Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[N:15]=[N:16][C:17]([N:10]2[CH2:11][CH2:12][C:6]3([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:7]3)[CH2:8][CH2:9]2)=[CH:18][CH:19]=1
Reactant: CN1CCOC2(CCNCC2)C1
Reactant: Clc1ccc(Cl)nn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCOC2(CCN(c3ccc(Cl)nn3)CC2)C1
Yield: 44.8 %

Procedure:
To a solution of compound 405 (406.0 mg, 2.39 mmol) in tetrahydrofuran (17 mL) was added 3,6-dichloropyridazine (361.7 mg, 2.43 mmol), followed by triethylamine (0.680 mL, 4.89 mmol). The resulting solution was stirred at reflux for 38 hours. The reaction mixture was then concentrated and the residue was purified by reverse phase HPLC (acetonitrile/H2O containing 0.1% TFA each, 25 min from 10 to 40%) to give compound 406 as a sticky yellow solid (303 mg, 45%). LCMS-ESI (POS), M/Z, M+1: Found 283.1, Calculated 283.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].Cl[CH2:17][S:18]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:13]([O-:15])=[O:14])=[C:7]([CH2:17][S:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1ccc([N+](=O)[O-])c(OCCCl)c1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c([N+](=O)[O-])c(OCCCl)c1
Reaction time: 4 h
Yield: 76.7 %

Procedure:
A mixture of 2-(2-chloro-ethoxy)-4-methoxy-1-nitrobenzene (1.4 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (1.4 g, 6 mmoles) was stirred in THF (50 mL) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (18 mL, 18 mmoles) over a half an hour period. Temperature was allowed to rise to −40° C., and the reaction mixture was stirred at this temperature for 4 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (2 g, 4.6 mmoles).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[CH3:23][NH2+:24][CH3:25]>>[CH3:23][N:24](/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH3:25]
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: C[NH2+]C
Agent: CC(=O)[O-]
Product: CN(C)/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 18 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-benzo[b]thiophen-3-ol and dimethylammonium acetate with a yield of 18% of theory; m.p. 179°-180° C. (ethyl acetate/petroleum ether 1:2). The product was identical to that prepared according to Example 4, based on its thin-layer chromatogram, elemental analysis and IR-spectrum.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:12][CH2:13][C@@H:14]1[O:18][C:17]([C:19]2[NH:23][C:22]([C:24]3[CH:25]=[C:26]([OH:36])[CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=3)=[CH:21][CH:20]=2)=[N:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:12][CH2:13][C@@H:14]1[O:18][C:17]([C:19]2[NH:23][C:22]([C:24]3[CH:25]=[C:26]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=3)[O:36][C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=3)=[CH:21][CH:20]=2)=[N:16][CH2:15]1
Reactant: CNC(=O)c1ccc(F)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](CO)O4)[nH]3)c2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
5-Fluoro-N-methylpyridine-2-carboxamide (150 mg, 0.97 mmol) synthesized in Example (123a) and 3-{5-[(5R)-5-(hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (438 mg, 1.27 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (269 mg, 1.95 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (281 mg, yield 60%) as a white solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[Cl:16])[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][NH2:1]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1c[nH]c2cc(Cl)c(Cl)cc12

Procedure:
2-(5,6-dichloro-1H-indol-3-yl)ethanamine was prepared according to method D Step V with 3-(2-azidoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole (0.497 g; 1.35 mmol) and triphenylphosphine (0.529 g; 1.35 mmol) in methanol (10 mL) and tetrabutylamonium fluoride (4.04 mL 1M) in THF (stirred for 36 hours).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)=[CH:20]2.C(N(CC)CC)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][C:21]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)=[CH:20]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(N)ccc3[nH]2)CC1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(NC(=O)C4(c5ccc6c(c5)OCO6)CC4)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (43 mg, 0.19 mmol) and tert-butyl 4-(5-amino-1H-indol-2-yl)piperidine-1-carboxylate (60 mg, 0.19 mmol) were dissolved in dichloromethane (1 mL) containing a magnetic stir bar and triethylamine (0.056 mL, 0.40 mmol). The resulting solution was allowed to stir for two days at room temperature. The crude product was then evaporated to dryness, dissolved in a minimum of N,N-dimethylformamide, and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield tert-butyl 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)piperidine-1-carboxylate. ESI-MS m/z calc. 503.2, found 504.5. (M+1)+. Retention time of 1.99 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C[O:11][CH:12]=[C:13]1C(=O)OC(C)(C)O[C:14]1=O>CC(O)C>[Cl:9][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]2[C:5]=1[C:12]([OH:11])=[CH:13][CH:14]=[N:8]2
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: Nc1cc(Cl)nc(Cl)c1
Solvent: CC(C)O
Product: Oc1ccnc2cc(Cl)nc(Cl)c12
Temperature: 100 °C
Yield: 61.8 %

Procedure:
To a flask equipped with a reflux condenser, 2,6-dichloropyridin-4-amine (2.00 g, 12.27 mmol) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.398 g, 12.88 mmol) were dissolved in IPA (12.00 mL) and heated to 100° C. for 1 hour. The reaction was cooled to room temperature and the solids were filtered. The solids were added to a microwave vial followed by dichlorobenzene (12.00 mL). The vial was capped and heated to 250° C. for 15 minutes. The reaction was purified via silica gel MPLC chromatography (40 g), eluting with 0 to 100% ethyl acetate in heptanes. The fractions were collected and the solvent was removed under reduced pressure to provide 1.63 g of 5,7-dichloro-1,6-naphthyridin-4-ol as an off white solid. m/z (ESI) 215.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:8][CH:9]=1
Reactant: O=C(Cc1ccccc1)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(NC(=O)Cc2ccccc2)nc1

Procedure:
A solution of N-(5-nitropyridin-2-yl)-2-phenylacetamide (4.35 g, 16.9 mmol) in EtOH (75 mL) and EtOAc (75 mL) is stirred at rt and ammonium formate (4.27 g) and 10% Pd/C (500 mg) are added. The mixture is heated at reflux for 30 min, cooled, filtered through celite and evaporated to afford the title compound as an off-white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[NH:11]1[CH2:10][CH:9]([O:8][C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2nccnc2Cl)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1nccnc1OC1CNC1
Reaction time: 72 h
Yield: 62.6 %

Procedure:
To a solution of tert-butyl 3-(3-chloropyrazin-2-yloxy)azetidine-1-carboxylate (see PREPARATION P20.2; 4.3 g, 15.05 mmol) and DCM (50 mL) was added 4M HCl in dioxane (3.76 mL, 15.05 mmol). After 72 hours, a precipitate coated the walls of the flask. The liquid was carefully decanted off and the rinsed with DCM (20 mL) and again carefully decanted off. The precipitate coated round bottomed flask was treated with DCM:saturated NaHCO3 (1:1, 150 mL). The aqueous layer was extracted with 10% MeOH in DCM (4×25 mL). The combined organic layers were concentrated in vacuo to give crude product. The aqueous layer still contained the majority of the product. The aqueous layer was concentrated in vacuo and the solids stirred with 10% MeOH in DCM (200 mL) for 2 hours, then filtered. The filtrate was concentrated in vacuo to give more crude product. The separate lots of crude product were combined to give crude 2-(azetidin-3-yloxy)-3-chloropyrazine (1.75 g, 62.6% yield), as a tan solid. The product was carried forward in the next step without further purification. MS (ESI) m/z 186.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18]([Mg]Br)[CH2:19][CH:20]=[CH2:21]>C1COCC1.CCOCC>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH2:21][CH2:20][CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C=CCC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (595 mg) in THF (3 mL) at −78° C. was added 3-butenyl magnesium bromide (7.8 mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 4 hr. The reaction was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of Et2O and triturated with hexanes to yield the title compound as a tan solid.
Reaction SMILES: [OH-:1].[Na+:2].CO.[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:17]([OH:20])([OH:19])=[O:18])([P:13]([OH:16])([OH:15])=[O:14])[OH:12])[CH:6]=1>O>[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:13]([O-:16])([OH:15])=[O:14])([P:17]([O-:19])([OH:20])=[O:18])[OH:12])[CH:6]=1.[OH2:1].[OH2:12].[OH2:12].[OH2:12].[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of sodium hydroxide (1.4 g) in a mixture of water (80% v/v)/Methanol (20% v/v, 10 volumes per grams of ZLD-Ac form 1) (38 ml) was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) in a mixture of water (80% v/v)/Methanol (20% v/v, 10 volumes per grams of ZLD-Ac) (212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 19 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The solution was then evaporated to dryness to obtain 6.1 g (99%) of Zoledronate disodium crystal form XXV (LOD by TGA=7.4%). Purity by HPLC 99.9%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[CH:41][C:40]=1[CH2:49]O.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:49][C:40]3[CH:41]=[N:42][C:43]4[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:39]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: OCc1cnc2ccccc2n1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Temperature: 60 °C
Yield: 69 %

Procedure:
To a solution of 4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol (50 mg) in dioxane (2 ml) was added triphenylphosphine (84 mg), quinoxaline-2-yl-methanol (48 mg) and di-t-butyl-aza-dicarboxylate (73 mg) and the reaction mixture was heated at 60° C. for 18 h. The reaction mixture was poured into 1N NaOH, extracted 3× methylene chloride, dried magnesium sulfate, filtered and concentration Purification via MPLC biotage chromatography provided the title compound (54 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.45 (d, J=6.2 Hz, 2H), 8.10 (m, 2H), 7.77 (m, 2H), 7.55 (s, 1H), 7.37 (d, J=9.1 Hz, 2H), 7.10 (d, J=6.9 Hz, 2H), 7.01 (d, J=8.7, 2H), 5.41 (s, 2H), 3.94 (s, 3H); MS: (M+H m/z=394.4).
Reaction SMILES: [C:1]1([C:7]([CH2:14][CH2:15][CH3:16])([CH2:11][CH2:12][CH3:13])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:25])=O>>[C:1]1([C:7]([CH2:14][CH2:15][CH3:16])([CH2:11][CH2:12][CH3:13])[C:8]([Cl:25])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(CCC)(C(=O)O)c1ccccc1
Solvent: CN(C)C=O
Product: CCCC(CCC)(C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the product of Example 1C (4.13 g, 18.77 mmol) and N,N-dimethylformamide (1.45 mL, 18.77 mmol) in hexanes (700 mL) was treated with oxalyl chloride (4.91 mL, 56.31 mmol) and stirred at 25° C. for 2 hours. The mixture was treated with Celite®, and then filtered through a pad of Celite®. The filtrate was concentrated in vacuo to afford the title compound which was used directly in the next procedure.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:15])[CH:3]=1.[F:16][C:17]1[C:22]([OH:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:18]=1[F:27].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([O:23][C:22]3[C:21]([F:24])=[C:20]([F:25])[C:19]([F:26])=[C:18]([F:27])[C:17]=3[F:16])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:15])[CH:3]=1
Reactant: Cn1cc(Br)c2ccc(S(=O)(=O)Cl)cc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c2ccc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc21
Reaction time: 0.75 h
Yield: 95.4 %

Procedure:
A vial was charged with 3-bromo-1-methyl-1H-indole-6-sulfonyl chloride (505.0 mg, 1.637 mmol), pentafluorophenol (452 mg, 2.455 mmol), and DCM (8.1 mL) to give a clear, light-yellow solution. Triethylamine (342 μl, 2.455 mmol) was added dropwise, and the resulting mixture was stirred for 45 min before being concentrated in vacuo. The crude product was purified by chromatography on silica gel (40% EtOAc/Heptane) to give perfluorophenyl 3-bromo-1-methyl-1H-indole-6-sulfonate (712.3 mg, 1.561 mmol, 95% yield) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.04 (t, J=1.1 Hz, 1 H), 7.82-7.67 (m, 2 H), 7.41 (s, 1 H), 3.91 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].Cl[C:26]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([CH3:26])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 91) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(2',3',5'-tribromobenzoyl)-1,4,α-trimethylpyrrole-2-acetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=O)=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.ClCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([Cl:15])=[O:11])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(Cl)ncc1C(=O)O
Agent: ClCl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)ncc1C(=O)Cl
Yield: 61.3 %

Procedure:
A solution of 2-chloro-4-methylpyrimidine-5-carboxylic acid (0.81 g, 4.70 mmol), oxalyl chloride (0.89 g, 7.05 mmol), DMF (2 drops) in CH2 Cl2 (23 mL) was stirred at room temperature under N2 for 4 h. The solution was concentrated and distilled to give the title compound (0.55 g, 61%); b.p. 90°-100° C., 1.3 mm/Hg; 1HNMR (CDCl3) δ d 9.02 (s, 1H), 2.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:14]([NH:15][NH:16][C:17]([NH:19][CH3:20])=S)=[CH:13][C:11](=[O:12])[N:10]([CH2:21][CH2:22][CH3:23])[C:8]2=[O:9])=[CH:4][CH:3]=1.CO>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:14]3[NH:15][N:16]=[C:17]([NH:19][CH3:20])[C:13]=3[C:11](=[O:12])[N:10]([CH2:21][CH2:22][CH3:23])[C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)cc(NNC(=S)NC)n(Cc2ccc(Cl)cc2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(Cl)cc2)c1=O
Yield: 64 %

Procedure:
A solution of 1-(4-chlorobenzyl)-6-(4-methylthiosemicarbazido)-3-propyluracil (4.8 g, 12.6 mM) in DMF (50 ml) was stirred at 100° C. for 40 hours. To the solution was added 50% methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless crystals (2.8 g, 50%), m.p. 305°-307° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH:24][OH:25]>C(Cl)Cl>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:24]1[C:9](=[O:10])[C:8]([CH3:15])([CH3:7])[C:12](=[O:13])[O:25]1
Reactant: ONCc1ccccc1F
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)C(=O)ON(Cc2ccccc2F)C1=O
Temperature: -25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
The procedure of Example III was utilized with 10.2 ml (0.128 mole) pyridine, 10.2 grams (0.060 mole) dimethylmalonyl chloride and 120 ml methylene chloride in solution under argon at -72° C., to which 8.5 grams (0.060 mole) of N-(2-fluorophenylmethyl)hydroxylamine (Intermediate F) in 25 ml methylene chloride was added in a single portion, raising the temperature immediately to -25° C., and stirring was continued at 0° C. for two hours. Gas chromatography on a sample of the reaction mixture showed only one major peak. The reaction mixture was washed with 2 N hydrochloric acid and water, the methylene chloride layer was separated and dried over sodium sulfate, and after removal of sodium sulfate by filtration, the solvent was removed under reduced pressure, leaving 13.0 grams of a yellow viscous liquid (91% yield). The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:32]=[C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:24][CH:25]=3)[N:31]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: CC(=O)Nc1ccc(NC(=N)N)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Solvent: O=[N+]([O-])O
Product: CC(=O)Nc1ccc(Nc2nccc(-c3sc(C)nc3C)n2)cc1

Procedure:
By condensation between 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-acetamidophenyl)-guanidine nitrate. Pale solid. Mp. 219-220° C. 1H-NMR (DMSO-D6) δ: 2.00 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 7.04 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 7.48 (d, 2H, J=8.8 Hz, Ph-H), 7.64 (d, 2H, J=8.8 Hz, Ph-H), 8.47 (d, 1H, J=5.4 Hz, pyrindinyl-H), 9.58 (s, 1H, NH), 9.82 (s, 1H, NH). MS (ESI+) m/z 340.02 [M+H]+ (C17H17N5OS requires 339.42).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[OH:11].Br>>[C:3]1([CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[OH:11])[OH:2]
Reactant: COc1cccc(OC)c1O
Agent: Br
Product: Oc1cccc(O)c1O
Yield: 90 %

Procedure:
The product of Example 3 was added to 48% aqueous hydrobromic acid (400 parts) and the mixture boiled under reflux in an atmosphere of nitrogen for one hour. The hydrobromic acid was then evaporated off under reduced pressure to leave crude pyrogallol (40 parts, 90% yield), melting point 124°-130° C., the structure of which was confirmed by its nuclear magnetic resonance spectrum.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[O:20]=[C:21]1[O:25][C@H:24]([C:26]([OH:28])=O)[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.[NH2:40][C@@H:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][C@H:42]1[NH:50][C:51]([C:53]1[NH:57][C:56]2[S:58][C:59]([Cl:61])=[CH:60][C:55]=2[CH:54]=1)=[O:52]>C(Cl)Cl>[Cl:61][C:59]1[S:58][C:56]2[NH:57][C:53]([C:51]([NH:50][C@@H:42]3[CH2:43][C:44]4[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=4)[C@H:41]3[NH:40][C:26]([C@@H:24]3[CH2:23][CH2:22][C:21](=[O:20])[O:25]3)=[O:28])=[O:52])=[CH:54][C:55]=2[CH:60]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Reactant: O=C1CC[C@@H](C(=O)O)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CC[C@@H](C(=O)N[C@@H]2c3ccccc3C[C@H]2NC(=O)c2cc3cc(Cl)sc3[nH]2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), (2S)-5-oxotetrahydrofuran-2-carboxylic acid (CAS Reg. No: [21461–84–7], 0.5 mmol, 65 mg) and EDAC (120 mg, 0.63 mmol) were added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 21, 223 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (5 mL), washed with water (2×5 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue triturated (EtOAc:hexane, 1:10), collected by filtration, washed with hexane (2×5 mL) and dried to give the title compound (112 mg, 56%) as a brown solid.