Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)([N:38]1C=CN=C1)=O.[OH-].[NH4+].O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:33][CH2:34]3)[CH:21]=1)[CH2:16][C:17]([NH2:38])=[O:19])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(N)=O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (100 mg, 0.22 mmol) in tetrahydrofurane was added carbonyldiimidazole (53 mg, 0.33 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added ammonium hydroxide (0.05 ml, 0.66 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionamide as a white solid (80 mg, 81%): mp 77–79° C.; 1HNMR (CDCl3): δ 0.32–0.38 (m, 2H), 0.60–0.67 (m, 2H), 1.20–1.31 (m, 1H), 2.27 (s, 3H), 3.03 (dd, J=5.5, 15.5 Hz, 1H), 3.70 (dd, J=8.4, 15.5 Hz, 1H), 5.28–5.40 (m, 1H), 5.74–5.80 (m,1H), 5.79 (dd, J=5.8, 10.5 Hz, 1H), 6.60 (t, JH-F=75 Hz, 1H), 7.09–7.13 (m, 3H), 7.47 (d, J=7.3 Hz, 1H), 7.63 (t, J=7.5 Hz, 1H), 8.75 (d, J=8.5 Hz, 1H), 9.49 (s, 1H). 13C NMR (CDCl3): δ 3.8, 3.9, 10.74, 25.6, 38.1, 51.9, 474.5, 112.5, 114.8, 115.8, 116.7, 118.7, 120.8, 123.5, 125.6, 131.8, 136.7, 137.8, 138.1, 140.8, 151.2, 168.6, 169.9, 170.5, 172.1; Anal. Calcd. for C24H23F2N3O6+0.5 H2O: C, 58.06%; H, 4.87; N, 8.46. Found: C, 57.77; H, 4.60; N, 8.33; 1% H2O.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[Cl:25][C:6]1[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(C2CCOC2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)cc(C2CCOC2)n1
Temperature: 110 °C
Yield: 41.1 %

Procedure:
A suspension of 2-amino-6-(tetrahydro-furan-3-yl)-3H-pyrimidin-4-one (1.5 g, 8.28 mmol), tetraethyl ammonium chloride (2.7 g 16.3 mmol) and dimethylaniline (1.4 mL, 11.1 mmol) in acetonitrile (15 mL) was treated with phosphorous oxychloride (2.4 mL, 26.2 mmol) and heated at 110° C. for 20 min. The resulting solution was cooled to rt and concentrated to minimum volume and pipetted onto ice chips. The aqueous portion was extracted with EtOAc (3×50 mL). The combined organic layers were basified with satd. aq. NaHCO3 solution to pH ˜7. The organic portion was separated, dried, and concentrated. The crude material was chromatographed (MeOH/CH2Cl2) to yield 680 mg (42%) of product as a light orange foam. 1H NMR (CDCl3): 6.59 (s, 1H), 5.16 (br s, 2H), 4.00-4.10 (m, 2H), 3.85-3.91 (m, 2H), 3.28-3.35 (m, 1H), 2.25-2.34 (m, 1H), 2.08-2.18 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Br:1]
Reactant: Cc1cccc(C)c1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CBr)c1Br
Yield: 47.4 %

Procedure:
A procedure similar to that described in Bull. Chem. Soc. Japan, 59, 3285–3286 (1986), fully incorporated herein by reference, was used. In a two liter round bottom flask equipped with an overhead stirrer and heating mantle was placed 2-bromo-meta-xylene (60.08 g, 0.325 mol) and carbon tetrachloride (650 ml). To this were added N-bromosuccinimide (57.78 g, 0.325 mol) and an additional 550 ml carbon tetrachloride. After stirring fifteen minutes benzoyl peroxide (0.72 g, 2.9 mmol, 0.9 mole %) was added, and the mixture was heated to reflux. After four hours the reaction was cooled, and the carbon tetrachloride was removed. The residue was taken up in 10% methylene chloride in n-hexane (600 ml) and filtered through silica (250 g). The filter cake was washed with an additional 400 ml of the in 10% methylene chloride in n-hexane. The filtrate was evaporated to give a clear liquid (74.22 g, 51% conversion by NMR). Vacuum distillation produced a fraction distilling at 72° C.–80° C. at 0.1 Torr as a water white liquid (40.62 g, 47% yield). NMR (CD2Cl2). 7.2 (m, 3H), 4.62 (s, 2H), 2.4 (s, 3H). Elemental analysis: C, 36.18%; H, 3.12%; Br, 61.14%; (theory: C, 36.40%; H, 3.06%; Br, 60.54%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C([CH:17]([Cl:23])[CH2:18][CH2:19][N:20]=[C:21]=[O:22])C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:21]([NH:20][CH2:19][CH2:18][CH2:17][Cl:23])=[O:22])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(Cl)CCN=C=O
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Product: COc1c(I)cc(NC(=O)NCCCCl)cc1C(C)(C)C

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethyl 3-chloropropyl isocyanate (0.103 mL, 1.000 mmol) were reacted in the same manner as Example 15 Part A to give the title compound which was used without purification.
Reaction SMILES: [N+](=[C:3]1[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]1=[O:13])=[N-].[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([C:17]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[N:11]([CH:18]=1)[C@@H:4]1[O:5][C@H:6]([CH2:9][OH:10])[C@@H:7]([OH:8])[CH2:3]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: [N-]=[N+]=C1[C@H](n2ccc(=O)[nH]c2=O)O[C@H](CO)[C@H]1O
Agent: [Na+]
Product: [N-]=[N+]=Nc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5-azido-2-'-deoxyuridine nucleoside and nucleotide compounds and a method of producing them. The method involves reacting a 5'-deoxyuridine compound with nitrosonium tetrafluoroborate to produce a 5-nitro-deoxyuridine compound. The 5-nitro-deoxyuridine compound is reduced to a 5-amino-deoxyuridine compound in the presence of metallic zinc. The 5-amino-deoxyuridine compound is acidified and reacted with sodium nitrite to produce a 5-diazo-deoxyuridine compound. The diazo-deoxyuridine compound is then reacted with sodium azide to produce a 5-azido-deoxyuridine compound. The latter, in the monophosphate form, is further reacted with diphenylchlorophosphate to produce the photoactive triphosphate, 5-azido-2'-deoxyuridine-5'-triphosphate or 5-azido-dUTP. The photoactive compound, when added to DNA in an in vitro synthesis reaction, produces photoactive DNA.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[CH:15][C:12]1[NH:11][C:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[C:6](=[O:17])[C:7]=2[C:13]=1[CH3:14]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 65.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 112 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-dimethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (40 mg, 65.5%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:7]2[C:12]3=[N:13][O:14][CH:15]=[C:11]3[C:10](=[O:16])[NH:9][C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]1([N:7]2[C:12]3=[N:13][O:14][CH:15]=[C:11]3[C:10](=[O:16])[N:9]([CH3:18])[C:8]2=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]c(=O)n(C2CCCCC2)c2nocc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)c2conc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.5 %

Procedure:
In 50 ml of dimethylformamide is dissolved 1 g of the 7-cyclohexyl-5H,7H-isoxazolo[3,4-d]pyrimidine-4,6-dione obtained in Example 18, followed by addition of 800 mg of potassium carbonate and 1 ml of methyl iodide. The mixture is stirred at room temperature for 20 hours, after which the insolubles are filtered off. The filtrate is concentrated to dryness and the concentrate is dissolved in chloroform. After the insolubles are filtered off, the chloroform is removed by distillation and the residue is recrystallized from water-ethanol. By the above procedure is obtained 0.8 g of the captioned compound as pale-white platelets. melting point: 194°-197° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:9]1(O)[CH:14]=[CH:13][CH:12]=[CH:11]C=1>>[C:1]([O:7][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)(=[O:6])[C:2]([O:4][C:5]1[CH:9]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: Oc1ccccc1
Reactant: COC(=O)C(=O)OC
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1

Procedure:
Diphenyl oxalate was prepared from dimethyl oxalate and phenol by using the apparatus shown in FIG. 3 including first and second distillation reactors and a refining distillation column.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>CN(C=O)C>[CH3:25][O:26][C:27](=[O:37])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:7]3[C:6]4[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[N:9][C:8]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: Cc1cccc2c(-c3cccc(N)c3)c(-c3ccccc3)nnc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(CNc2cccc(-c3c(-c4ccccc4)nnc4c(C)cccc34)c2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
3-(8-Methyl-3-phenyl-cinnolin-4-yl)-phenylamine (0.031 g, 0.1 mmol) and (4-formyl-phenyl)-acetic acid methyl ester (0.07 g, 0.4 mmol) were mixed in DMF (4 mL) and then treated with NaBH(OAc)3 (0.43 g, 2.0 mml) and acetic acid (0.4 mL). After stirring at 40° C. for 4 hours the mixture was quenched with water and then extracted with ethyl acetate. The organic residue was purified by silica gel chromatography using 5-50% EtOAc/hexanes as eluent to provide (4-{[3-(8-methyl-3-phenyl-cinnolin-4-yl)-phenylamino]-methyl}-phenyl)-acetic acid methyl ester as a gum which was used for the next reaction. MS (EI) m/z 474;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: Nc1cccc(C=O)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=Cc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Temperature: 110 °C

Procedure:
a mixture of 360 mg of 3-aminobenzaldehyde (0.3 mmoles) and 460 mg of 4-chloro-phenylisocyanate (0.3 mmoles) in 3 ml of DMF is heated under microwave irradiation at 110° C. for 10 minutes. The precipitate formed is filtered giving the desired 1-(4-Chloro-phenyl)-3-(3-formyl-phenyl)-urea. Analytical LC/MS method A: ([M+H]+): 351, RT: 5.30 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: C1COCC1.Br[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][N:8]=1.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:29]3[S:30][C:31](I)=[CH:32][C:33]=3[O:34][CH3:35])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]>CCOC(C)=O.[Zn].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>[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:29]3[S:30][C:31]([C:7]4[N:11]([CH3:12])[N:10]=[CH:9][N:8]=4)=[CH:32][C:33]=3[O:34][CH3:35])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: Cn1ncnc1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(I)cc3OC)c(C)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3OC)c(C)nc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a slurry of 0.05 g/mL of Reike® Zn in THF (2.8 mL, 2.11 mmol) is added 5-bromo-1-methyl-1H-[1,2,4]triazole and THF (2 mL). The solution is heated at 65° C. for 1 hour, cooled to ambient temperature and the excess Zn allowed to settle for 1 hour. The solution is transferred to a flask containing 8-(1-ethyl-propyl)-3-(5-iodo-3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.32 g, 0.70 mmol) and Pd(PPh3)4 (0.041 g, 0.035 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL) washed with sat. NH4Cl (30 mL). The aqueous phase is extracted with EtOAc (20 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The reside is purified by ISCO column chromatography (20%-65% EtOAc/hexane gradient) followed by ISCO column chromatography (100% Et2O) furnish the title compound (0.19 g, 0.46 mmol, 62%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.26-3.37 (m, 1H), 3.92 (s, 3H), 4.15 (s, 3H), 6.67 (s, 1H), 7.48 (s, 1H), 7.89 (s, 1H). LC/MS (m/z): calcd. for C21H26N6OS (M+H)+: 411.5. found: 411.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[BH4-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=Cc1ccc(Br)c2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(Br)c2cccnc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of 5-bromoquinoline-8-carbaldehyde ([CAS 885267-41-7] 423 mg, 1.79 mmol) in MeOH (5 mL) and THF (10 mL) was added sodium borohydride (68 mg, 1.79 mmol) at 0° C. After stirring at 0° C. for 30 min, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated under reduced pressure to give rise to 430 mg of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([NH:15][C:16](=O)[CH:17]([O:20][CH3:21])[CH2:18][CH3:19])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.O=C(Cl)OC(Cl)(Cl)[Cl:34]>C(Cl)Cl>[C:1]1([C:7]([N:15]=[C:16]([Cl:34])[CH:17]([O:20][CH3:21])[CH2:18][CH3:19])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCC(OC)C(=O)NC(=Cc1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(OC)C(Cl)=NC(=Cc1ccccc1)c1ccccc1
Yield: 153.9 %

Procedure:
A solution of 21 g of the product of Step B, 300 ml of methylene chloride and 49.5 ml of triethylamine was cooled to -40° C. and at -40° C. a solution of 9.42 g of diphosgene in 90 ml of methylene chloride was added. The residue, after returning the temperature to 20° C. and concentrating the mixture under reduced pressure, was taken up in ether and filtered. The filtrate was concentrated under reduced pressure to obtain 23 g of the expected product.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: OCCCCCCCCCl
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(-c2ccc(OCCCCCCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.1 %

Procedure:
A solution of diethyl azodicarboxylate (3.5 g; 20 mmol) and tetrahydrofuran (10 ml) was added dropwise at 0° C. to a solution of 4,4′-dihydroxybiphenyl (7.4 g; 40 mmol), 8-chloro-1-octanol (3.3 g; 20 mmol), triphenylphosphine (5.2 g; 20 mmol) and tetrahydrofuran (120 ml) and stirred at room temperature 72 h. The reaction mixture was added to water (400 ml) and extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (2×150 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuo. The residue (19.2 g) was purified by flash chromatography on a silica gel column using a toluene/ethyl acetate mixture (95:5) as eluent, to give 2.6 g (40%) of 4′-[(8-chlorooctyl)oxy]-4-biphenylol.
Reaction SMILES: [CH2:1]([C:4]1([NH:14][NH2:15])[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].CCN(CC)CC.CN(C)[CH:25]=[CH:26][CH:27]=O>CC(O)C>[CH2:1]([C:4]1([N:14]2[CH:27]=[CH:26][CH:25]=[N:15]2)[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: CN(C)C=CC=O
Reactant: C=CCC1(NN)CCOC2(CCCC2)C1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=CCC1(n2cccn2)CCOC2(CCCC2)C1
Reaction time: 48 h
Yield: 31 %

Procedure:
A solution of [9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]hydrazine (250 mg, 1.0 mmol) in 4 mL of i-PrOH were added Et3N and 3-dimethylaminoacrolein. The solution was refluxed for 3 h and then at 50° C. for 2 d. The solvent removed and the residue was purified on 25 g Biotage snap column, eluted with 0-18% EtOAc in Hex (12 CV) to give 1-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]-1H-pyrazole (80 mg, 31% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:1][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cncc(C)n1
Reactant: C1COCCN1
Agent: O=C1CCC(=O)N1Br
Product: COC(=O)c1cncc(CN2CCOCC2)n1

Procedure:
By using 3.42 g of methyl 6-methylpyrazine-2-carboxylate and 4.40 g of NBS, a bromination reaction was performed by the method similar to Preparation Example 62. Thereafter, by using 10 mL of morpholine as amine, the reaction similar to Preparation Example 9 was performed, thereby obtaining 987 mg of methyl 6-(morpholin-4-ylmethyl)pyrazine-2-carboxylate.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28]Br)[CH:22]=3)[O:20][C@@:6]1([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:7][O:8]2)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:58]=[CH:57][C:46]([O:47][C:48]3[CH:53]=[CH:52][C:51]([C:54](=[O:56])[CH3:55])=[CH:50][CH:49]=3)=[CH:45][CH:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>[Pd].O>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:43]4[CH:44]=[CH:45][C:46]([O:47][C:48]5[CH:53]=[CH:52][C:51]([C:54](=[O:56])[CH3:55])=[CH:50][CH:49]=5)=[CH:57][CH:58]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: CC(=O)c1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(Oc5ccc(C(C)=O)cc5)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 80 °C
Yield: 36.6 %

Procedure:
To a mixture of (1R,2S,3S,4R,55)-1-(acetoxymethyl)-5-(3-(bromomethyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (1.0 g, 1.77 mmol, Intermediate 2), 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)phenyl)ethanone (899.0 mg, 2.66 mmol), Pd (dppf) Cl2 (72 mg, 0.09 mmol) and sodium carbonate (563.0 mg, 5.31 mmol) under nitrogen atmosphere, was added DMF and H2O (9 mL, 1:1). The reaction mixture was heated at 80° C. for 1 h. After the completion of the reaction, as confirmed by TLC, the solution was cooled to r.t. and filtered through celite. The solvent was evaporated in vacuo and the crude compound was diluted with ethyl acetate (200 mL). The organic layer was washed with water (3×30 mL), separated, dried over Na2SO4 and concentrated in vacuo to afford crude compound which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet ether) to afford the title compound (450 mg, 36.6%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28](=[O:40])[C@H:29]([CH2:38][SH:39])[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH3:26][O:27][C:28](=[O:40])[CH:29]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:38][S:39][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:3]=1
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Product: COC(=O)C(CSc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3[nH]2)c1)NC(=O)OC(C)(C)C

Procedure:
The compound is synthesized from 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 72A) and N-Boc-Cysteine methyl ester using the method described in example 150; mixture of diastereomers. 1H NMR: 10.66 and 9.83 (sl, 1H), 7.90-7.70 (m, 2H), 7.50-7.35 (m, 2H), 7.35-7.18 (m, 5H), 5.87 and 5.85 (s, 1H), 5.58-5.30 (m, 1H), 4.65-4.40 (m, 1H), 3.70-3.20 (m, 6H), 2.82-2.62 (m, 2H), 2.28 and 2.26 (s, 3H), 2.22-1.65 (m, 6H), 1.53 and 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2](Cl)([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:1][CH:2]([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CCOP(=O)(OCC)C(Cl)(Cl)C(=O)OC(C)(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(OCC)C(Cl)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 100 %

Procedure:
The title compound of Step B (18.4 g, 0.0572 mol) was dissolved in ethanol (140 mL) and cooled to 0° C. A solution of sodium sulfite (14.4 g, 0.1144 mol) in H2O (63 mL) was added with stirring such that the internal temperature remained below 14° C. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with chloroform (5×), and the combined organic phase was dried (MgSO4), filtered and concentrated to afford 16.4 g of the title compound of Step C as a clear oil. 1H NMR (300 MHz, CDCl3): δ 4.43 (d,1H, J=15.9 Hz), 4.30-4.24 (m,4H), 1.52 (s,9H), 1.38 (t,6H, J=6.9 Hz).