Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].[NH2:32][CH:33]([C:35]1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=N[CH:36]=1)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C2C(=CC=CC=2C(O)=O)C=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][CH:31]=[C:2]4[C:3]=3[N:32]=[CH:33][CH:35]=[CH:36]4)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cccc2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc4cccnc34)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.123 g, 0.40 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.152 g, 0.40 mmol), quinoline-8-carboxylic acid (0.070 g, 0.40 mmol), diisopropylethylamine (0.14 mL, 0.80 mmol) in DMF (2 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)quinoline-8-carboxamide (0.180 g) as an orange solid. 1H NMR (CDCl3): δ8.95 (dd, J=4.4, 1.8 Hz, 1H), 8.83 (dd, J=7.4, 1.6 Hz, 1H), 8.50 (s, 1H), 8.30 (dd, J=8.2, 1.8 Hz, 1H), 7.99 (dd, J=8.3, 1.6 Hz, 1H), 7.71-7.65 (m, 1H), 7.53-7.48 (m, 1H), 7.42 (bs, 1H), 6.95 (s, 2H), 5.60 (p, J=7.1 Hz, 1H), 3.88 (s, 6H), 3.82 (s, 3H), 1.87 (d, J=7.1 Hz, 3H). MS m/z 461 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[NH:5][C:4](=[S:15])[N:3]=1.I[CH2:17][CH3:18].C(=O)(O)[O-].[Na+].O>CS(C)=O>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[N:5]=[C:4]([S:15][CH2:17][CH3:18])[N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: Nc1cc(-c2ccc(Br)cc2)[nH]c(=S)n1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1nc(N)cc(-c2ccc(Br)cc2)n1
Yield: 81.8 %

Procedure:
To a solution of 4-amino-6-(4-bromophenyl)pyrimidine-2(1H)-thione (53.90 g, 191.0 mmol) and iodoethane (16.96 mL, 210.1 mmol) in 200 mL of DMSO was slowly added 200 mL of aqueous saturated sodium bicarbonate at ambient temperature with stirring. The reaction was allowed to stir for 1 hour before iodoethane (8.0 mL, 99.1 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was poured into 500 mL of water and stirred for 20 minutes. The solid was collected by means of vacuum filtration and was dried under high vacuum overnight to afford 6-(4-bromophenyl)-2-(ethylthio)pyrimidin-4-amine (51.0 g, 156.2 mmol, 81.76% yield). MS (apci) m/z=310.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][N:14](B(N(C)C)N(C)C)[CH3:15].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC=CC=1P>[CH3:13][N:14]([CH3:15])[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: CN(C)B(N(C)C)N(C)C
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)c1ccc(OC(F)(F)F)cc1
Yield: 29.3 %

Procedure:
A mixture of 1-bromo-4-(trifluoromethoxy)benzene (2.41 g), tris(dimethylamino)borane (1.43 g), sodium t-butoxide (1.34 g), tris(dibenzylideneacetone)dipallidium (18 mg), and o-tolylphosphine (12 mg) in toluene (30 ml) was heated under reflux for 4 h. The mixture was cooled, diluted with water (30 mL) and extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane/EtOAc (99:1 increasing to (95:5) to give the title compound as an oil (600 mg). 1H NMR (360 MHz, CDCl3) δ2.95 (6 H, s), 6.66 (2 H, d, J 9 Hz), and 7.08 (2 H, d, J 8.5 Hz). m/z (ES+) m/z 206 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.[SH2]=N.[C:15]1([NH:21][C:22](C2C=CC=CC=2C(O)=O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:15]1([NH:21][C:22]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: NCc1ccccc1
Agent: N=[SH2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCc1ccccc1)Nc1ccccc1
Temperature: 5 °C
Yield: 87.3 %

Procedure:
A mixture of 1.1 g benzylamine and 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml aceton, under stirring. The reaction mixture was stirred for 35 minutes at room temperature, then diluted with 150 ml water and cooled to 5° C. The precipitated solid product was filtered, washed with water and dried. 1.02 g 1-phenyl-3-benzylurea was obtained with a melting point of from 170° to 172° C.
Reaction SMILES: OS(O)(=O)=O.C[O-].[Na+].[SH:9][CH:10]([C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12].[CH3:20][O:21][C:22](=[O:25])[CH2:23]Cl>CO.O>[CH3:20][O:21][C:22]([CH2:23][S:9][CH:10]([C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12])=[O:25]
Reactant: CC(C)CC(=O)C(S)C(C)C
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CSC(C(=O)CC(C)C)C(C)C
Temperature: 24 °C
Reaction time: 0.02 h

Procedure:
Into a 50 ml, round-bottom, three-necked flask equipped with magnetic stirrer, pot thermometer, "Y" tube, nitrogen inlet tube, reflux condenser with cotton plug, H2SO4 bubbler for nitrogen, and cold water bath is added a solution of 0.65 grams of sodium methoxide dissolved in 10 ml anhydrous methanol. At a reaction mass temperature of 25°-28° C and over a period of one minute, with stirring, is added a solution of 2.1 grams of 3-mercapto-2,6--dimethyl-4-heptanone dissolved in 2 ml anhydrous methanol. After stirring 8 minutes, 1.30 grams of methylchloroacetate (0.012 moles) is added over a period of 2 minutes to the reaction mass; the temperature of the reaction mass rising to 38° C. The reaction mass is allowed to cool to 24° C and is stirred for a period of 2 hours.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20](=O)[C:21]1[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>[OH-].[K+].CCO.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: COc1ccccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C=C1CCc2cc(OCCn3ccnc3)ccc2C1=O
Yield: 85.3 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with o-anisaldehyde (0.117 g, 0.87 mmol) in 2 mL of 4% KOH in EtOH at room temperature overnight. The reaction was diluted with water to induce the precipitation of a red gum. The aqueous layer was decanted, and the remaining residue was concentrated several times from EtOH and then chromatographed (SiO2, 30 g, 8% MeOH in DCM) to afford 0.249 g (84%) of the title compound as a yellow foam: APCI-MS m/e 375.3 M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37]>CN(C)C=O.C(OCC)(=O)C.ON1C2C=CC=CC=2N=N1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Nc1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)Nc1ccccc1O
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (0.97 g), (Peschke, Bernd; Ankersen, Michael; Hansen, Birgit Sehested; Hansen, Thomas Kruse; Johansen, Nils Langeland; Lau, Jesper; Madsen, Kjeld; Petersen, Hans; Thogersen, Henning; Watson, Brett. Eur. J. Med. Chem. (1999), 34(5), 363-380) in dimethylformamide (8.0 ml) was treated sequentially with EDC.HCl (0.76 g), 2-aminophenol (0.43 g) and 1-hydroxybenzotriazole (0.05 g). The mixture was stirred for 2 h, diluted with ethyl acetate and washed with water, dried (MgSO4) and solvent removed at reduced pressure to give the title compound (1.29 g) as a gum.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[Li+].[Si](=O)=[O:15].S(=O)(=O)(O)O>O>[N+:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[OH:15])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O=[Si]=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1O
Yield: 73.5 %

Procedure:
59.1 g (1 mol) of 2,4-difluoronitrobenzene and 300 g of water are initially introduced and 52.7 g (2.2 mol) of 50% strength lithium hydroxide solution are added dropwise at 45° C. The temperature is allowed to rise to 55° C. as a result of the exothermic reaction. After the end of this addition (5 hours) 60.1 g of silicon dioxide (Aerosil) are added and the pH is adjusted to 1.5 with sulfuric acid. The product is distilled over by the introduction of steam and isolated as described in example 1. 115.5 g (0.735 mol, 74% of theory) of 2-nitro-5-fluorophenol are obtained, which do not differ from the material prepared by example 1 with respect to purity.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[CH:12](=O)[CH2:13][CH2:14][CH3:15].[BH4-].[Na+].C(OCC)(=O)C>CO>[CH2:12]([NH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCC=O
Reactant: N#Cc1ccc(CCN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCNCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
700 mg 4-(2-Amino-ethyl)-benzonitrile and 63 μl Butyraldehyde were dissolved in 20 ml methanol. 1.0 g molecular sieves 4 Angström were added the mixture was stirred at room temperature for two hours. Then 270 mg sodium borohydride were added and the mixture was stirred for an additional hour at room temperature. 100 ml ethyl acetate were added, and the reaction was quenched by addition of 1 ml water. The reaction mixture was filtered through a pad of celite and MgSO4. The filtrate was evaporated in vacuo to provide 750 mg crude 4-(2-Butylamino-ethyl)-benzonitrile. This material was used without further purification.
Reaction SMILES: [C:1]([CH:4]([CH:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[CH3:11][N:12]1[CH2:19][C@@H:18]2[C@@H:14]([N:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[C:37](=[O:38])[CH:36]=[CH:35][CH:34]=[N:33]5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:17]2)[CH2:13]1.ClCCl>O>[OH2:2].[C:1]([C@@H:4]([C@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[CH3:11][N:12]1[CH2:19][C@@H:18]2[C@@H:14]([N:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[C:37](=[O:38])[CH:36]=[CH:35][CH:34]=[N:33]5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:17]2)[CH2:13]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Solvent: O
Solvent: ClCCl
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Temperature: 40 °C

Procedure:
2-{4′-[(3aR,6aR)-5-Methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridazin-3(2H)-one tartrate (Form A) was suspended in 1 mL of solution mixture, which was prepared by mixing 3.0 mL of dichloromethane with 1.5 mL of 20% water (in methanol). The suspension was vortexed and heated in a shaking water bath to about 40° C. and maintained for 1.5 hrs. It was further heated to about 70° C. The suspension was then filtered. The water bath was turned off, and the supernatant cooled to ambient temperatures naturally in the water bath. Single crystals were offered.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[C:19]([F:21])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]#[N:18])=[N:10]2)=[C:6]([F:22])[CH:5]=1)[CH3:2].C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:31]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:22])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17](=[NH:31])[NH2:18])=[N:10]2)=[C:19]([F:21])[CH:20]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOc1cc(F)c(Cn2nc(C#N)c3c2CCC3)c(F)c1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1cc(F)c(Cn2nc(C(=N)N)c3c2CCC3)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.73 g of 1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazole-3-carbonitrile 1-1-1 (25.5 mmol, 1.00 eq) were suspended in 100 mL methanol. 7.65 mL sodium methanolate in methanol (2.23 g, 41.3 mmol, 1.62 eq.) were added at rt. The reaction mixture was stirred for 4 h at rt. 2.36 mL acetic acid (2.45 g, 41.3 mmol, 1.62 eq.) and 2.05 g ammonium chloride (38.2 mmol, 1.50 eq.) were added and the reaction mixture was stirred at 50° C. for two days. The mixture was concentrated in vacuo and the residue was filtered off and washed with methanol. The filtrate was suspended in water and aqueous hydrochloric acid (4N). DCM was added, the aqueous layer was washed with DCM twice. To the aqueous layer aqueous sodiumhydroxid solution (2N) was added to reach pH 12. The aqueous layer was extracted with DCM/isopropanol (4:1) three times. The united organic layers were dried over a silicone filter, concentrated in vacuo to provide 2.67 g (7.99 mmol, 31.3%) of analytically pure target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10](O)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1.[N:16]([CH:19]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10]([NH:16][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1
Reactant: O=C=NC1CCCCCCC1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cc(Br)co1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC(NC1CCCCCCC1)C(Cl)(Cl)Cl)c1cc(Br)co1
Yield: 67.7 %

Procedure:
4-Bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide 125 (0.16 g, 0.47 mmol) and isocyanatocyclooctane (0.08 mL, 0.51 mmol) in benzene (2 mL) with triethyl amine (2 drops) was heated to 95° C. for 1.5 hours. The mixture was concentrated onto silica gel and purified by chromatography (7:3 to 6:4 hexane:CH2Cl2) to give 4-bromo-N-(2,2,2-trichloro-1-(cyclooctylamino)ethyl)furan-2-carboxamide (Compound-51) (142 mg, 67%). 1H NMR (300 MHz, CDCl3): δ=7.50 (d, J=0.9 Hz, 1H), 7.21 (d, J=0.9 Hz, 1H), 6.59 (d, J=9.6 Hz, 1H), 5.55 (t, J=9.3 Hz, 1H), 2.96-2.85 (m, 1H), 1.79-1.42 (m, 15H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH2:17][NH:18][CH3:19])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CC1C=CC=C(C)N=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:19])[S:35]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
To a solution of t-butyl 2-(2-bromo-4-((methylamino)methyl)phenoxy)acetate (2) (4.4 g, 13.4 mmol, 1 eq) in DCM (50 mL) was added 2,6-lutidene (3.1 ml, 26.8 mmol, 2 eq) and 4-fluorobenzenesulfonyl chloride (2.9 g, 14.7 mmol. 1.1 eq, Aldrich, Milwaukee, Wis., USA). After the mixture was stirred for 18 h at room temperature, it was washed with 1 N HCl (100 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The washed DCM layer was dried over Na2SO4 and concentrated in vacuo. Silica gel purification (linear gradient of 0% EtOAc/hexanes to 100% EtOAc/hexanes) of the resultant residue yielded 2.95 g (44.8%) of t-butyl 2-(2-bromo-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (3) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 7.82 (m, 2H), 7.44 (d, 1H), 7.22 (m, 3H), 6.72 (d, 1H), 4.57 (s, 2H), 4.04 (s, 2H), 2.58 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[CH3:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[N:36]=[CH:37][N:38]=[C:39]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:40]=2)[CH:20]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2nc(C3CCOCC3)[nH]c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2nc(C3CCOCC3)[nH]c12

Procedure:
33 mg (0.13 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 40 mg (0.12 mmol) 7-methyl-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 μL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 60° C. The reaction mixture was poured onto ice water and the precipitate formed was suction filtered. The precipitate was dissolved and then purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1O)([CH3:4])([CH3:3])[CH3:2].[OH-:16].[K+].O=O>>[C:1]([C:5]1[CH:6]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:9]([OH:16])[C:10]=1[C:8]1[C:9]([OH:16])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=O
Agent: [K+]
Product: CC(C)(C)c1cc(O)c(-c2c(O)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
Into a 500 ml autoclave equipped with an induction stirring device were charged 200 g of 2,6-di-t-butylphenol and 1 g of a 50% aqueous potassium hydroxide solution. The reaction was carried out for 0.5 hour at 200° C., while applying a pressure of up to 7 kg/cm2 with oxygen to the reaction apparatus, whereupon 147.5 g of 3,3',5,5'-tetra-t-butylbiphenol and 11.0 g of 3,3',5,5'-tetra-t-butyldiphenoquinone were formed in the reaction mixture, leaving 31.7 g of unaltered 2,6-di-t-butylphenol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[O:10][N:9]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:15]([S:22][C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[O:10][N:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)CC(Cl)=NO1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(SCc2ccccc2)=NO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
3.2 g (23.2 mmoles) of anhydrous potassium carbonate and 3.0 g (22.5 mmoles) of 3-chloro-5,5-dimethyl-2-isoxazoline were added, in a nitrogen atmosphere, to a solution of 2.8 g (22.5 mmoles) of benzylmercaptan dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.1 g (yield: 62.0%) of 3-benzylthio-5,5-dimethyl-2-isoxazoline as a yellow oily substance (nD20=1.5521).
Reaction SMILES: CN(C)CCN1C2C=CC=CC=2C2C1=CC=CC=2.[N+]([O-])(O)=O.[CH3:23][N:24]([CH3:43])[CH2:25][CH2:26][N:27]1[C:39]2[CH:38]=[CH:37][C:36]([N+:40]([O-])=O)=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>C(O)(=O)C>[CH3:23][N:24]([CH3:43])[CH2:25][CH2:26][N:27]1[C:39]2[CH:38]=[CH:37][C:36]([NH2:40])=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: CN(C)CCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Agent: CN(C)CCn1c2ccccc2c2ccccc21
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CN(C)CCn1c2ccccc2c2cc(N)ccc21
Temperature: 0 °C

Procedure:
23.7 g. (0.1 mol) 9-(β-dimethylaminoethyl)-carbazole (prepared in the manner described by O. Eisleb, Ber. dtsch. chem. Ges., 74, 1433/1941) in 100 ml. glacial acetic acid were placed in a 500 ml. three-necked flask equipped with a stirrer, thermometer and dropping funnel and placed in an ice-bath. A solution of 8.28 ml. (0.2 mol) anhydrous nitric acid in 50 ml. glacial acetic acid was added dropwise thereto at 15° - 20° C. The reaction mixture was further stirred for an hour at 20° - 25° C. and then poured into 500 ml. ice-water. The precipitated green crystals were filtered off with suction, well washed with water and dried at 80° C. in a drying cabinet. There were obtained 32.4 g. (94% of theory) 9-(β-dimethylaminoethyl)-3-nitrocarbazole which melted, with decomposition, at 190° C.
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(O[C:20](=[O:22])[CH3:21])(=O)C>>[CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][N:7]([CH3:8])[C:20](=[O:22])[CH3:21])[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: CNCCC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N(C)CCC(=O)C1CC1
Temperature: 25 °C

Procedure:
A crude solution of 1-cyclopropyl-3-methylamino-1-propanone was cooled to 8°-10°C. and 8.2 g. (0.06 mole) of potassium carbonate was added, followed by 50 g. (0.5 mole) of acetic anhydride. The mixture was stirred until it warmed to room temperature. The benzne layer was separated, dried over magnesium sulfate, concentrated, and the residual oil distilled at 99°-150°C./0.1 mm. The distillate weighed 65 g. It was calculated to contain 80% of 1-cyclopropyl-3-(N-methylacetamido)-1-propanone by the nuclear magnetic resonance spectrum.