Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:9][OH:10]>>[CH2:1]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCC=O
Agent: Cl
Product: CCCCCCN(O)CCCCCC
Yield: 67.5 %

Procedure:
Following the general procedure of Example 2, hexanal (5.0 g, 50 mmol) is reacted with only one half equivalent of hydroxylamine hydrochloride (1.9 g, 28 mmol) to give 3.4 g of crude N,N-di-n-hexylhydroxylamine as a white solid which 90 1H NMR confirmed to be essentially only one compound. Purification of the crude product as described in Example 2 gives 2.0 g of the title compound as a white solid melting at 67° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23]([OH:25])=[O:24]>COCCOC.CCCC>[C:23]([C:22]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([NH:19][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=2)[CH:21]=1)([OH:25])=[O:24]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: COc1ccc(C(=O)O)cc1N
Solvent: COCCOC
Solvent: CCCC
Product: COc1ccc(C(=O)O)cc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
A solution of 5.06 g (0.02 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane was mixed with a solution of 6.69 g (0.04 mole) of 3-amino-4-methoxybenzoic acid in 125 ml of 1,2-dimethyethane, and the mixture was stirred at 25° C. for about 16 hours. The reaction mixture was heated gently for 30 minutes and then allowed to cool before being filtered to remove the hydrochloride salt of the excess starting amine. The filtrate was concentrated under vacuum and then diluted with water. The resulting precipitate was collected and was then recrystallized three times from a mixture of ethanol and water to give 1.9 g of white solid N-(5-carboxy-2-methoxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 259°-261° C. Analysis: Calculated for C23H29NO5 : %C, 69.2; %H, 7.3; %N, 3.5; Found: %C, 69.3; %H, 7.3; %H, 3.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH3:19][O:20][CH2:21]Cl>C(Cl)Cl>[CH3:19][O:20][CH2:21][O:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COCCl
Reactant: COc1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 12.0 g (100 mmol) of 3-methoxyphenol in 100 mL of methylene chloride at 0° C. was added 29.5 g (229 mmol) of diisopropylethylamine followed by dropwise addition of 10 g of chloromethyl methyl ether. The reaction mixture was stirred at room temperature overnight, washed with 1N HCl (3×75 mL), 1N NaOH (3×75 mL) and brine and was dried over anhydrous MgSO4. The mixture was filtered and concentrated in vacuo to give 3-methoxymethyloxy-anisole. 6.0 g (36 mmol) of 3-methoxymethyloxy-anisole was dissolved in 100 mL dry THF and was cooled to −78° C. To the solution was added dropwise 20 mL (50 mmol) of 2.5M n-butyl lithium in hexanes. The solution was stirred at −78° C. for 1 hour, the ice bath was removed and the solution stirred at room temperature for a further 1 hour. The reaction mixture was cooled to −78° C. and treated with 5.56 g (54 mmol) of trimethyl orthoborate. The solution was stirred for 1 hour and then allowed to warm to room temperature over 1 hour. The solution was treated with 30 mL of saturated NH4Cl solution and 100 mL of ethyl acetate with stirring. The pH was immediately adjusted to 5.0 by addition of aliquots of 5% citric acid solution. The aqueous phase was promptly extracted with ethyl acetate (3×50 mL). The combined ethyl acetate phases were extracted with 1N NaOH solution (3×50 mL). The combined basic extracts were acidified with rapid stirring by dropwise addition of concentrated hydrochloric acid to pH 5.0. The mixture was extracted by ethyl acetate (3×75 mL). The combined EtOAc phases were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-methoxy-6-(methoxymethyloxy)phenylboronic acid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@@H:13]2[CH2:15][C@H:14]2[CH2:16][NH2:17])=[N:5]1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@@H:13]2[CH2:15][C@H:14]2[CH2:16][NH:17][C:25](=[O:27])[CH3:26])=[N:5]1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 1-[(1R,2R)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (2.00 g, 7.29 mmol) and triethylamine (4.07 mL, 29.2 mmol) in tetrahydrofuran (70 mL) was added acetic anhydride (828 μL, 8.75 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→20/80) to give the title compound (1.65 g, yield 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH:17]=[O:18])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.CI.[CH3:21]N(C=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=3)[N:8]2[CH3:21])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A flask is charged with 5-(6-chloro-1H-indol-2-yl)-pyridine-3-carbaldehyde (Example 104, 7.8 g, 28.9 mmol), MeI (5.33 g, 37.5 mmol) and DMF (300 mL), and 60% NaH in mineral oil (1.386 g, 34.6 mmol) is added at 0° C. The mixture is stirred for 2 h. Water (100 mL) is added. The mixture is extracted with EtOAc twice and the combined organic phase is washed with water (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography with a 0 to 2% methanol-DCM gradient to give 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole. MS (ESI) m/z 271.0, 272.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>C1COCC1>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]2)=[N:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A suspension of pre-washed NaH (0.1 g, 2.48 mmol, 60% percent dispersion in mineral oil) in THF (2 mL) was added to an ice cold solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.48 mmol) in dry THF (3 mL). The mixture was stirred for 20 minutes, and added to 2-chloro-5-nitro-pyridine (0.36 g, 2.26 mmol) in portions. After the addition was completed, the cooling bath was removed and the reaction mixture was stirred at 22° C. overnight. The reaction mixture was cooled in an ice bath and treated with a saturated aqueous sodium bicarbonate solution (5 mL). The reaction mixture was diluted with ethyl acetate (25 mL) and distilled water (25 mL). The separated aqueous phase was extracted with ethyl acetate (3×35 mL), and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:14][CH:13]3[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.Cl.[C:23]([OH:29])(=[O:28])[CH2:24][C:25]([OH:27])=[O:26]>C(O)C>[C:23]([OH:29])(=[O:28])[CH2:24][C:25]([OH:27])=[O:26].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[N:15]([CH3:16])[CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CN1C2CCC1CC(O)(c1ccc(Cl)cc1)C2
Agent: Cl
Agent: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CN1C2C=C(c3ccc(Cl)cc3)CC1CC2

Procedure:
The title compound was prepared from 3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (4 g, 16 mmol), glacial acetic acid (15 mL) and concentrated hydrochloric acid (15 mL). Yield of free base (3.6 g, 97%). Some of the free base (1.44 g, 6 mmol) was dissolved in ethanol (96%) and added malonic acid (0.62 g, 6 mmol) in ethanol (96%). The resulting solution was concentrated to an oil, the oil was trituated in diethyl ether, the title compound precipitated as powder and was isolated by filtration. Yield (1.4 g, 71%) as white crystals m.p. 100.8-102.1° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH:12]([SiH:17]([Cl:19])[Cl:18])[Si:13]([Cl:16])([Cl:15])[Cl:14])[Cl:11]>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.C1C=CC=CC=1>[Cl:11][Si:10]1([Cl:9])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[Si:17]([Cl:18])([Cl:19])[CH:12]1[Si:13]([Cl:16])([Cl:14])[Cl:15]
Reactant: C#Cc1ccccc1
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[Si](Cl)(Cl)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cl[Si](Cl)(Cl)C1[Si](Cl)(Cl)C=C(c2ccccc2)[Si]1(Cl)Cl
Yield: 43.9 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)trichlorosilylmethane in the presence of Pd(PPh3)4. Into the same apparatus as described in Example 1 were added 1.0 g of bis(dichlorosilyl)trichlorosilylmethane, 0.102 g of Pd(PPh3)4, and 25 ml of dried benzene to form a mixture. The mixture was brought to reflux temperature and 0.32 ml of phenylacetylene added over a 10 minute period. The mixture was stirred at reflux temperature for an additional 8 hours and then the solvent removed at atmospheric pressure. The residue was vacuum distilled at 67 Pa to yield a mixture comprising 0.348 g of 1,1,3,3-tetrachloro-2-trichlorosilyl-4-phenyl-1,3-disilacyclopent-4-ene (TCD-GC area 43.9%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH3:22])[CH2:10][CH2:9][C:8]2[C:11]([CH3:21])=[C:12]([O:17][CH2:18][CH:19]=[CH2:20])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1.C([O-])(=O)C.[Na+].[I:29]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCOCC.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH3:22])[CH2:10][CH2:9][C:8]2[C:11]([CH3:21])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][I:29])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1
Reactant: II
Reactant: C=CCOc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)OC)O2
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CC1(C)CCc2c(C)c(OCCCI)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
To a stirred, ice-cold solution of 1M borane in tetrahydrofuran (10 ml) was added, dropwise, a solution of 2 ml (1.64 g) of cyclohexene in 6 ml of dry tetrahydrofuran. The mixture was allowed to stir at 0°-5° C. for 1.5 hours. Tothe resulting slurry of dicyclohexylborane was added, dropwise a solution of 1.59 g of the allyl ether from Example 18 in 4 ml of tetrahydrofuran. The mixture was stirred at 0°-5° C. for 1 hour and at room temperature for 18 hours at which point 20 ml of 1M methanolic sodium acetate was added dropwise followed by 23.8 ml of 0.4M methanolic iodine. The resulting mixture was stirred at room temperature for 4 hours whereupon 3.1 ml of aqueous sodium thiosulfate was added. The reaction mixture was poured into water worked-up with ether in the usual manner. Chromatography of the crude product (4.4 g) on 100 g of silica gel afforded 1.71 g (76.7%) of racemic-3,4-dihydro-6-(3-iodopropoxy)2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid methyl ester as an oil, eluted with 19:1 and 9:1 hexane-ethyl acetate.
Reaction SMILES: [Li].[H-].[C:3]([N:11]1[CH2:24][CH2:23][C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:17][C:16]=3[NH:15][C:14]=2[CH2:13][CH2:12]1)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCOC(C)=O.CCCCCCC>O1CCCC1>[CH2:3]([N:11]1[CH2:24][CH2:23][C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:17][C:16]=3[NH:15][C:14]=2[CH2:13][CH2:12]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(-c4ccccc4)ccc3c2CC1
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: c1ccc(CN2CCc3[nH]c4cc(-c5ccccc5)ccc4c3CC2)cc1
Yield: 90.6 %

Procedure:
A solution of lithium alunmnum hydride (1.40 g, 36.9 mmol) in tetrahydrofuran (15.0 mL) and a solution of 3-benzoyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.40 g, 3.82 mmol) in tetrahydrofuran (30.0 mL) at 0° C. were reacted in a manner similar to Example 1 to give an oil. Column chromatography (silica gel, 20-30% EtOAc/heptane) afforded 1.22 g (90%) of the title compound as a white solid: mp 176-177° C.; 1H NMR (400 MHz, CDCl3) δ 7.74, 7.63-7.61, 7.48, 7.45-7.40, 7.36, 3.84, 3.00-2.92; 13C NMR (100 MHz, CDCl3) δ 142.5, 139.3, 136.9, 135.2, 134.5, 128.9, 128.6, 128.5, 128.3, 127.3, 127.0, 126.4, 119.1, 117.8, 112.8, 108.8, 60.7, 55.7, 53.8, 28.6, 23.9; IR (drift) 3385, 3371, 1467, 1344, 1328, 1120, 1027, 870, 820, 765, 756, 750, 735, 728, 698 cm−1; MS (EI) m/z 352 (M+); Anal. Calcd for C25H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.24; H, 6.89; N, 8.05.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:16][C:17]1[N:18]=[C:19]([C:24]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]2[OH:15])=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)nc1Cl
Yield: 92 %

Procedure:
The same operation as in Example (196b) was performed using tert-butyl trans(±)-4-amino-3-hydroxypiperidine-1-carboxylate synthesized in Example (201a) (600 mg, 2.77 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (2405d) (484 mg, 2.77 mmol), 1-hydroxybenzotriazole hydrate (562 mg, 4.16 mmol), WSC hydrochloride (798 mg, 4.16 mmol) and triethylamine (580 μL, 4.16 mmol), to obtain 950 mg of the title compound (92%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C:7](=[N:11][OH:12])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:18])(=O)=O>O.CO>[C:1]([O:5][C:6](=[O:13])[C:7](=[N:11][O:12][CH3:18])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: CON=C(C(C)=O)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 215 g of Na2CO2 in 2200 ml of water is added at room temperature a solution of 128 g of 2-hydroxyiminoacetoacetic acid-tert.butyl ester in 475 ml of methanol. 255 g of dimethyl sulphate are added, dropwise, at 8°-10°, and after 3 hours at 8°-10° and 15 hours at room temperature, the mixture is filtered. The filtrate is extracted 3 times with ethyl acetate extracted 3 times with ethyl acetate, dried over magnesium sulphate and evaporated to obtain the heading compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.CC1(C)CC(C)OB([C:31](=[CH2:36])[C:32]([F:35])([F:34])[F:33])O1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.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.COCCOC>[CH3:22][C:21]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:31](=[CH2:36])[C:32]([F:35])([F:34])[F:33])=[N:3][N:4]=[CH:5]2
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
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: ClCCl
Solvent: CCO
Solvent: COCCOC
Product: C=C(c1nncc2cc(-c3cc(C(=O)OC)ccc3C)ccc12)C(F)(F)F
Temperature: 80 °C
Yield: 31.3 %

Procedure:
Methyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (563 mg, 1800 μmol), 4,4,6-trimethyl-2-(1,1,1-trifluoroprop-2-en-2-yl)-1,3,2-dioxaborinane (799 mg, 3600 μmol), tetrakis(triphenylphosphine)palladium (208 mg, 180 μmol), ethyl alcohol (200 proof; 2000 μl), 1,2-dimethoxyethane (8000 μl), and potassium carbonate (2M aqueous solution; 2700 μl, 5400 μmol) were combined in a sealed tube and heated at 80° C. for 2 h, during which LC-MS indicated 100% conversion. The cooled reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. CombiFlash purification (20% to 80% EtOAc/Hexanes) afforded methyl 4-methyl-3-(1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-yl)benzoate (210 mg, 31% yield) as a golden yellow foam. MS (ES+): 373.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([OH:13])=[O:12].[O-]CCCC.[K+]>CC(N(C)C)=O>[C:11]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([OH:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(O)COc1ccccc1O
Agent: CCCC[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)COc1ccccc1Oc1ccc([N+](=O)[O-])cc1

Procedure:
4-nitro-fluorobenzene and 2-(carboxymethoxy)phenol were reacted together in DMA in the presence of potassium butoxide for 2 hours at 150° C. to yield 4-(2-carboxymethoxyphenoxy)nitrobenzene.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH:10](O)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH:10]([Cl:3])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1

Procedure:
Forty-two milliliters of thionyl chloride were gradually added to 75 g of 4,4'-dichlorobenzhydrol. When the addition was complete, the reaction was heated on a steam bath for 2 hours. The excess thionyl chloride was removed in vacuo. One hundred milliliters of carbon tetrachloride were added, and the solvent was again evaporated. The carbon tetrachloride treatment was repeated and upon evaporation the resulting oil was crystallized from petroleum ether to provide 65.3 g of the desired sub-titled intermediate, m.p. 63° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10]Br.O>C(Cl)(Cl)Cl>[Br:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: BrBr
Reactant: O=Cc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxybenzaldehyde (10.0 g, 81.9 mmol) in chloroform (100 mL) was added with bromine (4.30 mL, 83.5 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was added with water (100 mL), and the solvent of the organic layer was evaporated under reduced pressure to obtain 3-bromo-4-hydroxybenzaldehyde as a pale yellow solid (quantitative yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CC#N>[CH3:13][S:14]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:16])=[O:15]
Reactant: OCCCCl
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)C(O)CCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 3-chloro-1-propanol (283 g, 2.99 mol) and triethylamine (629 mL, 4.5 mol) in CH3CN (3500 mL) at 10° C. was added dropwise methanesulfonyl chloride (518 g, 4.52 mol). The resulting reaction mixture was stirred overnight at room temperature, filtered and concentrated in vacuo to an oil. The oil was dissolved in CH2Cl2 and purified by filtration through silica gel. The appropriate fractions were combined and concentrated in vacuo to give the title compound 335 g (65%). TLC (Rf: 0.3; 20% EtOAc/Hexane). 1H NMR (CDCl3) δ 2.1 (m, 2H, CH2), 2.96 (s, 3H, CH3), 3.59 (t, 2H, CH2), 4.28 (t, 2H, CH2). 13C NMR (CDCl3) δ 31.5 (CH2), 37.0 (CH3), 40.2 (CH2), 66.3 (CH2).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:11]\[OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O/N=C\c1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
To a suspension of 4-fluoro-benzaldehyde (30.4 g, 0.24 mol) in water (50 mL) was added at 0-5° C. within 5 minutes a solution of hydroxylamine hydrochloride (17.7 g, 0.25 mol) in water (30 mL) and the resulting mixture stirred for 15 minutes at 0-5° C. The mixture was then treated at 15-25° C. within 15 minutes with 32% NaOH (24.44 mL, 0.26 mol) and the resulting suspension was stirred for one additional hour and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×100 mL) and subsequently concentrated to dryness to afford 31.9 g (95%) of the title oxime as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:17]1([NH:16][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1c2ccccc2nn1-c1ccccc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Yield: 17.5 %

Procedure:
To a solution of 2-phenyl-2H-indazol-3-amine (800 mg, 4 mmol; Shirtcliff, Laura D.; Rivers, Jazmin; Haley, Michael M, Journal of Organic Chemistry (2006), 71(17), 6619-6622) in CH2Cl2 (43 ml) was added cyclohexanone (1.97 ml, 19 mmol; [108-94-1]), acetic acid (0.22 ml, 4 mmol) and sodium triacetoxyborohydride (2.43 g, 11 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was heated under reflux conditions for 12 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting brown oil was dissolved in MeOH (20 ml) and heated under reflux conditions for 30 min. Removal of the solvent under reduced pressure left a brown oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (206 mg, 0.7 mmol; 18%) as yellow oil. MS: m/e=292.4 [M+H+].