Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19]Br.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Fc1ccc(CBr)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCN(Cc2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (5 g, 25.0 mmol), 3,4-difluorobenzyl bromide (4.7 g, 22.7 mmol) and diisoproylethylamine (5.9 ml, 34.0 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (31 ml) was added and the reaction was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D7 (5.2 g, 93%) as a solid. C12H16F2N2 requires 226. Found 227 (MH+).
Reaction SMILES: CC(C)CN[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:17](=[S:19])=[S:18].C(O)C>[OH-].[Na+]>[S:18]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:17]1[SH:19]
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nc2cnc3ccccc3c2s1

Procedure:
N4-(2-methylpropyl)quinoline-3,4-diamine (5.4 g, 25 mmol) was combined with carbon disulfide (9 mL, 150 mmol) and ethanol (55 mL) and then heated at reflux on a steam bath for 2 hours. The resulting precipitate was isolated by filtration, washed with ethanol and then air dried to provide 4.4 g of crude product. A portion (1 g) was dissolved in hot dilute sodium hydroxide and then reprecipitated with acetic acid. The precipitate was isolated by filtration while still hot, washed with hexane and then air dried to provide thiazolo[4,5-c]quinoline-2-thiol as a solid, m.p. 282-284° C. Analysis: Calculated for C10H6N2S2: % C, 55.02; % H, 2.77; % N, 12.83: Found: % C, 54.96; % H, 2.69; % N, 12.74.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10]Cl)[N:7]=[C:4]2[S:5][CH:6]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O>[CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:7]=[C:4]2[S:5][CH:6]=1
Reactant: Cc1csc2nc(CCl)cn12
Reactant: C1COCCN1
Solvent: O
Product: Cc1csc2nc(CN3CCOCC3)cn12
Reaction time: 1 h

Procedure:
3.4 g of 3-methyl-6-chloromethyl-imidazo-(2,1-b)thiazole are slowly added into 50 ml of cooled and stirred morpholine. The stirring is continued for 1 hour at room temperature and another hour at 40°-50°. The suspension obtained is filtered and the filtrate is evaporated. The residue obtained is dissolved in water and the aqueous solution obtained is extracted with chloroform. The chloroform solution is washed at pH 5-6 with water and after drying it is evaporated. Ethyl acetate is added to the residue to yield 4.5 g of 3-methyl-6-morpholinomethyl-imidazo-(2,1-b)thiazole; m.p. 203°-204° (methyl-ethyl-ketone).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:29])[C:27]=1[F:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.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>[NH2:20][C:4]1[N:3]=[C:2]([C:24]2[CH:23]=[C:22]([F:21])[C:27]([F:28])=[C:26]([F:29])[CH:25]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: OB(O)c1cc(F)c(F)c(F)c1
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1nc(-c2cc(F)c(F)c(F)c2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 6.5 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 3,4,5-trifluorophenylboronic acid (107 mg, 0.609 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 30 s) for 40 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (30 mL) and washed with sat. aq. NaHCO3 (20 mL×2) and brine (20 mL) and dried over MgSO4. Purification by flash column chromatography (normal phase, ICN silica, 50 g, 18-32%, gradient 2.5-15% ethanol in DCM, residue dry loaded, product eluted in 15% ethanol) and by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 50% acetonitrile) afforded (2R,3R,4S,5R)-2-{6-amino-2-(3,4,5-trifluorophenyl)-9H-purin-9-yl}-5-(hydroxymethyl) tetrahydrofuran-3,4-diol 12 as a white solid (13.2 mg, 7%).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3][CH:2]1O.C1(P(=[CH:32][C:33]([O:35][CH3:36])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(O)C.[C].[Pd]>[OH:3][CH2:4][CH2:5][C:6]1([CH2:1][CH2:2][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OC1CC2(CCCCC2)CCO1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCCC1(CCO)CCCCC1
Yield: 34 %

Procedure:
To a solution of 3oxaspiro[5.5]undecan-2-ol (460 mg) in dichloromethane (15 mL) was added methyl triphenylphosphoranylideneacetate (1.36 g). After stirring the solution under reflux for 3 hours, methyl triphenylphosphoranylideneacetate (1.36 g) was further added thereto. The solution was stirred under reflux for 14 hours. The solution was concentrated under reduced pressure, and the resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1) to give a mixture of an unsaturated ester derivative and 3-oxaspiro[5.5]undecan-2-ol (520 mg) To a solution of the resulting mixture in ethanol (30 mL) was added 10% palladium-carbon (60 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 63 hours. The catalyst was filtered off, concentrated under reduced pressure and the resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1) to give the title compound (210 mg) 1HNMR (CDCl3) δ: 1.23-1.48 (m, 12H), 1.52-1.68 (m, 4H), 2.29 (t, 2H, J=7.2 Hz), 3.62-3.71 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:2]=1.[O-:14][Mn](=O)(=O)=O.[K+].[OH2:20]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:14])=[O:20])=[CH:11][CH:12]=2)[CH:2]=1
Reactant: Cc1ccc(-c2cccnc2)cc1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(-c2cccnc2)cc1
Yield: 76 %

Procedure:
To a mixture of 4-tolylboronic acid (38 g, 0.28 mol), 3-bromopyridine (44 g, 0.28 mol), Na2CO3 (200 g) in toluene (500 ml) and water (500 ml) was added Pd(PPh3)4 (16 g, 0.014 mol), and refluxed for 16 h. The reaction mixture was cooled, and the separated organic layer was washed with water and brine, and dried. The solvent was removed to give 4-(3-pyridyl)toluene (42 g, 90%). To a mixture of 4-(3-pyridyl)toluene (35 g, 0.207 mol) in pyridine (400 ml) and water (400 ml) was added KMnO4 (163 g, 1.03 mol) in portions and refluxed for 12 h. The reaction mixture was filtered through celite and acidified with conc. HCl. The product was washed with water and dried to give 4-(3-pyridyl)benzoic acid (32 g, 76%) as a white solid. To a mixture of 4-(3-pyridyl)benzoic acid (22 g, 0.11 mol) in THF (2.51), mCPBA (152 g, 0.44 mol, 50%) was added and stirred at RT for 12 h. The solid was filtered, and washed with THF to give 4-(1-oxido-3-pyridinyl)benzoic acid (20 g, 86%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH2:12]COCC)=[O:10].[H][H].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CN(C=O)C.CCCCCC>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][C:5]2([C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:7][CH2:8][C:4]2=[O:3])=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: CCOCCOC(=O)C1CCCC1=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)C1(Cc2ccc(F)cc2)CCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of n-hexane-washed sodium hydride (0.94 g, 39.0 mmol, 1.3 eq) there was added a solution of ethoxyethyl 2-oxocyclopentane-carboxylate (4.26 g, 30.0 mmol, 1.0 eq) in DMF (15 ml) at 0° C. The resulting solution was warmed to room temperature and then stirred for 30 min: the solution became orange. After terminal evolution of hydrogen had been confirmed, p-fluorobenzyl bromide (6.80 g, 36.0 m mol, 1.2 eq) was added to the resulting solution at 0° C. The reaction mixture was then warmed to room temperature and stirred overnight.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([SH:20])[S:18][CH:19]=2)=[CH:11][CH:10]=1.[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22].O>CN(C=O)C>[C:21]([O:25][C:26](=[O:29])[CH2:27][S:20][C:17]1[S:18][CH:19]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Sc1nc(-c2ccc(Cl)cc2)cs1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CSc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
888.7 mg (8.78 mmol) of triethylamine were added dropwise with caution to a solution of 1000 mg (4.39 mmol) of 4-(4-chloro-phenyl)-thiazole-2-thiol and 856.5 mg (4.39 mmol) of bromoacetic acid tert-butyl ester in 15 ml of DMF. The reaction mixture was stirred at room temperature for 1.5 h. Then water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated. Yield: 1.44 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[CH:18]=2)[N:14]([C@H:29]([C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=2)[CH3:30])[N:13]=1.Cl.[C:41]([O:45][C:46](=[O:50])[CH2:47][CH2:48][NH2:49])([CH3:44])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[CH:18]=2)[N:14]([C@H:29]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([NH:49][CH2:48][CH2:47][C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:50])=[O:37])=[CH:38][CH:39]=2)[CH3:30])[N:13]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: COc1ccc2cc(-c3cc(-c4cc(C(F)(F)F)ccc4F)nn3[C@@H](C)c3ccc(C(=O)O)cc3)ccc2c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3cc(-c4cc(C(F)(F)F)ccc4F)nn3[C@@H](C)c3ccc(C(=O)NCCC(=O)OC(C)(C)C)cc3)ccc2c1
Reaction time: 0.17 h

Procedure:
4-{(1S)-1-[3-[2-Fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoic acid (2.93 g, 5.48 mmol), beta-alanine t-butyl ester hydrochloride (2.73 g, 15 mmol), and DIEA (3.5 ml, 20 mmol) were dissolved in DMF (35 ml), followed by slow addition of PyBOP (2.93 g, 5.62 mmol) in DMF (10 ml). The reaction was stirred for 10 min, and diluted with ethyl acetate (200 ml), washed with 1N HCl 2×, 5% K2CO3 2×, and brine 2×. The solvent was evaporated and resulting residue was purified by flash chromatography (SiO2, 0-6% ethyl acetate in DCM gradient) to give tert-butyl N-(4-{(1S)-1-[3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alaninate as a dry foam. NMR (500 MHz, DMSO-d6) δ: 1.35 (s, 9H); 1.92 (d, J=6.9 Hz, 3H); 2.44 (t, J=7.0 Hz, 2H); 3.41 (q, J=7.0 Hz, 2H); 3.89 (s, 3H); 5.80 (q, J=6.9 Hz, 1H); 6.94 (d, JF-H=3.8 Hz, 1H); 7.21 (d, J=8.3 Hz, 2H); 7.22 (dd, J=2.6 Hz, 9.0 Hz, 1H); 7.39 (d, J=2.6 Hz, 1H); 7.44 (dd, J=2.6 Hz, 8.5 Hz, 1H); 7.58 (t, J=9.7 Hz, 1H); 7.72 (d, J=8.3 Hz, 2H); 7.79 (m, 1H); 7.83 (d, J=9.0 Hz, 1H); 7.89 (d, J=2 Hz, 1H); 7.90 (d, J=8.5 Hz, 1H); 8.33 (dd, J=2.8 Hz, 6.6 Hz, 1H); 8.44 (t, J=5.5 Hz, NH). MS C37H35F4N3O4 Cald: 661.26; Obsd (M+1): 662.29.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[N:24][S@@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH3:23])=[C:18]([CH3:31])[CH:17]=1.O>O1CCCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][S@@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH3:23])=[C:18]([CH3:31])[CH:17]=1
Reactant: CC(=N[S@](=O)C(C)(C)C)c1ccc(Br)cc1C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1[C@H](C)N[S@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium tri-sec-butylborohydride (1 mol/L in tetrahydrofuran, 59.2 mL) was added to a solution of (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methyl-phenyl)-ethylidene]-amide (6.24 g) in tetrahydrofuran (50 mL) chilled in an ice bath. The solution was stirred for 2 h while warming to room temperature in the cooling bath. The solution was then cooled again in an ice bath prior to the careful addition of water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with water, saturated aqueous NaHCO3 solution, and brine. After drying (MgSO4) and evaporating the solvent, the title compound was obtained that was directly submitted to the next reaction step. Yield: 8.85 g (ca. 75% pure); Mass spectrum (ESI−): m/z=318/320 (Br) [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:28][C@@H:29]1[O:33][C:32](=[O:34])[NH:31][CH2:30]1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:31]5[CH2:30][C@H:29]([CH3:28])[O:33][C:32]5=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: C[C@H]1CNC(=O)O1
Product: C[C@H]1CN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)cc2)C(=O)O1
Yield: 76.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 95 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (343 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:29]([N:32](CC3C=CC(OC)=CC=3)[C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:31])=[O:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[S:29]([NH:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)(=[O:31])=[O:30])[N:20]=[CH:19][CH:18]=[C:17]2[C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3nccc(Cl)c3cc2OC)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Nc3nccs3)c(OC)cc12

Procedure:
To a microwave vial charged with (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (35.6 mg, 0.162 mmol), 4-chloro-6-methoxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (70 mg, 0.147 mmol), potassium phosphate tribasic (36.5 μl, 0.441 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (10.41 mg, 0.015 mmol) was added Dioxane (590 μl) and Water (197 μl). The mixture was irradiated at 100° C. for 30 mins affording conversion to desired product according to LC-MS. The mixture was dried under reduced pressure. To the crude oil was added DCM (0.9 ml) and TFA (0.3 ml) was added at room temperature. After 1 hr of stirring LC-MS indicated complete PMB cleavage. The mixture was dried under reduced pressure and purified with a 25 g (15 μm spherical silica) column ramping EtOAc in heptane (0-100%, 10% DCM throughout) providing product, obtained as a film. The material was lyophilized from MeOH/H2O providing 6-methoxy-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (53 mg, 0.107 mmol, 72.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.62 (s, 3H) 3.80 (s, 3H) 6.83 (s, 1H) 6.88 (d, J=4.60 Hz, 1H) 7.28 (d, J=4.60 Hz, 1H) 7.47-7.54 (m, 3H) 7.57 (d, J=7.63 Hz, 1H) 8.52 (s, 1H) 8.91 (d, J=4.40 Hz, 1H) 12.80 (br. s., 1H). m/z (ESI) 496.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[F:13][C:14]([F:40])([F:39])[C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[CH:22][CH:21]=1>CS(C)=O.C(O)(=O)C.C(OCC)(=O)C>[F:13][C:14]([F:39])([F:40])[C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc12
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(NN=Cc1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc12)c1ccc(O)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 mL) was added 4-(3,5-bis-trifluoromethylbenzyloxy)-1-naphthaldehyde (440 mg, 1.1 mmol) and a catalytic amount of glacial acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO4. The organic volume was concentrated under vacuo to give the crude product. The product was purified by silica gel column chromatography using CH2Cl2/MeOH as the mobile phase.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[CH:21]=[CH:20][S:19][C:18]=12)=[O:13])[CH3:10].O>C(Cl)Cl>[CH2:9]([O:11][C:12]([C:14]1[C:15]([Br:1])=[CH:16][N:17]2[CH:21]=[CH:20][S:19][C:18]=12)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1ccn2ccsc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(Br)cn2ccsc12

Procedure:
N-Bromosuccinimide (0.56 mmol) is added to a solution of pyrrolo[2,1-b]thiazole-7-carboxylic acid ethyl ester (0.56 mmol) in DCM (6.0 mL). After 30 min water (5.0 mL) is added, the layers are separated and the aqueous layer is extracted with DCM (5.0 mL). The combined organic layers are dried over Na SO and the solvents are removed in vacuo to give the desired product which is used without further purification. LC-MS: tR=1.02 min; [M+H]+=273.9.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+].[Na+].[CH2:7]=[CH:8][CH2:9][NH2:10].[CH2:11]1[O:13][CH:12]1[CH2:14][Cl:15].Cl>O>[CH2:7]=[CH:8][CH2:9][NH3+:10].[CH2:11]1[O:13][CH:12]1[CH2:14][Cl:15].[C:1]([O-:4])([OH:3])=[O:2]
Reactant: C=CCN
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCC1CO1
Solvent: O
Product: C=CC[NH3+]
Product: O=C([O-])O
Temperature: 32.5 °C
Yield: 63.7 %

Procedure:
A 5 L reactor, equipped with a mechanical stirrer, temperature probe, dropping funnel and a condenser topped with a nitrogen inlet, was charged with water (4 L), sodium carbonate (250 g), and the solution was brought at 35° C. Sevelamer hydrochloride (400 g) are added portion wise for 1 h, in portions of 20 g each, while stirring, maintaining the temperature from 30 to 35° C. The solid is then filtered and suspended in water (3 L), at 30-35° C. The mixture is allowed to stir for 20 minutes. The solid was filtered again and rinsed with water until disappearance of chloride ions. The product is dried under reduced pressure at 70° C. to afford Sevelamer carbonate (290 g), with a phosphate binding capacity of 17.2-17.6 mEq/g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(OCC)(=O)C.ClCCl>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1

Procedure:
A mixture of 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol (XIV, Step 1, 8.37 g, 28.1 mmol) and concentrated hydrochloric acid/H2O (1/1, 28 ml) is heated at 76° for 3 min. The resulting slurry is cooled and aqueous sodium hydroxide is added to make the mixture basic. The mixture is extracted several times with dichloromethane and the combined organic extracts are backwashed with saline, dried over magnesium sulfate, concentrated, and the resulting material chromatographed on silica gel eluting with methanol/dichloromethane (4/96). The appropriate fractions are pooled and concentrated to give 1-benzyl-1,2,3,6-tetrahydro-4-(4-methoxyphenyl)pyridine (XVI), MS (m/z) 279; IR (mineral oil) 1515, 738, 1030, 1258, 1250 and 1241 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:11](=[O:18])[O:10][CH:9]1[CH2:19][O:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](/[C:8](=[CH:9]/[CH2:19][O:20][CH3:21])/[CH2:17][C:12]1([C:11]([OH:18])=[O:10])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCC1OC(=O)C2(CCCC2)CC1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC/C=C(\CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 29 %

Procedure:
To a solution of the product from stage b) above (6.11 g, 20.49 mmol) in toluene (50 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.7 ml, 24.58 mmol), and the resultant solution was then heated at reflux under nitrogen for 5 h. The solution was then cooled to room temperature and the solvent was removed under reduced pressure. To the resultant residue was then added deionised water (100 ml) and the mixture was then extracted with tert-butyl methyl ether (30 ml). The phases were then separated and the aqueous phase was acidified to pH 2 with hydrochloric acid (15 ml of a 2 M solution) and then extracted with tert-butyl methyl ether (2×30 ml). The combined organic extracts were then washed with water (30 ml) and then brine (30 ml) and dried over magnesium sulfate. The solvent was then removed under reduced pressure to give the crude title compound (6.29 g), which was then crystallised from heptane (15 ml) at 0° C. The resultant solid was collected by filtration was then washed with ice-cold heptane (2×5 ml) to give the title compound as a white solid (1.79 g, 6.0 mmol, 29%, E-isomer assigned on basis of chemical shifts); 1H NMR (400 MHz, CDCl3), δ: 1.47 (s, 9H), 1.45-1.70 (m, 6H), 2.05-2.10 (m, 2H), 2.74 (s, 2H), 3.36 (s, 3H), 4.09 (d, 2H), 6.75 (t, 1H); 13C NMR (100 MHz, CDCl3) δ: 23.9, 28.0, 34.1, 35.0, 55.0, 58.6, 69.2, 80.8, 132.7, 139.1, 167.1, 183.3.