Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=[C:8]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:7]3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:19]=O.Cl>C(O)=O>[CH3:19][CH:17]1[CH2:16][CH2:15][C:8]2=[CH:9][CH:10]=[N:11][CH:12]=[CH:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][CH:7]2[CH2:18]1
Reactant: C=O
Reactant: C1=Cc2ccccc2OC2CCCCC2=CC=N1
Agent: Cl
Solvent: O=CO
Product: CC1CCC2=CC=NC=Cc3ccccc3OC2C1
Temperature: 100 °C

Procedure:
1 gram of 6,7,8,9-tetrahydro-5H-dibenz(b,i)(1,6)oxazecine was mixed with 4 ml formic acid and 3.8 ml of 37% formalin. This mixture was heated for 1 hour at 100° C. After cooling 0.5 ml of concentrated hydrochloric acid was added and the reaction mixture was evaporated. The residue was then dissolved in dilute NaOH, and the mixture extracted with ether. The ether extract was washed, dried and evaporated to dryness.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH2:31][C:32]([NH2:34])=[O:33].CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:31][C:32]([NH2:34])=[O:33])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NC(=O)CI
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(N)=O)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 123.2 %

Procedure:
A solution of 50 mg of amine prepared in Example 11, 33 mg of iodoacetamide and 0.05 mL of DIPEA in 0.5 mL of acetonitrile was heated in a sealed vial at 50° C. for 2 h (or room temperature for 16 h). The volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with 5% MeOH in methylene chloride to afford 70 mg of title compound. Mass spec (NH3 /CI): 475 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:19])[CH:14]=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:19])[C:14]([Br:23])=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: O=C1c2c(O)c(O)c(Br)c(=O)n2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (0.1 g, 0.33 mmol) in chloroform (5 mL), N-bromo-succinimide (64 mg, 0.36 mmol) was added and stirred at room temperature overnight. The product mixture was concentrated and the residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [Na].Cl.N[OH:4].[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH2:18])=[O:17]>CO>[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH:18][OH:4])=[O:17]
Reactant: NC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)NO

Procedure:
To a solution of 1.84 g of sodium in 80 ml of methanol is added, at 50°, a solution of 1.82 g of hydroxylamine hydrochloride in 30 ml of methanol. To the suspension is added, with stirring, a solution of 5.8 g of [o-(2,6-dichloroanilino)-phenyl]-acetamide (M.P. 188° - 189°) in 80 ml of methanol, and the whole subsequently refluxed for 18 hours. After cooling, the red suspension is concentrated at 40° under 11 Torr to dryness. The residue is shaken with 600 ml of water and 100 ml of ether. The aqueous phase is separated and acidified with 2 N hydrochloric acid. The suspension is extracted with 200 ml of ether, the ether solution separated, washed with water, dried over magnesium sulphate, and concentrated at 40° under 11 Torr. The residue is crystallised from ether, whereby [o-(2,6-dichloroanilino)-phenyl]-acetohydroxamic acid is obtained, M.P. 164° - 165°.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH:6]([OH:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9].[CH3:23][N:24]=[C:25]=[O:26].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH:6]([O:12][C:25](=[O:26])[NH:24][CH3:23])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9]
Reactant: CC(C)(CF)C(O)C(Oc1ccc(Cl)cc1Cl)n1cncn1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)OC(C(Oc1ccc(Cl)cc1Cl)n1cncn1)C(C)(C)CF
Yield: 86 %

Procedure:
8.4 g (0.024 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-ol were dissolved in 100 ml of dioxane, and 2 ml of methyl isocyanate and 3.5 ml of triethylamine were added. The mixture was heated under reflux for 10 hours and concentrated by distilling off the solvent in vacuo. The residue was heated in 50 ml of ethyl acetate and the mixture was filtered. 8 g (86% of theory) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-methylcarbamoyloxy-1-(1,2,4-triazol-1-yl)-butane were obtained in the form of colorless crystals of melting point 124°-27° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:39]=[CH:38][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][O:33]C(=O)C)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][OH:33])=[O:22])=[CH:38][CH:39]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OCCOc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(2-acetoxyethoxy)phenyl]benzamide and potassium carbonate (129 mg) in methanol (15 ml) was stirred at ambient temperature for 2 hours and the mixture was diluted with ethyl acetate (30 ml). The solution was washed with water and brine and the organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(2-hydroxyethoxy)phenyl]benzamide (450 mg) as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7].[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:7][C:24](=[O:25])[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH:14]([CH3:15])[CH3:16])=[CH:18][CH:19]=1
Reactant: NC(c1ccccc1)c1ncco1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CC(=O)NC(c2ccccc2)c2ncco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
The crude 1-(1,3-oxazol-2-yl)-1-phenylmethanamine (0.10 g, 0.57 mmol) was mixed with 4-isopropylpheylacetic acid (0.10 g, 0.57 mmol), HOAt (0.086 g, 0.63 mmol) and EDC (0.12 g, 0.63 mmol) in DMF (1.0 mL) and stirred at room temperature for 0.5 h. Purification by reverse-phase HPLC gave the product (0.025 g, 13%). ES-MS [M+1]+: 335.1. 1H NMR (CDCl3, 400 MHz) δ 7.58 (s, 1H), 7.31-7.28 (m, 3H), 7.22-7.20 (m, 6H), 7.07 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.32 (d, J=7.6 Hz, 1H), 3.62 (s, 2H), 2.90 (m, J=6.8 Hz, 1H), 1.24 (d, J=6.8 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(C(C)C)CC)(C)C.[F:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([CH2:37][NH2:38])=[CH:26]2>C(O)CCC>[F:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([CH2:37][NH:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]3[C:3]=1[NH:4][CH:5]=[N:6]3)=[CH:26]2
Reactant: Brc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(F)c2nc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1cccc2cc(CNc3ncnc4nc[nH]c34)c(-c3ccccc3)nc12
Temperature: 110 °C

Procedure:
To a reaction flask was added 6-bromopurine (19 mg, 95 μmol, 1.2 eq), diisopropylethylamine (42 μl, 238 μmol, 3 eq), (8-fluoro-2-phenylquinolin-3-yl)-methanamine (20 mg, 79 μmol, 1 eq), and n-butanol (0.75 mL). The reaction was heated to 110° C. for 8 h. The reaction was cooled to rt and the solvent was removed in vacuo. The compound was purified by reverse phase HPLC. The fractions were concentrated and freebased with sat. NaHCO3. The organic layer was extracted into DCM, dried over MgSO4, filtered, and concentrated to afford a white solid, N-((8-fluoro-2-phenylquinolin-3-yl)methyl)-7H-purin-6-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.68 (m, 2H), 7.45 (m, 6H), 6.78 (br s, 1H), 5.07 (br s, 2H). Mass Spectrum (ESI) m/e=370.9 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:38][C@@H:39]([C:41]1[CH:45]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[O:43][N:42]=1)[CH3:40]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:38][C@@H:39]([C:41]1[CH:45]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[O:43][N:42]=1)[CH3:40])=[O:12]
Reactant: CCOC(=O)c1cc([C@@H](C)N)no1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([C@@H](C)NC(=O)c2cc3ccccc3o2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 2-dram vial containing benzofuran-2-carboxylic acid (0.0243 g, 0.150 mmol) was added HATU (0.057 g, 0.150 mmol.) in DMF (1.0 mL), and TEA (0.120 mL, 0.858 mmol). After shaking at rt for 30 min, (R)-ethyl 3-(1-aminoethyl)isoxazole-5-carboxylate hydrochloride (0.032 g, 0.143 mmol) was added. The mixture was shaken at rt for 16 h. The solvent was evaporated. To the residue was added water (1.0 mL) and DCE (3 mL). After separation, the aqueous layer was extracted with DCE (3 mL). The combined organic phases were concentrated to give (R)-ethyl 3-(1-(benzofuran-2-carboxamido)ethyl)isoxazole-5-carboxylate as a solid residue.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[NH:11]1[C:19]2[C:14](=[CH:15][C:16](B(O)O)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][CH:12]=[CH:13]3)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc3[nH]ccc3c2)s1
Yield: 61.9 %

Procedure:
5-Bromothiophene-2-carboxylic acid methyl ester (0.5 g, 2.26 mmol), 1H-indol-5-ylboronic acid (0.36 g, 2.26 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) and sodium carbonate (0.48 g, 4.52 mmol) were dissolved in dioxane (30 mL) and refluxed for 5 h. Ethyl acetate (30 mL) was added, and the mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.36 g, 62% Yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.Br[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)ccc1S
Reactant: CCOC(=O)CCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCSc1ccc(Cl)cc1OC

Procedure:
4-Chloro-2-methoxythiophenol (5.78 g, 33 mmol), triethylamine (5.0 mL, 36 mmol) and ethyl 3-bromopropanoate (4.6 mL, 36 mmol) were dissolved in ethyl acetate (50 mL) and refluxed for 2 h. Water was added and the liquid phases were separated. The aqueous phase was extracted two times with ethyl acetate. The combined organic fractions were washed with 1 M aq. HCl and then concentrated in vacuo. Purification by flash chromatography (SiO2; heptane: dichloromethane (1:1, 0:1)) afforded the sub-title compound as a yellow solid. Yield: 3.0 g (30%). Estimated purity: 75% (NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][CH2:27][CH2:26][O:25][CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24][O:19]4)=[CH:30][CH:31]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1ccc(OCCOC2CCCCO2)cc1
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(OCCOC3CCCCO3)cc2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 11) (0.3 g, 1 mmol), 4-{[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]oxy}aniline (Intermediate 18) (0.28 g, 1.2 eq), HATU (0.8 g, 2 eq), and NEt3 (440 μL, 3 eq) in DMF was stirred at 45° C. for 18 hours. The solvent was evaporated and the residue was washed with water and extracted with a mixture of ether and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained and used in the next step without purification and isolation.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1Cl)[C:12](Cl)=[O:13])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:19]([C:21]1[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:19]([C:21]1[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([S:6](=[O:8])(=[O:7])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=1)[CH3:20]
Reactant: CCCCNS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CCc1cc2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCNS(=O)(=O)c1cccc(C(=O)c2c(CC)oc3ccccc23)c1

Procedure:
is obtained as described in Example 1 from 10 g of 3-butylsulfamoyl-4-chlorobenzoyl chloride and 5.1 g of 2-ethylbenzo[b]-furan in the presence of 9.4 g of aluminum chloride, in the form of a colorless to slightly yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)[CH:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(C)=O>[C:22]12([C:10]3[CH:9]=[C:8]([C:5]4[N:6]=[CH:7][C:2]([NH:1][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:3][N:4]=4)[CH:13]=[CH:12][C:11]=3[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]3)[CH2:31]1)[CH2:29]2
Reactant: Nc1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CNc1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a suspension of 5-amino-2-[3-(1-adamantyl)-4-benzyloxyphenyl]pyrimidine (49 mg, 0.12 mmol) and K2CO3 (69 mg, 0.50 mmol) in acetone (5 mL) was added ethyl bromoacetate (53 μl, 0.48 mmol). The mixture was heated at reflux under argon for 19 h and cooled to room temperature. After removal of acetone at reduced pressure, the residue was diluted with water (8 mL) and extracted with EtOAc (60 mL). The extract was washed (H2O and brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (14% EtOAc/hexane) to give 53 mg (89%) of 2-[3-(1-adamantyl)-4-benzyloxyphenyl]-5-(carbethoxymethylamino)pyrimidine as a pale-tan solid, mp 153-156° C. IR 3455, 2901, 1710, 1179 cm−1; 1H NMR (CDCl3) δ 1.33 (t, J=7.2 Hz, 3H, OCH2CH3), 1.75 (bs, 6H, AdCH2), 2.07 (bs, 3H, AdCH), 2.24 (m, 6H, AdCH2), 4.31 (q, J=7.2 Hz, 2H, OCH2CH3), 4.60 (m, 1H, NH), 4.73 (s, 2H, NHCH2CO), 5.20 (s, 2H, C6H5CH2), 7.03 (d, J=8.4 Hz, 1H, 5′-ArH), 7.32-7.55 (m, 5H, C6H5), 8.17 (dd, J=8.4 Hz, 2.1 Hz, 1H, 6′-ArH), 8.32 (d, J=2.1 Hz, 1H, 2′-ArH), 8.46 ppm (s, 2H, 4-ArH, 6-ArH). HRMS calcd C31H35N3O3 [M+H]+ 498.2757. found 498.2762.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[S:30](=[O:33])(=[O:32])[CH2:31][C:22]=3[C:21]([C:34](OCC)=[O:35])=[N:20]2)[CH:16]=[CH:17][CH:18]=1.O>C1COCC1>[N:5]1([C:34]([C:21]2[C:22]3[CH2:31][S:30](=[O:32])(=[O:33])[C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:23]=3[N:19]([C:15]3[CH:14]=[C:13]([CH2:12][OH:11])[CH:18]=[CH:17][CH:16]=3)[N:20]=2)=[O:35])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1nn(-c2cccc(CO)c2)c2c1CS(=O)(=O)c1ccccc1-2
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1nn(-c2cccc(CO)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of aluminium chloride (5.13 g; 38.49 mmol; 4.93 eq.) in THF (30 mL) stirred for 25 min at 4° C. is added morpholine (5.40 ml; 61.36 mmol; 7.86 eq.) and the reaction mixture is stirred at 4° C. for 1 h. Ethyl 1-[3-(hydroxymethyl)phenyl]-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (3.11 g; 7.81 mmol; 1 eq.) is added and the reaction mixture is allowed to warm up to rt. After 22 h, the reaction mixture is cooled down to 0° C. then water is added slowly (total volume 25 mL). After 30 min stirring, the product is extracted with DCM. The organic phase is washed with an aqueous solution of Rochelle salts (˜0.7 m; pH=5), brine then dried over MgSO4. The solvent is removed under reduced pressure to afford 3.39 g (99%) of the title compound as a pale yellow solid. HPLC (max plot) 95.6%; Rt 3.08 min. MS (ESI+): 440.0.
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: COC(=O)C1=CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=CCCN(CCC2COc3ccccc3C2)C1
Reaction time: 16 h
Yield: 97.6 %

Procedure:
First 3.3 g (14.8 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 6.1 g (47.3 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 4.5 g (13.5 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 70 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.97 g (97.7%) of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and melts at 175°-177°.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([NH:18][C:19]([S:23][CH3:24])=[N:20]3)=[C:16]([NH2:25])[N:15]=2)=[N:6]1.[C:30](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([S:23][CH3:24])[N:20]3[CH3:30])=[C:16]([NH2:25])[N:15]=2)=[N:6]1
Reactant: CSc1nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2n1C
Temperature: 70 °C
Reaction time: 48 h
Yield: 24.2 %

Procedure:
100 mg (0.255 mmol) of the compound from example 29 were dissolved in 5 ml of dimethylformamide, and 49 mg (0.357 mmol) of potassium carbonate were added. The mixture was heated to 70° C. for 10 min and, after cooling, 18 μl (0.291 mmol) of iodomethane were added and the mixture was stirred at RT for 48 h. The mixture was concentrated and the residue was taken up in water and acidified with acetic acid. A solid precipitates out, which was filtered off and washed with water. The purification was effected by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 26 mg of the title compound were obtained (24% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:5][CH:4]=1.[C:17]([O:20][C@@H:21]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@@H:22]1OC(=N)C(Cl)(Cl)Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:20][C@@H:21]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@H:22]1[O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:19])[CH3:18]
Reactant: COc1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Product: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 2-(4-methoxybenzyl)phenol (46 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.13 g) in dichloromethane (2 mL) was added boron trifluoride diethyl ether complex (0.033 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: dichloromethane) to give 2-(4-methoxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.11 g).