Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:12])[CH3:11].[Br:26][C:27]1[N:32]2[N:33]=[CH:34][N:35]=[C:31]2[C:30](Br)=[N:29][CH:28]=1>CC(O)C>[Br:26][C:27]1[N:32]2[N:33]=[CH:34][N:35]=[C:31]2[C:30]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([CH:16]3[CH2:15][CH2:14][N:13]([CH:10]([CH3:12])[CH3:11])[CH2:18][CH2:17]3)=[CH:24][CH:23]=2)=[N:29][CH:28]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: CC(C)N1CCC(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)N1CCC(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1

Procedure:
N,N-Diisopropylethylamine (200 μL, 1.2 mmol) is added to a mixture of 4-(1-isopropylpiperidin-4-yl)phenylamine (220 mg, 1.0 mmol) and 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (280 mg, 1.0 mmol) in iPrOH (5 mL) and heated at reflux for 48 h. The mixture is cooled and the solvent evaporated under reduced pressure to afford an orange-brown solid. This is partitioned between DCM (50 mL) and water (20 mL) and the layers are separated. The organic phase is washed with citric acid (10% aq., 3×25 mL). The combined washings are extracted with DCM (25 mL) and then made basic by addition of NaHCO3 (s). The mixture is extracted with DCM (3×25 mL) and the combined extracts dried over MgSO4 and evaporated. The crude product was purified by chromatography on silica gel, eluting with 5%-10% MeOH in DCM to afford the desired compound, contaminated with the starting aniline. This was recrystallised from MeOH to afford the pure title compound (110 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1.[CH3:34][I:35]>>[I-:35].[C:9]([N:8]([CH2:7][C:4]1[CH:3]=[CH:2][N+:1]([CH3:34])=[CH:6][CH:5]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:18]=1)(=[O:11])[CH3:10]
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(Cc2ccncc2)C(C)=O)cc1
Reactant: CI
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2cc[n+](C)cc2)C(C)=O)cc1
Product: [I-]

Procedure:
The title compound is prepared by the procedure of Example 28 using 0.741 g of product from Example 77 and 5.1 ml of methyl iodide. The residue is recrystallized from methyl alcohol to give 0.933 g of the desired product as orange crystals. The spectral data indicates 2 rotomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: NCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)c(OC)c3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: Br[CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]([C:14]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]=1[OH:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[C:15](=[O:16])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19]([OH:21])([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[CH:20]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: BrCOc1ccccc1
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Product: COc1ccccc1C1(O)C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1

Procedure:
Using the method described in Example 1, 2-bromomethoxybenzene is reacted with 2,6-di(t-butyl)hydroquinone to provide 2,6-di(t-butyl)-4-hydroxy-4-(2'-methoxyphenyl)-2,5-cyclohexadienone. This product is dissolved in ethanol and reduced with hydrogen gas on a Parr apparatus using palladium on charcoal as the catalyst. The white solid product is recrystallized from benzene to provide 2,6-di(t-butyl)-4-(2'-methoxyphenyl)phenol, m.p. 98.5°-100° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CS(O[CH:13]([CH3:37])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:26][N:25]=2)=[CH:18][CH:17]=1)(=O)=O>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]#[C:22][C:19]3[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([N:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)[CH3:37])=[CH:21][CH:20]=3)=[N:25][CH:26]=2)=[CH:31][CH:32]=1
Reactant: CC(COc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)OS(C)(=O)=O
Reactant: CC1CCNCC1
Solvent: CN(C)C=O
Product: CC1CCN(C(C)COc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
0.21 mL (1.80 mmol) 4-methylpiperidine are added to a solution of 133 mg (0.30 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl methanesulphonate in 2 mL DMF and the mixture is stirred for 16 h at 60° C. and 6 h at 80° C. The solvent is eliminated i.vac., the residue is triturated with isopropanol, suction filtered and dried at 30° C. in the circulating air dryer.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18]C3C(=O)[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)CC)C.[O:42]1CC[CH2:44][CH2:43]1>C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:18][C:32]3[C:31](=[O:33])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH3:30])[C:43](=[O:42])[CH3:44])=[CH:26][CH:27]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of the compound (85 mg) obtained in Example 4, acetyl chloride (18 mg), triethylamine (53 mg) and tetrahydrofuran (2 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2:1, volume ratio) to give the title compound (60 mg) as a colorless powder.
Reaction SMILES: CO[C:3](=O)[C@@H:4]([N:6]([C:15](=[O:26])[C@H:16]([NH:18][C:19](OC(C)(C)C)=[O:20])[CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)C.FC(F)(F)C(O)=O>ClCCl>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C@@H:4]([CH3:3])[C:19](=[O:20])[NH:18][C@H:16]([CH3:17])[C:15]2=[O:26])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](C)N(Cc1ccc(F)cc1)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1NC(=O)[C@H](C)N(Cc2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of (2S)-2-[(2R)-(2-tert-butoxycarbonylamino-propionyl)-(4-fluoro-benzyl)-amino]-propionic acid methyl ester (43 g, 382 mmol) in dichloromethane (120 mL) at 0° C. was added trifluoroacetic acid (60 mL). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction was cooled to 0° C. and slowly quenched by addition of 3 N sodium hydroxide until basic. The resulting mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (22 g).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:18]1[CH:19]=[C:20]([CH:23]=[O:24])[S:21][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[C:20]([CH:23]=[O:24])[S:21][CH:22]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(B(O)O)cc1
Reactant: O=Cc1cc(Br)cs1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCOc1ccc(-c2csc(C=O)c2)cc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A mixture of commercial available 4-(hexyloxy)phenylboronic acid (25, 5.55 g, 25.0 mmol), 4-bromothiophene-2-carbaldehyde (5.25 g, 27.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.6 g, 0.13 mmol), toluene (25 mL), ethanol (15 mL) and aqueous sodium carbonate (2 M, 25 mL) was stirred under reflux for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated sodium chloride (50 mL), and dried over magnesium sulfate. After filtration and concentration, the crude material was purified by recrystallization from ethyl acetate/petroleum ether (1/2, v/v) to afford the compound 1026 (3.8 g).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]([O:16][CH:17]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:18][CH3:19])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:31][C:13]([CH3:12])([CH3:32])[C:14]([O:16][CH:17]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH2:18][CH3:19])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)(C)C
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]propyl 2,2-dimethylpropanoate (290 mg, 0.96 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 31 (147 mg, 45% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 5H), 1.12 (s, 9H), 1.16-1.38 (m, 3H), 1.64-1.76 (m, 4H), 1.82-1.91 (br. m, 2H), 2.09 (tt, J=12.0, 3.2 Hz, 1H), 2.72-2.90 (m, 2H), 6.51 (t, J=5.6 Hz, 1H), 7.44 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 366.21 (M+Na)+; 342.16 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:33][CH3:34])=[CH:7][CH:6]=2.C(OCC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:33][CH3:34])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCNCC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A mixture of 2.6 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)-piperidine-4-carboxylate in 40 cm3 of dioxane, to which was added 14 cm3 of 4 N hydrochloric dioxane, was stirred for 16 hours at a temperature in the region of 20° C. The suspension obtained was diluted by addition of 100 cm3 of diethyl ether, stirred at about 20° C. for 1 hour and then filtered. The cake was washed with twice 40 cm3 of diethyl ether and then dried in a desiccator under reduced pressure (5 kPa). 1.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate were obtained in the form of a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1.[Na+].[I-:16]>CC(=O)CC.CCOCC>[I:16][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1(CCCCCl)CCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCOC(=O)C1(CCCCI)CCC1
Yield: 99.4 %

Procedure:
To a solution of ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (21.21 g, 97.0 mmol) in 2-butanone (125 mL) was added NaI (19.07 g, 127 mmol). The reaction mixture was stirred under reflux for 20 h and diluted with Et2O (500 mL). The resulting mixture was washed with aqueous Na2S2O3 (10% (%), 250 mL), brine (250 mL), dried (Na2SO4) and evaporated in vacuo to give ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (29.91 g, 99%) as a slightly yellow oil. 1H NMR (CDCl3): δ=4.14 (q, J=7.1 Hz, 2H), 3.17 (t, J=6.9 Hz, 2H), 2.49-2.32 (m, 2H), 1.98-1.69 (m, 8H), 1.37-1.19 (m, 2H), 1.27 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3): δ=176.5, 60.3, 47.5, 36.9, 33.7, 30.1 (2×), 26.0, 15.7, 14.5, 6.8. HRMS calcd for C11H20IO2 (MH+): 311.0508. found: 311.0511.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Sn](C)(C)[C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[N:34][CH:33]=1>CN1C(=O)CCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[N:34][CH:33]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: C[Sn](C)(C)c1cncc2ccccc12
Reactant: COC(=O)c1ccc(Br)[nH]1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-c2cncc3ccccc23)[nH]1
Yield: 55 %

Procedure:
5-Bromo-1H-pyrrole-2-carboxylic acid methyl ester (1.49 mmol, 0.30 g, prepared according to the procedure described in Method 4 of Example 2) in NMP (10 ml) was treated with triphenylarsine (0.30 mmol, 91 mg), tris(dibenzylideneacetone) dipalladium(0) (0.07 mmol, 68 mg), and 4-(trimethylstannyl)-isoquinoline (2.22 mmol, 0.65 g), then heated to reflux under an argon atmosphere overnight. The resulting mixture was concentrated under reduced pressure, then purified by silica gel chromatography to provide 0.21 g (55%) of 5-isoquinolin-4-yl-1H-pyrrole-2-carboxylic acid methyl ester. 1H NMR (CDCl3) δ9.81 (1H, br s), 9.35 (1H, s), 8.66 (1H, s), 8.31 (1H, d, J=8.5), 8.10 (1H, d, J=8.1), 7.91 (1H, t, J=15.2), 7.79 (1H, t, J 15.2), 7.11 (1H, dd, J=3.8, 2.5), 6.64 (1H, dd, J=3.7, 2.7), 3.90 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+].CN(C)C=O>O>[N:19]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[N+:20]=[N-:21]
Reactant: Cc1ccc(-c2c(Cl)ncnc2OCCO)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(N=[N+]=[N-])ncnc2OCCO)cc1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 2-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yloxy}-ethanol (21.85 g), sodium azide (10.7 g) and dimethyformamide (260 ml) is heated with stirring at 75°-80° C. overnight. After cooling, the mixture is treated with water, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is crystallized from hexane to give 2-{6-azido-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (19.6 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].CN(C([O:19]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:37][CH2:38][C:39]([O:40][CH2:41][CH3:42])=[O:19])=[O:8])=[O:2]
Reactant: CN1CCOCC1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 3-formylbenzoic acid 20 (0.1 g, 0.819 mmol) in DMF (2 mL) were added glysine ethyl ester (0.13 g, 0.98 mmol), HATU (0.37 g, 0.98 mmol), and NMM (0.2 g, (2.04 mmol). The reaction mixture was stirred at RT for 16 h. The reaction was monitored by LCMS. The reaction mixture was concentrated and column chromatographed to afford ethyl 2-(3-formylbenzamido)acetate 35 (146 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH3:28]>>[BrH:1].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:26]([CH2:27][CH3:28])[CH2:25][CH2:24][O:23][CH3:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNCCOC
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Br
Product: CCN(CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCOC

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and N-(2-methoxyethyl)ethylamine were converted to yield (without extraction) [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-ethyl-(2-methoxy-ethyl)-amine hydrobromide as colorless oil, MS: 449 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH2:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:21](OC(=O)C)=[O:22].C(OC(=O)C)(=O)C.C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH:13][CH:21]=[O:22])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(=O)OC=O
Reactant: NC(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=CO
Product: O=CNC(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanamine (315 mg, 1.1 mmol) in CH2Cl2 (2 mL) at 0° C. was added acetic formic anhydride (314 uL, formed by heating a 2:1 v/v ratio of acetic anhydride and formic acid at 60° C. for 2 h). The reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified on a 40 g column of silica gel, eluting with 0 to 100% EtOAc/hexane, to give N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 94% yield) as a clear, viscous oil. LCMS: RT=1.37 min [M+H] 316.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 6.13 (bs, 1H), 6.34 (d, J=7.47 Hz, 1H), 7.05-7.20 (m, 5H), 7.27-7.34 (m, 2H), 8.35 (s, 1H). To a solution of N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 1.04 mmol) in THF (5 mL) at 0° C. was added Et3N (0.79 mL, 5.7 mmol) followed by phosphorous oxychloride (0.125, 1.35 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ice-water (25 mL) and extracted with Et2O (3×20 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over anhydrous Na2SO4, the filtered through basic alumina. The filtrate was concentrated to give 1-fluoro-3-((4-fluorophenyl)(isocyano)methyl)-5-(trifluoromethyl)benzene (268 mg, 93% yield) as a pale brown oil. LCMS: RT=1.71 min [M-NC] 271.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); IR vmax cm−1 neat: 2139 (N═C); NMR: 500 MHz 1H (CDCl3) δ ppm 5.94 (s, 1H), 7.12 (t, J=8.52 Hz, 2H), 7.25-7.29 (m, 1H), 7.30-7.35 (m, 3 H), 7.41 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[CH:35][N:34]([CH:42]([CH3:44])[CH3:43])[C:33]2=[O:45])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[C:33](=[O:45])[N:34]([CH:42]([CH3:44])[CH3:43])[CH:35]=2)=[O:40])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)c1cn(C(C)C)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. LCMS m/z=601 (M+1); 1H NMR (CDCl3) δ: 11.0 (s, 1H), 8.68 (s, 1H), 8.54 (d, 1H J=9 Hz), 8.5 (d, 1H, J=6 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.25-7.23 (m, 3H), 6.81 (dd, 1H, J=3.9 Hz), 6.74 (d, 1H, J=3 Hz), 6.52 (d, 1H, J=6 Hz), 4.96 (p, 1H, J=7 Hz), 4.05 (d, 6H), 3.83 (s, 3H), 1.47 (d, 6H, J=6 Hz).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=[CH:15][C:16]2N(O)N=[N:19][C:17]=2C=1.C(N)CC.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:19][CH2:17][CH2:16][CH3:15])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: On1nnc2ccccc21
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCCN
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.3 %

Procedure:
4-Azidobenzoic acid (866 mg, 5.20 mmol), HOBt (710 mg, 5.20 mmol, 1.0 eq.) and n-propylamine (0.568 ml, 7.60 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.22 g, 6.24 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid (2.0 g, including residual solvent).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([C:11]([O:13][CH3:14])=[O:12])[OH:10].[C:15]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.N>CC(C)=O.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][CH3:15]
Reactant: COC(=O)N(O)c1c(C)cccc1C
Reactant: O=C([O-])[O-]
Agent: N
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: ClCCl
Product: COC(=O)N(OC)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.4 g (7.2 mmol) of N-(2,6-dimethylphenyl)-N-methoxycarbonyl-hydroxylamine (Example 1a), 1.3 g (9 mmol) of K2CO3 and 10 g (8 mmol) of dimethyl sulfate in 10 ml of acetone is stirred overnight at room temperature. The reaction mixture is then diluted with CH2Cl2 and stirred with dilute NH3 solution. The phases are then separated and the organic phase is extracted another twice with water. The organic phase is dried over MgSO4 and evaporated down, and the residue is purified by column chromatography with mixtures of cyclohexane and ethyl acetate. There is obtained 1.2 g (6 mmol=83%) of the title compound as a colorless solid (mp=81° C.).