Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](O)([CH3:17])([CH3:16])[CH3:15].CCCCCC>C1(C)C=CC=CC=1>[C:14]([C:11]1[CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]=1[OH:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
Into a 300 ml reactor thoroughly dried and purged with nitrogen, 34.04 g (200.0 mmol) of 4-phenylphenol, 3.40 g of Umberist-15E (trade name, available from Organo Co.) and 150 ml of toluene were introduced. To the reactor, a solution containing 48.20 g (200.0 mmol) of t-butyl alcohol diluted with 10 ml of a toluene was dropwise added at 105° C., followed by stirring for 16 hours. After the system was cooled to room temperature, the solution was introduced into 500 ml of hexane and filtered with washing with hexane. After concentration, the resulting liquid was purified by silica gel column chromatography to obtain 31.15 g (yield: 69%) of 2-t-butyl-4-phenylphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C@H:29]1(O)[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH:29]3[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: O[C@H]1CC[C@H](O)CC1
Product: O=C1c2ccccc2C(OC2CCC(O)CC2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 67.9 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis/trans-1,4-cyclohexanediol (586 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (338 mg, 68%). 1H NMR (300 MHz, CDCl3): mixture of diastereoisomers: 7.93-7.90 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.56-7.51 (m, 2H, Ar—H), 7.18-7.02 (m, 7H, Ar—H), 4.78 and 4.24 (d: AB, J=15.0 Hz, 2H, N—CH2); 3.70-3.62 (m, 1H, HOCH—), 3.26-3.09 (m, 1H, OCH), 1.86-1.26 (m, 10H, CH2). 13C NMR (75 MHz, CDCl3): mixture of diastereoisomers: 168.33, 147.16, 146.01, 144.80, 137.66, 134.74, 132.72, 131.58, 130.21, 130.16, 129.68, 128.31, 128.28, 128.23, 128.19, 123.81, 123.09, 94.30, 94.28, 71.41, 69.22, 68.61, 67.66, 42.65, 32.51, 32.32, 30.95, 30.65, 30.33, 29.19, 29.03. m/z (ES): 493 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]([NH:22][C:23]3[N:27]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:26]=[C:25]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:39]([N:41]=[C:42]=[O:43])[CH3:40].CN(C=O)C>C(Cl)Cl>[C:35]([C:25]1[CH:24]=[C:23]([NH:22][C:20]([NH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:42]([NH:41][CH2:39][CH3:40])=[O:43])[CH:7]=3)=[CH:10][CH:11]=2)=[O:21])[N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:26]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CCN=C=O
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cc3ccnc(N)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Cc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
To a solution of 1-(4-((2-aminopyridin-4-yl)methyl)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea (55 mg, 0.11 mmol) in dry DCM (4.0 mL) under N2 at 0° C. was added ethyl isocyanate (22 μL, 0.27 mmol). The reaction mixture was maintained at 0° C. for 20 min, was then warmed to RT for 2 hr and dry DMF (200 μL) was added. Additional aliquots of ethyl isocyanate were added after 3.5 hr (22 μL, 0.27 mmol), after 21 hr (43 μL, 0.54 mmol) and after 28 hr (65 μL, 0.81 mmol). After 43 hr the reaction was quenched by the addition of a solution of NH3 (1% in MeOH, 3.0 mL) and after 45 min the resulting mixture was evaporated in vacuo. The residue was subjected to SCX capture and release and the crude product so obtained was purified by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-80%, gradient elution) to afford the title compound, Example 23, as a white solid (26 mg, 40%); Rt 2.22 min (Method 2); m/z 576 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.04 (3H, t), 1.28 (9H, s), 2.39 (3H, s), 3.14 (2H, m), 4.33 (2H, s), 6.40 (1H, s), 6.76 (1H, dd), 7.16 (1H, s), 7.36 (2H, d), 7.39 (1H, d), 7.45 (2H, d), 7.53 (2H, m), 7.87 (1H, d), 7.92 (1H, d), 8.01-8.04 (2H, overlapping m), 8.15 (1H, br t), 8.78 (1H, s), 9.04 (1H, s), 9.07 (1H, s).
Reaction SMILES: [F:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][CH:31]([CH3:37])[CH2:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:31]([CH3:37])[CH2:32][CH2:33][C:34]([O:22][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:35]
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(F)nc2n1
Reactant: CC(C)CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(F)nc2n1
Yield: 18 %

Procedure:
The procedure is as in Example 7, but starting with 2-(7-fluoro-1,8-naphthyridin-2yl)-3-hydroxy-1-isoindolinone (5 g) in methylene chloride (60 cc), triethylamine (6.5 g), 4-methylpentanoyl chloride (3.66 g) and 4-dimethylaminopyridine (10 mg). After recrystallization in ethanol, 2-(7-fluoro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-methylpentanoate (1.2 g), m.p. 154° C., is obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13](OC)=[O:14])[CH:8]=[CH:7][C:6]=1[CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([NH:2][NH2:3])=[O:14])[CH:8]=[CH:7][C:6]=1[C@H:18]1[CH2:23][CH2:22][C@H:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1
Reactant: CCOC(=O)C(C)C1CCC(c2ccc(NC(=O)C(=O)OC)cc2Cl)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of hydrazine hydrate (86 mg, 1.73 mmol) in ethanol (1 mL) was added dropwise to a stirred solution of ethyl 2-[4-(2-chloro-4-{[methoxy(oxo)acetyl]amino}phenyl)cyclo-hexyl]propanoate (0.58 g, 1.44 mmol) in ethanol (14 mL) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered to leave a solid, which was washed with ethanol to give the title compound (Intermediate 106) (0.45 g, 81%) as a white solid; 1H NMR δ 1.14 (3H, d), 1.16-1.28 (2H, m), 1.27 (3H, t), 1.4-1.58 (2H, m), 1.6-1.7 (1H, m), 1.71-1.93 (4H, m), 2.29-2.39 (1H, m), 2.82-2.94 (1H, m), 4.15 (2H, dq), 4.7 (2H, s), 7.4 (1H, d), 7.8 (1H, dd), 8.01 (1H, d), 10.4 (1H, s), 10.8 (1H, s); MS m/e MH+ 396.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([NH:32][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:16]=1[N+:22]([O-:24])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1c(F)cccc1OCc1ccccc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(NCc2ccccc2)cccc1OCc1ccccc1
Temperature: 110 °C
Yield: 88 %

Procedure:
Potassium carbonate (5.71 g., 41.4 mmol) was added to a solution of 1-benzyloxy-3-fluoro-2-nitro-benzene (6.818 g, 27.6 mmol) and benzylamine (3.32 mL, 30.34 mmol) in tetrahydrofuran, and the resulting suspension was heated to 110° C. for 2 hours. After cooling to room temperature, the mixture was poured onto 1 L of ice water and extracted twice with 150 mL ethyl acetate and twice with 75 mL dichloromethane. The combined organic fractions were dried over sodium sulfate and concentrated in vacuo in the presence of 25 g. silica gel. The preloaded silica gel was submitted to flash chromatography (8% to 35% ethyl acetate in hexanes) to give 8.118 g (24.28 mmol, 88%) of benzyl-(3-benzyloxy-2-nitro-phenyl)-amine as an orange solid. MS: 335 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(O)(=O)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:22][N:23]3[C:24](=[O:33])[C:25]4=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]4[C:27]3=[O:28])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1COc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the red dye, 4-(4-nitro-phenylazo)phenol (0.5 g), in DMF was added sodium hydride (0.1 g of a 50% dispersion). After stirring for 5 minutes at room temperature, N-(chloromethyl)phthalimide (0.5 g) was added and stirring continued overnight. The solution was acidified with acetic acid and the product precipitated by pouring into ice water. The product recrystallized from ethyl acetate/cyclohexane, was obtained in 0.72 g yield, m.p. 182°-190° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]([NH2:22])[CH3:21])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:23](N1C=CN=C1)([N:25]1C=CN=C1)=[O:24]>C(O)=O>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH:20]([NH:22][C:23]([NH2:25])=[O:24])[CH3:21])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(N)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Solvent: O=CO
Product: CC(CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)NC(N)=O

Procedure:
3-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-1-methylpropylamine (115 mg, 0.38 mmol) was reacted with formic acid and 1,1′-carbonyldiimidazole in analogy to example 44. Yield: 5 mg (4%), M+H+: 344.19.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)c1ccc(N)c(Br)c1
Product: CC(C)c1ccc(N)c(-c2ccc(Cl)cc2)c1

Procedure:
2-bromo-4-isopropylaniline and 4-chlorobenzene boronic acid were combined to form 2-(4-chlorophenyl)-4-isopropylaniline, and
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([N:9]=[C:10]=S)[N:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:3][C:2]=1[Cl:1]
Reactant: NCC1(O)CN2CCC1CC2
Reactant: S=C=Nc1ccc(Cl)c(Cl)n1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1ccc(NC2=NC[C@@]3(CN4CCC3CC4)O2)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To 2,3-dichloro-6-isothiocyanatopyridine (0.47 g, 2.29 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.8 mL, 5.7 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.54 g, 2.34 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours, cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (1.07 mL, 6.88 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5,6-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.36 g, 1.08 mmol, 47% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.31 (d, J=1.22 Hz, 1H), 7.84 (s, 1H), 6.80 (s, 1H), 3.85 (d, J=10.07 Hz, 1H), 3.57 (d, J=10.38 Hz, 2H), 2.98 (s, 3H), 2.69-2.78 (m, 3H), 2.65 (t, J=7.78 Hz, 3H), 2.00 (s, 2H), 1.86 (s, 2H), 1.58 (dd, J=7.48, 2.90 Hz, 2H), 1.56 (s, 1H), 1.41-1.49 (m, 2H). MS (LC/MS) R.T.=0.81; [M+H]+=327.1.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:27])[OH:26])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[Cl:38][C:39]1[C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[S:42][C:43]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([N:8]([CH3:28])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:26])[OH:27])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:44]([C:43]2[S:42][C:41]3[CH:47]=[CH:48][CH:49]=[CH:50][C:40]=3[C:39]=2[Cl:38])=[O:45])[CH2:13][CH2:14]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of boronic acid 4 (1.95 g, 4.99 mmol) in DCM (20 mL) is treated with DIPEA (1.04 mL, 5.98 mmol), followed by 3-chlorobenzo[b]thiophene-2-carbonyl chloride (1.38 g, 5.98 mmol) in one portion. The resulting solution is stirred 16 h at RT. LC/MS at this juncture showed the reaction had reached completion. The reaction mixture is washed with water (3×10 mL) and brine (1×10 mL). The organic layer is dried over MgSO4 and the solvent removed in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:24]=[CH:23][C:17]3[N:18]([CH3:22])[C:19](=[O:21])[S:20][C:16]=3[CH:15]=2)[CH:11]=[N:12][CH:13]=1>N1C=CC=CC=1>[CH3:22][N:18]1[C:17]2[CH:23]=[CH:24][C:14]([C:10]3[CH:9]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:13]=[N:12][CH:11]=3)=[CH:15][C:16]=2[S:20][C:19]1=[O:21]
Reactant: Cn1c(=O)sc2cc(-c3cncc(N)c3)ccc21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cncc(-c2ccc3c(c2)sc(=O)n3C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
General sulfonylation procedure: EtSO2Cl (51.4 mg, 0.4 mmol) was added dropwise to a solution of 6-(5-aminopyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one (Example 50: 28 mg, 0.1 mmol) in pyridine (2 mL) at 0° C. The resulting mixture was slowly warmed up to room temperature and stirred for additional 3 hrs at this temperature. After concentration, the residue was purified by flash column (MeOH/CH2Cl2, v/v, 1-3%) and yielded yellow solid (20 mg), MS (ESI) m/z 350.4 (M±H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.35 (t, J=7.4 Hz, 3H), 3.22 (q, J=7.4 Hz, 2H), 3.51 (q, 3H), 7.38 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.87 (s, 1H), 7.95 (s, 1H), 8.40 (s, 1H), 8.58 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH:11][C:12](=[O:20])[CH2:13][CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:13][C:12]([NH:11][CH3:10])=[O:20])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CNC(=O)CCNCC(C)C
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)CCN(CC(C)C)c1nc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
5-Bromo-2,4-dichloropyrimidine (Aldrich; 2.82 g, 12.37 mmol), N-methyl-3-(2-methylpropylamino)propanamide (Intermediate 86; 1.78 g; 11.25 mmol), Triethylamine (1.65 mL, 11.81 mmol) and DCM (40 mL) were combined and stirred over the weekend at room temperature. The reaction mixture was washed saturated aqueous sodium bicarbonate solution and gravity filtered through a PTFE cup and solvent evaporated. The residue was dissolved in DCM and passed through a silica column eluting with a gradient of 30-50% Ethyl Acetate/iso-hexane over 10 column volumes then 50% Ethyl Acetate/iso-hexane. Fractions containing product combined and evaporated to give the title compound as a white solid. (3.26 g, 83%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:33])=[C:13]([C:15]2(O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:33])=[C:13]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(O)c1cc(OCc2ccccc2)ccc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cc(OCc3ccccc3)ccc2O)c2ccccc2N1Cc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
To a solution of 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chloro-2-thienyl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (4.90 g, 10.3 mmol) in dichloromethane (100.0 mL) were added trifluoroacetic acid (12.9 g, 113.2 mmol) and triethylsilane (13.2 g, 113.2 mmol). The reaction mixture was stirred at ambient temperature for 4 h, then concentrated in vacuo to dryness. The gummy residue was diluted with ethyl acetate (100.0 mL), washed with water (3×100.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with diethyl ether, filtered and dried to afford 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one (2.90 g, 61%) as a colourless solid: mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ9.11 (s, 1H), 7.3-7.27 (m, 5H), 7.18 (dd, J=7.5, 7.5 Hz, 1H), 7.09 (d, J=3.8 Hz, 1H), 7.06 (dd, J=7.9 Hz, 1H), 6.97-6.86 (m, 3H), 6.79-6.68 (m, 3H), 5.04 (ABq, 2H), 4.91 (s, 2H), 4.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ175.9, 151.5, 149.7, 142.8, 138.8, 137.8, 130.2, 128.8, 128.2, 128.1, 128.1, 128.0, 127.4, 126.8, 125.2, 124.2, 122.7, 117.6, 117.6, 116.3, 114.9, 109.1, 70.2, 48.1, 38.6; MS (ES+) m/z 464.3 (M+1), 462.3 (M+1).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([O:20][CH3:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.[C:22](O)([C:24]([F:27])([F:26])[F:25])=[O:23].ClCCl>>[CH3:21][O:20][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:5])=[O:7])[O:9][C:10]=2[CH:17]=[CH:16][C:15]=1[CH2:18][O:19][C:22](=[O:23])[C:24]([F:27])([F:26])[F:25]
Reactant: COc1c(CO)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(COC(=O)C(F)(F)F)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 190 mg of 4-methoxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 3 h. When the reaction was done, the solvents were removed under vacuum and the residue was triturated with acetonitrile. Filtration of the suspension gave 184 mg of 4-methoxy-3-methyl-5-(2,2,2-trifluoro-acetoxymethyl)-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[S:42]([N:45]([CH2:49][CH2:50][O:51][CH2:52][C:53](O)=[O:54])[CH:46]1[CH2:48][CH2:47]1)(=[O:44])=[O:43].[F:56][C:57]1[CH:58]=[C:59]([C:63]2([O:69][CH2:70][CH2:71][N:72]3[CH2:76][CH2:75][CH2:74][CH2:73]3)[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)[CH:60]=[CH:61][CH:62]=1>O1CCCC1>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[S:42]([N:45]([CH:46]1[CH2:48][CH2:47]1)[CH2:49][CH2:50][O:51][CH2:52][C:53]([N:66]1[CH2:65][CH2:64][C:63]([C:59]2[CH:60]=[CH:61][CH:62]=[C:57]([F:56])[CH:58]=2)([O:69][CH2:70][CH2:71][N:72]2[CH2:76][CH2:75][CH2:74][CH2:73]2)[CH2:68][CH2:67]1)=[O:54])(=[O:44])=[O:43]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Reactant: Fc1cccc(C2(OCCN3CCCC3)CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCC(OCCN2CCCC2)(c2cccc(F)c2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
DIPEA (2 eq.) and HATU (1.2 eq.) were added to a solution of tetrahydrofuran and 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetic acid [acid K] (1 eq.) at 0° C. 4-(3-Fluorophenyl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidine [amine C] (1.2 eq.) was taken up in tetrahydrofuran (2 ml/mmol) and the solution was rendered basic with DIPEA (2 eq.) and added to the reaction mixture at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated to dryness on a rotary evaporator, the residue was taken up in methylene chloride and the mixture was washed with water and sat. sodium chloride solution and dried over sodium sulfate. The organic phase was concentrated and the crude product was purified by means of column chromatography (5% methanol in methylene chloride). Yield: 60%. MS, Rt=3.6 min, m/z=622.4 [MH]+
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:16]([C:18]2[C:19]([CH:34]3[CH2:36][CH2:35]3)=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:22][CH:23]=2)[CH3:17])=[CH:11][C:10]=1[CH3:37])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:34]1([C:19]2[C:18]([CH:16]([S:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:38])=[O:5])=[C:10]([CH3:37])[CH:11]=3)[CH3:17])=[CH:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)[N:20]=2)[CH2:35][CH2:36]1
Reactant: Cc1cc(SC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)ccc1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(SC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)ccc1OCC(=O)O
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of 146 mg (0.268 mmol) [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester in 2 ml dichloromethane was added 0.5 ml trifluoroacetic acid. The reaction mixture was stirred for 4 h and then the trifluoroacetic acid was removed under reduced pressure. The crude product was suspended in AcOEt/heptane 1:19. The resulting crystalline product was filtered off to give 118 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid.