Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:17]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[CH:32]([Mg]Cl)([CH3:34])[CH3:33].[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22]([OH:24])([CH:32]([CH3:34])[CH3:33])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-c1cnc(C)o1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)(O)C(C)C)n2)ccc1-c1cnc(C)o1
Reaction time: 0.08 h

Procedure:
1-(2-(3-Methoxy-4-(2-methyloxazol-5-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidin-4-yl)ethanone (60 mg, 0.14 mmol) was dissolved in THF (5 mL) and was added slowly to a solution of isopropyl magnesium chloride (2 M in THF, 0.206 mL, 0.41 mmol) in THF (5 mL). The mixture was stirred for 5 min. The mixture was cooled on an ice bath, ammonium chloride (sat, aq, 5 mL) was added. The mixture was stirred for 5 min. The mixture was extracted with EtOAc (×2). The solvents were evaporated and the residue was purified by column chromatography on silica eluting with a gradient of MeOH in DCM to give the title compound as a solid, 40 mg (61%).
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][OH:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[Li]CCCC.[CH2:18]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[C:24]1=[O:33])[CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1>[OH:32][C:25]1([C:2]2[C:3]([CH2:11][OH:12])=[CH:4][C:5]3[O:9][CH2:8][O:7][C:6]=3[CH:10]=2)[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:24]1=[O:33]
Reactant: OCc1cc2c(cc1Br)OCO2
Reactant: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2CO)OCO3)c2ccccc21
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 17.1 %

Procedure:
To a solution of (6-bromo-1,3-benzodioxol-5-yl)methanol (Mann, J., et al, J. Chem. Soc. Perkin Trans. 1 (1984):2081-8) (1.27 g, 5.50 mmol) in THF (45.0 mL) was added n-BuLi (5.00 mL, 2.0 M, 10.0 mmol) dropwise at −75° C. The reaction mixture was stirred at −75° C. for 45 min followed by the addition of a solution of 1-pentyl-1H-indole-2,3-dione (1.00 g, 4.60 mmol) in THF (20.0 mL) at −75° C. The resulting mixture was stirred at ambient temperature for 12 hrs and quenched with ammonium chloride solution (5.00 mL). More ethyl acetate and water were added and separated. The organic layer was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with 50% EtOAc:Hexanes to yield the title compound (0.29 g, 25%) as a solid: 1H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 2H), 7.11 (t, 1H), 6.91 (d, 1H), 6.81(s, 1H), 6.43 (s, 1H), 5.90-5.87 (m, 2H), 4.77 (dd, 2H), 3.75-3.56 (m, 2H), 1.75-1.58 (m, 2H), 1.26-1.35 (m, 2H), 0.89-0.83 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 147.4, 147.2, 142.8, 133.5, 132.2, 131.1, 130.1, 125.3, 123.8, 111.4, 109.2, 108.1, 101.5, 79.5, 64.7, 40.4, 29.0, 26.8, 22.3, 13.9; MS (ES+) m/z 352.1 (M−17).
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1>CC(C)=O>[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:5][C:3](=[NH:6])[CH3:4])=[O:15])=[CH:9][CH:8]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CC(=N)NC(=O)Nc1ccc(C)cc1

Procedure:
Following a procedure similar to that described in Example 23 but using 4.6 g. sodium in 500 ml. dry acetone, 18.8 g. acetamidine hydrochloride and 26.6 g. 4-tolyl isocyanate in 120 ml. of dry acetone, there was obtained after recrystallization from isopropyl alcohol 27.1 g. 1-(4-tolyl)-3-(acetimidoyl) urea hydrochloride; m.p. 210°-212°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7](=[O:15])[C:6]=2[CH:16]=1.II>CC(C)=O>[CH3:6][C:5]1([CH3:14])[CH:4]=[C:3]([CH3:2])[C:16]2[C:2](=[CH:3][CH:4]=[C:5]3[C:6]=2[C:7](=[O:15])[O:8][C:9]2[C:14]3=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:1]1
Reactant: Nc1ccc2c(c1)c(=O)oc1ncccc12
Agent: II
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1ncccc13
Temperature: 105 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
In a pressure tube, 8-amino-4-azabenzo[c]chromen-6-one (Reference Compound No. 1-3-(5), 258 mg, 1.21 mmol) was dissolved in acetone (10 mL), then iodine (123 mg, 0.48 mmol) was added thereto, then the pressure tube was sealed, and then the reaction mixture was stirred at 105° C. for 1 day. After cooling down, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (82.5 mg) as a yellow solid. (Yield 23%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[OH:8].C(N(CC)C(C)C)(C)C.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30]Cl>ClCCl.Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[O:8][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]
Reactant: COCCOCCl
Reactant: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(Br)cc(CC(=O)OC)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5-L round-bottom flask was added methyl (3-bromo-5-formyl-4-hydroxy-phenyl)acetate (210 g, 769 mmol, prepared in Reference A above), dichloromethane (2 L), and N,N-diisopropylethylamine (161 mL, 119 g, 923 mmol). A solution of 2-methoxyethoxymethyl chloride (MEM chloride, obtained from TCI America; 106 mL; 923 mmol) in dichloromethane (500 mL) was added dropwise via an addition funnel over 2 h. The reaction was allowed to stir at ambient temperature for overnight, after which time HPLC analysis showed that the reaction was complete. The reaction mixture was diluted with 0.5 N aqueous HCl (1 L) and the solution was allowed to stir at ambient temperature for 0.25 h, then the layers were separated. The organic layer was washed with additional 0.5 N aqueous HCl, followed by saturated aqueous sodium chloride (1 L). The organic layer was concentrated under vacuum to give an oil, which later solidified upon standing. The solid could be crystallized from ethyl acetate and hexane to yield methyl [3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)phenyl]-acetate (237 g) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:7][C:6]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CO.[Zn]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])=[CH:7][C:6]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1N
Temperature: 25 °C

Procedure:
81 g (1.24 mol) of zinc powder were added to a solution of 25.19 g (77.9 mmol) of 2-t-butyl-5-(t-butyldimethylsilyloxymethyl)-1-nitrobenzene (prepared as described in Preparation 11) in 270 ml of methanol, and then 10.8 ml of acetic acid were added to the resulting mixture, with ice-cooling. After the exothermic reaction had subsided, the reaction mixture was heated under reflux for 3 hours and then allowed to cool to room temperature, after which it was filtered using a Celite (trade mark) filter aid, and the zinc used was washed with methanol. The filtrate was combined with the washings and the combined mixture was concentrated by evaporation under reduced pressure. The concentrate was dissolved in ethyl acetate, and the resulting solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give 22.9 g (a quantitative yield) of the title compound as an oily substance. The compound could be used without purification.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:19]=[C:18]([F:20])[C:17]([NH:21][C:22](=[O:33])[CH2:23][C:24]([NH:27][C:28](OCC)=[O:29])=[CH:25][CH3:26])=[CH:16][C:4]=1[C:5]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6].Cl>OC(C)(C)C(OCC)=O>[Cl:2][C:3]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:22](=[O:33])[CH:23]=[C:24]([CH2:25][CH3:26])[NH:27][C:28]2=[O:29])=[CH:16][C:4]=1[C:5]([O:7][C:8]([CH3:14])([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6]
Reactant: CC=C(CC(=O)Nc1cc(C(=O)OC(C)(C)C(=O)OCC)c(Cl)cc1F)NC(=O)OCC
Agent: CCOC(=O)C(C)(C)O
Agent: Cl
Agent: [Na]
Product: CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(CC)[nH]c2=O)c(F)cc1Cl
Temperature: 120 °C
Reaction time: 4 h

Procedure:
0.6 g of sodium is dissolved completely in 50 ml of ethyl α-hydroxyisobutyrate. This solution is combined with the crude ethyl 2-{2-chloro-4-fluoro-5-[3-(ethoxycarbonyl)amino-pent-3-enoyl]amino-benzoyloxy}-2-methylpropionate and stirred at 120° C. for 4 hours. After cooling,this reaction mixture is introduced into 100 ml of 1N hydrochloric acid at 0° C. The mixture is extracted twice with 150 ml of ethyl acetate each time, back-washed twice with 200 ml of water each time, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel with ethyl acetate/n-hexane (3:2). There is obtained ethyl 2-{2-chloro-4-fluoro-5-[3,6-dihydro-2,6-dioxo-4-ethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methylpropionate which is recrystallized from diethyl ether/n-hexane; m.p. 166°-167° C.
Reaction SMILES: [C:1]1(=O)[C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[CH2:4][CH2:3][O:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[C:1]1(=[S:21])[C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[CH2:4][CH2:3][O:2]1
Reactant: O=C1OCCc2ccncc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1OCCc2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.5 %

Procedure:
3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.676 mmol) was dissolved in anhydrous toluene and stirred overnight at room temperature after adding Lawesson reagent (420 mg, 1.005 mmol). The mixture was evaporated under reduced pressure and a silica gel column chromatography (70% EtOAc/Hexane) was performed on the resulting residue and obtained 200 mg (72%) of 3,4-dihydro-pyrano[3,4-c]pyridine-1-thione in yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.II.[CH:12]([C@@H:14]1[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][C@@H:15]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:13].[NH4+].[Cl-]>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C@H:12]([C@@H:14]2[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][C@@H:15]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: Clc1cccc(CBr)c1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)Cc1cccc(Cl)c1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A portion of a mixture of 3-chlorobenzyl bromide (0.53 mL, 4.0 mmol) and Et2O (0.5 mL) was added to Mg turnings and I2 (catalytic amount) in Et2O (4 mL). Once the reaction was initiated, the rest of the 3-chlorobenzyl bromide was added. When the reaction subsided, the resulting green mixture was transferred into a −78° C. suspension of CeCl3 (1.05 g, 4.3 mmol) in THF (4 mL). A solution of the (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 1M in THF, 3 mL, 3 mmol) was added and the reaction mixture was allowed to warm to room temperature, then was treated with a saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure. The crude green oil was purified by flash chromatography (EtOAc) to give (±)-(4R*,5R*)-5-[(1R*)-2-(3-chlorophenyl)-1-hydroxyethyl]-1-methyl-4-phenylpyrrolidin-2-one (340 mg, 34%): mp 50-52° C.; TLC (EtOAc) Rf 0.25.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:27])[C:7](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[N+:14]=[N-:15])#[N:2].[NH2:28]/[C:29](/[CH3:35])=[CH:30]\[C:31]([O:33][CH3:34])=[O:32]>CCO>[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8]1[NH:28][C:29]([CH3:35])=[C:30]([C:31]([O:33][CH3:34])=[O:32])[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:7]=1[C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:27])=[N+:14]=[N-:15]
Reactant: N#CCCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCCN=[N+]=[N-]
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)OCCC#N)C1c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 7-azido-2-[(4-nitrophenyl)methylene]-3-oxoheptanoicacid2-cyanoethyl ester (2.87 g, 7.73 mmol) and methyl 3-aminocrotonate (0.900 g, 7.73 mmol) in 50 ml of EtOH was refluxed for 48 hrs. After the EtOH was removed in vacuo, the residue was dissolved in 150 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3 :MeOH=95:5). 2-(4-Azidobutyl)-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(4-nitrophenyl)pyridine was obtain as a yellow oil (2.43 g, 67% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[CH:6]=1)=[O:4].ClCC(C1C=CC(Br)=C(Cl)C=1)=O.[BH4-].[Na+].C[O-].[Na+]>C(O)C.CC(OC)(C)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:6][C:7]=1[Cl:12]
Reactant: O=C(CBr)c1ccc(Br)c(Cl)c1
Agent: C[O-]
Agent: O=C(CCl)c1ccc(Br)c(Cl)c1
Agent: [BH4-]
Solvent: CCO
Solvent: COC(C)(C)C
Product: Clc1cc(C2CO2)ccc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of the mixture of 2-bromo-1-(4-bromo-3-chlorophenyl)ethanone and 2-chloro-1-(4-bromo-3-chlorophenyl)ethanone (18.4 g) in ethanol (200 ml) at 5° C. was added portionwise over 5 min NaBH4 (2.23 g). The reaction mixture was then stirred at room temperature for 90 min to afford a yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (1.59 g) was then added and the reaction mixture was stirred at 50° C. for 4 h. TLC analysis showed the reaction was complete. The reaction mixture was then poured into TBME and washed with saturated brine. The organic layer was separated, then dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-(4-bromo-3-chloro-phenyl)-oxirane (15.2 g) as a brown oil which was used in the next step without further purification.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([S:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]2[CH2:37][O:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[ClH:1].[C:15]1([S:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]2[CH2:37][O:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)(=[O:22])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 91 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(phenylsulfonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (122 mg, 0.223 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 82.4 mg (91%) of the desired product as a yellow solid. LC-MS: RT=3.71 min, [M+H]+=334.1.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccccc1OCCCc1oc(N2CCN(c3ccccc3)CC2)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 1-phenylpiperazine (810 mg) and 2-butanone (15 ml) was stirred with heating under reflux for 12 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was washed with a 10% aqueous solution of citric acid (100 ml), dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(4-phenyl-1-piperazinyl)oxazole was obtained as an oil (168 mg, 33%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[SH:10])=[O:4].C(N(CC)CC)C.Br[CH2:19][CH2:20][C:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)([F:23])[F:22]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[S:10][CH2:19][CH2:20][C:21]([F:23])([F:22])[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:4]
Reactant: COC(=O)c1scnc1S
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
4-Mercapto-thiazole-5-carboxylic acid methyl ester (0.41 g, 2.16 mmol) is dissolved in DMF (6 ml) and triethylamine (0.45 ml, 3.24 mmol) and 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (synthesized according to the methods described in sections a) to e) of example 1) (0.55 g, 2.16 mmol) are added successively. The resulting mixture is stirred at RT for 16 h. After completion of the reaction, the mixture is poured onto water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layers are washed with brine (20 ml), dried over sodium sulfate and concentrated to dryness. The crude is purified by column chromatography (silica gel, 20% EtOAc/hexane) yielding 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid methyl ester (0.42 g, 1.2 mmol, 56%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[Br:1][C:2]1[S:6][C:5](/[CH:7]=[C:14](/[C:13]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:11]([O:10][CH3:9])[CH:12]=2)\[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(Br)s1
Product: COc1ccc(/C(C#N)=C/c2ccc(Br)s2)cc1OC
Yield: 51.4 %

Procedure:
5-Bromothiophene-2-carboxaldehyde (381 mg) was condensed with 3,4-dimethoxybenzyl cyanide (355 mg) through Method A (production step 2), to thereby yield the target product (yield: 359 mg, 51%).
Reaction SMILES: CN(C([O:8][N:9]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:27]=[C:28]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[S:29][C:30]=1[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([C@@H:39]2[CH2:41][C@H:40]2[C:42](O)=[O:43])=[CH:35][CH:34]=1.Cl.NO.C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:8][NH:9][C:42]([C@@H:40]1[CH2:41][C@H:39]1[C:36]1[CH:35]=[CH:34][C:33]([NH:32][CH2:31][C:30]2[S:29][C:28]([C:45]3[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=3)=[N:27][C:26]=2[CH3:25])=[CH:38][CH:37]=1)=[O:43]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
HATU (0.154 g, 0.41 mmol) and (+)-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (III-3c) (0.135 g, 0.31 mmol) in DMF (10 mL) were stirred at RT for 15 min, then hydroxylamine hydrochloride (0.50 g) was added. The solution was stirred at RT for 1 h, then saturated NaHCO3 solution (20 mL) was added. The resulting solid was filtered, washed with water (10 mL) and dissolved in ethyl acetate (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to give the title compound as a white powder (0.067 g, 48%). 1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 8.68 (s, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 6.82 (d, J=8.5 Hz, 2H), 6.51 (d, J=8.6 Hz, 2H), 6.21 (t, J=5.7 Hz, 1H), 4.38 (d, J=5.9 Hz, 2H), 2.42 (s, 3H), 2.07-2.02 (m, 1H), 1.48-1.43 (m, 1H), 1.21-1.16 (m, 1H), 1.06-1.01 (m, 1H).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Br[CH2:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=1>CN(C=O)C>[C:20]1([N:19]2[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=[C:15]2[CH2:14][N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ncnc2[nH]cnc12
Reactant: BrCc1nc2ccccc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.5 %

Procedure:
To a mixture of 9H-purin-6-ylamine (61 mg, 0.454 mmol) in DMF (1 mL) was added NaH (60% in mineral oil, 18 mg, 0.454 mmol) and the suspension was stirred at RT for 10 min under a nitrogen atmosphere. 2-Bromomethyl-1-phenyl-1H-benzoimidazole from Example 5 (0.454 mmol) in DMF (3 mL) was subsequently added and the reaction mixture was stirred at RT for 1 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM), then triturated with diethyl ether and purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 20-98% 0.1% HCO2H in acetonitrile/water). Crystallization from EtOAc/MeOH afforded 106 as a white solid (10 mg, 6%). LCMS: RT 3.47 min [M+H]+ 342.1. 1H NMR (CDCl3, 400 MHz): δ 8.21 (1H, s), 7.87 (1H, s), 7.84 (1H, d, J=8.01 Hz), 7.48-7.43 (3H, m), 7.36-7.20 (4H, m), 7.12 (1H, d, J=8.03 Hz), 5.57 (2H, s), 5.50 (2H, br)