Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3C(C#N)[C:4]=2[CH:3]=1.O.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:22]([C:21]([OH:24])=[O:23])[C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: N#CC1c2ccccc2CSc2ccc(Br)cc21
Agent: Cl
Solvent: O
Product: O=C(O)C1c2ccccc2CSc2ccc(Br)cc21

Procedure:
After 4.72 g of 2-bromo-11-cyano-6,11-dihydrodibenzo[b,e]thiepine was dissolved in 90 ml of hydrochloric acid-acetic acid (1:2), the mixture was heated under reflux for 48 hours. The reaction mixture was allowed to stand at room temperature, and 50 ml of water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water. The organic layer was extracted 3 times with saturated sodium bicarbonate aqueous solution. The aqueous layer was adjusted to pH 2 with 4N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride aqueous solution successively, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to obtain 2.68 g of 2-bromo-6,11-dihydrodibenzo[b,e]thiepin-11-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.C(#N)C>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1
Reactant: Nc1ccc(F)c(C23CN(c4ncc(F)cn4)CC2CSC(NC(=O)c2ccccc2)=N3)c1
Solvent: CO
Solvent: CC#N
Product: Nc1ccc(F)c([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1

Procedure:
Racemic N-[7a-(5-amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (1.694 g, 3.63 mmol) is chirally purified by HPLC (Column: Chiralcel OJ, 8×35 cm; eluent: 90% methanol (0.2% dimethylethylamine) and 10% acetonitrile; flow 400 mL/min at UV 280 nm). Analysis of the first eluting isomer (Column: Chiralcel OJ-H 0.46×15 cm; eluent: 10:90 acetonitrile:methanol (with 0.2% dimethylethylamine); flow: 0.6 mL/min at UV 280 nm) confirms the enantiomerically enriched (99% ee) enantiomer with Rt=6.70 minutes, (723 mg, 43%). ES/MS (m/e): 467 (M+H).
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:31][CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)/[CH:3]=[CH:4]/[C:5]1[CH:18]=[CH:17][C:8]([CH2:9][O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1>CCO>[O:1]=[C:2]([N:19]1[CH2:31][CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1
Reactant: CCOC(=O)COCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Solvent: CCO
Product: O=C(O)COCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 40 %

Procedure:
The same method as employed in the preparation of Example 79 but starting a solution of (E)-(4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-βcarbolin-2-yl)propenyl]benzyloxy)acetic acid, ethyl ester in EtOH gave after recrystallization from MeOH:H2O the title compound as an off-white solid in a 40% yield.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20](N)=[CH:19][C:18]=1[CH3:25])(=[O:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]([O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:12][C:9]2[CH2:10][CH2:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:19][C:18]=1[CH3:25])(=[O:15])[CH3:14]
Reactant: CC(=O)Oc1c(C)cc(N)cc1C
Reactant: NC1=NN(c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(C)cc(NC2=NN(c3ccccc3)CC2)cc1C
Yield: 46.7 %

Procedure:
4,5-Dihydro-1-phenyl-1H-pyrazol-3-amine (0.16 g), 4-amino-2,6-dimethylphenyl acetate (0.2 g), and toluene-4-sulfonic acid (0.02 g) were refluxed in toluene under nitrogen for 8 hours. Evaporation and chromatography (silica, dichloromethane/ethyl acetate [95:5]) of the residue gave the title product (0.15 g), as a solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:18][C:19]2[N:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[CH:20]=2)=[N:14][C:15]=1[O:16][CH3:17])#[N:9]>ClCCl>[CH3:17][O:16][C:15]1[C:10]([C:8]#[N:9])=[N:11][CH:12]=[C:13]([NH:18][C:19]2[CH:20]=[C:21]([NH:25][CH2:26][CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[N:22]=[CH:23][N:24]=2)[N:14]=1
Reactant: COc1nc(Nc2cc(NCC3CCN(C(=O)OC(C)(C)C)CC3)ncn2)cnc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(Nc2cc(NCC3CCNCC3)ncn2)cnc1C#N
Reaction time: 2 h
Yield: 64.8 %

Procedure:
TFA (0.1 mL) was added to a solution of tert-butyl 4-((6-(5-cyano-6-methoxypyrazin-2-ylamino)-pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (3 mg, 0.0068 mmol) in dichloromethane (3 mL) at room temperature. After 2 hr, the solution was evaporated to dryness and purified by ion exchange on SCX-II acidic resin (500 mg), eluting with methanol then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo to give the title compound as yellow oil (1.5 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[N:10]1([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:18]2[CH2:19][CH2:20][CH:15]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16][CH2:17]2)[N:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=Cc1cccc(Br)n1
Solvent: ClCCl
Product: Brc1cccc(CN2CCC(N3CCCC3)CC2)n1

Procedure:
7] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 4-(1-pyrrolidinyl)-piperidine (500 mg, 3.22 mmol) in dry CH2Cl2 (15 mL) to give 2-bromo-6-[4-(1-pyrrolidinyl)-piperidinylmethyl]pyridine as a pale yellow solid. MS m/z: 326.1(M+2H). Calc'd for C15H22BrN3: 324.26.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].Cl.[NH2:14]O>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[O:12][N:14]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: NO
Reactant: O=c1ccoc2ccc(F)cc12
Agent: Cl
Solvent: CCO
Product: Oc1ccc(F)cc1-c1ccno1
Reaction time: 18 h
Yield: 12 %

Procedure:
The product from above (6-fluorochromen-4-one (5.25 g, 32.0 mmol) and hydroxylamine hydrochloride (4.65 g, 67.2 mmol) are dissolved in ethanol (180 ml) and the resulting mixture is heated to reflux. The reaction is allowed to stir for 18 hours before cooling and concentrating. The residue is taken up in toluene and filtered to give 690 mg of 4-fluoro-2-isoxazol-5-yl-phenol and from the filtrate 594 mg of 4-fluoro-2-isoxazol-3-yl-phenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:18]=[CH:17][N:16]([CH3:19])[C:5]2=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+].[Br:22]N1C(=O)CCC1=O>CN(C=O)C>[Br:22][C:18]1[C:4]2[C:5](=[N:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[C:2]([F:1])[CH:3]=2)[N:16]([CH3:19])[CH:17]=1
Reactant: Cn1ccc2cc(F)c(OCc3ccccn3)nc21
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2cc(F)c(OCc3ccccn3)nc21
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
To a stirred solution of 5-fluoro-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 3.89 mmol) in DMF (30 mL), cooled to 15° C. under a nitrogen atmosphere, is added sodium hydroxide (0.171 g, 4.28 mmol), followed by N-bromosuccinimide (0.761 g, 4.28 mmol) portionwise over 5 minutes. After 15 minutes, the reaction is poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 2×30 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 100% EtOAc in hexane, to give the title compound as a light yellow solid (1.195 g, 3.55 mmol). MS (m/z): 336/338 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=1>>[F:23][C:22]([F:25])([F:24])[C:21]1[C:16]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: NC1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
The title compound was prepared from D7 and 2-chloro-3-trifluoromethyl-pyridine using the procedure outlined for Descriptions D11 and D12.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:3].[C:12]([O:20][C@@H:21]1[C@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCOCC1>[C:12]([O:20][C@@H:21]1[C@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:24]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:23][C@H:22]1[N:45]1[C:46]2[N:47]=[C:48]([Cl:55])[N:49]=[C:50]([NH:3][N:2]([CH3:1])[CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:51]=2[N:52]=[CH:53]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CN(N)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CCc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 163.1 %

Procedure:
The above hydrochloride salt of 1-methyl-1-(2-phenylethyl)hydrazine (0.67 g, 1.05 mmol), 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.90 g, 3 mmol) and triethylamine (1.24 ml, 9 mmol) were dissolved in 1,4 -dioxan (20 ml). The solution was stirred at ambient temperature for 20 h. The cooled reaction mixture was evaporated to a gum and purified by flash chromatography on silica gel. Bution with cyclohexane/ethyl acetate (4/1) initially and then with a 1/1 mixture of these solvents provided 2',3',5'-tri-O-benzoyl-2-chloro-N-(N-methyl-N-(2-phenylethyl)amino)adenosine (1.28 g, 60%) as a foam, 1H NMR (DMSO-d6)γ 2.63 (3H, s,--CH3), 4.66 (1H, dd, H-5'a), 4.77 (1H, dd, H-5'b), 4.86 (1H, q, H-4'), 6.23 (1H, t, H-3'), 6.36 (1H, t, H-2'), 6.54 (1H, d, H-1'), 7.11-7.98 (20H, m, Ar-H), 8.44 (1H, s, H-8), 9.40 (1H, br s, N-H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH3:17][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:13][C:14](=[O:16])[N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:18]
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N1CCCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(benzyloxycarbonylamino)-3-methylbutanoic acid (11.8 g, 46.8 mmol) in DMF (100 mL) was added CDI (7.60 g, 1 equiv, 46.8 mmol) in one portion and stirred at room temperature for 2 h. Piperidine (9.27 mL, 2 equiv, 93.6 mmol) was added and the reaction was left to stir for 17 h. The solvent was removed on a rotovap and the residue was dissolved into a mixture of ethyl acetate (300 mL) and water (100 mL). The organic layer was separated and washed with saturated NaHCO3 solution (2×150 mL), 1 N HCl solution (150 mL) and brine (150 mL). It was dried over anhydrous MgSO4, filtered and concentrated to an oil. The crude material was purified on an ISCO system using a 220 g column and ethyl acetate and hexanes as eluent. The desired fractions were collected and concentrated to a colorless oil (8.84 g, 60%). 1H NMR (CDCl3, 400 MHz): δ 1.45 (s, 6H), 1.48-1.57 (m, 4H), 1.60-1.66 (m, 2H), 3.40-3.44 (m, 2H), 3.52-3.58 (m, 2H), 5.04 (s, 2H), 6.15 (s, 1H), 7.27-7.37 (m, 5H). LRMS (ESI+) for C18H26N2O3 (318.2); Found: 319 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[N:6][CH:7]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Oc1ccc(Br)cn1)C(F)(F)F
Solvent: CN(C)C=O
Product: Brc1ccc(N2CCCCC2)nc1
Temperature: 40 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 5-bromopyrid-2-yl ester (see step (a) above; 1.5 g, 4.9 mmol), piperidine (1.07 mL, 10.8 mmol) and DMF (5 mL) was heated at 40° C. for 3 h. DMF was then removed in vacuo, water (20 mL) was added to the residue and the product extracted with EtOAc (3×15 mL) and CH2Cl2 (15 mL). The combined organic extracts were washed with brine and dried (Na2SO4). After removal of the solvent, the residue was dissolved in Et2O and HCl (4M in dioxane; 4 mL) was added.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH2:10][C:11](O)([CH2:13][O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)[CH:10]=[C:11]([CH2:13][O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(COCc3ccc4ccccc4n3)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(COCc3ccc4ccccc4n3)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(2-quinolylmethoxy)methyl]-4,5-dihydro-1H-imidazole (1 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL) is heated to reflux for 48 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is purified by chromatography on silica gel using hexane/ethyl acetate to give 2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-[(2-quinolylmethoxy)methyl)-1H-imidazole.
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[C@@H:12]1[OH:28])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].[Na].S(OC)(O[CH3:34])(=O)=O.[OH-].[Na+]>O.C(O)(=O)C>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]([CH3:34])[CH2:17]2)[C@H:13]([OH:27])[C@@H:12]1[OH:28])([O:4][P:5]([OH:7])([OH:8])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN1CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a clean, dry 2000 mL round bottom flask equipped with a stifling bar and under a stream of argon slowly dissolve dry and finely powdered guanosine 5′-diphosphate (1), (10.0 g, 20.5 mmol), either in free acid or sodium as a counter ion form, in 200 mL water, adjusting pH to 4.0 with glacial acetic acid. Dimethyl sulfate (20 mL, 119.04 mmol) was then added over a period of one hour with constant stirring at room temperature and the reaction continued for an additional hour during which time a decrease in pH was observed but pH was kept between pH 3.8 to 4.0 by drop-wise addition of 10 mM NaOH and methylation was monitored by analytical HPLC for progress. Methylation was determined to be 98% complete within 2 hr. After 2 hr, the reaction mixture was extracted with CHCl3(3×200 mL) to remove unreacted excess dimethyl sulfate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(O)c([N+](=O)[O-])c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Yield: 46.8 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-4-(4-hydroxy-3-nitrobenzoyl)piperidine (1.50 g, 4.3 mmol), potassium carbonate (0.77 g, 5.6 mmol), and methyl bromoacetate (0.66 g, 4.3 mmol) in acetone (20 mL) was stirred at reflux for 18 h. The reaction mixture was cooled and evaporated in vacuo, and the residue partitioned between water (20 mL) and dichloromethane (20 mL). The organic layer was separated and washed with 1N NaOH (aq) (20 mL), water (20 mL), and brine (10 mL), dried (Na2SO4) and evaporated in vacuo to give crude product which was purified by chromatography on silica gel (˜20 g) eluting with 10–100% EtOAc in hexane to give the title compound (0.85 g, 47%) as a yellow oil. 1H NMR (CDCl3) δ: 1.47 (9H, s), 1.62–1.89 (4H, m), 2.91 (2H, m), 3.35 (1H, m), 3.82 (3H, s), 4.17 (2H, m), 4.88 (2H, s), 7.04 (1H, d, J=9 Hz), 8.13 (1H, dd, J=9, 2 Hz), 8.44 (1H, d, J=2 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:17][C:18]1[C:19]([CH:26]=[O:27])=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:25][O:24][C:21]1[CH:20]=[C:19]([CH:26]=[O:27])[C:18]([O:17][CH2:2][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[N:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][N:22]=1
Reactant: COc1cc(C=O)c(O)cn1
Reactant: COc1ccccc1-c1ncccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccccc2OC)cn1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(2-methoxyphenyl)pyridine (306 mg, 1.31 mmol, 1.00 equiv) in CH3CN (20 mL). 5-Hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), potassium carbonate (364 mg, 2.63 mmol, 2.00 equiv), and KI (44 mg, 0.27 mmol, 0.20 equiv) were added to the reaction mixture. The resulting solution was stirred for 5 h at 60° C., and then it was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% HCOOH and MeCN (10.0% MeCN up to 40.0% in 10 min, up to 95.0% in 2 min, down to 10.0% in 2 min); Detector, Waters 2545 UvDector 254 & 220 nm. This resulted in 65 mg (9%) of 2-methoxy-5-[[2-(2-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid. The compound exhibited a melting point of 105-107° C. 1HNMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 8.69 (s, 1H), 7.93 (m, 2H), 7.36 (m, 3H), 6.99 (m, 3H), 5.35 (s, 2H), 3.86 (m, 6H); MS (ESI) m/z 351 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:14]=[CH2:13]
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(Cl)ccc1C(=O)OC
Yield: 99.3 %

Procedure:
A mixture of methyl 4-chloro-2-hydroxybenzoate (2f) (96.3 g, 0.52 mol), allyl bromide (134 ml, 1.55 mol) and ground potassium carbonate (107 g, 0.77 mol) in 1500 ml of dry acetone was heated under reflux for 20 hours. The inorganic salt was removed by filtration, and the solvent and excess allyl bromide evaporated to dryness to give 3f (117 g, 99.6% yield) as a yellow solid, mp 47°-55° C. NMR (CDCl3) δ7.73 (d, 1H, J=8 Hz, aromatic proton meta to Cl), 6.97 (m, 2H, aromatic protons alpha to Cl), 6.40-5.17 (m, 3H, olefinic orotons), 4.57 (m, 2H, CH2) and 3.90 (s, 3H, CH3).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:22][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Product: Cn1c(C(=O)Nc2ccccc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and aniline the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=267.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:19])[C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])=[O:4].[H][H]>O1CCCC1.[Ni]>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:19])[C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)COC(=S)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)COC(=S)c1cc(N)c(F)cc1Cl
Yield: 91.6 %

Procedure:
10.4 g of the resulting 2-chloro-4-fluoro-5-nitrothiobenzoic acid (methoxycarbonylmethyl) ester are hydrogenated with hydrogen under normal pressure in 150 ml of tetrahydrofuran at a temperature of from 20° to 25° C. in the presence of 2 g of Raney nickel catalyst. When the stoichiometric amount of hydrogen has been consumed, the catalyst is separated off and the solution is concentrated by evaporation to yield 8.6 g of 5-amino-2-chloro-4-fluorothiobenzoic acid (methoxycarbonylmethyl) ester having a melting point of from +88° to +89° C.
Reaction SMILES: C[O-].[Na+].C([O:7][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][CH:39]=1)[C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:17]([NH:19][C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:23]=[C:22]([F:32])[CH:21]=1)=[O:18])=[O:12])(=O)C>CO>[Cl:36][C:35]1[CH:34]=[CH:33][C:16]([C:17]([NH:19][C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:23]=[C:22]([F:32])[CH:21]=2)=[O:18])=[CH:15][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:37]=[CH:38][CH:39]=[C:8]([OH:7])[CH:9]=1
Reactant: CC(=O)Oc1cccc(C(=O)Nc2cc(C(=O)Nc3cc(F)cc(N4CCOCC4)c3)ccc2Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1cc(F)cc(N2CCOCC2)c1)c1ccc(Cl)c(NC(=O)c2cccc(O)c2)c1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
Sodium methoxide (95%, 0.26 g) was added to a stirred solution of 3-(3-acetoxybenzamido)-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (1.23 g) in methanol (75 ml) which had been cooled to 0° C. The resultant solution was stirred at ambient temperature for three hours. The mixture was concentrated by evaporation to a volume of about 15 ml and water (20 ml) was added. The solution was acidified to pH3 by the addition of 1N aqueous hydrochloric acid solution. The precipitate so formed was isolated and dried under vacuum. There was thus obtained the title compound (0.86 g); NMR Spectrum: (DMSOd6) 2.47 (s, 3H), 3.08 (t, 4H), 3.7 (t, 4H), 6.53 (d, 1H), 6.98 (m, 1H), 7.14 (s, 1H), 7.19 (d, 1H), 7.33 (m, 1H), 7.42 (d, 1H), 7.70 (d, 1H), 7.84 (m, 1H), 8.15 (d, 1H), 9.75 (s, 1H), 10.08 (s, 1H), 10.29 (s, 1H); Mass Spectrum: M+H+ 470.