Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:25])[CH2:18][C@@H:19]([OH:24])[CH2:20][C:21]([O-:23])=[O:22])=[C:13]([CH:26]([CH3:28])[CH3:27])[N:12]=[C:11]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[N:10]=2)=[CH:5][CH:4]=1>C(#N)C>[CH3:9][NH2:10].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:25])[CH2:18][C@@H:19]([OH:24])[CH2:20][C:21]([OH:23])=[O:22])=[C:13]([CH:26]([CH3:28])[CH3:27])[N:12]=[C:11]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Product: CN
Reaction time: 1 h

Procedure:
The obtained (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid sodium salt was dissolved in acetonitrile (100 ml), and purified water (190 ml) and a 1.0M hydrochloric acid aqueous solution (81 ml) were added thereto at 0° C., followed by stirring for 1 hour. Diisopropyl ether (250 ml) was added to the reaction liquid, followed by separation of the organic layer, and acetonitrile (81 ml) and a 40% methyl amine aqueous solution (7.3 ml) were added thereto at 0° C., followed by stirring at room temperature for 3 hours. The reaction liquid was stirred at 0° C. for 1 hour, and the precipitated solid was filtered, washed with acetonitrile (100 ml) and then dried under reduced pressure at 50° C. for 4 hours to give a (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid methylamine salt (10.25 g). Purified water (60 ml) was added to the solid to which a 2M sodium hydroxide aqueous solution (10 ml) was then added, followed by stirring for 1 hour, and the reaction solvent was distilled off under reduced pressure. Purified water (100 ml) was additionally added thereto, followed by another distillation under reduced pressure. To the resulting oil was added purified water (60 ml), and anhydrous calcium chloride (3.0 g) dissolved in purified water (10 ml) was added thereto, followed by stirring for 1 hour. The precipitated solid was filtered and washed with purified water (100 ml) to give the title compound (8.5 g, 77%). [α]D20 was +7.2 in 1% methanol, and the chiral purity was 99.9% ee, as confirmed by a HPLC method using the following chiral column.
Reaction SMILES: [OH-:1].[K+].[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[CH3:18])[CH:8]=[CH:9][CH:10]=1)#[N:4]>C(O)C.O>[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[CH3:18])[CH:8]=[CH:9][CH:10]=1)(=[O:1])[NH2:4]
Reactant: Cc1cc(I)ccc1-c1cccc(C#N)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(I)ccc1-c1cccc(C(N)=O)c1
Yield: 23 %

Procedure:
Potassium hydroxide (1.21 gm, 21.6 mmol) was added to a solution of 1-(3-cyanophenyl)-4-iodo-2-methylbenzene (1.27 gm, 4.0 mmol) in ethanol (50 mL) and heated under reflux for 16 h. After being cooled, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give crude product (1.08 gm). The crude product (540 mg) was purified by flash chromatography (gradient elution with dichloromethane:sat. methanolic ammonia 100:2.5 to dichloromethane:ethyl acetate 1:1 to dichloromethane:ethyl acetate:acetic acid 100:100:4), then azeotroped with ethanol, ethyl acetate and diethyl ether to give 1-(3-carbamoylphenyl)-4-iodo-2-methylbenzene (310 mg, 46%) as a buff solid.
Reaction SMILES: CC(N1CC2C=C(SC)C=CC=2N(CC=C)S1(=O)=[O:19])C.[Cl:21][CH2:22][CH2:23][N:24]1[C:29]2[CH:30]=[CH:31][C:32]([S:34][CH3:35])=[CH:33][C:28]=2[CH2:27][N:26]([CH:36]([CH3:38])[CH3:37])[S:25]1(=[O:40])=[O:39].ClC1C=CC=C(C(OO)=O)C=1.[OH-:52].[Na+]>O.C(Cl)(Cl)Cl>[Cl:21][CH2:22][CH2:23][N:24]1[C:29]2[CH:30]=[CH:31][C:32]([S:34]([CH3:35])(=[O:19])=[O:52])=[CH:33][C:28]=2[CH2:27][N:26]([CH:36]([CH3:38])[CH3:37])[S:25]1(=[O:40])=[O:39]
Reactant: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2CCCl
Reactant: C=CCN1c2ccc(SC)cc2CN(C(C)C)S1(=O)=O
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)N1Cc2cc(S(C)(=O)=O)ccc2N(CCCl)S1(=O)=O
Reaction time: 0.25 h

Procedure:
A 500 mL 3 necked flask equipped thermometer, pressure equalized dropping funnel, nitrogen bubbler and magnetic stirrer bar was charged with 1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-6-methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide (10.0 g, 0.0299 mol) and chloroform (200 ml). To this solution was added in one portion m-chloroperbenzoic acid (20.6 g , ˜4 equivalents, nominal purity 56-86%), this resulted in an exotherm which raised the temperature from 20° C. to 50° C. This solution was then stirred for 15 mins, water (100 ml) was added then 2M sodium hydroxide (100 ml). The organic layer was separated, washed again with 2M sodium hydroxide (100 ml), then water (100 ml) dried (MgSO4), filtered and the filtrate evaporated under reduced pressure to leave a white-cream foam, which was dried at 45° C. in vacuo to yield the product.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:3].[CH2:11]([O:13][N:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])C.Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:11][O:13][N:14]1[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]
Reactant: C=C(C)C1CCCCC1=O
Reactant: CCCCCC=NOCC
Agent: CCCCCC1C/C(C)=C/CCCCC(=O)N1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCCCC1CC(C)=CCCCCC(=O)N1OC

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cyclohexanone (0.88 g, 6.38 mmol), hexanal O-ethyl oxime (0.99 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.00 g, 59% yield). E isomer>98%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:16])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Br)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: BrCc1cccc(Br)n1

Procedure:
A mixture of 2-bromo-6-methylpyridine (5.7 ml), NBS (8.9 g) and benzoyl peroxide (50 mg) in CCl4 (50 ml) were heated to reflux for 16 h. The reaction was filtered and the solution obtained was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ 7.56 (1H, t, J=7.8 Hz), 7.45–7.40 (1H, m), 7.28 (1H, d, J=8.2 Hz), 4.50 (2H, s). b) (6-Bromopyridin-2-ylmethyl)dimethylamine 2-Bromo-6-bromomethyl-pyridine and NHMe2 (10 ml of 2M solution in THF) were reacted at RT for 16 h. The reaction mixture was poured into H2O, extracted into CH2Cl2 and the concentrated residue purified by column chromatography on silica, eluting with 1% MeOH/CH2Cl2 to give the title compound (440 mg). 1H NMR (400 MHz, CDCl3) δ 7.53 (1H, t, J=7.6 Hz), 7.40 (1H, d, J=7.5 Hz), 7.36 (1H, d, J=7.8 Hz), 3.57 (2H, s), 2.29 (6H, s). c) Dimethyl-{6-[3-(5-methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindol-8-yl]pyridin-2-ylmethyl}amine Prepared in a similar manner to Example 26 using (6-bromopyridin-2-ylmethyl)-dimethylamine to give the title compound (40 mg, 39%). 1H NMR (360 MHz, CDCl3) δ 8.63 (1H, d, J=1.1 Hz), 8.13 (1H, dd, J=8.1, 1.5 Hz), 7.78 (1H, t, J=7.7 Hz), 7.67 (1H, d, J=7.7 Hz), 7.56–7.54 (2H, m), 7.47–7.34 (5H, m), 4.06 (2H, s), 3.70 (2H, s), 2.73 (3H, s), 2.37 (6H, s), m/z (ES+) 449 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][C:11](=CN(C)C)[C:10](=O)[C:9]=2[N:8]([CH3:20])[N:7]=1)=[O:5])[CH3:2].[C:21]([O-])(=O)C.[K+].S(O)(O)(=O)=O.[CH3:31][NH:32][C:33](=[NH:35])[SH:34]>CN(C)C=O>[CH3:20][N:8]1[C:9]2[C:10]3[N:35]=[C:33]([S:34][CH3:21])[N:32]=[CH:31][C:11]=3[CH2:12][CH2:13][C:14]=2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7]1
Reactant: CCOC(=O)c1nn(C)c2c1CCC(=CN(C)C)C2=O
Reactant: CNC(=N)S
Reactant: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(SC)nc1-2
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
9 g (69 mmol) of ethyl-6-[(dimethylamino)methylene]-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate were dissolved in 350 mL of anhydrous dimethylformamide and 13.4 g of anhydrous potassium acetate (138 mmol) and 19.18 g (69 mmol) of methylisothiourea sulfate were added. The mixture was maintained at 90° C. under stirring for 8 hours. The solvent was then evaporated, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude was finally triturated with diethyl ether and collected by filtration to give 15.5 g (74% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:5]=1[OH:31])[CH2:2][CH3:3].Br[C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[C:33]([O:31][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3])([CH3:40])[CH3:39])[CH3:38]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1OC(C)(C)C(=O)OCC
Temperature: 55 °C

Procedure:
A mixture of 2-propyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-propylphenoxy}-2-methylpropionic acid ethyl ester, 1H NMR (400 MHz, CDCl3), δ 8.04 (d, J=8.3 Hz, 2H), 7.65 (dd, J=11.0, 8.1 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.70 (d, J=2.9 Hz, 1H), 6.64-6.57 (m, 2H), 4.27-4.17 (m, 4H), 2.96 (t, J=6.8 Hz, 2H), 2.54 (t, J=7.1 Hz, 2H), 2.38 (s, 3H), 1.59 (quintet, 7.6 Hz, 2H), 1.53 (s, 6H), 1.26 (t, J=6.8 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H), MS (ES) m/e 528 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2([F:36])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][P:23](=[O:34])([O:29]C(C)(C)C)[O:24]C(C)(C)C)[C:9]2=[O:35])[CH:7]=1.FC(F)(F)C(O)=O.[C:46]([NH2:50])([CH3:49])([CH3:48])[CH3:47]>ClCCl>[C:46]([NH2+:50][C:6]([CH3:8])([CH3:7])[CH3:5])([CH3:49])([CH3:48])[CH3:47].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C@@:8]2([F:36])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][P:23](=[O:24])([O-:29])[O-:34])[C:9]2=[O:35])[CH:7]=1.[C:46]([NH2+:50][C:6]([CH3:8])([CH3:7])[CH3:5])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)N
Reactant: COc1ccc(Cl)cc1C1(F)C(=O)N(COP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[NH2+]C(C)(C)C
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COP(=O)([O-])[O-])c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.9 %

Procedure:
To a 100 mL flask containing phosphoric acid di-tert-butyl ester 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indol-1-ylmethyl ester ((S)-III) (0.500 g, 0.860 mmol) was added 10 mL anhydrous dichloromethane, and trifluoroacetic acid (0.196 g, 1.72 mmol). The reaction was allowed to stir at room temperature for 24 hours. The dichloromethane was evaporated in vacuo, and the crude foam was purified by reverse phase chromatography (C18 2:1CH3CN:H2O), then the isolated free phosphate was dissolved in ethyl acetate and t-butyl amine (0.251 g, 3.44 mmol) was added and the solvent was evaporated in vacuo producing the title compound (0.100 g, 19%) as a white powder. 1H NMR (D2O 500 MHz): δ=7.89 (s, 1H), 7.78 (s, 1H), 7.50 (m, 2H), 7.41 (d, 1H, J=6.4 Hz), 7.03 (d, 1H, J=6.4 Hz), 5.63 (dd, 1H, J=12.0, 6.8 Hz), 5.56 (dd, 1H, J=12.0, 6.8 Hz), 3.56 (s, 3H), 1.36 (s, 18H); 31P NMR (D2O 202 MHz) δ=1.68; LRMS [M−H]−467.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[C:4]([OH:12])[CH:3]=1.[H-].[Na+].[C:15]([CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O)([F:18])([F:17])[F:16].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH2:19][C:15]([F:18])([F:17])[F:16])[N:5]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)(C)c1cc(Br)cc(O)n1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(Br)cc(OCC(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-6-(tert-butyl)pyridin-2-ol (5.00 g, 21.8 mmol) in dry DMF (50 mL) was added NaH (1.75 g, 43.7 mmol) at 0° C. under N2 and the mixture was stirred at 0° C. for 30 min. Then CF3CH2OTs (11.1 g, 43.7 mmol) was added and the solution was stirred at 70° C. overnight. Water was added and the mixture was extracted with EA twice. The combined organic layers were washed with water (3×) and brine twice, concentrated and purified by CC (PE/EA=30/1) to give compound P2a (1.13 g, 17%) as a white oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]([C:18]([NH:20][CH:21]([CH:30]([OH:33])[CH2:31][F:32])[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16].[C:34]1([C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[O:42][CH2:43][C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[O:42][CH2:43][C:44]([NH:12][C@H:13]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][F:32])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])=[O:45])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)COc1ccccc1-c1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C[C@H](NC(=O)COc1ccccc1-c1ccccc1)C(=O)NC(CC(=O)O)C(=O)CF

Procedure:
Starting with (3RS,4RS)-3-(leucinyl)amino-5-fluoro-4-hydroxypentanoic acid, tert-butyl ester, p-toluenesulfonate salt and following the methods described in Example 53, Parts C through E utilizing (2-phenylphenoxy)acetic acid in place of (1-naphthyloxy)acetic acid in Part C, gave the title compound as a white solid. MS(ES) for C25H29FN2O6 (MW 472.51): positive 495(M+Na), 511(M+K); negative 471(M−H), 585(M+TFA).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Br:31]
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.750 g, 2.2 mmol) in dry CHCl3 (100 mL), NBS (0.320 g, 1.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (700 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[CH:6][CH:5]=1.[CH2:20]=[C:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C.C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH2:20][C:21]12[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19]
Reactant: C=C1CCCC1
Reactant: COC(=O)c1ccc(/N=C/c2cccc(Br)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)C1(CCCC1)CC(c1cccc(Br)c1)N2
Temperature: 80 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a stirred solution 4-{[1-(3-bromo-phenyl)-meth-(E)-ylidene]amino}-benzoic acid methyl ester (3.2 g, 10.0 mmol) in acetonitrile (16.0 mL) were added methylene-cyclopentane (4.0 mL, 40.0 mol) and scandium(III) trifluoromethanesulfonate (Sc(OTf)3) (980.0 mg, 2.0 mmol). The resulting mixture solution was stirred at 80° C. for 16 h in sealed tube. The mixture solution was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2′-(3-bromo-phenyl)-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-quinoline]-6′-carboxylic acid methyl ester (1.6 g, 40%) as a light yellow solid: MS (ESI) M+1=400.0.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20](O)=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([N:30]3[CH2:31][CH2:32][CH2:33][CH:29]3[C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:34])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 18 h
Yield: 77.9 %

Procedure:
3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid (0.25 g, 0.80 mmol) was dissolved in N,N-dimethylformamide (3 ml), and proline tert-butyl ester (0.15 g, 0.88 mmol), WSC (0.31 g, 1.6 mmol) and HOBt (0.22 g, 1.6 mmol) were successively added thereto. The reaction mixture was stirred for 18 hrs, concentrated under reduced pressure and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from isopropyl ether to give the titled compound (0.29 g, 78%) as white crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2)=O.Cl.[OH:18][NH2:19].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:18][N:19]=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2
Reactant: CCC(=O)NC1CCc2cc(C=O)ccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(=O)NC1CCc2cc(C=NO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
1.18 g of N-(5-formylindan-1-yl)propionic acid amide were suspended in 20 ml of ethanol and 10 ml of water. 0.57 g of hydroxyamine hydrochloride and 0.67 g of sodium acetate were added to this suspension followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure followed by pouring into ice water and extracting with ethyl acetate. After washing the organic layer with saturated aqueous sodium bicarbonate and saturated brine, the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.25 g of the target compound. Yield: 100%
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1C)[CH:7]=[O:8])[CH3:2].[OH:13][C:14]1C=C(C=C(O)[CH:21]=1)C=O.C(I)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:11]=1)[CH:7]=[O:8])[CH3:21]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(OCC)c1

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate E10, vide infra) by reaction of 3,5-dihydroxybenzaldehyde with ethyl iodide in DMF using K2CO3 as base.
Reaction SMILES: C[S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(=O)(=O)[NH:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=CC=1C(O)=O.N1CCCC1>>[CH:32]1([CH2:31][NH:30][S:2]([C:5]2[CH:6]=[CH:7][C:8]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:34][CH2:33]1
Reactant: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: C1CCNC1
Product: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1N1CCCC1
Yield: 38 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(cyclopropylmethyl-sulfamoyl)-benzoic acid and pyrrolidine and obtained in 38% yield.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[Br:21]Br.O>O>[Br:21][C:18]1[C:17]([Cl:20])=[CH:16][C:5]2[N:6]([C@@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:2]([Cl:1])=[N:3][C:4]=2[CH:19]=1
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: BrBr
Solvent: O
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)c(Cl)cc32)[C@H](O)[C@@H]1O
Reaction time: 3 h

Procedure:
To a suspension of 0.319 g (1.0 mmol) of 2,6-dichloro-1-β-D-ribofuranosylbenzimidazole (67) in 10 mL of H2O, was added dropwise a sat. solution of Br2 /H2O at room temperature. After the addition had been completed, stirring was continued for 3 hr. The reaction mixture was filtered and the solid was washed with portions of H2O and then recrystallized from MeOH to give 0.335 g (78%, as M MeOH) of 95 as white crystalline needles. MP 140°-142° C. MS (EI) m/e 395.9274 (2%, M+ =395.9279). 1H NMR (DMSO-d6): δ 8.88 (s, 1, 7-H), 8.08 (s, 1, 4-H), 5.89 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.49 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.40 (t, 5'-OH, J5'-5'OH =4.0 Hz), 5.28 (d, 1, 340 -OH, J3'-3'OH =4.5 HZ), 4.42 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.13 (m, 1, 3'-H, J3'-4' =1.5 Hz), 4.01 (m, 1, 4'-H, J4'-5' =J4'-5" =2.5 Hz), 3.70 (m, 2, 5'-H J5'-5" =12.0 Hz). Anal. Calcd. for C12H11BrCl2N2O4MeOH: C, 36.30; H, 3.51; N, 6.51. Found: C, 35.98; H, 3.60; N, 6.39.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Br:9][CH:10]([CH3:18])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>COCCOC>[Br-:9].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N+:3]=1[CH:10]([C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:18]
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)C(=O)C(C)Br
Solvent: COCCOC
Product: CCOC(=O)C(=O)C(C)[n+]1cc(F)ccc1N
Product: [Br-]
Yield: 61.5 %

Procedure:
A solution 2-amino-5-fluoropyridine (5-A, 3.04 g, 27.1 mmol) and ethyl 3-bromo-2-oxobutanoate (5-B, 5.67 g, 27.1 mmol) in DME (15 mL) was stirred at rt for 1 day. The resultant solid precipitate was collected by filtration, and washed with Et2O, to afford compound 5-C as an off-white solid (5.35 g, 82%), which was used without purification in the subsequent step.