Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][C@H:23]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:29]=1)[CH:24]([CH3:26])[CH3:25])[C@@H:10]([OH:21])[CH2:11][C:12](=[CH2:20])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[CH2:16]([NH:15][C:13](=[O:14])[C@H:12]([CH3:20])[CH2:11][C@H:10]([OH:21])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:22][C@H:23]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:29]=1)[CH:24]([CH3:25])[CH3:26])[CH2:17][CH2:18][CH3:19]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
A solution of 2-[3(S)-(tert-butoxycarbonyl)amino-5(S)-(3-benzyloxy-4-methoxy-benzyl)-2(S)-hydroxy-6-methyl-heptyl]-N-butyl-acrylamide (3.5 g) in absolute methanol (30 ml) is hydrogenated under an inert atmosphere in the presence of 20 mg of [Ru2Cl4 ((S)-BINAP)2 ]·NEt3 at room temperature and 25 bar for 5 hours. The reaction mixture is filtered and after concentration of the filtrate the residue is purified by FC (200 g of silica gel, hexane/ethyl acetate 1:1). The title compound is obtained: Rf (hexane/ethyl acetate 1:1)=0.16; FAB-MS (M+H)+ =599.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9]C(=O)OC(C)(C)C)[C:4]=1[I:17].[OH-].[Na+]>O>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[C:4]=1[I:17]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nccc(Cl)c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A solution of aqueous HBr (48%, 10 mL, 13.26 mmol) was added to tert-butyl (4-chloro-3-iodopyridin-2-yl)carbamate (4.7 g, 13.26 mmol) and the suspension was stirred at RT for 3 h. The reaction mixture was diluted with water (40 ml), basified with 2N NaOH and the resultant suspension was filtered, washed with water (4×1 mL) and dried to afford 4-chloro-3-iodopyridin-2-amine as white solid (3.05 g, 90% yield). MS (ESI) m/z: 254.9 (M+H+).
Reaction SMILES: Br.[C:2]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]1=[O:12])(=[NH:4])[NH2:3].C[O-].[Na+].[CH3:16][N:17]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[C:18](=[O:26])[C:19]([C:24]#[N:25])=[CH:20]OCC>C(O)CC.CO>[C:24]([C:19]([C:18](=[O:26])[N:17]([CH3:16])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[CH:20][NH:4][C:2](=[NH:3])[N:5]1[CH2:9][C:8]([CH3:10])([CH3:11])[NH:7][C:6]1=[O:12])#[N:25]
Reactant: CC1(C)CN(C(=N)N)C(=O)N1
Reactant: CCOC=C(C#N)C(=O)N(C)c1cccc(C(F)(F)F)c1
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCO
Product: CN(C(=O)C(C#N)=CNC(=N)N1CC(C)(C)NC1=O)c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
4.74 g (20 mmol) of 1-amidino-4,4-dimethyl-2-oxoimidazolidine hydrobromide were dissolved in 47 ml of boiling 1-propanol and, at 88°-90° C., 3.60 g (=3.67 ml, 20 mmol) of a 30% strength solution of sodium methylate in methanol were added. The resulting suspension was cooled to 45° C., stirred at 45° C. for 30 min and then cooled to 20° C., and 5.97 g (20 mmol) of 2-cyano-3-ethoxyacrylic acid N-methyl-N-(3-trifluoromethylphenyl)amide were added at 20° C., and the mixture was stirred at room temperature for 1.8 hours. The solid which had separated out was, after dilution of the pasty mass with 50 ml of ether, filtered off with suction and washed with ether. This product (initial crystals) and the residue from the original filtrate (mother liquor) were worked up further as described in Example 1 and dried. 6.23 g (=76.3% yield) of, according to TLC, virtually pure compound IV were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10]Br>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Br:10])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: BrBr
Reactant: COc1ccccc1F
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 91.3 %

Procedure:
306 g of 2-fluoroanisole was dissolved in 750 ml of chloroform. To the resulting solution, was added dropwise 389 g of bromine under stirring at room temperature. After the completion of the addition, the reaction mixture was heated under reflux for nine hours and then allowed to cool to room temperature. The mixture was washed with 500 ml of a 5% aqueous solution of sodium hydroxide and then the organic layer was washed with 500 ml portions of water thrice. The organic layer was separated and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by distillation (main fraction: 14 mmHg, 98°-100° C.) to thereby give 454 g of 2-fluoro-4-bromoanisole. Yield: 91%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH:25]([S:28](Cl)(=[O:30])=[O:29])([CH3:27])[CH3:26]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH:13][S:28]([CH:25]([CH3:27])[CH3:26])(=[O:30])=[O:29])=[CH:4][CH:3]=1
Reactant: Nc1ccsc1-c1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Add slowly to a solution of 2-(4-bromo-phenyl)-thiophen-3-yl amine(0.6 g, 2.36 mmol) in dry dichloromethane (10 mL) at 0° C., DBU 1.41 mL (9.45 mmol) and isopropylsulfonyl chloride (0.53 mL, 4.72 mmol) (Temp. always <0° C.). Remove the ice bath and stir the mixture at RT overnight. Add satd. aq. NH4Cl (10 mL) and extract the solution with EtOAc (2×10 mL). Dry the combined organic layers and concentrate under vacuum. Purify the crude residue by flash chromatography (Silica gel-Hexane /EtOAc 4:1) to give 0.8 g (94%) of propane-2-sulfonic acid [2-(4-bromo-phenyl)-thiophen-3-yl]-amide.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:37]#[N:38])=[CH:7][N:6]=1)([CH3:3])[CH3:2].O.O[Li].O>C1COCC1>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([C:37]#[N:38])=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(Nc4ccccc4)cnc32)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Nc1ncc(C#N)c(-c2c[nH]c3ncc(Nc4ccccc4)cc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
2-(isopropylamino)-4-(5-(phenylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (0.083 g, 0.158 mmol) was stirred in THF (7 mL) and water (1.5 mL) and treated with LiOH.H2O (0.066 g, 1.60 mmol, 10.0 Eq) and allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated and purified by column chromatography (50% EtOAc/Petroleum ether) to yield the product as a yellow solid (29 mg, 50%)
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.CCCCCC.C[O:27][B:28]([O:31]C)[O:29]C.Cl>O1CCCC1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH2:10][O:11][CH3:12])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:27][B:28]([OH:31])[OH:29]
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (20.0 g, 76.6 mmol) in tetrahydrofuran (200 mL) which had been cooled in a dry ice-acetone bath was added 1.58M n-butyllithium in hexane (50.9 mL, 80.4 mmol) under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. A solution of trimethoxyborane (8.75 g, 84.2 mmol) in tetrahydrofuran (20 mL) was then added to the reaction mixture, and the reaction temperature was increased to 0° C. while stirring. After adding 1N hydrochloric acid (200 mL) to the reaction mixture, it was stirred for 30 minutes at room temperature. After the reaction terminated, toluene (200 mL) was added to the reaction mixture and the organic layer was separated off, after which the aqueous layer was extracted with toluene (100 mL). The combined organic extracts were washed with water (100 mL) and then concentrated under reduced pressure. The residue was dissolved in tert-butyl methyl ether (75 mL) and the reaction mixture was stirred for 30 minutes, after which heptane (223 mL) was added thereto and the reaction mixture was further stirred for 2 hours. The precipitate was filtered out and washed with a mixed solution of tert-butyl methyl ether and heptane (1:3, 3.75 mL), and then dried at 40° C. for 24 hours to afford 12.4 g of the title compound (71.8% yield).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][CH2:15][OH:16])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.CC(C)=[O:22]>>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]([OH:22])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCC1(c2ccccc2)CCCCO1
Reactant: CC(C)=O
Solvent: ClCCl
Product: O=C(O)CCC1(c2ccccc2)CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-phenyltetrahydro-2H-pyran-2-yl)propan-1-ol (640 mg, 2.91 mmol) in acetone (10 mL) at 0° C. was added 4.15 mL of 0.7 M Jone's reagent, and the mixture was stirred for 30 mins at 0° C. and for 1 hr at room temperature. It was added to CH2Cl2 and washed with water twice. The extract was dried over Na2SO4 and evaporated to give an oily residue. The residue was purified by Combiflash (40 g silica gel) eluting with 4:6 EtOAc-hexane to 3-(2-phenyltetrahydro-2H-pyran-2-yl)propanoic acid (346 mg). LC/MS: m/e 235.21 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]([N+:22]([O-])=O)=[C:4]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.C1(C)C=CC=CC=1>[Pt].C(O)(C)C>[NH2:22][C:5]1[C:4]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCNC(=O)OC(C)(C)C)c1C
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Yield: 87.6 %

Procedure:
Tert-butyl 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butylcarbamate (9.17 g, 21.3 mmol), toluene (50 mL), isopropanol (5 mL) and 5% platinum on carbon (7.0 g) were combined and maintained under hydrogen pressure (50 psi, 3.5 Kg/cm2) overnight on a Parr apparatus. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting brown oil was dried under high vacuum to provide 7.47 g of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14](B(O)O)=[CH:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:13]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc2cc(-c3ccccc3-c3ccccc3)ccc2c1
Yield: 57.8 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 2-naphthalene boronic acid in place of phenylboronic acid was used, and then 7.5 g of 1-bromo-4-(naphthalene-2-yl)naphthalene of white crystal was obtained (yield: 43%). Synthesis Example 3 (Synthesis of 2-(biphenyl-2-yl)-6-bromonaphthelene) 15 g of 2,6-dibromonaphthalene on the market, 12.5 g of 2-biphenylboronic acid and 1.8 g of tetrakis(triphenylphophine)palladium were mixed, followed by argon displacement. After adding 250 ml of toluene and 90 ml of 2M sodium carbonate aqueous solution thereto, it was refluxed on heating for 7 hours. After standing to cool, the organic layer was extracted by toluene, and then it was washed by water and saturated salt water. Subsequently the organic layer was dried by using sodium sulfate anhydride, and then the solvent was removed by distillation. The product was refined through a silica gel chromatography and then 10.9 g of 2-(biphenyl-2-yl)-6-bromonaphthalene of white crystal was obtained (yield: 58%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([OH:9])[N:4]=1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N12CCN(CC1)CC2.O>CN(C)C=O.[Cl-].[Na+].O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:18]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:19])[N:4]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Oc1nccc(C(F)(F)F)n1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1nccc(C(F)(F)F)n1)N1CCOCC1
Yield: 79.4 %

Procedure:
A solution of 4-trifluoromethyl-2-hydroxypyrimidine (0.49 g, 3.00 mmol), 4-morpholinecarbonyl chloride (0.45 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water and brine were added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70→50:50)) yielding the title compound (0.66 g, 80% yield) as a white solid.
Reaction SMILES: C(S)C.[Cl-].[Cl-].[Cl-].[Al+3].C[O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CN(CC(C)C)S(=O)(=O)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)CN(CC(C)C)S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of ethanethiol (15 mL) and methylene chloride (15 mL) is cooled to 0° C. Aluminum trichloride (9.62 g, 72.2 mmol) is added (the solution turns green), and the reaction is warmed to room temperature. Ethyl 2-[[4-methoxybenzenesulfonyl](isobutyl)amino]acetate (4.75 g, 14.44 mmol) is added in methylene chloride (5 mL), and the reaction is stirred for 3.5 hours at room temperature. The reaction is then slowly quenched with water, and the crude reaction is partitioned between water and methylene chloride. The aqueous layer is extracted well with methylene chloride, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (25% to 50% ethyl acetate/hexane) to give ethyl 2-[[4-hydroxybenzenesulfonyl](isobutyl)amino]acetate.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4](Cl)=[C:3]([CH:8]=O)[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:23][NH2:24].C(=O)(O)[O-].[Na+]>>[NH:23]1[C:4]2=[N:5][CH:6]=[CH:1][CH:2]=[C:3]2[CH:8]=[N:24]1
Reactant: O=Cc1cccnc1Cl
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: c1cnc2[nH]ncc2c1
Temperature: 120 °C
Yield: 61.5 %

Procedure:
2-Chloro-3-pyridinecarboxyaldehyde (1.0 g, 7.0 mmol) and p-toluenesulfonic acid monohydrate (700 mg) were dissolved in hydrazine monohydrate (1.4 mL, 28.0 mmol). The resulting mixture was heated at 120° C. for 10 minutes in a sealed tube under irradiation with a macrowave of 100 watts. After cooled to room temperature, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution and extracted with DCM (50 mL) three times. The organic layer was dried over anhydrous sodium sulfate. The concentrated residue was purified by silica gel (Fuji Silysia, BW300, 30 g, n-hexane:ethyl acetate=1:1) to give 1H-pyrazolo[3,4-b]pyridine (513 mg, yield: 62%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.Cl.[NH2:13][OH:14].CC([O-])=O.[Na+]>C(O)C>[OH:14][N:13]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1
Reactant: NO
Reactant: O=C1CCOc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCOc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 4-chromanone (5 g, 33.7 mmol), hydroxylamine hydrochloride (2.34 g, 33.7 mmol and NaOAc (2.766 g, 33.7 mmol) in 100 mL of ethanol was refluxed for 18 h. After cooling to RT, the solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc layer was dried (MgSO4), and the solvent was removed. The solid obtained was triturated with hexane and filtered to provide 4.1 g of 4-hydroxyiminochroman.
Reaction SMILES: [CH:1](=[N:5]/[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])\[CH2:2][CH2:3][CH3:4].C[Si](C)(C)[O:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].O.[OH-].[Na+]>CC1CCCO1>[CH2:23]([O:22][C:18]([O:19][CH2:20][CH3:21])([C@@H:1]([NH:5][C@H:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])[CH2:2][CH2:3][CH3:4])[C:17]([O:25][CH2:26][CH3:27])=[O:16])[CH3:24]
Reactant: CCC/C=N/[C@@H](C)c1ccccc1
Reactant: CCOC(OCC)=C(OCC)O[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: CCC[C@H](N[C@@H](C)c1ccccc1)C(OCC)(OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
With HBF4OEt2: (S,E)-N-butylidene-1-phenylethanamine (Example 1, 10.0 g, 57.0 mmol) was dissolved in 250 mL 2-methyltetrahydrofuran and cooled to 0° C. HBF4OEt2 (9.24 g, 57.0 mmol) was added to the mixture followed by a solution of trimethyl((1,2,2-triethoxyvinyl)oxy)silane (Example 10, 11.34 g, 45.6 mmol) in 80 mL 2-methyltetrahydrofuran, and the mixture was stirred at 0° C. for three hours and fifteen minutes. Water (400 mL) was added to quench the reaction, the mixture was neutralized (pH=7.6) with 10N NaOH, the phases were separated and the organic phase was extracted once more with further 400 mL water. Water (300 mL) and 2-methyltetrahydrofuran (50 mL) were added to the mixture, the pH was acidified (pH=5.6) with 2N HCl and the phases were separated. The organic phase was extracted with further 300 mL water and 50 mL 2-methyltetrahydrofuran and the solvent of the organic phase was removed in vacuo to yield 17.1 g crude (S)-ethyl 2,2-diethoxy-3-(((S)-1-phenylethyl)amino)hexanoate as a 86.14 (syn:anti) diastereomeric mixture.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(O)C.[CH2:17]([CH2:19][NH2:20])[OH:18]>O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:20][CH2:19][CH2:17][OH:18])([O-:13])=[O:12]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
25 g (0.123 mol) of 1-chloro-2,6-dinitrobenzene are placed in a three-necked, round-bottomed flask containing 180 ml of ethanol. The reaction mixture is heated to 70° C., 22.3 g (0.365 mol) of ethanolamine are added dropwise over 15 minutes and the mixture is left stirring at this temperature for 30 minutes. The temperature of the reaction mixture is left to return to room temperature and 1 liter of water is then added. The product crystallizes, is sucked dry, is washed with water and is dried. There are obtained 25 g of product which is used as is in the following stage.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([CH2:7][C:8](O)=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>C(Cl)(Cl)Cl.CN(C)C=O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([CH2:7][C:8]([Cl:20])=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccccc1-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Biphenylacetic acid (6.0 g (0.028 mol)) manufactured by Sigma-Aldrich Co. LLC was dissolved in dehydrated chloroform (60 ml). To this, oxalyl chloride (3.7 g (0.029 mol)) and N,N-dimethylformamide (0.04 ml (0.51 mmol)) were added. The mixture was stirred at room temperature for 72 hours. Chloroform, excessive oxalyl chloride and N,N-dimethylformamide were distillated away under reduced pressure to obtain biphenylacetyl chloride (6.5 g (0.028 mol)).
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][CH3:4].Cl[C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][N:8]=1>O>[I:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([O:5][CH2:2][CH2:3][CH3:4])[CH:12]=1
Reactant: Clc1cc(I)ccn1
Reactant: CCCO
Agent: [Na]
Solvent: O
Product: CCCOc1cc(I)ccn1
Reaction time: 0.75 h

Procedure:
0.58 g (25 mmol) sodium are carefully added to 40 mL n-propanol in several portions. The mixture is stirred for 45 min. After that time, 6.0 g (25 mmol) 2-chloro-4-iodo-pyridine are slowly added to the mixture. The mixture is stirred at reflux for 3 h. Subsequently, water is added and the solvent is removed in vacuo. The residue is taken up in 20 mL DMF/MeOH, filtrated and the filtrate is purified by RP-HPLC (MeOH/H2O/NH3).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br.C(O)(=O)C.C([O-])(O)=O.[Na+]>O>[NH2:13][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(O)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 81 %

Procedure:
To a round bottom flask was added 3-methoxy-5-trifluoromethyl-phenylamine (1.0 g, 5.23 mmol), 10 ml HBr (49% aq.), and 8 mL glacial acetic acid. A reflux condenser was attached and the solution heated to 140° C. for 20 h. The reaction was then diluted with water and neutralized to ˜pH 7 by slow addition of saturated NaHCO3. The aqueous solution was then extracted into EtOAc twice. The organic layers were combined, washed once with brine, dried over Mg2SO4, filtered, and concentrated in vacuo to yield the title compound as a tan solid (750 mg). MS (M+H)+=178; Calc'd 177.12 for C7H6F3NO.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)cc1

Procedure:
38.1 g (0.2 mol) of 4-methylbenzenesulphonyl chloride are dissolved in 300 ml of carbon tetrachloride, 35.6 g (0.2 mol) of N-bromosuccinimide are added and, after addition of 0.2 g (1.2 mmol) of azobisisobutyronitrile (ABU), the mixture is heated under reflux for 4 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography (petroleum ether/toluene 4:1, 50 μm particle size) and subsequent recrystallisation from 100 ml of cyclohexane give 24.0 g (45% of theory) of the title compound.