=[CH:13][CH:12]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([N:19]1[CH2:18][C@@H:17]2[CH2:22][C@H:20]1[CH2:21][N:16]2[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:27][CH:26]=1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1CC2CC1CN2Cc1ccc(Cc2nc3ccccc3s2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.2 %

Procedure:
To a solution of 1-[5-(4-benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-ethanone (0.2 g, 0.49 mmol) in CH2Cl2 (5 mL) was added Et3N (0.41 mL, 3.0 mmol) and methanesulfonyl chloride (57 μL, 0.74 mmol) and the resulting solution was stirred at rt for 14 h. The reaction mixture was concentrated and the crude residue was partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was separated, dried (Mg2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 15% CH3OH in CH2Cl2) afforded the title compound as clear oil (0.13 g, 62%). MS (ESI): mass calcd. for C21H23N3O2S2, 413.56; m/z found, 414.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.01 (d, J=7.8 Hz, 1H), 7.81 (dd, J=7.8, 0.5 Hz, 1H), 7.49-7.45 (m, 1H), 7.37-7.34 (m, 5H), 4.44 (d, J=2.0 Hz, 2H), 4.31 (br s, 1H), 3.80 (d, J=13.8 Hz, 1H), 3.75 (d, J=13.8 Hz, 1H), 3.62-3.60 (m, 1H), 3.57 (br s, 1H), 3.24 (dd, J=9.3, 2.3 Hz, 1H), 2.90-2.89 (br m, 4H), 2.85-2.83 (br m, 1H), 1.96-1.94 (m, 1H), 1.74-1.72 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O)([O-:3])=[O:2].C(P(CCCC)(CCCC)[CH2:22][CH:23]1[O:27][CH2:26][CH2:25][O:24]1)CCC.CC([O-])(C)C.[K+].O>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:22][CH:23]1[O:27][CH2:26][CH2:25][O:24]1)([O-:3])=[O:2]
Reactant: CCCC[PH](CCCC)(CCCC)CC1OCCO1
Reactant: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1-n1cccc1C=CC1OCCO1
Yield: 66 %

Procedure:
2.98 g (13.8 mmol) 2a, 1.2 eqv. of tributyl-[1,3]dioxolan-2-ylmethyl-λ5-phosphane and 1.5 eqv. KOtBu in DMSO was stirred at 60° C. for 24 hours. The reaction was monitored by TLC (EtOAc:petroleum ether 1:2). After cooling, the reaction mixture was poured into water and extracted with ether and the solvent was evaporated. The semi-solid residue was diluted with ether and filtrated to remove residual Bu3PO and the product was purified by column chromatography (EtOAc: petroleum ether 1:2) to yield 2.6 g (66%) of 3a.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:14]([C:9]1[N:10]([CH3:13])[N:11]=[N:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[CH:16]
Reactant: Cn1nnc(-c2ccc(F)cc2)c1C=O
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: C#Cc1c(-c2ccc(F)cc2)nnn1C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a mixture of 5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carbaldehyde (616 mg, 3.0 mmol) in MeOH (13 mL) was added potassium carbonate (829 mg, 6.0 mmol) followed by a solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (634 mg, 3.3 mmol) in MeOH (4 mL) at room temperature and the resulting mixture stirred for 1 h. The mixture was then poured into sodium carbonate solution (1 M) and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (556 mg, 92%) as a light red solid. MS: m/e=202.2 [M]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>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.CN(C)C=O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[NH:12][C:11]([C@@H:13]4[CH2:17][CH2:16][CH2:15][N:14]4[C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[N:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: OB(O)c1ccc(Cl)cc1
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: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(Cl)cc3)cc2)[nH]1
Temperature: 75 °C
Yield: 85.4 %

Procedure:
A mixture of (S)-benzyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4.7 g, 11.0 mmol), 4-chlorophenylboronic acid (2.0 g, 12.1 mmol), tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.1 mmol), 2M aqueous potassium carbonate solution (22 mL, 44 mmol), and dimethylformamide (100 mL) was degassed under a stream of argon for 15 minutes. The reaction was heated to 75° C. for 3 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(4′-chlorobiphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4.3 g, 85%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=O.Cl.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1>>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:30]=[C:28]([NH:27][C:23]3[CH:22]=[C:21]([OH:20])[CH:26]=[CH:25][CH:24]=3)[N:29]=2)=[CH:8]1)[CH3:17]
Reactant: N=C(N)Nc1cccc(O)c1
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc(O)c3)n2)c2cccnc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one and 1-(3-hydroxyphenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 1.18 (t, 3H, J=7.2 Hz, CH3), 4.37 (q, 2H, J=7.2 Hz, CH2), 6.40 (m, 1H, Ph-H), 7.08 (t, 1H, J=7.6 Hz, Ph-H), 7.18 (m, 1H, Ar—H), 7.24 (d, 1H, J=5.6 Hz, Pyrimidin-H), 7.37 (s, 1H, Ph-H), 8.36 (m, 2H, Pyrimidin-H and Ar—H), 8.59 (s, 1H, Ar—H), 9.00 (d, 1H, J=8.0 Hz, Ph-H), 9.24 (s, 1H, Ar—H), 9.33 (s, 1H, NH). MS (ESI+) m/z 332.1355 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C[N:34](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:34])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccc3c(c2)ncn3-c2nc(-c3cccc(Cl)c3)c(C(=O)O)s2)CC1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc3c(c2)ncn3-c2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a mixture of 0.048 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid (I.3a), 0.046 g (0.12 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.008 g (0.15 mmole) of ammonium chloride and 1 mL of dimethylformamide was added 0.052 mL (0.3 mmole) of diisopropylethylamine. The mixture was stirred at ambient temperature for 1 hour, then filtered and purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 10:90-90:10) to give 0.030 g of 4-(3-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.3) as a white powder. MH+/Z=467
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH3:9]CN(CC)CC.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=CC=C[CH:18]=1>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:16](=[O:23])[C:17]([CH3:9])([CH3:22])[CH3:18])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)C(C)(C)C

Procedure:
10.00 g of glycine ethyl ester hydrochloride (71.6 mmol) and 21.97 ml of NEt3 (2.2 eq.) were dissolved in 210 ml of CH2Cl2 and treated between 0° and 5° dropwise with 9.256 ml of benzoyl chloride (1.05 eq.), dissolved in 30 ml of CH2Cl2. The reaction mixture was allowed to reach ambient temperature (2.5 h) and then quenched by carefully pouring onto crashed ice/HCl/AcOEt. Separation of the layers, additional extraction of the aqueous phase with AcOEt, washing with Na2CO3 and brine, drying of the combined organic phase over sodium sulfate, and evaporation of the solvents left finally 13.06 g of pure title compound as colorless liquid.