Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(F)c(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)ccc3F)cccc2c1N
Yield: 82.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-5-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (142 mg, 83% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.92 (m, 1H), 7.82-7.69 (m, 2H), 7.12 (m, 1H), 7.02-6.89 (m, 2H), 3.81 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.66 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.78 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: COCCOCn1nc(I)c2cc(Br)cnc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCOCn1nc(-c2ccccc2OC)c2cc(Br)cnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A mixture of 5-bromo-3-iodo-1-(2-methoxy-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (180 mg, 0.44 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (18 mg, 25 μmol) and 2-methoxyphenylboronic acid (82 mg, 0.51 mmol) in acetonitrile (3 mL) and 2 M aqueous solution of sodium carbonate (3 ml) in a sealed vial was stirred at 60° C. for 2 h. The crude mixture was distributed between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-bromo-1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine (80 mg, 0.2 mmol, 46% yield) as a yellow oil. 1H-NMR (500 MHz, d6-DMSO) δ 8.70 (d, 1H), 8.40 (d, 1H), 7.62 (dd, 1H), 7.49 (ddd, 1H), 7.22 (d, 1H), 7.09 (dt, 1H), 5.85 (s, 2H), 3.85 (s, 3H), 3.68-3.70 (m, 2H), 3.39-3.41 (m, 2H), 3.18 (s, 3H). MS: m/z 316, 318 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[NH:19][C:20]1[N:24]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:23]2[CH:31]=[CH:32][C:33]([CH2:35][OH:36])=[CH:34][C:22]=2[N:21]=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][C:40]=1B(O)O.ClCCl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:25]1([N:24]2[C:23]3[CH:31]=[CH:32][C:33]([CH2:35][OH:36])=[CH:34][C:22]=3[N:21]=[C:20]2[NH:19][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:40]4[CH:41]=[N:42][CH:43]=[CH:44][C:39]=4[O:38][CH3:37])[CH:3]=3)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[N:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccncc1B(O)O
Reactant: C[Si](C)(C)CCOCn1nc(Nc2nc3cc(CO)ccc3n2C2CCCCC2)c2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(CO)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Yield: 16.9 %

Procedure:
In a small microwave tube was added (2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1-cyclohexyl-1H-benzo[d]imidazol-5-yl)methanol (164 mg, 0.000287 mol), 4-methoxypyridin-3-ylboronic acid (79.1 mg, 0.000517 mol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (47 mg, 0.000057 mol). To this mixture was added 1,4-dioxane (4.3 mL, 0.055 mol) and the resultant mixture was stirred under an argon atmosphere. To this mixtrure was then added 2 M sodium carbonate in water (700 uL) and the reaction mixture was microwaved for 21 minutes at 120° C. The reaction mixture filtered through a syringe filter cartridge and the cartridge washed 3 times with methanol. The residue after concentration was purified by flash chromatography using a 40 g silica gel cartridge and 10-60% ethyl acetate/hexane gradient. The product fractions were concentrated to give the title compound (29 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:22](=N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3ccccc3)o2)CC1
Yield: 20.9 %

Procedure:
To a stirred solution of 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 4.73 mmol, 1.0 eq) in EtOH (15 mL) was added benzimidic acid ethyl ester hydrochloride (921 mg, 4.96 mmol, 1.05 eq.) and the reaction mixture was refluxed for 48 h. The inorganic precipitate was filtered off, washed with ethyl acetate, and the solvent of the mother liquor was evaporated in vacuo. The residue was purified by column chromatography (ethyl acetate/heptanes) to give the title compound as a white solid (327 mg, 0.99 mmol). MS (m/z, MH+): 330.2
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]3=[O:32])=[CH:18][C:17]=2[F:33])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH:6]=[N:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]3=[O:32])=[CH:18][C:17]=2[F:33])[CH2:14][CH2:15]1)[CH3:5]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N)CC3)c(F)c2)C(=O)O1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N=CN(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 84 %

Procedure:
N,N-dimethylformamide dimethylacetal (0.8 ml) and 1.0 g of the (S)-N-{3-[4-(4-amino-piperidin-1-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 6) which was synthesized in Example 4 were added to toluene (10 ml) and the mixture was heated under reflux for 24 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was washed with hexane to remove excess dimethylacetal. The resulting precipitate was suspended in dichloromethane and the insolubles were separated by filtration. The filtrate was concentrated under vacuum to afford the title compound (985 mg) in a yield of 84%.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][C@H:9]([N:13](C(OCC1C=CC=CC=1)=O)[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])[CH3:3].C1CCC(NC2CCCCC2)CC1.[CH:38]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)([CH3:40])[CH3:39].[ClH:48].CO>>[ClH:48].[C:2]([O:5][C:6](=[O:7])[CH2:8][C@H:9]([NH:13][CH3:14])[C:10]([NH:45][C:44]1[CH:46]=[CH:47][C:41]([CH:38]([CH3:40])[CH3:39])=[CH:42][CH:43]=1)=[O:11])([CH3:3])([CH3:4])[CH3:1]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CN(C(=O)OCc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: CO
Product: CN[C@@H](CC(=O)OC(C)(C)C)C(=O)Nc1ccc(C(C)C)cc1

Procedure:
Z-N-Me-Asp(OtBu)—OH DCHA salt (1:1) and 4-Isopropylaniline according to 1.2., followed by deprotection (6.1.) and treatment with HCl/MeOH to give (S)-N-(4-Isopropyl-phenyl)-3-methylamino-succinamic acid tert-butyl ester-HCl, MS: 321 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[Cl:28][C:29]1[S:30][C:31]([CH2:34]Cl)=[CH:32][CH:33]=1>>[Cl:28][C:29]1[S:30][C:31]([CH2:34][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:17]([CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:27])[CH2:16][CH2:15]3)=[CH:18]2)=[CH:32][CH:33]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: COC(=O)c1cccc(CN2CCC(c3c[nH]c4cc(F)ccc34)CC2)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4ccc(Cl)s4)c4cc(F)ccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.07 g (0.19 mmol) of 3-[4-(6-fluoro-1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester and 0.05 g (0.29 mmol) of 2-chloro-5-chloromethyl-thiophene. After standard purification, 0.01 g (10% of the yield) of the expected acid were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([C:24]#[N:25])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([C:24]#[N:25])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(C#N)c1
Temperature: 77.5 °C
Yield: 52 %

Procedure:
To a solution of 38 (220.0 mg; 0.58 mmol) in tetrahydrofuran (4 mL) and methanol (1 mL) was added aqueous lithium hydroxide (1.45 mL; 2M. The reaction mixture was heated at 75-80° C. for 6 hours, allow ed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude white solid residue was purified by preparative HPLC to yield the title compound as a white solid (110 mg).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:33])[C:9]1=[O:34])(=O)C.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]2[C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[C:9](=[O:34])[N:10]([CH3:33])[C:11]=3[CH:17]=[C:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:31][CH:30]=1
Reactant: CC(=O)OCCCn1c(=O)c2c(cc(-c3cccc(Cl)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c1cc(-c1cccc(Cl)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (40 mg, 0.08 mmol) in THF (1.5 mL) and water (1.5 mL) was added LiOH.H2O (30.0 mg, 0.6 mmol). The reaction was stirred at RT for 30 min diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-3-(3-hydroxypropyl)-1-methyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (3 mg, 3.3% yield) as a white solid. 1H NMR (CDCl3) δ: 7.47-7.31 (m, 3H), 7.24-7.15 (m, 3H), 6.84 (d, J=8.4 Hz, 2H), 6.08 (s, 1H), 5.58 (s, 2H), 4.26-4.14 (m, 2H), 3.60 (s, 1H), 3.51 (s, 5H), 1.93-1.82 (m, 2H). LCMS: MH+ 458 and TR=2.885 min.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[Na+].Cl[CH2:14][C:15]([OH:17])=[O:16]>O>[C:15]([CH2:14][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])([OH:17])=[O:16]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of salicylic acid (20 g, 145 mmol) in water (200 mL) is added carefully sodium hydroxide (60 g, 1.45 mol) followed by chloroacetic acid (27 g, 290 mmol). The mixture is refluxed for 5 d, cooled to room temperature and the precipitate is filtered and dried. Trituration with hexanes yielded the title compound (6.84 g, 24%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ 7.65-7.66 (dd, 1H, J=8.0, 2.0 Hz), 7.45-7.47 (dd, 1H, J=8.0, 2.0 Hz), 6.97-7.05 (m, 2H), 4.77 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][OH:20])=[O:17])=[N:14][CH:15]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][O:20][CH2:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[O:17])=[N:14][CH:15]=1
Reactant: OCc1cccnc1
Reactant: Cc1cc(C(=O)NCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C(=O)NCOCc2cccnc2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Yield: 24.7 %

Procedure:
A benzene solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridine-2-carboxamide (155 mg, 0.344 mmol) obtained in Example 85, 3-pyridinemethanol (40 μl, 0.413 mmol) and p-toluenesulfonic acid dihydrate (98 mg, 0.516 mmol) was heated to reflux for 2 hours while distilling off water. The reaction solution was returned to room temperature, subsequently saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with 70% ethyl acetate/hexane was concentrated under reduced pressure. Ether was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (46 mg, 0.085 mmol, 25%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15].O>C1C=CC=CC=1.[I-].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][CH:30]=3)=[CH:20][CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
To a solution of 3.21 g of p-chlorophenol, 1.19 g of sodium methoxide and 50 mg of potassium iodide was added 7.54 g of methyl α-bromo-α-[p-(p-tert-butylphenoxy)phenyl]acetate in 10 ml of benzene. The mixture was refluxed overnight and cooled to room temperature. The mixture was then poured into 100 ml of water and extracted with 2×75 ml of ether. The combined extracts were washed with 50 ml of 5% NaOH, 2×50 ml of water, 50 ml saturated brine and dried (MgSO4). Evaporation of the solvent yielded an amber oil. Chromatography on 100 g of silica gel (benzene) afforded 7.36 g of product as a pale yellow glass.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:13]1[CH:18]=[C:17]2[C:19]([C:22]([C:24](Cl)=[O:25])=[O:23])=[CH:20][NH:21][C:16]2=[CH:15][CH:14]=1>O>[NH:21]1[C:16]2[C:17](=[CH:18][CH:13]=[CH:14][CH:15]=2)[C:19]([C:22](=[O:23])[C:24]([N:1]2[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]2)=[O:25])=[CH:20]1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C(=O)N1CCC(O)C1)c1c[nH]c2ccccc12

Procedure:
--A solution of 1.25 g. (0.014 mole) of 3-pyrrolidinol and 3.0 g. of sodium carbonate in 35 ml. of water was treated all at once with 3 g. (0.014 mole) of indole-3-glyoxyloyl chloride and the mixture stirred at room temperature for 24 hours. The product was isolated by filtration and recrystallized from absolute alcohol. The yield was 2.6 g. (70%) and the material melted at 216°-218° C.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH:26]([CH3:28])[CH3:27])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.S(Cl)([Cl:31])=O.O1CCCC1>CN(C)C=O.O>[Cl:31][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH:26]([CH3:28])[CH3:27])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)N(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-isopropylthiophene-2-sulfonamide (2.12 g), thionyl chloride (0.70 mL), N,N-dimethylformamide (2 drops) and tetrahydrofuran (30 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated brine, aqueous sodium bicarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was crystallized from diethyl ether. The crystals were collected by filtration, washed with diethyl ether, and dried to give the title compound (2.00 g, yield 90%) as yellow crystals. melting point 184-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]=1[N+:27]([O-:29])=[O:28])=[O:4].C([SiH](CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:17])([F:18])[F:16])=[N:12]2)=[CH:7][C:6]=1[N+:27]([O-:29])=[O:28])=[O:4]
Reactant: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nc(C(F)(F)F)ccc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A solution of 6-Nitro-5-trifluoromethanesulfonyloxy-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (12.0 g, 24.094 mmol, step d, example H-18) is dissolved in dimethylformamide (50 ml) under argon and then treated with palladium(II)acetate (0.16 g, 0.723 mmol) and 1,1′bis(diphenylphosphino)ferrocene (0.4 g, 0.723 mmol). To this mixture at room temperature is added triethyl silane (7.0 g, 7.234 mmol) and the reaction then stirred overnight at room temperature. The reaction mixture is diluted with ethyl acetate and washed with brine. The ethyl acetate phase is dried over sodium sulphate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (hexane:ethyl acetate, 6:1 as eluent) gives the title compound (4.5 g, 62%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[S:17]([N:20]=C=O)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][S:17](=[O:19])(=[O:18])[NH2:20])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Yield: 58.4 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 9.9 g (0.05 mole) of 4-hydroxybenzophenone, 7.1 g (0.0505 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 8.1 g (58%) of the title compound as off-white flakes, mp 131°-133° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[NH2:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][CH:27]=O.O>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]3[CH:26]=[CH:27][N:24]=[C:16]23)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCl
Reactant: Nc1nc2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: c1ccc(COc2ccc(-n3c4ncccc4n4ccnc34)cc2)cc1

Procedure:
A solution of 3-[4-(benzyloxy)phenyl]-3H-imidazo[4,5-b]pyridin-2-amine (1.58 g) and 6.1 M aqueous chloroacetoaldehyde solution (1.64 mL) in DMA (20 mL) was stirred at 90° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) and recrystallized from hexane/THF to give the title compound (0.665 g).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10](CC2C=CC=CC=2)[C:11]=1[NH2:12])=[O:6].CO.O.[H][H]>[Pd].C(O)(=O)C>[ClH:1].[ClH:1].[NH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][NH:10][C:11]=1[NH2:12])=[O:6]
Reactant: [H][H]
Reactant: NCC(=O)c1ncn(Cc2ccccc2)c1N
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: NCC(=O)c1nc[nH]c1N

Procedure:
A solution of 1.0 g. of 2-amino-1-[5-amino-1-(phenyl-methyl)-1H-imidazol-4-yl]ethanone dihydrochloride in 100 ml. of 70:20:10 methanol:water:acetic acid is hydrogenated over 0.52 g. of 20% palladium-on-carbon at 50 p.s.i. until hydrogen uptake ceases. The catalyst is removed by filtration and the filtrate is evaporated at reduced pressure to give 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride; m.p. above 250° dec.
Reaction SMILES: Cl.[NH2:2][NH2:3].O.NN.C[O:8][C:9]([C@@H:11]1[CH:26]=[C:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][C:18]=3[CH3:28])[N:13]([CH3:14])[CH2:12]1)=O>C(O)CC>[CH3:28][C:18]1[NH:19][C:20]2[C:27]3[C:17]=1[CH2:16][C@@H:15]1[C:25]([C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:26][C@H:11]([C:9]([NH:2][NH2:3])=[O:8])[CH2:12][N:13]1[CH3:14]
Reactant: NN
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Agent: Cl
Solvent: CCCO
Solvent: O
Product: Cc1[nH]c2cccc3c2c1C[C@@H]1C3=C[C@H](C(=O)NN)CN1C
Reaction time: 15 h

Procedure:
15.9 g hydrazine hydrochloride and 18.4 ml hydrazine hydrate are added under stirring to 22.5 g of the product of step (a) in 20 ml n-propanol and the obtained reaction mixture is heated under reflux for 5 hours. The mixture is concentrated, treated with 500 ml H2O, filtered and washed with H2O (fraction A). The mother liquor is extracted with ethyl acetate and the extract evaporated. To the residue (7.5 g) are added 100 ml n-propanol and 20 ml triethylamine and the mixture is stirred and heated at reflux. The reaction is followed by thin layer chromatography. After approximately 15 hours when all of the β-product is converted into the 8α-product, H2O is added and the mixture is filtered. The filter cake is combined with fraction A and recrystallized twice from hot ethanol to afford the heading compound, m.p. 235°-240°, which is the pure α-isomer by NMR.