Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[C:9](N)[CH:10]=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+].[ClH:22]>O>[Cl:22][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: Cl
Reactant: COc1cccc(N)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
A solution of sodium nitrite (180 mg, 2.60 mmol) in water (0.5 mL) was added dropwise to a solution of 3-methoxy-2-nitro-phenylamine (400 mg, 2.38 mmol, Example 86(A)) in HCl (37%, 3.9 mL) at 0° C. over one hour period. Then the reaction mixture was added to a cold (0° C.) solution of CuCl2 (640 mg, 4.76 mmol) in HCl (6N, 3.5 mL). The resulting green solution was stirred at room temperature for 2 days. Then, the reaction mixture was poured onto ice and neutralized carefully with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The resulting organic phase was washed with brine, dried over MgSO4, filtered and evaporated to yield 293 mg (1.56 mmol, 66%) of 1-chloro-3-methoxy-2-nitrobenzene as a brown oil.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[C:10]1([N:9]=[C:1]([Cl:18])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccccc1)c1ccccc1
Product: ClC(=Nc1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 100.5 %

Procedure:
5MeO-TPT was prepared by a modified version of the routes described by D. Enders et al. in Synthesis 2003, page 1292, and by K. Potts et al. in J. Org. Chem. 32, page 224. A mixture of 98.6 g (0.5 mol) benzanilide and 75 mL (1.0 mol) thionyl chloride was heated on steam for 20 hours after initial vigorous outgassing. The resulting mixture was then stripped at about 26.67 kPa (20 mmHg) and 60° C. for 3 hours, leaving 108.4 g of N-phenylbenzimidoyl chloride as a low-melting green solid. The solid was dissolved in 250 mL ethyl acetate and stirred at 5° C. while adding a mixture of 54.05 g (0.5 mol) phenylhydrazine and 51.0 g (0.5 mol) triethylamine dropwise, with the temperature of the solution slowly rising to 20° C. The resulting mixture was washed with 1000 mL of 2 weight percent acetic acid. Solid product was present and another 400 mL of ethyl acetate was added to the washed mixture, with some solid still observed. The ethyl acetate portion of the mixture was separated and filtered, yielding 25.1 g of desired product, and the resulting mother liquor was stripped, 150 mL isopropanol and 50 mL water were added, and the resulting solid was filtered and dried to provide 35.9 g initially and 4.4 g as the final crop, for a total yield of 65.4 g (0.227 mol, 46 percent) of N-phenylbenzamide phenylhydrazone as a brown solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:25][C@H:26]3[CH2:31][CH2:30][C@@H:29]([CH3:32])[CH2:28][CH2:27]3)[N:8]=2)[CH2:2]1.Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:32][C@@H:29]1[CH2:30][CH2:31][C@H:26]([NH:25][C:9]2[N:8]=[C:7]([O:6][CH2:5][CH:3]3[CH2:2][N:1]([C:34]([O:36][CH3:37])=[O:35])[CH2:4]3)[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[CH:11][N:10]=2)[CH2:27][CH2:28]1
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CNC3)n2)CC1
Reactant: COC(=O)Cl
Product: COC(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 5, 4-((azetidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine was reacted with methyl chloroformate to provide the title compound at 83% yield. 1H NMR (CDCl3, 400 MHz) 8.10 (s, 1H), 7.35 (d, 2H), 6.92 (d, 2H), 5.16 (sb, 1H), 4.47 (d, 2H), 4.12-4.08 (m, 3H), 3.88-3.84 (m, 6H), 3.67 (s, 3H), 3.20-3.18 (m, 4H), 3.10-2.90 (m, 1H), 1.85-1.52 (m, 6H), 1.30-1.20 (m, 3H), 0.94 (d, 3H); MS (ESI) m/z: Calc: 495.3 (M+). Found. 496.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29][O:18][C:15]1[CH:16]=[CH:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=3)[CH:8]=2)[C:13](=[O:19])[CH:14]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1cc2ccccc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4cc5ccccc5o4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), 1-benzofuran-2-ylmethanol (58 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (16 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][C@H:14]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15](O)=[O:16])=[CH:11][N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]([NH:34][C@@H:35]([CH2:39][SH:40])[C:36]([NH2:38])=[O:37])(=[O:33])[CH3:32].C(N(CC)CC)C.CCCP(=O)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[C:31]([NH:34][C@H:35]([C:36]([NH2:38])=[O:37])[CH2:39][S:40][C:15](=[O:16])[C@@H:14]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C:12]1[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]=[N:10][CH:11]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)N[C@@H](CS)C(N)=O
Reactant: CC(C)(C)OC(=O)NCCC(=O)N[C@@H](Cc1cncn1C(=O)OC(C)(C)C)C(=O)O
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CSC(=O)[C@H](Cc1cncn1C(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)C(N)=O
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
To a stirring suspension at room temperature under N2 of (S)-3-(1-(tert-butoxycarbonyl)-1H-imidazol-5-yl)-2-(3-(tert-butoxycarbonylamino)propanamido)propanoic acid (45c, 35.74 g, 83.80 mmol) and (R)-2-acetamido-3-mercaptopropanamide (45b, 13.59 g, 83.78 mmol) in 500 mL of THF:EtOAc (1:1) was added dropwise triethylamine (26 mL, 186 mmol). After addition, the suspension was stirred for 15 minutes then propylphosphonic anhydride, 50 wt. % solution in EtOAc (55 mL, 92 mmol) was added dropwise. The resultant cloudy solution was stirred at room temperature for 2 h then saturated NaHCO3 solution (˜500 mL) was added. The layers were separated and the organic extract was washed with saturated KH2PO4 and then saturated NaCl solution. The aqueous phases were back extracted (in the same order) with fresh EtOAc (2×500 mL). The combined organic extracts were dried using MgSO4, filtered, concentrated and chromatographed twice (silica gel, 50% THF in EtOAc) to give 35.53 g (74%) of tert-butyl 5-((S)-3-((R)-2-acetamido-3-amino-3-oxopropylthio)-2-(3-(tert-butoxycarbonylamino)propanamido)-3-oxopropyl)-1H-imidazole-1-carboxylate (45d) as white foamy solid. MS (APCI) m/z 571 [M+H]+.
Reaction SMILES: C([Mg]Br)C.Br[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1.CON(C)[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16]>C(Cl)Cl>[CH3:11][N:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16]
Reactant: CON(C)C(=O)c1cncnc1
Reactant: Cn1ccnc1Br
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1ccnc1C(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (3 M in Et2O, 1.05 mL, 3.14 mmol) was added dropwise to a solution of 2-bromo-1-methyl-1H-imidazole (505 mg, 3.14 mmol) in DCM (6 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature 30 min, then was cooled in an ice bath prior to addition of a solution of N-methoxy-N-methylpyrimidine-5-carboxamide (419 mg, 2.51 mmol, Intermediate 28, step a) in DCM (1 mL). The resulting suspension was stirred at room temperature for 24 hours. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water, and extracted three times with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 0-60% CH3CN-DCM), affording the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)c(F)c1
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2ccc(F)cc2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To the suspension of 4-(2,4-difluoro-phenyl)-1H-indole (6.42 g, 28 mmol) in t-BuOH: ethanol: acetic acid (177 mL: 105 mL: 55 mL) was added pyridinium tribromide (27 g, 84 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (136 mL). Zinc dust (9.8 g, 150 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), neutralized with 1N HCl, washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 5.16 g (75%) of 4-(2,4-difluoro-phenyl) 1,3-dihydro-indol-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Li+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)cc2cc[nH]c12
Yield: 99.4 %

Procedure:
Methyl 5-bromo-1H-indole-7-carboxylate (5 g, 19.7 mmol) was dissolved in methanol (200 mL) and a solution of lithium hydroxide (0.99 g, 41 mmol) in water (10 mL) was added. The mixture was heated at reflux for 50 hours. The methanol was removed in vacuo and the residue diluted with aqueous hydrochloric acid (2 M). The resulting precipitate was filtered off and dried in a heated vacuum pistol to give 4.7 g (99%) of the title compound as a beige solid.
Reaction SMILES: [Br:1][C:2]1([C:5]([NH:7][CH2:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13])=O)[CH2:4][CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].[OH-].[Na+]>O1CCOCC1>[Br:1][C:2]1([C:5]2[S:16][C:9]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: CCCCC(=O)CNC(=O)C1(Br)CC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCc1cnc(C2(Br)CC2)s1
Yield: 193.4 %

Procedure:
500 mg of amide 86 and 212 mg of phosphorus pentasulfide are heated in 2 ml of dioxane for 25 minutes to 100° C. and, after cooling, poured into dilute sodium hydroxide solution. After extraction with ethyl acetate and drying on sodium sulfate, it is concentrated by evaporation, and the oily residue is chromatographed on silica gel with ethyl acetate/hexane. 240 mg of title compound 89 is obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8](=[O:9])[NH:7][C:5]2[S:6][C:2]([S:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])=[CH:3][N:4]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(=O)NCCS
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: CC(=O)NCCSc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 34.9 %

Procedure:
N-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-yl-sulfanyl}-ethyl)-acetamide (156 mg, 35%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol), and N-(2-mercapto-ethyl)-acetamide (240 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([N:11]([CH2:17][CH2:18]OS(C)(=O)=O)[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])(=[O:10])=[O:9].[Cl-:24].[Li+]>CC(C)=O>[CH3:7][S:8]([N:11]([CH2:17][CH2:18][Cl:24])[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])(=[O:10])=[O:9]
Reactant: [Cl-]
Reactant: CS(=O)(=O)NN(CCOS(C)(=O)=O)S(C)(=O)=O
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CS(=O)(=O)NN(CCCl)S(C)(=O)=O
Yield: 20 %

Procedure:
A three-step process with a total yield less than 10% has been previously reported published in the following patents and journal articles: U.S. Pat. No. 5,637,619 (Jun. 10, 1997 for VNP40101M); U.S. Pat. No. 4,684,747 (Aug. 4, 1987 for intermediate VNP4090CE); WO97/02029 (Jan. 23, 1997); Journal of Medicinal Chemistry, 1990, 33(8): 2259-2264; Journal of Medicinal Chemistry, 1996, 39(3): 796-801, as illustrated in FIG. 1. 2-Hydroxyethylhydrazine (HEH) was used a starting material and reacted with methanesulfonyl chloride to obtain 1,2-bis(methylsulfonyl)-1-[2-(methylsulfonyloxy)ethyl]hydrazine (BMH) at −20° C. for 18 hours, using pyridine as base. The crude intermediate BMH was treated with lithium chloride in acetone under reflux for 3 days to afford 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (VNP4090CE). After purification by flash column chromatography, an approximately 20% yield was reached for the two steps. VNP4090CE was condensed with methyl isocyanate at room temperature using triethylamine (TEA) as a base. After crystallization from ethanol, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylcarbamoyl)hydrazine (VNP40101M) with an approximately 42% yield. The total yield of this process was less than 10%. It is noted that the process used methyl isocyanate, which is extremely dangerous for manufacturing in scaleup kilogram amounts. For this reason, the present inventors investigated the synthesis and have developed new methods to prepare VNP40101M.
Reaction SMILES: CC1C=CC(S([N:11]2[N:15]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=[C:18]([NH2:26])[C:17]=4[N:27]=[C:14]3[CH:13]=[CH:12]2)(=O)=O)=CC=1.[O-]CC.[Na+].C(OC)(C)(C)C>C(O)C>[CH:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:16]1[N:15]3[NH:11][CH:12]=[CH:13][C:14]3=[N:27][C:17]=1[C:18]([NH2:26])=[N:19]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc4c(N)nc5ccccc5c4n32)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COC(C)(C)C
Product: Nc1nc2ccccc2c2c1nc1cc[nH]n12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.4 %

Procedure:
A solution of 10-[(4-methylphenyl)sulfonyl]-10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinolin-6-amine (0.13 g, 0.34 mmol) and sodium ethoxide (0.032 g, 0.38 mmol) in ethanol (3.5 mL) was heated to 85° C. After 1.5 h, the reaction was cooled to ambient temperature, quenched with silica gel (1.3 g) and concentrated under reduce pressure. The material was loaded onto a 40 g silica gel cartridge and purified by prep. HPLC (eluted with 10-30% CMA in chloroform) to give a red/orange solid. The solid was treated with methyl tert-butyl ether (10 mL) and heated to boiling. The hot mixture was filtered through fine filter paper and the filtrate concentrated to yield 20 mg of 10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinolin-6-amine as a mauve solid, mp, dec>200° C.; 1H NMR (500 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.53 (dd, J=7.9, 1.1 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.53-7.50 (m, 1H), 7.41-7.38 (m, 1H), 6.73 (s, 2H), 6.04 (d, J=2.1 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 147.5, 145.9, 143.5, 143.3, 127.2, 125.8, 123.9, 122.4, 121.2, 117.7, 113.4, 80.4; MS (ESI) m/z 224.22 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:9]([CH:14]=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:9]([CH2:14][OH:15])=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccnc1CO
Reaction time: 0.67 h

Procedure:
To a solution of (2-formyl-pyridin-3-yl)-carbamic acid tert-butyl ester (0.581 g, 2.66 mmol) in dry MeOH (10 mL) was slowly added NaBH4 (0.200 g, 5.32 mmol). The mixture was stirred for 40 min, and saturated aqueous NaHCO3 (10 mL) was added. The MeOH was removed, and the aqueous residue was extracted with CH2Cl2 (5×25 mL). The organic extracts were combined, and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, affording (2-hydroxymethyl-pyridin-3-yl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [F:1]/[C:2](=[C:8](/[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[O:16][C:15]([CH3:23])([CH3:22])[CH:14]=[C:13]2[C:24]([CH3:27])([CH3:26])[CH3:25])\[CH3:9])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>>[C:24]([C:13]1[C:12]2[C:17](=[CH:18][C:19]([O:20][CH3:21])=[C:10](/[C:8](/[CH3:9])=[C:2](/[F:1])\[CH2:3][OH:4])[CH:11]=2)[O:16][C:15]([CH3:23])([CH3:22])[CH:14]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure L, ethyl (2E)-fluoro-3-(4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)but-2-enoate (Compound 70, 148 mg, 0.39 mmol) and diisobutylaluminum hydride (1 M in dichloromethane, 1.1 mL, 1.1 mmol) were reacted to give the title compound as yellow solid after purification by flash chromatography (silica gel, 1:9 to 1:4 ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:24]3[CH:23]=[C:22]([CH3:21])[O:26][N:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-3-isoxazolecarboxylic acid as starting materials, MS (LC/MS): 412.2 (M+H).
Reaction SMILES: Br[CH:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[N:11][CH:12]=1)[C:3]([O-:5])=[O:4].[CH2:27]1CCN2C(=NCCC2)CC1.C1(C)C=CC=CC=1>O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:15]=1[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7](/[CH:6]=[CH:2]/[C:3]([O:5][CH3:27])=[O:4])=[CH:12][N:11]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CC(Br)C(=O)[O-])cn1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)/C=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 2-bromo-3-[2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-5-pyridyl]propionate (4.00 g), 1,8-diazabicyclo[5,4,0]-7-undecene (1.41 g) and toluene (80 ml) was stirred 2 hours at 90°-100° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residual oily product was subjected to a silica gel chromatography. From the fractions eluted with ethyl acetate-hexane (1:3, v/v) was obtained methyl (E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridyl]acrylate (2.71 g, 83%). Recrystallization from diethyl ether-isopropyl ether gave colorless prisms, m.p. 116°-117° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O[CH:7]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH2:8][NH:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=3)[CH:7]=[CH:8][N:9]=2)=[CH:13][CH:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1ccc(CC(=O)NCC(O)c2cccc(OC)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1ccc(Cc2nccc3cc(OC)ccc23)cc1
Yield: 15.8 %

Procedure:
Phosphorus oxychloride (1.6 ml) was added to a solution of the compound of Example B145 (600 mg, 1.7 mmol) in acetonitrile (15 ml), and the mixture was stirred under reflux for 1 hour 30 minutes. The mixture was cooled on ice, made alkaline with a 5% aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (82 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].[P:22](Cl)(Cl)[Cl:23]>>[C:11]([C:9]1[CH:8]=[C:7]2[C:6](=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=1)[O:21][P:22]([Cl:23])[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C:15]2=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: ClP(Cl)Cl
Reactant: CC(C)(C)c1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)C1=C2CCCC1
Yield: 87.8 %

Procedure:
A mixture consisting of 28.7 g (0.10 mol) of 2,4-di-tert-butyl-6-cyclohexen-1-yl-phenol (compound 102, Example 1b) and 17.5 ml (0.20 mol) of phosphorus trichloride is refluxed under nitrogen for 5 hours. Excess phosphorus trichloride is removed by distillation and the residue is then distilled under vacuum at 165-167° C./0.01 mbar, giving 30.8 g (88%) of 6,8-di-tert-butyl-10-chloro-2,3,4,10-tetrahydro-l H-9-oxa-10-phosphaphenanthrene, a colourless thick liquid which slowly crystallises when standing; 31P--NMR (CDCl3): δ=130.5 ppm (s); 1H--NMR (CDCl3): δ(ppm): 1.34 (s, 9H, (CH3)3C--), 1.44 (s, 9H, (CH3)3C--), (compound (202), Table 2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([B:14]2[O:22][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:15]2)[CH:11]=[CH:12][CH:13]=1.[CH3:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH3:23][O:24][CH2:25][CH2:26][O:7][C:8]1[CH:9]=[C:10]([B:14]2[O:22][C:19]([CH3:21])([CH3:20])[C:16]([CH3:17])([CH3:18])[O:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: COCCBr
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 100 °C
Yield: 86.9 %

Procedure:
Potassium carbonate (1.88 g, 13.65 mmol) was added to a solution of 3-hydroxyphenylboronic acid pinacol ester (Apollo, 1.0 g, 4.55 mmol) in DMF (10 mL). 2-Bromoethyl methyl ether (0.41 mL, 5.46 mmol) was added and the reaction mixture was heated to 100° C. for 1 hr. The reaction mixture was allowed to cool and then partitioned between ethyl acetate (50 mL), and water (150 mL). The phases were separated and the organic phase was washed with brine (150 mL), dried over anhydrous sodium sulphate, filtered and the filtrate solvents removed in vacuo, to afford the title product as a light-brown oil (1.1 g) which was used without further purification.