Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:29]=[CH:28][C:11]([O:12][CH:13]([CH3:27])[C:14]([O:16][CH2:17][CH2:18][S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[CH:10][CH:9]=1.Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1>CS(C)=O>[F:38][C:37]([F:40])([F:39])[C:34]1[CH:35]=[CH:36][C:31]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:27])[C:14]([O:16][CH2:17][CH2:18][S:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:15])=[CH:28][CH:29]=2)=[N:32][CH:33]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCSCc1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)OCCSCc1ccccc1
Temperature: 90 °C
Yield: 76.1 %

Procedure:
15.2 g of potassium carbonate were added to a solution of 33.2 g of 2-benzylthioethyl 2-(4-hydroxyphenoxy)-propionate in 100 ml of dimethyl sulfoxide at room temperature whilst stirring. The mixture was heated to 90° C. for 1 hour with stirring. Then, 20.0 g of 2-chloro-5-trifluoromethyl-pyridine were added thereto while maintaining the temperature between 80° and 90° C. After the addition was completed, the reaction mixture was further stirred at this temperature for 2 hours, and then cooled to room temperature. Then the reaction mixture was poured into ice water and extracted with chloroform. After drying the organic phase, the chloroform was removed under reduced pressure. There were obtained 36.3 g of 2-benzylthioethyl 2-[4-(5-trifluoromethyl-2-pyridyloxy)-phenoxy]-propionate in the form of a pale yellow viscous oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]2([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH2:36](Br)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C(O)C>[CH2:53]([O:21][C:20](=[O:22])[CH2:19][CH2:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CC(C)(C)c1cc(C2(c3ccc(O)c(C(C)(C)C)c3)CCCCC2CCC(=O)O)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCC1CCCCC1(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1

Procedure:
45.2 g (0.1 mol) of 2,2-bis-(3'-tert.butyl-4'-hydroxyphenyl)-cyclohexanepropionic acid are dissolved in ethanol and neutralizaed with an ethanolic solution of 5.7 g (0.1 mol) of potassium hydroxide. The solution is concentrated nearly to dryness, taken up in 250 ml of toluene and mixed with 33.3 g (0.1 mol) of octadecyl bromide. The batch is refluxed for 3 hours, filtered off from the precipitated KBr and concentrated to about 100 ml. The product precipitated after some time is recrystallized from toluene/heptane. Yield 50 g, which corresponds to 71 % of the theory. Melting point 155° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].S(=O)(=O)([OH:15])N.CCOC(C)=O.[Cl:24]([O-:26])=[O:25].[Na+:27]>O>[Cl:24]([O-:26])=[O:25].[Na+:27].[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[C:4]([OH:15])=[O:5]
Reactant: COc1cc(Br)c(C=O)cc1O
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Br)c(C(=O)O)cc1O
Temperature: 5 °C
Yield: 89 %

Procedure:
1 Kg of 2-bromo-5-hydroxy-4-methoxy benzaldehyde (B2) and 1.255 Kg of sulfamic acid were added with stirring into a mixture of 4.473 Kg of EtOAc and 8 L of water. The reaction mixture was stirred until all of the solid had dissolved. The reaction mixture was cooled to between −10 and 0° C. An aqueous solution of sodium chlorite was prepared by dissolving 505 g of sodium chlorite in 3 L of water. The sodium chlorite solution was added to the pre-cooled B2 solution at a rate that maintained the reaction temperature under 5° C. After the complete addition of sodium chlorite solution, the reaction mixture was stirred for another hour at 0° C. and was then allowed to warm up to room temperature. The reaction was monitored by TLC. After the TLC analysis showed completion of the reaction, the aqueous layer was separated. The aqueous layer was extracted with EtOAc (1.789 Kg) and the combined organic layer was transferred to another flask and EtOAc was removed by vacuum distillation at 40° C. 6.92 Kg of toluene was added at between 30 to 40° C., the slurry was cooled to between −10 to 0° C. and the precipitate was collected by filtration to give about 950 g (89% (yield) of 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13). 1H NMR (CDCl3) δ 3.95 (3H, s, CH3), 7.22 (1H, s, CH), 7.46 (1H, s, CH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.C[NH:14]CC1C=CC=CC=1>>[NH2:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=1
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: CNCc1ccccc1
Product: Nc1ccc2ccccc2n1

Procedure:
6-Bromo-2-chloroquinoline (200 mg, 0.8 mmol) and N-methylbenzylamine (2 mL) were heated at 120° C. for 16 hours. Extraction from 2M NaOH into DCM and drying on Na2SO4 gave the crude 2-aminoquinoline. This was converted, via Methods 3 and 5, to compound 204 (110 mg, 46%). [M−H]−=291.1 m/z. Activity: A
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9].[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][CH2:30]2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCc1cccs1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1cccs1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(thiophen-2-ylmethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8](O)([CH3:10])[CH3:9].B(F)(F)F>P(=O)(O)(O)O>[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH3:10])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CC(C)O
Agent: FB(F)F
Agent: O=P(O)(O)O
Product: CC(C)c1ccccc1O

Procedure:
A process according to claim 1 wherein phenol is reacted with isopropanol in the presence of a diethyl ether complex of boron trifluoride in phosphoric acid diluent at a temperature of between about 70°-90° C. to produce ortho-isopropyl phenol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=1)[CH2:8][C@@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O)([CH3:4])([CH3:3])[CH3:2].Br>>[C:28]([C:26]1[CH:25]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:27]=1)[CH2:8][C@@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1)([CH3:30])([CH3:31])[CH3:29]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Br
Product: CC(C)(C)c1cc(C[C@@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
(2S,4R)-Methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (619 mg, 1.44 mmol) (from example 146, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 10 mL, 57.10 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3,5-di-tert-butylbenzyl)piperidin-4-yl)isoxazol-3(2H)-one (330 mg, 61%). 1H NMR (600 MHz, cd3od) δ 1.30 (s, 18H), 1.63 (q, 1H), 1.80 (dq, 1H), 2.19-2.27 (m, 2H), 2.86-3.18 (m, 4H), 3.43-3.56 (m, 2H), 5.73 (s, 1H), 7.10 (d, 2H), 7.37-7.40 (m, 1H). HRMS Calculated for [C23H34N2O2+H]+: 371.2698. Found: 371.2693
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:29]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Br:2][CH:3]=[C:36]1[CH2:37][CH2:38][N:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:34][CH2:35]1
Reactant: CC(C)(C)N1CCC(=O)CC1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)N1CCC(=CBr)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (bromomethyl)triphenylphosphonium bromide (1.52 g, 3.48 mmol) in dry THF (15 mL) at −78° C. was added potassium tert-butoxide (3.5 mL, 1.0M) slowly. After stirring 20 minutes, 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) (595 mg, 3.83 mmol) in THF (2 mL) was added, and the reaction mixture was warmed up to rt slowly over 2 h. The reaction mixture was quenched with brine, and it was extracted with CH2Cl2. The combined extracts were dried over Na2SO4 then concentrated in vacuo. The crude material was purified by flash chromatography eluting first with hexane then gradually increasing to 5% acetone/hexane to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 5.85 (s, 1H); 2.56 (m, 4H); 2.43 (t, J=5.6 Hz, 2H); 2.28 (t, J=5.6 Hz, 2H); 1.08 (s, 9H).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([CH3:19])=[CH:14][CH:15]=2)[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[N:22]=2)[CH:9]=1)=[O:7])C.O.Cl>CO>[Br:27][C:23]1[N:22]=[C:21]([CH2:20][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:19])[N:12]=3)[C:17](=[O:18])[C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(=O)c(C(=O)O)cn(Cc3cccc(Br)n3)c2n1
Yield: 69.4 %

Procedure:
0.110 g (4.62 mmol) of lithium hydroxide was added to 0.620 g of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester dissolved in 50 mL methanol and 100 mL of water and was heated at 60° C. for 3 hours. After the reaction was cooled to room temperature 1M HCl was added until the product precipitated from solution. The white solid was collected by vacuum filtration to yield 0.400 g of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)[CH3:2].C([BH3-])#N.[Na+].[CH:30](=O)[CH2:31][CH2:32][CH3:33]>C(O)(=O)C.O1CCCC1>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:30][CH2:31][CH2:32][CH3:33])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Reactant: CCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Yield: 83 %

Procedure:
Following general procedure Q and using 4-[(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 79, 0.2 g, 0.64 mmol), sodiumcyanoborohydride (0.121 g, 1.92 mmol) and butyraldehyde (1 mL, 11.09 mmol) in 5 mL of acetic acid and 5 mL of tetrahydrofuran, the title compound (0.21 g, 88%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.86 (d, 2H, J=9.1 Hz), 7.11 (d, 1H, J=8.7 Hz), 7.07 (d, 1H, J=8.1 Hz), 6.90 (s, 1H), 6.68 (d, 2H, J=8.9 Hz), 4.32 (q, 2H, J=7.1 Hz), 3.70 (t, 2H, J=7.8 Hz), 1.74-1.62 (m, 2H) 1.55 (s, 6H), 1.51 (s, 6H), 1.45-1.33 (m, 2H), 1.35 (t, 3H, J=7.1 Hz), 0.95 (t, 3H, J=7.4 Hz).
Reaction SMILES: Cl.[F:2][C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:13]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:6]2[CH2:5][CH2:4][C:3]([F:2])([C:9]3[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=4)[N:13]=3)[CH2:8][CH2:7]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3(F)CCNCC3)n2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(F)(c3nc(COc4ccc(S(C)(=O)=O)cc4)cs3)CC2)nc1

Procedure:
A solution of 4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (4.0 g, 9.01 mmol), 2-chloro-5-ethyl-pyrimidine (1.55 g, 1.2 eq.) and DIPEA (4.7 g, 4 eq.) in 2-propanol (30 mL) in a sealed pressure vessel was stirred at 160° C. (oil bath temperature) overnight. After cooling, the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 8.19 (2H, s), 7.87 (2H, d, J=9.2 Hz), 7.36 (1H, s), 7.10 (2H, d, J=9.2 Hz), 5.23 (2H, s). 4.69 (2H, m), 3.44 (2H, m), 3.03 (3H, s), 2.48 (2H, q, J=7.6 Hz), 2.15˜2.39 (4H, m), 1.21 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[I:26]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:26][C:8]1[CH:7]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2ccc(C(=O)OCc3ccccc3)nc2C)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1ccc(-c2ccc(C(=O)OCc3ccccc3)nc2C)cc1I

Procedure:
Benzyl 5-(4-methoxyphenyl)-6-methylpyridine-2-carboxylate (150 mg, 0.45 mmol), iodine (228 mg, 0.898 mmol), silver sulfate (402 mg, 1.29 mmol) were stirred in methanol (3 mL) at room temperature overnight. More iodine (57 mg, 0.22 mmol) and silver sulfate (100 mg, 0.32 mmol) were added into reaction mixture after 25 hours. Added aqueous NaHSO3 solution (sat., 20 mL) into the reaction mixture after additional 1.5 hours to quench the reaction. The reaction mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration to afford a clear oil. The crude oil was purified by preparative TLC on SiO2 (eluted with 30% ethyl acetate in hexanes) to afford benzyl 5-(3-iodo-4-methoxyphenyl)-6-methylpyridine-2-carboxylate. LCMS calc.=459.03; found=460.17 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[C:49]1([S:55](Cl)(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:55]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)(=[O:57])=[O:56])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of benzenesulphonyl chloride (50 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1M, 1 ml) and heated at 60° C. for 8 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether/pentane, filtered and dried to afford the title compound as a solid (85 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[C:10]2[CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C)cn2Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 4) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-2-ethoxy-3-{3-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>>[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([O:10][CH2:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:13]=1
Reactant: OCCCc1ccccn1
Reactant: Clc1cncc(Cl)n1
Product: Clc1cncc(OCCCc2ccccn2)n1

Procedure:
The title compound was prepared according to the procedure of example 50, step 1, starting from 2-pyridinepropanol (4.08 g, 29.7 mmol), K-t-BuO (3.17 g, 28.3 mmol) and 2,6-dichloropyrazine (3.69 g, 24.8 mmol). The yield of the title compound was 5.18 g (84%) and was obtained as an oil. Anal. (C12H12ClN3O) C, H, N.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:12]=[P:13](Cl)([Cl:15])[Cl:14].C(N(CC)CC)C>CC(OC)(C)C>[P:13]([Cl:15])([Cl:14])(=[O:12])[O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cccc2ccccc12
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reaction time: 3 h
Yield: 86.3 %

Procedure:
In a 22 L 3-neck flask equipped with a mechanical stirrer, an internal thermocouple, a cooling bath of dry/acetone, an additional funnel and a nitrogen inlet was placed 1-naphthol (780 g, 5.41 mol, 491 g used from Aldrich, ≧99% grade, Product No N1000 and 289 g used from Alfa Aesar 99% grade, Product No A11862) in 10 L of MTBE at room temperature. POCl3 (495 mL, 5.41 mol, ReagentPlus® 99%, Product No 201170, Aldrich) in an additional funnel was dropwise added in 5 min (note: no exothermic observed) under nitrogen pressure. To this solution at −25° C. (an internal temperature) was slowly added by triethylamine (754 mL, 5.41 mol, ≧99.5% grade, Product No 471283, Aldrich) for one h (note: exotherm observed) and then the cooling bath was removed after the addition was completed. The reaction mixture was aged for 3 h at room temperature under nitrogen pressure. The triethylamine hydrochloride salt was filtered off using a 3 L sintered funnel (Medium size) and the filtrate was concentrated to dryness under reduced pressure at <20° C. of water bath to give desired product as clear dark yellow oil (1219 g, 86.3%) which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:23][N:22]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: Nc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(NCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 11.7 %

Procedure:
A mixture of 1.0 g of 1-(3-bromopropyloxy)-2,6-dichloro-4-(3,3-dichloro-2propenyloxy)benzene and 4.0 g of 2-amino-5-(trifluoromethyl)pyridine was stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and subjected to silica gel chromatography, which afforded 0.14 g of 3,5-dichloro-1-(3,3-dichloro-2propenyloxy)-4-(3-(5-(trifluoromethyl)-2-pyridylamino)propyloxy)benzene (12% yield), nD25.0 1.5525.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:15]([C:31]#[N:32])=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:13][C:14]1[C:15]([C:31]#[N:32])=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: N#Cc1c(Cl)cccc1Oc1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Oc3cccc(Cl)c3C#N)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-(3-chloro-2-cyanophenoxy)benzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (41.4 mg) with purity >90%. LCMS (pos) m/z 478.0.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14].CN(C)CCN(C)C.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:46])(=O)=O)=CC=1>O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]([F:46])([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CCC(F)(C(=O)OC)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl 2-(1,3-dioxoisoindolin-2-yl)-pentane-1,5-dioate (1.0 g, 3.3 mmol) and tetramethylethylene diamine (0.5 g, 4.3 mmol) in tetrahydrofuran (10 mL) is added 2.5M n-butyl lithium (1.6 mL, 4 mmol,) at -79° C. After 30 minutes, N-fluorobenzenesulfonimide (1 g, 3.2 mmol) is added to the mixture which then is allowed to reach room temperature. The solvent is removed in vacuo and the residue is stirred with methylene chloride (100 mL) for 10 minutes. The organic layer is washed with water and brine (30 mL each), and dried over sodium sulfate. The solvent is removed in vacuo to yield dimethyl 2-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-1,5-dioate which is further purified by chromatography and converted to 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline as described above in Part D of Example 9.