Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[CH:17]1([O:8][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:9][CH3:10])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(Br)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC1CCCC1
Temperature: 60 °C
Yield: 96.6 %

Procedure:
A stirred solution of 5-bromo-2-methoxyphenol (74 g) and anhydrous potassium carbonate (73.6 g) in dry dimethylformamide (500 mL) is treated with cyclopentyl bromide (80.5 g) and the solution is heated at 60° C. for 16 hours. It is then concentrated, and the resulting residue is triturated with water (250 mL), and extracted with dichloromethane (3×250 mL). The combined extracts are dried and evaporated, to give 3-cyclopentyloxy-4-methoxyphenyl bromide (95.5 g), in the form of a light brown oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1>C1CCCCC1.CCOC(C)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[N:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]2=[N:14]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: BrCCCCC#Cc1ccccn1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C(#Cc1ccccn1)CCCCn1nc2ccccc2n1
Yield: 13.3 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05 mmol) and benzotriazole (125 mg, 1.05 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-benzo[d][1,2,3]triazole (38 mg, 0.14 mmol, 13%) as a brown oil and (cyclohexane/AcOEt 1:1) to yield 1-(6-(pyridin-2-yl)hex-5-ynyl)-1H-benzo[d][1,2,3]triazole (48 mg, 0.17 mmol, 16%) as a brown oil.
Reaction SMILES: [CH2:1]1[C@@H:4]([C:5]([OH:7])=O)[NH:3][CH2:2]1.[CH3:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[NH:19]C(=O)O[C:15](=[O:16])[C:14]=12>CS(C)=O>[CH3:8][C:9]1[C:14]2[C:15](=[O:16])[N:3]3[CH2:2][CH2:1][C@H:4]3[C:5](=[O:7])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CS(C)=O
Product: Cc1cccc2c1C(=O)N1CC[C@H]1C(=O)N2

Procedure:
13.0 g (128.4 mmol) of L-azetidine-2-carboxylic acid and 22.7 g (128.4 mmol) of 6-methyl-isatoic acid anhydride in 150 ml of dimethyl sulphoxide are heated to 95° for 3 hours, evaporated to dryness in a high vacuum and the residue obtained is heated to 140° for 2.25 hours. By crystallization from ethyl acetate there is obtained (S)-1,10a-dihydro-5-methyl-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione of melting point 159°-160°.
Reaction SMILES: [C:1](NCC(O)=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C(N(CC)C(C)C)(C)C.[NH2:32][CH2:33][C:34]([NH:36][C:37]1[CH:51]=[CH:50][C:40]([CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:39][CH:38]=1)=[O:35]>CN(C=O)C>[C:45]([O:44][C:43]([NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:34](=[O:35])[CH2:33][NH:32][C:1](=[O:2])[O:3][CH2:4][CH:5]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:51][CH:50]=1)=[O:49])([CH3:46])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CN)cc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of Fmoc-Glycine (16 g, 54 mmol, 1.0 eq.) in dry DMF (160 mL) at 0° C. was added N,N-diisopropylethylamine (14 g, 108 mmol, 2.0 eq) and N N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (16 g, 54 mmol, 1.0 eq). The mixture was stirred at 0° C. for 30 min and a solution of tert-butyl [4-(glycylamino)benzyl]carbamate (12 g, 54 mmol, 1.0 eq.) in dry DMF (50 mL) was added. The mixture was stirred at room temperature overnight poured into ice water (400 mL) and extracted with EtOAc (400 mL×2). The organic layer was washed with brine (200 mL×2), dried over Na2SO4 and concentrated in vacuum. The residue was re-crystallized from EtOAc (200 mL) and petroleum ether (400 mL) to afford #B118 (18 g, 66.6%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ 9.93 (s, 1H), 7.91 (d, 2H), 7.75 (d, 2H), 7.61 (m, 1H), 7.52 (d, 2H), 7.43 (m, 2H), 7.36 (m, 3H), 7.18 (d, 3H), 4.32 (d, 2H), 4.26 (m, 1H), 4.07 (d, 2H), 3.80 (d, 2H), 1.39 (s, 9H)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1)=[CH2:3].[H][H]>[Pd]>[CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10])[CH3:3]
Reactant: C=C(C)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)c1cccc(N)c1
Yield: 78.1 %

Procedure:
Treatment of 3-nitroacetophenone (10 g) with methyltriphenyl phosphonium bromide (28 g) and n-butyllithium in hexane (78.4 mmol), as described in Example 1a, gave 3-(1-methylethenyl)nitrobenzene (9.5 g), δ (60 MHz, CDCl3) 2.1 (3H, s, CH3), 5.2 and 5.5 (2H, 2s, CH2), 7.2 to 8.2 (4H, m, ArH). Treatment of the above 3-(1-methylethenyl)nitrobenzene (9.5 g) with hydrogen and palladium on carbon (10%, 1.9 g) as described in Example 1a, gave 3-(1-methylethyl)aniline (6.15 g), δ (60 MHz, CDCl3) 1.1 (6H, d, (CH3)2), 2.6 (1H, m, CH) 3.4 (2H, bs, NH2) and 6.1 to 7.0 (4H, m, ArH).
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[OH-].[Na+]>C(O)C>[OH:2][CH2:1][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(c2nn(CO)c3ccccc23)CC1
Yield: 38 %

Procedure:
A solution of 0.52 g of paraformaldehyde, 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole, 15 ml of ethanol and 0.34 ml of 5% aqueous sodium hydroxide was refluxed for 3 hrs. The ethanol was removed in vacuo and the residue diluted with water. The aqueous suspension was extracted with dichloromethane (2x, 50 ml) and the combined extracts were washed with water and dried over anhydrous magnesium sulfate. The dichloromethane was evaporated in vacuo to yield an oil, which crystallized upon standing. The solid was recrystallized twice from ethyl acetate to yield 1.3 g (57.8%) of product, mp 128°-130° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11](Cl)[NH:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:30])([F:29])[C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([N:26]3[CH2:27][CH2:28][N:23]([C:18]4[C:17]([C:16]([F:30])([F:15])[F:29])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:24][CH2:25]3)[NH:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: CC(C)(C)c1ccc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The reaction of 6-tert-butyl-2-chloro-1H-benzoimidazole (0.209 g, 1 mmol, Example 17b) with 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.346 g, 1.65 mmol, Maybridge) under the conditions of Example 3c afforded the title compound as a white solid. M.P. 247-249° C. MS (ESI, pos. ion) m/z: 404 (M+1).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:35][C:36]([NH2:38])=[NH:37])[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:35][C:36]2[N:38]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[C:5]=3[N:37]=2)[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(O)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(O)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-hydroxy-cyclohexanone (188 mg, 1 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (223 mg, 0.60 mmol) using in analogous manner the procedure described in example 45b). Obtained as a white solid (36 mg, 17%). MS ISP (m/e): 352.3 (100) [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][C@H:6]([NH:24][C:25](=[O:27])[CH3:26])[C@H:7]([OH:23])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[CH2:12][CH2:11]1.[OH-].[NH4+]>CO.ClCCl>[F:31][C:29]1[CH:28]=[C:4]([CH:3]=[C:2]([F:1])[CH:30]=1)[CH2:5][C@H:6]([NH:24][C:25](=[O:27])[CH3:26])[C@H:7]([OH:23])[CH2:8][NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[CH2:12][CH2:11]1
Reactant: CCc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)CCN2C
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)CCN2C
Yield: 32 %

Procedure:
Silica gel chromatography of approximately 0.1 g of N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino]-2-hydroxypropyl}acetamide using methanol/dichloromethane (8/92) with 0.1% ammonium hydroxide gave 0.032 g of N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-hydroxypropyl)acetamide [Rf (MeOH/CH2Cl2/NH4OH)=0.40; MS (ESI+) for C24H31F2N3O2 m/z 432.2 (M+H)+]. Re-chromatography of mixed fractions gave 0.011 g of a 9:1 mixture of the 4R isomer [Rf (MeOH/CH2Cl2/NH4OH)=0.35; MS (ESI+) for C24H31F2N3O2 m/z 432.2 (M+H)+] and the 4S isomer.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(=O)C1C=CC=CC=1>>[OH:29][CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc2ccccc2n1
Agent: O=C(O)c1ccccc1
Solvent: c1ccc2ncccc2c1
Product: OC(Cc1ccc2ccccc2n1)c1ccccc1
Temperature: 25 °C
Yield: 17.5 %

Procedure:
The method used is that of SKIDMORE and TIDD[The Quinoline series, Part I, 1641-1645, (1959)]. 5.3 ml of 2-methylquinoline (0.039 mol) and 3.56 ml of benzaldehyde 0.035 mol) are mixed with a little benzoic acid. The mixture is stirred at room temperature and the product is then left to crystallize for several weeks. The solution is filtered through sintered glass and the filter is rinsed with cold ethanol. The crystals remaining on the sintered glass are recrystallized in ethanol and then placed in a heating desiccator. 1.53 g of 2-(2-hydroxy-2-phenylethyl)quinoline are thereby obtained (Yld=24%). The filtrates are combined, the solvent is evaporated off therefrom and the products are then deposited on a silica column. 3.66 g of 2-methylquinoline and 1.9 g of 2-styrylquinoline are then obtained (Yld=18%). 69% of the starting 2-methylquinoline is recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:11]2[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[N:10]2[N:9]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:37]>C1(C)C=CC=CC=1>[Cl:37][C:15]1[N:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[C:11]2[N:12]=[C:13]([CH3:17])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (I-2A-1a; 30.0 g, 80.8 mmol) in toluene (400 ml) at room temperature was added diisopropylethylamine (30.3 ml, 173 mmol) and then POCl3 (15.9 ml, 168 mmol) over 10 minutes. The mixture was heated at 80° C. for 5 hours, cooled to room temperature, and then slowly quenched by slow addition to half saturated brine (300 ml). The biphasic mixture was flitered through Celite® to remove the brown solids that formed on quench. The organic layer was separated and washed with saturated aqueous NaHCO3 (200 ml) and then brine (200 ml). The organic solution was concentrated, in vacuo, to ½ volume and then filtered through a cotton plug. The solution was further concentrated to ¼ volume, at which point, a yellow solid began to precipitate. Hexane (300 ml) was then added and stirred for 1 hour. The solids were collected on a sintered glass funnel and dried, in vacuo, to afford the desired product I-2A-1b (22.3 g, 71%) as a dark-yellow solid: +APcI MS (M+1) 389.1; 1H NMR (400 MHz, CD2Cl2) δ 7.50-7.39 (m, 6H), 7.28 (d, J=8.7 Hz, 2H), 2.73 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[BH4-].[Na+]>CO>[CH:29]1([NH:32][CH2:18][C:17]2[CH:16]=[C:15]([CH:14]3[C:5]4=[N:4][NH:3][C:2](=[O:1])[C:11]5[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=54)[NH:12][CH:13]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1cccc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
A mixture of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (70 mg, 0.19 mmol) and cyclopropanamine (32.55 mg, 0.57 mmol) in anhydrous methanol (10 mL) was stirred at room temperature for 1.5 h. Then the mixture was cooled to 0° C., sodium borohydride (10.82 mg, 0.286 mmol) was added portion-wise. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), extracted with 1N hydrochloric acid (20 mL), the aqueous layer was separated. The organic layer was washed with 1N hydrochloric acid (20 mL). The combined aqueous layers were adjusted to pH=9 with potassium carbonate, extracted with ethyl acetate (25 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated to give 9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (15 mg, yield 19%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.19-0.29 (m, 4H), 1.74-1.80 (m, 1H), 3.55 (s, 2H), 4.16-4.19 (d, J=8.8 Hz, 1H), 4.60-4.62 (d, J=8.8 Hz, 1H), 6.88-6.90 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 7.01-7.10 (m, 6H), 7.13-7.15 (m, 2H), 7.42-7.44 (d, J=7.6 Hz, 1H), 7.48-7.75 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 408 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C@@H:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([O:34]CC)=[O:33].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][C@@H:9]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCCC[C@@H](Sc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC[C@@H](Sc1ccc(OCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
To a solution of ethyl {[2-methyl-4-({(1R)-1-[4′-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetate (10 mg, 0.02 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (2M, 1 mL) and the resulting mixture agitated for 1.5 hours at rt. The mixture was then reduced under vacuum, acidified with aqueous HCl (2M), extracted with DCM (2 mL) and reduced to afford the title compound as colourless oil (9 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:9]1([S:15]([NH:1][CH2:2][CH2:3][C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCc1ccco1
Solvent: c1ccncc1
Product: O=S(=O)(NCCc1ccco1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.2 g of 2-(2-aminoethyl)-furan are dissolved in 45 ml of pyridine and at 5° C. a solution of 8.8 g of benzenesulphonic acid chloride in 50 ml of pyridine is added. The resulting mixture is then stirred overnight at ambient temperature, the reaction product is evaporated down, the residue is taken up in water and extracted with methylene chloride. After the organic phase has been dried over magnesium sulphate the solution is concentrated by evaporation and chromatographed over a silica gel column using ethylene chloride.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:10]=2)[O:5][C:4]([CH3:18])([CH3:17])[CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH3:17])([CH3:18])[CH2:3][CH:2]2[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1ccc2c(c1)C(N)CC(C)(C)O2
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOc1ccc2c(c1)C(NS(C)(=O)=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
A reaction mixture of 3.0 g (12 mmol) of 4-amino-6-butoxy-2,2-dimethylchroman, 4.9 g (48 mmol) of triethylamine and 1.65 g (14.4 mmol) of methanesulfonyl chloride in 25 ml of THF was stirred at RT for 3 h. After concentrating, the residue was taken up in water and extracted with EA. After drying and concentrating, the product was crystallized using PE and 2.25 g of 6-butoxy-4-(methylsulfonyl)amino-2,2-dimethylchroman were obtained; m.p. 123-127° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>CN(C=O)C.[Cu]I.[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>[Br:8][C:6]1[N:7]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 120 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (10 g, 40 mmol), copper(I) iodide (0.91 g, 4.7 mmol), diisopropylethylamine (53 mL, 0.55 mol), and tetrakis(triphenylphosphine)-palladium(0) (2.3 g, 1.9 mmol) in DMF (120 mL) that was de-gassed with Ar was added trimethylsilylacetylene (6.7 mL, 48 mmol). The resulting mixture was stirred under an Ar atmosphere for 1 h at 120° C., after which it was evaporated to dryness in vacuo. The residue was subjected to silica gel chromatography eluting with 35% EtOAc in hexanes to give a brown oil that was triturated with hexanes to give the title compound (5.0 g, 47%). 1H NMR (CDCl3, 300 MHz): δ 8.04 (s, 1H), 5.10 (s, 2H), 0.28 (s, 9H). HPLC retention time: 2.75 minutes. MS ESI (m/z): 270.0, 272.0 (M+H)+, calc. 269.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:36])(=[O:35])[N:15]([C@H:20]([CH2:33][OH:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[C:29]([O:28][C:26]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]([N:15]([S:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:37])=[CH:13][CH:12]=1)(=[O:36])=[O:35])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:33][O:34][C:38](=[O:40])[CH3:39])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CC(=O)OC[C@H](CCCCNC(=O)OC(C)(C)C)N(CC(C)C)S(=O)(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamic acid tert-butyl ester (intermediate product (VII) of example 1, step D, 97 mg, 0.18 mmol) in anhydrous CH2Cl2 (3 mL) was added N,N-dimethylaminopyridine (22 mg, 0.18 mmol) and acetic anhydride (0.014 mL, 0.18 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated. Ethyl acetate (50 mL) was added and the organic layer was washed with water (30 mL), then dried with Na2SO4 and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate. The yield obtained was quantitative (100 mg).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:13]#[C:14][C:15]2[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[S:11][CH:12]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1>O1CCOCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:8]2[CH:9]=[C:10]([C:13]#[C:14][C:15]3[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[S:11][CH:12]=2)=[CH:32][CH:31]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Brc1csc(C#Cc2ccc(OCCN3CCCC3)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2csc(C#Cc3ccc(OCCN4CCCC4)cc3)c2)cc1

Procedure:
Under an N2 atmosphere 5 mL 2 M Na2CO3 solution and 47 mg (0.41 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 310 mg (0.82 mmol) 1-{2-[4-(4-bromo-thiophen-2-ylethynyl)-phenoxy]-ethyl}-pyrrolidine and 129 mg (0.82 mmol) 4-chlorophenyl-boric acid in 10 mL 1,4-dioxane and the reaction mixture is refluxed for 1 h. The hot solution is filtered through a fibreglass filter, the filtrate is extracted with EtOAc, the organic phase is washed with water and dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)C>CO>[CH2:13]([NH:21][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCN
Solvent: CCO
Solvent: CO
Product: CCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 65 °C

Procedure:
54 g of glucose (0.3 mol) are added to a solution of 40 g of octylamine (0.3 mol) in 50 ml of absolute methanol. The reaction mixture is heated to 65° C. for 20 min and then 50 ml of 95% hot ethanol are added. The N-octyl-β-D-glucopyranosylamine which precipitates on cooling (complete precipitation after 2 hours) is filtered off on a Buchner and then recrystallized from absolute ethand (1.5 1).