Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]1(C)[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C@H:4]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Br:19])=[CH:13][C:12]=2[OH:20])[C:3]1=[CH2:21].O[C@]1(C)CCC(C)(C)[C@H](CC2C=C(OC)C(Br)=CC=2O)C1=C>>[CH2:21]=[C:3]1[C@@H:4]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Br:19])=[CH:13][C:12]=2[OH:20])[C:5]([CH3:8])([CH3:9])[CH2:6][CH2:7][C:2]1=[O:1]
Reactant: C=C1[C@@H](Cc2cc(OC)c(Br)cc2O)C(C)(C)CC[C@]1(C)O
Agent: C=C1[C@@H](Cc2cc(OC)c(Br)cc2O)C(C)(C)CC[C@@]1(C)O
Product: C=C1C(=O)CCC(C)(C)[C@@H]1Cc1cc(OC)c(Br)cc1O

Procedure:
To a flame-dried 50 mL round-bottomed flask containing a solution of (3S)-2-methylidene-3-(2-hydroxy-4'-bromo-5'-methoxyphenyl)methyl-4,4-dimethylcyclohexan-1-one (61) (150.0 mg, 0.322 mmol) in 15 mL THF at -70° C. under nitrogen atmosphere was added methyllithium (0.60 mL of a 1.40M solution in ether, 0.840 mmol, 2.61 equiv), and the mixture was allowed to stir for 5 min before quenching with saturated aqueous NH4C1. Upon warming to room temperature, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over Na2SO4, and concentrated under diminished pressure gave a 3:1 (1R,3S: 1S,3S) mixture of the diastereomeric tertiary hydroxyls. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 28 mg (18%) of the less polar, minor 1S,3S isomer (63), along with 88 mg (57%) of the more polar, major 1R,3S isomer (62), as well as 30.2 mg (20%) recovered starting material. The diastereomeric alcohols were then independently converted to the corresponding free phenols in the usual manner, providing the trans, 1R,3S isomer (62) 1H NMR (400MHz, CDCl3) δ0.84 and 1.04 (2s, 2×3 H, geminal-CH3 's), 1.39 (s, 3H, 5-CH3), 2.43 (br dd, 1H, J-- 11.3, 2.9 Hz, 3-H), 2.72 and 2.85 (d of ABq, 2H, JAB =16.1 Hz, JA =3.1 Hz, JB =11.5 Hz, benzylic-CH2) 3.77 (s, 3H, OCH3), 4.57 and 5.16 (2s, 2×1H, methylidene-CH2), 6.63 (s, 1H, 6'-H), 6.93 ppm (s, 1H, 3'-H); and the cis, 1S,3S isomer (63) 1H NMR (400MHz, CDCl3) δ0.77 and 1.08 (2s, 2×3H, geminal-CH3 's), 1.36 (s, 3H, 5-CH3), 2.65 and 2.82 (d of ABq, 2H, JAB =16.0 Hz, JA =3.0 Hz, JB =11.8 Hz, benzylic-CH2), 2.97 (br dd, 1H, J=11.7, 2.5 Hz, 3-H), 3.79 (s, 3H, OCH3), 4.64 and 4.96 (2s, 2×1H, methylidene-CH2), 6.73 (s, 1H, 6'-H), 6.92 ppm (s, 1H, 3'-H). [Compound 63 is hereinafter also referred to as COMPOUND "J" or 120286, and Compound 62 is hereinafter also referred to as COMPOUND "P" or 120273] ##STR12##
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]([O:14][CH3:15])[NH:8][CH:9]=[C:10]([C:11](O)=[O:12])[C:5]=2[N:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1.C([N:23](CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(#N)C>[Br:1][C:2]1[C:6]2[CH:7]([O:14][CH3:15])[NH:8][CH:9]=[C:10]([C:11]([NH2:23])=[O:12])[C:5]=2[N:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: COC1NC=C(C(=O)O)c2c1c(Br)cn2C1CCCC1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: COC1NC=C(C(N)=O)c2c1c(Br)cn2C1CCCC1
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (894 mg), HOBt ammonium salt (1155 mg) and triethylamine (1.41 mL) in acetonitrile (8 mL) was added EDCI hydrochloride (1179 mg), and the mixture was stirred overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (654 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:37]([NH2:40])(=[O:39])[CH3:38].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:37]([NH:40][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:39])[CH3:38]
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Temperature: 100 °C
Yield: 39.9 %

Procedure:
A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (36 g, 69.9 mmol), acetamide (12.4 g, 209 mmol), Xantphos (4 g, 6.9 mmol), Cs2CO3 (45.5 g, 140 mmol) and Pd2(dba)3 (3.84 g, 4.2 mmol) in dioxane (500 mL) was heated at 100° C. under nitrogen for 2 h. The reaction mixture was cooled to RT, filtered to remove inorganic salts, and concentrated under vacuum. The residue was treated with water (300 mL) and extracted with EtOAc (3×400 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated dryness. The residue was purified by silica gel chromatography to afford N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (15 g, 44% yield). 1H NMR (400 MHz, DMSO-d6): 11.23 (s, 1 H), 10.60 (s, 1 H), 8.34 (dd, J=12.8, 7.2 Hz, 1 H), 8.20 (d, J=5.6 Hz, 1 H), 7.94 (d, J=8.0 Hz, 1 H), 7.68 (s, 1 H), 7.56-7.51 (m, 3 H), 7.40-7.36 (m, 2 H), 6.73 (dd, J=5.6, 2.4 Hz, 1 H), 6.56 (d, J=8.0 Hz, 1 H), 4.30 (q, J=6.8 Hz, 2 H), 2.05 (s, 3 H), 1.35 (t, J=6.8 Hz, 3 H); MS (ESI) m/z: 539.1 (M+H+).
Reaction SMILES: [F:1]C1C=CC(CC2SC=CC=2)=CC=1.II.OS(O)(=O)=O.F[C:22]1[CH:34]=C[C:25]([CH2:26][C:27]2[S:31][C:30]([I:32])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1>[Cl-].[Na+].O.C(O)(=O)C.C(OCC)(=O)C>[F:1][C:23]1[CH:22]=[CH:34][C:26]([C:27]2[S:31][C:30]([I:32])=[CH:29][CH:28]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(Cc2cccs2)cc1
Reactant: Fc1ccc(Cc2ccc(I)s2)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(-c2ccc(I)s2)cc1
Temperature: 35 °C

Procedure:
A mixture of 2-(4-fluorobenzyl)thiophene (8.4 g, 43.7 mmol), HIO3 (1.86 g, 10.6 mmol), I2 (4.86 g, 19.2 mmol), ethyl acetate (66 ml), acetic acid (7.7 ml) and conc. H2SO4 (0.79 ml) was heated at 35° C. overnight (GC-MS showed that all the starting material is converted to 5-(4-fluorobenzyl)-2-iodothiophene). To the reaction mixture was added brine solution (33 ml), the organic layer was separated and washed with sodium hydroxide/sodium thiosulfate solution (33 ml) (prepared from 2.3 g of NaOH, 3.3 g of Na2S2O3 in 27 ml of H2O), followed by 10% of NaHCO3 solution (33 ml). The organic layer was concentrated to yield 13.9 g of 5-(4-fluorophenyl)-2-iodothiophene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15](Br)[CH:16]=[C:11]2[N:10]=[N:9]1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)[CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: OB(O)c1ccsc1
Reactant: Cn1ncnc1COc1nc2c(cc1Br)nnn2-c1ccccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1-c1ccsc1)nnn2-c1ccccc1F
Temperature: 100 °C
Yield: 58.6 %

Procedure:
A mixture of 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.10 g, 0.247 mmol) (Example 3, step c), 3-thiopheneboronic acid (0.080 g, 0.60 mmol), caesium carbonate (0.26 g, 0.80 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.03 g, 10 mol %) in DMF (4 ml) and water (1 ml) was purged with nitrogen, then heated in a sealed tube at 100° C. for 5 h. The solution was cooled, diluted with water (50 ml) and extracted with 10% methanol-dichloromethane (2×30 ml). The extracts were washed with brine (30 ml), dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 4% methanol-dichloromethane, gave a brown gum that solidified on trituration with ethyl acetate. The material was recrystallised from ethyl acetate to give 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-(thien-3-yl)-1,2,3-triazolo[4,5-b]pyridine (0.059 g, 59%) as a beige solid, m.p. 133-135° C. (EtOAc). Found: C, 55.31; H, 3.38. C19H14N7OFS requires C, 55.40; H, 3.55%. δH (360 MHz; CDCl3) 3.73 (3H, s), 5.60 (2H, s), 7.36-7.46 (4H, m), 7.56-7.62 (1H, m), 7.66 (1H, dd, J=3 and 1), 7.71 (1H, dd, J=8 and 8), 7.86 (1H, s) and 8.46 (1H, s); m/z (ES+) 408 (M+H+).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.Cl.C([O-])(O)=O.[Na+]>ClCCl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10]
Reactant: C1=COCCC1
Reactant: OCCCCCCCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCCCCCCCCOC1CCCCO1
Yield: 99.7 %

Procedure:
1,8-Octanediol (16.8 g) (115 mmol) and 4.83 g of dihydropyran (57.5 mmol) in 1400 ml of dichloromethane containing 5 drops of concentrated HCl were stirred for 2 hours. Then 10 g of NaHCO3 were stirred in and the solution was filtered. Dichloromethane was removed with a rotary evaporator, and the resulting residue was triturated with pentane; the undissolved solid was 1,8-octanediol. The solid was filtered from the pentane solution, and the pentane was removed with a rotary evaporator to give 13.2 g (99.8%) of crude product oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=1[NH2:21]>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([NH:21][C:20]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=4[F:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(Br)ccc1OC2
Reactant: Nc1ccc(F)cc1F
Product: O=C(Nc1ccc(F)cc1F)c1cc2c(s1)-c1cc(Br)ccc1OC2

Procedure:
8-Bromo-4H-thieno[3,2-c]chromene-2-carbonyl chloride 4bp is reacted with 2,4-difluoroaniline to give 5bp, as in General Procedure B-bp.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[O-:10][C:11]#[N:12].[Na+].[O-]C#N>O>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:11]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: NCc1ccncc1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1ccncc1
Reaction time: 5 h

Procedure:
5.1 ml of 5N HCl was added to a solution of 2.53 ml of 4-picolylamine and 1.66 g of sodium cyanate in 50 ml of water. After 5 hours, a further 0.166 g of cyanate were added and the pH adjusted to 7.5. After 18 hours the reaction mixture was evaporated to dryness, the residue extracted with 100 ml of hot 2-propanol. The filtrate was concentrated, cooled and the solid collected to give the title compound (3.03 g) mp 194-6° C. A further 0.63 g could be isolated as second and third crops.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[C:17]([N:19]([CH2:22]C)[CH2:20]C)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]=O)=[C:27]([O:34][C:35]([F:38])([F:37])[F:36])[CH:26]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[ClH:57]>C(Cl)Cl.CCOC(C)=O>[ClH:57].[ClH:57].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:1][C@@H:2]2[CH2:3][CH2:4][C@H:5]([NH:8][C:9]3[N:18]=[C:17]([N:19]([CH3:20])[CH3:22])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:6][CH2:7]2)=[C:27]([O:34][C:35]([F:36])([F:37])[F:38])[CH:26]=1
Reactant: O=CCc1ccc(Br)cc1OC(F)(F)F
Reactant: CCN(CC)c1nc(N[C@H]2CC[C@@H](N)CC2)nc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NCCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a suspension of cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step C of example 9 (300 mg, 1.05 mmol) in CH2Cl2 (3 mL) were added (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde (357 mg, 1.26 mmol), AcOH (76 mg, 1.26 mmol), and NaBH(OAc)3 (334 mg, 1.57 mmol). The reaction mixture was stirred at ambient temperature for 4.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give a pale yellow solid. To a solution of above solid in EtOAc (0.8 mL) was added 4 M hydrogen chloride in EtOAc (0.25 mL). The mixture was stirred at ambient temperature for 30 min and concentrated. A solution of the residue in Et2O (2 mL) was stirred at ambient tempareture for 30 min. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give cis-N2-{4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N4,N4-dimethyl-quinazoline-2,4-diamine dihydrochloride (161 mg, 25%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].C([Li])(CC)C.[CH3:24][O:25][C:26]1[C:31]([O:32][CH2:33][O:34][CH3:35])=[CH:30][C:29]([O:36][CH3:37])=[C:28]([O:38][CH2:39][O:40][CH3:41])[C:27]=1[CH2:42][CH:43]=[O:44]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:8]=1[CH:43]([OH:44])[CH2:42][C:27]1[C:28]([O:38][CH2:39][O:40][CH3:41])=[C:29]([O:36][CH3:37])[CH:30]=[C:31]([O:32][CH2:33][O:34][CH3:35])[C:26]=1[O:25][CH3:24]
Reactant: COCOc1cc(OC)c(OCOC)c(CC=O)c1OC
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CC(O)c2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
351 Milligrams (1.36 mM) of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in a mixed solvent of 10 ml of tetrahydrofuran with 1 ml of hexamethylphosphoric triamide, and the solution was cooled to -78° C. in a dry ice-acetone bath. Then 1.60 ml (1.05M cyclohexane solution, 1.68 mM) of sec-butyllithium was added to the reaction mixture and stirred for 30 minutes. Next, a tetrahydrofuran solution containing 334 mg (1.11 mM) of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]acetoaldehyde in 2 ml of tetrahydrofuran was added thereto and stirred for 8 hours. The reaction mixture was concentrated under a reduced pressure, and the residue obtained was purified by a silica gel column chromatography (diameter 2 cm×length 10 cm, eluent: 40% ethyl acetate-n-hexane) to yield 503 mg of 1,2-bis[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethanol. Colorless oily substance.
Reaction SMILES: N[C:2]1[CH:3]=C(C=C([N+]([O-])=O)[C:10]=1C1C=CC=CC=1)C(O)=O.C(Br)C1C=CC=CC=1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([S:44](=[O:47])(=[O:46])[NH2:45])[C:37]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]([OH:34])=[O:33].C(Br)C=C>>[CH2:3]([NH:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([S:44](=[O:47])(=[O:46])[NH2:45])[C:37]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]([OH:34])=[O:33])[CH:2]=[CH2:10]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1
Agent: BrCc1ccccc1
Solvent: C=CCBr
Product: C=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step D, 3-amino-5-nitro-4-phenylbenzoic acid and benzyl bromide with equimolar amounts of 3-amino-4-phenyl-5-sulfamylbenzoic acid and allyl bromide respectively, and following the procedure described, 3-allylamino-4-phenyl-5-sulfamylbenzoic acid is obtained with a melting point of 169°-172.5° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15]Br)[CH:12]=[CH:11][C:10]=1[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH2:22]>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:22][CH3:21])[CH:12]=[CH:11][C:10]=1[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)NS(=O)(=O)c1cc(CBr)ccc1S(C)(=O)=O
Solvent: C1CCOC1
Product: CNCc1ccc(S(C)(=O)=O)c(S(=O)(=O)NC(C)(C)C)c1
Reaction time: 2.5 h
Yield: 73.7 %

Procedure:
At 0° C., 51 g of N-tert-butyl-5-bromomethyl-2-methanesulfonylbenzenesulfonamide (55% by weight A 28.05 g=0.669 mol) dissolved in 250 ml of THF are added to a solution of 59.5 ml (0.69 mol) of a 40% strength aqueous methylamine solution in 150 ml of THF. Stirring is continued at 0-5° C. for 2-3 h. For work-up, the solution is completely concentrated, the residue is taken up in plenty of 2N HCl and extracted with diethyl ether (2×200 ml). The acidic aqueous phase is adjusted to pH 9 with 4N NaOH and extracted with ethyl acetate (3×200 ml). The combined ethyl acetate extracts are washed with water, dried over Na2SO4 and evaporated in vacuo. 17 g (73.7%) of N-tert-butyl-5-methylaminomethyl-2-methanesulfonylbenzenesulfonamide of melting point 76-78° C. are obtained as residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([S:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].C([Si]([O:37][C:38]([O:40][CH3:41])=[CH2:39])(C)C)(C)(C)C.C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C.[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.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:41][O:40][C:38](=[O:37])[CH2:39][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([S:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: Cc1nc2c(Cl)ccc(OS(=O)(=O)C(F)(F)F)c2c(C)c1Sc1ccc(Cl)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(C)c12
Temperature: 120 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-3-(4-chlorophenylsulfanyl)-2,4-dimethylquinolin-5-yl ester (0.31 g), tert-butyl-(1-methoxyvinyloxy)dimethyl silane (0.71 mL), sodium acetate (0.064 g), bis(dibenzylideneacetone) palladium (0.018 g) and 1,1′-bis(diphenylphospino) ferrocene (0) (0.018 g) in N,N-dimethylformamide (4.0 mL) was heated by microwave irradiation at 120° C. for 15 minutes. The mixture was diluted with ethyl acetate, and this solution was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (1:1 to 2:0 by volume) gave title compound as a pale yellow solid, 0.15 g.
Reaction SMILES: [OH:1][C@@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].N1CCCCC1>CCO.C(O)(=O)C>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:23]2[S:19][C:20](=[O:25])[NH:21][C:22]2=[O:24])=[CH:7][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OC[C@@H](O)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3ccccc3)cc2)S1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
To a stirring solution of 4-[(2S)-2-hydroxy-2-phenylethoxy]benzaldehyde (2.63 g, 10.8 mmol) in absolute EtOH (75 ml) was added 2,4-thiazolidinedione (1.27 g, 10.8 mmol) and piperidine (0.54 mL, 5.4 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight. The reaction mixture was allowed to cool to RT. No precipitate formed. The pH of reaction mixture was ca. 5. Acetic acid (20 drops) was added. The reaction was evaporated in vacuo. The material was adsorbed onto silica gel and chromatographed eluting with 30-40% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 3.18 g (86%) of the title compound as a light yellow solid. MS (ESI−) for C18H15NO4S m/z 340.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([NH2:5])[CH2:3][NH2:4].[C:7]1([CH2:13][C:14](Cl)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[CH3:1][C:2]([NH2:5])([CH3:6])[CH2:3][NH:4][C:14](=[O:15])[CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(N)CN
Solvent: CCOCC
Product: CC(C)(N)CNC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of 1,1-dimethylethylenediamine (8.8 g.) in ether (250 ml.) was added during 2 hours to a stirred solution of phenylacetyl chloride (15.4 g.) in ether (250 ml.). This mixture was further stirred for 2 hours. The solid was separated by filtration, and dissolved in warm water (150 ml.). The solution obtained was filtered. The filtrate was basified by addition of an excess of saturated aqueous sodium carbonate solution (50 ml.), and then extracted with chloroform (3×250 ml.). The extracts were dried (MgSO4) and evaporated to give an oil which crystallised on addition of a 1:1 v/v mixture of ether and petrol (60°-80°) to give 1,1-dimethyl-2-(2-phenylacetamido)ethylamine (13.1 g., 63%), m.p. 47°-48° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([CH3:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:14])[C:6]=4[N:7]=[C:8]3[CH3:13])=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(c(=O)n(C)c(=O)n2C)n1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 1,3,8-trimethylxanthine (0.97 g) in DMF (20 ml) were added potassium carbonate (0.83 g) and 4-(4-chlorobenzoyl)benzyl bromide (1.55 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with acetone to provide the title compound as white powder (1.34 g, 61%). 1H-NMR (CDCl3) δ: 2.46(3H,s), 3.41(3H,s), 3.60(3H,s), 5.63(2H,s), 7.25-7.80(8H,m).