Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH2:16][N:17]1[C:28](=[O:29])[C@@H:27]([NH:30][C:31](=[O:35])[C@@H:32]([NH2:34])[CH3:33])[C:21]3([CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[O:20][C:19]3[CH:36]=[CH:37][CH:38]=[CH:39][C:18]1=3)=[C:11]([O:40][CH3:41])[CH:10]=[CH:9]2.[CH2:42]1OC(O)C[O:44][CH:43]1O.C(O)(=O)C>CO.Cl.O>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH2:16][N:17]1[C:28](=[O:29])[C@@H:27]([NH:30][C:31](=[O:35])[C@@H:32]([NH:34][CH2:42][CH2:43][OH:44])[CH3:33])[C:21]3([CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[O:20][C:19]3[CH:36]=[CH:37][CH:38]=[CH:39][C:18]1=3)=[C:11]([O:40][CH3:41])[CH:10]=[CH:9]2
Reactant: OC1COC(O)CO1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N)C2(CCOCC2)Oc2ccccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)NCCO)C2(CCOCC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.3 %

Procedure:
Sodium cyanoborohydride (5.14 mg, 81.8 μmol, Eq: 1.50) was added to a solution of (S)-N-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-yl)-2-amino-propanamide (31 mg, 54.5 μmol, Eq: 1.00), glycolaldehyde dimer (3.6 mg, 30.0 μmol, Eq: 0.55) and acetic acid (3.27 mg, 3.15 μl, 54.5 μmol, Eq: 1.00) in MeOH (1 mL) and the mixture was stirred at RT overnight. The mixture was diluted with 1 N HCl and H2O/1 N NaOH was added to adjust the pH to ˜8-9. The mixture was extracted with EtOAc, the combined extracts were washed with brine, dried over Na2SO4 and concentrated. The resulting material was purified by flash chromatography to afford the title compound (30 mg, 90% yield). MS m/z 613.8 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2.CO>CC(N(C)C)=O>[CH3:3][NH:4][CH2:5][CH2:6][O:7][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2
Reactant: CNCCO
Reactant: O=c1[nH]cnc2cccc(F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CNCCOc1cccc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 732 mg, 18.3 mmol) was suspended in DMA (50 ml) and N-methylethanolamine (734 μl, 9.15 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature, and 5-fluoroquinazolin-4(3H)-one (1.0 g, 6.10 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 85° C. for 90 minutes. The mixture was cooled to ambient temperature, and the resulting slurry poured into methanol (100 ml). Dowex resin (50WX4-400, 25 g) was added, and the mixture stirred for 1 hour at ambient temperature. The resin was collected by filtration, and washed with methanol (100 ml). The resin was suspended in a solution of ammonia in methanol (2.3 N, 150 ml), and the mixture stirred for 30 minutes. The mixture was filtered and the residue washed with ammonia in methanol (2.3 N, 100 ml). The combined filtrates were concentrated in vacuo, and dried in vacuo (1 mbar, 60° C.) for 16 hours to give 5-[2-(methylamino)ethoxy]quinazolin-4(3H)-one as an off white solid (1.09 g, 82%); NMR Spectrum (DMSO-d6, 400) 2.36 (s, 3H), 2.85 (t, 2H), 5.11 (t, 2H), 6.97 (d, 1H), 7.14 (d, 1H), 7.61 (dd, 1H), 7.97 (s, 1H); Mass spectrum MH+ 220.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]([CH3:34])([CH2:21][N:22]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:33])=[C:26]([Cl:32])[CH:27]=[C:28]2[Cl:31])=[N:23]1)[C:19]#[N:20]>C1COCC1>[C:19]([C:18]([NH:17][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)([CH3:34])[CH2:21][N:22]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:33])=[C:26]([Cl:32])[CH:27]=[C:28]2[Cl:31])=[N:23]1)#[N:20]
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-phenoxybenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=499, RT=0.79 min.
Reaction SMILES: [C:1]1([C:14]([O:16][CH3:17])=[O:15])[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:4]([C:7]([O-])=[O:8])=[CH:5][CH:6]=1>O1CCCC1>[OH:8][CH2:7][C:4]1[CH:3]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[C:1](=[CH:6][CH:5]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1C(=O)OC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.43 g of 1,2-dimethyl 1,2,4-benzenetricarboxylate was dissolved in 20 ml of tetrahydrofuran, and 20 ml of a 1M tetrahydrofuran solution of a borane-tetrahydrofuran complex, was added, followed by stirring at room temperature overnight. The reaction solution was extracted by an addition of ethyl ether and water, and the organic layer was post-treated in accordance with a usual method. Then, the product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→1/1) to obtain 1.31 g of the above identified compound as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:67][CH2:68][C:69]([NH2:71])=[O:70]>CN(C=O)C.CCOC(C)=O>[C:69]([CH2:68][NH:67][C:29]([CH2:28][C@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]4[CH2:11][CH2:10][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:14][CH2:13]4)[C:27]=3[C:26]1=2)=[O:31])(=[O:70])[NH2:71]
Reactant: NCC(N)=O
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)NCC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Into a 50-mL round-bottom flask, a solution of 2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetic acid (270 mg, 0.58 mmol, 1.00 equiv) in 30 mL of distilled DMF was added HATU (331 mg, 0.87 mmol, 1.50 equiv), DIEA (375 mg, 2.90 mmol, 5.00 equiv) and 2-aminoacetamide hydrochloride (128 mg, 1.16 mmol, 2.00 equiv) subsequently at room temperature under nitrogen. The resulting solution was stirred for 1 h at room temperature. After completion, the reaction was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was purified by a silica gel column with DCM/MeOH (30:1-10:1) to provide 280 mg (92%) of tert-butyl N-(4-[[(3R)-3-[[(carbamoylmethyl)carbamoyl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate as a yellow solid. MS: m/z 518 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:16][C:17]1[N:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-6 using tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 6-chloropyridin-3-ol (0.10 g, 54%); MS: 271 (M−56).
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[CH2:12][CH:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].S(=O)(=O)(O)O.[H][H]>[Pd].CO>[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[CH2:12][CH:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][NH2:25])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]
Reactant: CC(CN1C(=O)c2ccccc2C1=O)c1c[nH]c2ccc(C#N)cc12
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(CN1C(=O)c2ccccc2C1=O)c1c[nH]c2ccc(CN)cc12
Yield: 232.9 %

Procedure:
A suspension of 3-[2-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl]1-methylethyl]-1H-indole-5-carbonitrile (1.4 g) and pre-reduced 10% palladium on charcoal (1.4 g) in methanol (100 ml) containing concentrated sulphuric acid (0.5 ml) was hydrogenated at room temperature and pressure until hydrogen uptake ceased. The catalyst was filtered off and the filtrate was evaporated to dryness to give a red oil (3.3 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10](=[O:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cccc(CC(=O)Cl)c1
Product: COc1cccc(CC(=O)Nc2ccc(F)cc2)c1
Yield: 97.9 %

Procedure:
The title compound was prepared as described in Example 1.A, using 3-methoxyphenylacetyl chloride (3.29 g, 18.0 mmol) and 4-fluoroaniline (1.98 g, 18.0 mmol) to afford the title compound (4.57 g, 98% yield): ES-MS (m/z) 259.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:7]=1.[C:25]([OH:37])(=[O:36])[CH2:26][NH:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:12]([CH3:14])[CH3:13])[CH:15]([CH3:16])[CH3:17])[CH:7]=1.[C:25]([O-:37])(=[O:36])[CH2:26][NH:27][C:28]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:29]
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Solvent: CC(C)=O
Product: O=C([O-])CNC(=O)c1ccccc1

Procedure:
3.25 g of tolterodine dissolved in 50 mL of acetone was mixed at room temperature (25° C.) with 1.79 g of hippuric acid, which was suspended in 50 mL of acetone, and then stirred. Acetone in the above mixture was removed by nitrogen reflux apparatus, and when about 10 20 mL of acetone was removed there started to appear a solid precipitate. After stirring the mixture at room temperature (25° C.) for 1 hour, the solid precipitate was filtered and then washed with hexane. The resultant was dried at room temperature (25° C.) for 24 hours and 4.66 g (theoretical yield: 92.3%) of the final product in white solid was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:6]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[CH:23]=1>>[CH3:27][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[CH:8][CH:9]=2)[O:26][N:25]=1
Reactant: Cc1nc(-c2ccc(O)cc2)cs1
Reactant: Cc1cc(CCCCCCCBr)on1
Product: Cc1cc(CCCCCCCOc2ccc(-c3csc(C)n3)cc2)on1

Procedure:
3-Methyl-5-{7-[4-(2-methyl-4-thiazolyl)phenoxy]heptyl}-isoxazole [I; Z=N, Het=4-(2-methyl-4-thiazolyl), R1 and R2 =H, Y=(CH2)7 ] was prepared from 7.3 g of 4-(2-methyl-4-thiazolyl)phenol and 5-(7-bromoheptyl)-3-methylisoxazole according to the procedure of Example 4: yield 10.6 g, m.p. 100-101° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH3:28].[H-].[Na+]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH2:28][C:2]1[C:11]2[C:6](=[C:7]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: COc1ccc2c(Cl)nncc2c1Cc1ccncc1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1Cc1ccncc1
Yield: 41.4 %

Procedure:
Operating analogously to what described in example 15 starting from 1-chloro-6-methoxy-5-pyridin-4-ylmethyl-phthalazine (1.38 g, 4.66 mmoles), prepared as described in example 142, 3,5-dichloro-4-methylpyridine (1.887 mg, 11.65 mmoles), DMF (20 ml), NaH (466 mg, 11.65 mmoles), 793 mg of the title compound were obtained.
Reaction SMILES: O[CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][C@H:15]([CH2:17][O:18][C:19]4[CH:23]=[CH:22][O:21][N:20]=4)[O:14][C:13]3=[O:24])=[CH:8][C:7]=2[F:25])[CH2:3]1.FC1C=C(N2C[C@H](CO)OC2=O)C=C[C:32]=1[N:33]1C=C(C)N=C1>>[F:25][C:7]1[CH:8]=[C:9]([N:12]2[CH2:16][C@H:15]([CH2:17][O:18][C:19]3[CH:23]=[CH:22][O:21][N:20]=3)[O:14][C:13]2=[O:24])[CH:10]=[CH:11][C:6]=1[N:4]1[CH:3]=[C:2]([CH3:5])[N:33]=[CH:32]1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)cn1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CC(O)C2)c(F)c1
Product: Cc1cn(-c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)cn1

Procedure:
Using essentially the same procedure as for the intermediate of Example 65, but starting with 3-(3-fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (see Example 141; 81 mg, 0.29 mmol), and purifying by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 2.5% MeOH in dichloromethane, gave the title compound (80 mg). MS (ESP): 359 (MH+) for C17H15FN4O4.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[C:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1ccc2cc(O)ccc2n1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reaction time: 72 h

Procedure:
To a solution of 2-Methyl-quinolin-6-ol (4.13 g, 0.0259 mol), cis 4-tert-Butyl-cyclohexanol (4.86 g, 0.0311 mol) and triphenylphosphine (9.53 g, 0.0363 mol; Supplier=Aldrich) in tetrahydrofuran (100 mL, 1 mol; Supplier=Acros), cooled in an ice bath, was added diisopropyl azodicarboxylate (7.61 mL, 0.0363 mol; Supplier=Acros) in Tetrahydrofuran (10 mL, 0.1 mol; Supplier=Acros). The reaction mixture was stirred for 72 h allowing to reach room temperature. The solvent was removed under reduced pressure and the residue was taken up in methylene chloride, adsorbed onto silica gel and purified by flash chromatography (0-30% ethyl acetate in hexanes) to give the title compound in 56% yield. ESI-MS (M+H+): 298.3.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:43]=[CH:42][C:25]([C:26](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1>O1CCOCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:25]2[CH:42]=[CH:43][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OCCOCCOCCOCCO
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
Tetraethyleneglycol (14.0 g, 72 mmol) was coevaporated with dry pyridine (2×50 mL), dissolved in dry dioxane and 4,4′-dimethoxytrityl chloride (8.0 g, 23.6 mmol) was added portion-wise to the stirred solution. The reaction was monitored by TLC. After overnight stirring at ambient temperature, the reaction mixture was evaporated and dissolved in CH2Cl2 (200 mL), and washed with saturated aq. NaHCO3 (3×100 mL) and brine (100 mL). The organic phase was dried over Na2SO4 and concentrated. Purification on silica gel column using a stepwise gradient of MeOH (0 to 10%) in H2Cm2 containing 0.2% pyridine yielded 8.5 g (73%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18][CH3:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+]>O>[Br:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18][CH3:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(SC)c(OCCOC)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOc1c(SC)ccc(C(=O)O)c1Br
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Ethyl 2-bromo-3-(2-methoxyethoxy)-4-methylsulphenylbenzoate (24.3 g) was added to a solution of potassium hydroxide (9.1 g) in water (25 ml) and industrial methylated spirits (300 ml). The resultant mixture was heated at reflux for 4 hours and then allowed to cool to room temperature overnight. The mixture was evaporated and the residue dissolved in water and washed with ether. The aqueous layer was acidified to pH 1 with 2M HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 2-bromo-3-(2-methoxyethoxy)-4-methylsulphenyl benzoic acid (19.4 g) as a white solid, NMR (CDCl3) 2.2(3H,s), 3.25(3H,s), 3.6(2H,t), 3.8(2H,t), 7.0(2H,m).
Reaction SMILES: OCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([NH2:29])=[O:28])=[C:19]2[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1)(=[O:15])=[O:14].[Br:39]C1C=C(SC2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)C=CC=1>>[Br:39][C:10]1[CH:11]=[C:12]([S:13]([C:16]2[CH:17]=[C:18]3[C:23](=[C:24]([CH3:26])[CH:25]=2)[N:22]=[CH:21][C:20]([C:27]([NH2:29])=[O:28])=[C:19]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)(=[O:15])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCCCCCCCCCCO)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(Sc4cccc(Br)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(Br)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 61, using Intermediate 59 as a substrate. ES/MS calcd. for C24H2BrN3O4S+ 526.0. Found m/z=526.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(-c2ccc(C(C)O)cc2)cc1
Temperature: 100 °C

Procedure:
10 g of 4-hydroxy-4'-(1-hydroxyethyl)biphenyl (4) obtained in Example 3 was dissolved in 20 ml of acetic anhydride. A small amount of concentrated sulfuric acid was added to the solution. The mixture was heated to 100° C. to obtain 4-acetoxy-4'-(1-hydroxyethyl)biphenyl (2) quantitatively: ##STR56## The product was recrystallized from an acetone/hexane solvent mixture.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:13][CH:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:19][C:16]1([CH3:20])[O:15][CH:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:18][O:17]1
Reactant: CC1(C)OCC(CCl)O1
Reactant: c1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC1(C)OCC(Cn2ccc3ccccc32)O1
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a stirred room temperature solution of indole (5.9 g, 50 mmol) in THF (100 mL) was added sodium hydride (2.4 g of 60% in mineral oil, 60 mmol) in one portion. After 30 minutes, 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (10.6 mL, 75 mmol) was added followed by tetra-n-butylammonium iodide (1.9 g, 5 mmol) and the mixture was warmed at reflux. After 24 hours, LCMS showed about 50% conversion [MS m/z 232 (MH+)]. Additional 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (11.4 mL) was added and the refluxing continued. After 18 hours, the mixture was cooled, diluted with THF (300 mL), filtered, and concentrated in vacuo to afford a brown oil. The residue was purified by column chromatography over silica gel eluting with 0-100% methylene chloride in hexanes and the product-rich fractions were collected to afford 3.3 g of 1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-1H-indole as a brownish oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](OC(C)(C)C)=[O:11])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1.C[O-].[Na+].O>CO>[Br:17][C:5]1[CH:6]=[C:7]2[C:2](=[N:3][CH:4]=1)[NH:1][C:10](=[O:11])[CH:9]=[CH:8]2
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Br)cnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1ccc2cc(Br)cnc2[nH]1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of (E)-tert-butyl 3-(2-amino-5-bromopyridin-3-yl)acrylate (2.5 g, 8.35 mmol) in anhydrous methanol (50 mL) was treated with sodium methoxide (8.5 mL of a 4.9 M solution, 41.75 mmol). The solution was heated at reflux for 2 h then cooled to room temperature. The mixture was cooled in an ice-H2O bath and treated with H2O (100 mL) under rapid stirring to give a precipitate. The solid was filtered and washed with H2O (20 mL). The filtrate was neutralized with 1 M HCl(aq) to form a precipitate. The solid was filtered and washed with H2O (20 mL). The solids were combined and dried under reduced pressure to give an off-white solid (1.75 g, 93%). NMR (300 MHz, DMSO-d6) δ 8.43 (d, 1H, J=2.5 Hz), 8.06 (d, 111, J=2.5 Hz), 7.60 (d, 1H, J=9.1 Hz), 6.44 (d, 1H, J=9.1 Hz); ESI MS m/z 225 (100%); 227 (100%) [C8H5N2OBr+H]+
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:10]=[C:11]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH:12]=[C:13]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=1.[ClH:32]>C(#N)C>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:11]1[CH:12]=[C:13]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=[C:9]([Cl:32])[CH:10]=1)=[O:31]
Reactant: Cl
Reactant: Nc1cc(NC(=O)c2cccc(Cl)c2)cc(Oc2cccnc2)c1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cc(Oc2cccnc2)c1)c1cccc(Cl)c1
Temperature: 55 °C
Yield: 63 %

Procedure:
CuCl2 (47.5 mg, 0.353 mmol, 1.20 eq) was dissolved in acetonitrile (2 mL) in a flame-dried 3-neck flask flushed with argon and equipped with a condenser. t-Butyl nitrite (45.5 mg, 0.441 mmol, 1.50 eq) was added and the reaction heated at 55° C. Compound 2 (100 mg, 0.294 mmol, 1.00 eq) was dissolved in acetonitrile (0.1 mL) and added dropwise to the reaction. After 10 minutes the reaction was cooled to rt, poured into 20% HCl and extracted with CH2Cl2 (3×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 67 mg (63%) of the title compound as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 8.47 (d, J=2.8 Hz, 1H), 8.45 (dd, J=4.6, 1.3 Hz, 1H), 7.96 (t, J=1.8 Hz, 1H), 7.86 (dt, J=7.9, 1.2 Hz, 1H), 7.77 (t, J=1.8 Hz, 1H), 7.68-7.66 (m, 1H), 7.58 (ddd, J=8.4, 3.0, 1.5 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.48 (dd, J=8.4, 4.6 Hz, 1H), 7.40 (t, J=2.0 Hz, 1H), 6.94 (t, J=2.0 Hz, 1H); ES-MS [M+1]+: 359.0.