Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]=[N+:9]=[N-:10].[C:17]([O:23][CH3:24])(=[O:22])[CH2:18][C:19]([CH3:21])=O.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:19]([CH3:21])=[C:18]([C:17]([O:23][CH3:24])=[O:22])[N:10]=[N:9]1
Reactant: [N-]=[N+]=NCc1ccccc1-c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nnn(Cc2ccccc2-c2ccccc2)c1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 68.8 %

Procedure:
To a solution of 2-biphenylylmethyl azide (Intermediate 2) (1.1 g, 5.2 mmol) and methyl acetoacetate (0.9 g, 7.8 mmol) in DMSO (10 mL) was added potassium carbonate (2.9 g, 20 mmol). The reaction mixture was stirred at 40° C. for 48 hours. After cooling, water was added and the mixture was extracted with ethyl acetate, the organic layer was dried on sodium sulphate and after filtration was evaporated to dryness. The residue was purified by flash column chromatography eluting with DCM and DCM/MeOH: 98/2 to give the title compound as an oil (1.1 g, 68.7%). LC/MS: m/z 308 (M+H)+, Rt: 3.14 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:12]([C:17]1[CH:18]=[N:19][C:20](Cl)=[N:21][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[N:19]=[CH:18][C:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][N:21]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCCCCc1cnc(Cl)nc1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: CCCCCc1cnc(-c2cc(F)cc(F)c2)nc1

Procedure:
80 mmol of 3,5-difluorophenylboronic acid are coupled to 80 mmol of 5-pentyl-2-chloropyrimidine analogously to Example IB
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][OH:12]>>[CH3:11][O:12][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: CO
Product: COCCCc1ccccc1
Temperature: 0 °C

Procedure:
In 600 ml of CH3OH was dissolved 20 g of Na, and 120 g of 3-bromopropylbenzene was added dropwise with heating under reflux. After aging under reflux for 6 hours, the reaction solution was poured into 2 liters of ice water, and the separated oil layer was extracted with benzene. The benzene was distilled off, after which the residue was distilled under reduced pressure to obtain 3-methoxypropylbenzene. The boiling point of this compound was 96°-98° C/15 mmHg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[S].[C:13](=[S:15])=[S:14]>>[C:1]([C:5]1[CH:11]=[CH:10][C:9]2[S:14][C:13]([SH:15])=[N:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: S=C=S
Reactant: CC(C)(C)c1cccc(N)c1
Agent: [S]
Product: CC(C)(C)c1ccc2sc(S)nc2c1
Yield: 88.3 %

Procedure:
In a autoclave of 3 liters, 1341g of meta-tert-butylaniline, 820g of carbon disulfide and 288g of sulfur were placed, the reaction was carried out under the same conditions as above. After cooling, 1765g of 5-tert-butyl-(2-mercapto)benzothiazole was obtained. (yield: 88.3%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Br)[CH:31]=1>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)[CH:31]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c1

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and (3-bromomethyl-benzoic acid methyl ester CAS Reg. No. 1129-28-8). Brown sticky solid (90%). MS (Turbo Spray): m/z=524.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=[C:5]2[C:4](=O)[NH:3]1.P(Br)(Br)([Br:16])=O.O>C(#N)C>[Br:16][C:4]1[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:2]([CH3:1])[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CSc1ncc2c(=O)[nH]n(C)c2n1
Solvent: CC#N
Solvent: O
Product: CSc1ncc2c(Br)nn(C)c2n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
1-Methyl-6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one (2.0 g, 0.01 mol) was refluxed with phosphorus oxybromide (6 g) in acetonitrile (60 mL). Water (100 mL) was then added and the reaction mixture cooled to 5° C., hold for 1 hour and filtered to give 1.6 g (61%) of pure 3-bromo-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine; 1H-NMR (DMSO): δ 2.61 (s, 3H), 3.96 (s, 3H), 9.00 (s, 1H), LC/MS (m/e)=260.8 (MH+), Rt=1.89 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:38][C@H:39]([C:43]([OH:45])=[O:44])[CH2:40][CH2:41][CH3:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34]([NH:38][C@@H:39]([CH2:40][CH2:41][CH3:42])[C:43]([OH:45])=[O:44])=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(I)cc3)cc2)cc1
Reactant: CCC[C@H](N)C(=O)O
Product: CCC[C@H](Nc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
2-(4′-tert-Butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole (191 mg, 0.3 mmol) was treated as described in general procedure R using L-norvaline (352 mg, 3 mmol) to give (S)-2-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-pentanoic acid, which was then treated as described in general procedure F to give (4S)-5-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-propyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:15]([CH3:16])=[CH:14][N+:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[C:5]([CH3:19])[CH:4]=1.C[O-].[Na+:22]>CO>[CH3:9][C:7]1[C:6](=[C:10]2[C:11]([CH3:18])=[CH:12][N:13]([CH3:17])[CH:14]=[C:15]2[CH3:16])[C:5]([CH3:19])=[CH:4][C:3](=[O:2])[CH:8]=1.[Na+:22].[I-:1]
Reactant: Cc1cc(O)cc(C)c1-c1c(C)c[n+](C)cc1C
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC1=CC(=O)C=C(C)C1=C1C(C)=CN(C)C=C1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the methylpyridinium iodide salt 7 (0.184 g, 0.500 mmol) was added dropwise a solution of sodium methoxide in methanol (1.2 mL, 0.5 M). The color of the mixture immediately changed from yellow to red. After stirring at room temperature for 10 min, the solvent was removed under reduced pressure. The resulting solid was then recrystallized from anhydrous methanol/THF to afford the orange title compound as a complex with NaI (0.382 g, 98%): 1H NMR (400 MHz, DMSO-d6): δ 8.818 (s, 2H), 5.983 (s, 2H), 4.265 (s, 3H), 2.055 (s, 6H), 1.566 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ 161.235, 142.173, 137.851, 132.019, 118.598, 114.039, 46.917, 19.574, 16.754; MS (ESI): m/z 242.4 [(M+H)+,100]; HRMS (EI): m/z 241.1463 [M+]; calcd, 241.1467. Anal. Calcd. for C16H19NO.NaI: C, 49.12; H, 4.90; N, 3.58. Found; C, 49.04; H, 5.40; N, 3.49.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[O:22][CH3:23])[C:10]([CH3:12])([CH3:11])[C:6]=2[C:5]([F:25])=[C:4]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:47][N:48]1[CH:52]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:50]=[N:49]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:10]([CH3:12])([CH3:11])[C:6]2[C:5]([F:25])=[C:4]([NH:26][C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[N:3]=[C:2]([C:51]3[CH:50]=[N:49][N:48]([CH3:47])[CH:52]=3)[C:7]=2[C:8]1=[O:24]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN2C(=O)c3c(Cl)nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2(C)C)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3c(-c4cnn(C)c4)nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2(C)C)c(OC)c1
Temperature: 160 °C
Yield: 15.4 %

Procedure:
In a sealed tube, a mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1,1-dimethyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (30 mg, 0.052 mmol), Na2CO3 aq (2M, 0.065 mL, 0.130 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12.98 mg, 0.062 mmol), bis(triphenylphosphine)palladium chloride (3.65 mg, 5.20 μmol), and DMF (1 mL) was heated at 160° C. for 0.5 h in a microwave oven. The reaction mixture was then heated at 160° C. for an additional 4 h in a microwave oven and was subsequently purified by preparative HPLC to give the title compound as a light yellow solid (5 mg, 18%). [M+H] calc'd for C28H35FN6O3, 524. found 524.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=O.[OH-].[Na+]>O>[F:9][C:10]1[CH:11]=[C:12]([C:13]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1ccncc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(-c2nc3cnccc3[nH]2)c1
Temperature: 200 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
A mixture of 3,4-diaminopyridine (1.09 g., 1 mmoles), 3-fluorobenzoic acid (1.40 g., 10 mmoles), and polyphosphoric acid (PPA, 40 g.) was heated to about 200° C. with stirring for 3.5 hours. The solution was then slowly added to water. The solution was then neutralized by the addition of 50% aqueous sodium hydroxide and the resulting precipitate was collected by filtration. Crystallization from isopropanol/water gave 1.72 g. (81% yield) of 2-(3-fluorophenyl)imidazo[4,5-c]pyridine (base), m.p. about 290°-291° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH:39]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)([CH3:41])[CH3:40]>>[NH2:30][C:29]1[S:28][C:27]([C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH:39]([CH3:41])[CH3:40])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: CC(C)c1ccccc1-c1nc(C(=O)Nc2cnn(C)c2N2CCC(CN)CC2)c(N)s1
Yield: 41 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-isopropylbenzene boronic acid gave 269 as a red gum (38 mg, 41% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.55 (s, 1H), 7.54-7.33 (m, 6H), 7.28 (t, J=7.5 Hz, 1H), 3.71 (t, J=9.2 Hz, 1H), 3.62 (s, 3H), 3.11-2.93 (m, 4H), 2.42 (d, J=5.4 Hz, 2H), 1.73 (d, J=11.3 Hz, 2H), 1.27-1.21 (m, 9H). Alkyl NH2 not seen. LCMS (ES+) m/z 454 (M+1)
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([CH:16]([CH3:18])[CH3:17])[C:5]=1[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+:23].C(C(C)=O)C(C)C>O>[CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([CH:16]([CH3:18])[CH3:17])[C:5]=1[C:6]([O-:8])=[O:7])([CH3:3])[CH3:2].[Na+:23]
Reactant: CC(C)c1cc(C(C)C)c(C(=O)O)c(C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC(C)c1cc(C(C)C)c(C(=O)[O-])c(C(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A 1-L eggplant shaped flask was charged with 39.7 g of 2,4,6-triisopropylbenzoic acid (prepared in Synthesis Example 1-1), 13.4 g of sodium hydrogencarbonate, 160 g of methyl isobutyl ketone, and 40 g of water, which were stirred at room temperature for 24 hours. At the end of stirring, the reaction solution was concentrated, followed by twice of azeotropic dehydration with 100 g of methyl isobutyl ketone. To the solid precipitate, 300 g of diisopropyl ether was added, whereupon solid-liquid washing was conducted for 30 minutes. The solid was filtered and dried, obtaining the target compound, sodium 2,4,6-triisopropylbenzoate as white crystal. Amount 30.7 g, yield 80%.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(N(CC)CC)C.[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[C:12]1([S:22]([NH:3][CH2:2][CH2:1][NH2:4])(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NCCNS(=O)(=O)c1cccc2ccccc12
Reaction time: 1 h
Yield: 3.5 %

Procedure:
To a solution of ethylenediamine (1.06 g, 17.6 mmol) in dimethylformamide (10 ml), triethylamine (1.79 g, 17.7 mmol) was added, followed by stirring. With stirring at room temperature, a solution of 1-naphtalenesulfonyl chloride (4.00 g, 17.6 mmol) in dimethylformamide (15 ml) was dropwise added thereto, and the reaction was carried out in an ice bath for 1 hour. Insoluble materials were removed by filtration, and the filtrate was concentrated. To the residue, chloroform and water were added, and insoluble materials were filtered off. Furthermore, the aqueous layer was separated, washed with ethyl acetate twice and adjusted to pH 11 with potassium carbonate, followed by extraction with ethyl acetate three times. The extracts were collected, washed with water twice, dried over anhydrous sodium sulfate and concentrated. The residue was allowed to stand in a refrigerator overnight, and the precipitate was collected and recrystallized from ethyl acetate to give Compound (10) (153 mg). Yield, 4%.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O>[CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1cc(C(=O)OC)ccc1OCC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)ccc1OCC1CCCCC1
Reaction time: 40 h

Procedure:
To a solution of 23-5 (290 mg, 1.0 mmol) in 7.6 mL of THF and 10 mL of water was added 210 mg (5.0 mmol) of LiOH. The resulting solution was stirred for 40 h, then acidified by the addition of 10 mL of 1N HCl. The aqueous phase was extracted with 2×20 mL of EtOAc. The organic extracts were washed with brine (5 mL) and dried over MgSO4. Evaporation of the solvent afforded acid 23-6 which was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>S(=O)(=O)(O)O.O>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Yield: 99.7 %

Procedure:
50 Grams (234 mmol) of 4′-hydroxybiphenyl-4-carboxylic acid and 238 g (2.34 mol) of acetic anhydride were placed in a reactor, and while these stirred, 0.1 g of concentrated sulfuric acid was added. The mixture was stirred until heat generation ceased, and the mixture was further heated at 80° C. for 4 hours with stirring and then gradually cooled to room temperature. While the reaction mixture was cooled in an ice bath, 500 g of water was gradually added, and the mixture was stirred at room temperature for 3 hours to quench unreacted acetic anhydride. A precipitated white solid was recovered by filtration, washed with water to remove acetic acid, and dried with a vacuum drier to give 59.8 g of an end compound (yield 99%).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]c(-c3ccccc3)c(Cc3ccccc3)c2c1
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c(Cc1ccccc1)c(-c1ccccc1)n2Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 3-benzyl-5-bromo-2-phenyl-1H-indole (1.811 g, 5 mmol) was reacted with k-t-butoxide (0.589 g, 5.25 mmol) and benzyl bromide (0.901 g, 5.25 mmol) in DMF (20 ml) to give the product (1.932 g, 4.271 mmol, 85%) as a white solid, mp 155-157° C. 1H NMR (DMSO-d6) δ 3.99 (s, 2H), 5.32 (s, 2H), 6.82 (d, J=7.2 Hz, 2H), 7.07 (d, J=7.3 Hz, 2H), 7.09-7.23 (m, 7H), 7.34-7.39 (m, 3H), 7.43-7.49 (m, 3H), 7.53 (d, J=1.8 Hz, 1H); [ESI(+)], m/z 453/455 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)Oc1ccccc1[N+](=O)[O-]

Procedure:
Starting from 2-nitrophenol (10 g, 1 eq, 71.9 mmol) and ethyl 2-bromopropionate (10.2 ml, 1.1 eq, 79.09 mmol) the procedure of Step (i), preparation 17 was followed to obtain ethyl 2-(2-nitrophenoxy)propanoate in crude form (16 g) which was used for step (ii).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2cc(Oc3c(F)cccc3F)ccc2c1O
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O
Temperature: 150 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 1-bromo-7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (156 mg) and CuCN (66 mg) in NMP was stirred at 150° C. for 1 h; then cooled, diluted with DCM, filtered, then washed with water, dil. NaCl solution, dried over sodium sulphate, filtered, concentrated, the residue was column purified to give the desired product (100 mg). LC MS ESI: 371 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:44](OS(C(F)(F)F)(=O)=O)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[O:35][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Methyl 3,4-di-O-benzyl-6-O-(4-chlorobenzyl)-β-D-glucopyranoside (0.258 g, 0.517 mmol) was dissolved in 3 mL CH2Cl2. 2,6-lutidine (240 μL, 2.06 mmol) and tert-butyldimethylsilyltrifluoromethane sulfonate (0.284 mL, 1.24 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. The solution was filtered through silica, eluted with EtOAc and concentrated. Purification by flash column chromatography on silica gel (10% EtOAc/Hexanes) gave 283 mg (89%) of 22 as a colorless oil. [α]24D: −9.2° (c 2.01, CH2Cl2); IR (thin film) 2928, 2855, 1492, 1069 cm−1; 1H-NMR (CDCl3) δ 7.41-7.29 (m, 12H), 7.16-7.13 (m, 2H), 4.97 (d, J=11.3 Hz, 1H), 4.90 (d, J=11.3 Hz, 1H), 4.82 (d, J=11.0 Hz, 1H), 4.61 (d, J=12.5 Hz, 1H), 4.56-4.53 (m, 2H), 4.17 (d, J=7.3 Hz, 1H), 3.78-3.76 (m, 1H), 3.71 (dd, J=4.6, 10.7 Hz, 1H), 3.63-3.53 (m, 6H), 0.95 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H), 13C-NMR (CDCl3) δ 138.8, 138.1, 136.8, 133.5, 129.2, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.5, 104.9, 86.0, 78.3, 75.8, 75.4, 75.1, 74.9, 72.8, 69.1, 57.9, 26.1, 18.4, −4.1, −4.2; FAB MS m/z (M+Na)+: calcd 635.2572, obsd 635.2574.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:27]C(=O)C2C=CN=C(OCC)C=2)[CH:18]=[CH:19][C:20]=1[C@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([NH:27][C:10](=[O:12])[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[N:9][CH:8]=2)[CH:18]=[CH:19][C:20]=1[C@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1
Reactant: CCOc1ccc(C(=O)O)cn1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Agent: Cl
Product: CCOc1ccc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)cn1

Procedure:
In analogy to Example 83, step a) using 6-ethoxy-3-pyridinecarboxylic acid (CAS 97455-65-7) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (+)-(R)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. Off-white solid. MS (ISP): 362.0 ([M+H]+)
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:13])=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)[CH:2]=[CH2:3].[H-].[Na+].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CN(C=O)C>[CH2:1]([C:4]1[C:5]([Cl:13])=[C:6]2[CH:12]=[CH:11][N:10]([S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:7]2=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cnc2[nH]ccc2c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
5-Allyl-4-chloro-1H-pyrrolo[2,3-b]pyridine (2.24 g, 11.6 mmol) in DMF (25 mL) was cooled to about 0° C. then treated with 60 wt % NaH (0.558 g, 13.9 mmol). The mixture was stirred for about 30 min then TsCl (2.44 g, 12.8 mmol) was added. The mixture was stirred for about 15 min at about 0° C. then warmed to rt for about 30 min. The solvents were evaporated under reduced pressure then the residue was stirred with DCM (40 mL) and saturated aqueous NaHCO3 (35 mL) for about 15 min. The layers were separated then the aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 5-allyl-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (4.0 g, 111%, crude): LC/MS (Table 2, Method a) Rt=3.18 min; MS m/z 347 (M+H)+.