Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH2:11][N:12]3[CH:17]=[CH:16][C:15]4[C:18]([C:21](=[O:31])[C:22]5[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=5[F:30])=[CH:19][NH:20][C:14]=4[C:13]3=[O:32])=[N:8][C:5]2=[N:6][CH:7]=1.C(OC([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C.O>[NH:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH2:11][N:12]3[CH:17]=[CH:16][C:15]4[C:18]([C:21](=[O:31])[C:22]5[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=5[F:28])=[CH:19][NH:20][C:14]=4[C:13]3=[O:32])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3nc4ncc(Br)cc4[nH]3)ccc12
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3nc4ncc(-c5ccc[nH]5)cc4[nH]3)ccc12
Temperature: 135 °C
Yield: 8.2 %

Procedure:
A microwavable vial was charged with 6-[(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (20 mg, 0.04 mmol), [1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]boronic acid (12.6 mg, 0.06 mmol), cesium carbonate (39 mg, 0.119 mmol), bis(triphenylphosphine)palladium(II) chloride (2.8 mg, 3.98 umol) and acetonitril/water (0.6/0.2 ml). The vial was sealed, purged by 3 cycles of freeze-pump-thaw. The resultant suspension was heated to 135° C. by microwave irradiation for 15 min. LCMS showed complete consumption of the starting material and formation of the desired product. The reaction mixture was diluted with acetonitrile, and filtered through a 0.45 micron membrane filter and then concentrated to dryness under reduced pressure. The crude reaction mixture was purified by HPLC on Xbridge (C18 5u particle size, 30×75 mm) preparative column eluting with a linear gradient of 15-40% acetonitrile/water (0.01% NH4OH) at 70 ml/min. to give the title compound (1.6 mg, 8%). MS (ESI): m/z 489 (M+H). 1H-NMR (500 MHz, d6-DMSO): δ 11.35 (br. s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.58 (d, 1H), 7.36 (m, 2H), 7.00 (d, 1H), 6.86 (s, 1H), 6.54 (s, 1H), 6.11 (s, 1H), 5.47 (s, 2H),
Reaction SMILES: [CH3:1][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:13])[CH:9]=[C:10]([NH2:12])[N:11]=1)=[O:6])[CH3:3].[CH3:14][N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[C:16]1[C:23](Cl)=[O:24]>C1COCC1.C(Cl)Cl>[CH3:3][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:13])[CH:9]=[C:10]([NH:12][C:23]([C:16]2[N:15]([CH3:14])[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=2)=[O:24])[N:11]=1)=[O:6])[CH3:1]
Reactant: CN(C)NC(=O)c1nc(N)cn1C
Reactant: Cn1cc([N+](=O)[O-])nc1C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)NC(=O)c1nc(NC(=O)c2nc([N+](=O)[O-])cn2C)cn1C
Temperature: -20 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
The amine from above was dissolved in dry THF (20 mL) and cooled to -20° C. The stirring reaction mixture was placed under argon and a solution of 1-methyl-4-nitroimidazole-2-carbonyl chloride (2.18 g, 11.5 mmol) in dry CH2Cl2 (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight then concentrated to dryness and water was added. The suspension was filtered and the solid was washed with carbon tetrachloride and water, then dried in-vacuo (80° C.) to provide N-(N',N'-dimethylamino)-1-methyl-4-[1-methyl-4-nitroimidazole-2-carboxamido]imidazole-2-carboxamide as a pale yellow crystalline solid, 2.18 g (68.8% yield). A sample for analysis was obtained by recrystallization from water: mp 239° C. (dec.). TLC (5% MeOH/CHCl3) Rf 0.66. 1H--NMR (CDCl3); δ2.69 (s, 6H, N(CH3)2), 4.07 (s, 3H, N--CH3), 4.21 (s, 3H, N--CH3), 7.43 (s, 1H, NH). IR (nujol: υ3397 and 1678 cm-1. MS(El) m/z (rel. intensity) 336 (M+, 100), 293 (M+1-N(CH3)2, 85).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1>CC(O)=O>[NH2:3][C:4]1[C:11]([Br:1])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: N#Cc1ccc(N)nc1
Solvent: CC(=O)O
Product: N#Cc1cnc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
Br2 (0.52 mL, 0.01 mol) was added to a solution of 6-aminonicotinonitrile (1.1901 g, 0.01 mol) in AcOH (10 mL) at room temperature. The mixture was stirred at room temperature for 2 h. Then the mixture was concentrated and the residue was purified by flash column chromatography to give the title product (980.0 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[C:20]([F:21])[CH:19]=3)[CH2:15][CH2:16]2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Fc1cc2c(cc1F)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccnc(Cl)c1)N1CCc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.35 g (2.2 mmol) 2-chloroisonicotinic acid, 0.34 g (2.2 mmol) 5,6-difluoro-2,3-dihydro-1 H-indole, 0.70 mL (5.0 mmol) TEA and 10 mL DMF were mixed with 0.77 g (2.4 mmol) TBTU and stirred for 2 h at RT. The reaction mixture was purified by HPLC. The product fractions were combined and evaporated down.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2c1cccc(Cl)c1

Procedure:
The title compound was synthesized from methyl 4-(3-chlorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.179 g, 0.65 mmol) and lithium hydroxide (0.272 g, 6.5 mmol), according to General Procedure 7. A 1:1 mixture of THF and methanol (4 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound. 0.124 g. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.19 (ddt, J=12.73, 8.52, 6.46, 6.46 Hz, 1H), 2.69-2.97 (m, 3H), 4.17 (t, J=7.13 Hz, 1H), 6.53 (s, 1H), 7.11 (d, J=7.57 Hz, 1H), 7.13-7.18 (m, 2H), 7.20-7.26 (m, 1H); LCMS-MS (ESI−) 260.2 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([NH:11][C:12]1[NH:18][C:17]2[N:19](C(C)=O)[CH:20]=[N:21][C:16]=2[C:14](=O)[N:13]=1)=[O:10].P(Cl)(Cl)([Cl:27])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[C:9]([NH:11][C:12]1[N:18]=[C:17]2[C:16]([NH:21][CH:20]=[N:19]2)=[C:14]([Cl:27])[N:13]=1)(=[O:10])[CH3:8]
Reactant: CC(=O)Nc1nc(=O)c2ncn(C(C)=O)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
60.0 g (0.36 mol) of tetraethylammonium chloride and 20.3 g (0.2 mol) of triethylamine are added to a suspension of 42.6 g (0.18 mol) of 2,9-diacetylguanine in 450 ml of acetonitrile. 165.3 g (1.08 mol) of phosphorus oxychloride are then added at a temperature of the reaction mixture of 0° C. to 5° C. The mixture is stirred at 25° C. for 20 hours and then worked up as in Example 1. 30.9 g of 2-acetamido-6-chloropurine are obtained.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[CH3:12][C:13]([CH3:15])=[O:14]>>[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[CH:12][C:13](=[O:14])[CH3:15]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixed solution of acetone (294 ml) and an aqueous solution (1.4 l) of sodium hydroxide (22.0 g) was added 2-chlorobenzaldehyde (70.3 g), and the mixture was stirred at room temperature for 5 hours. Excess acetone was evaporated under reduced pressure, and to the residue was added ethyl acetate (1.4 l). The mixture was subjected to extraction, and the ethyl acetate layer was washed with brine and dried (anhydrous magnesium sulfate). Under reduced pressure, ethyl acetate was evaporated to give crude 2-chlorobenzalacetone (94.6 g) as yellow oil, which was used for the following reaction without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.Cl[S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[N:17][CH:18]=1)(=[O:12])=[O:11].Cl.[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:8][C:5]1[S:4][C:3]([NH:2][S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=2)(=[O:11])=[O:12])=[N:7][CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cn1
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cn1
Temperature: 25 °C
Yield: 7.4 %

Procedure:
2-Amino-5-chlorothiazole hydrochloride (2.63 g, 15.4 mmol, 3.96 eq) was dissolved in pyridine (10 ml) and stirred at room temperature for 10 minutes before the addition of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate (Preparation 16, 915 mg, 3.8 mmol, 1 eq) portionwise and the resulting reaction mixture stirred at room temperature for a further hour. The mixture was dropped slowly into 6M HCl (20 ml), extracted into ethyl acetate (15 ml), washed with saturated sodium hydrogen carbonate (15 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was suspended in dioxane (5 ml), a solution of sodium hydroxide (300 mg, 7.5 mmol, 1.9 eq) in water (2 ml) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was washed with ethyl acetate (10 ml). The remaining aqueous phase diluted with brine (10 ml), acidified to pH 1, extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound as an orange solid (90 mg, 0.28 mmol, 7%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)(=[O:3])[CH3:2].BrC[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[CH:24]=2)[CH:19]=1.O>C(O)C>[C:1]([NH:4][CH:5]([CH2:6][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=3[Cl:34])[CH:24]=2)[CH:19]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Clc1cccc(Cl)c1-c1ccc2cc(CBr)ccc2c1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2cc(-c3c(Cl)cccc3Cl)ccc2c1)NC(C)=O
Reaction time: 1 h

Procedure:
To a solution of Na (0.092 g) in ethanol (5 ml) is added diethyl 2-(acetylamino)malonate (0.870 g). The mixture is stirred for 1 h. A solution of 2-(bromomethyl)-6-(2,6-dichlorophenyl)naphthalene 288 (0.978 g) in ethanol (5 ml) is added, under argon. The mixture is stirred under reflux for 5 h. After addition of water (5 ml), the solution is concentrated under vacuum and then diluted with AcOEt (5 ml). The aqueous phase is extracted with AcOEt (3×15 ml). The organic phases are dried over MgSO4, filtrated and evaporated under vacuum. The residue is purified by silica gel chromatography using AcOEt/cyclohexane 20/80 then (40/60) as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:27]([OH:29])=O)[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:35][NH2:36]>>[Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:27]([NH:36][CH3:35])=[O:29])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCCNC1
Agent: Cl
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCNC1

Procedure:
3-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-3-carboxylic acid (Isomer 1) was coupled with methylamine hydrochloride using an analogous method to that described for the equivalent step in Example 20 to give 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylpiperidine-3-carboxamide (Example 89.1 Isomer 1); 1H NMR Spectrum: (DMSO d6) 1.43 (m, 1H); 1.66 (m, 1H); 1.84 (m, 1H); 2.11 (m, 1H); 2.29 (s, 3H); 2.58 (m, 1H); 2.73 (d, 3H); 2.84 (m, 2H); 3.28 (d, 1H); 3.69 (d, 1H); 3.78 (d, 1H); 4.00 (s, 3H); 7.24 (s, 1H); 7.35 (t, 1H); 7.56 (t, 1H); 7.64 (t, 1H); 7.79 (m, 1H); 8.37 (s, 1H); 8.48 (s, 1H); 9.75 (s, 1H); Mass Spectrum: (M+H)+ 487.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:18][C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:19])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)([CH3:20])[C:15]([OH:17])=[O:16]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(C)(C)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2 g of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanoic acid dissolved in 100 ml THF were treated with 9.6 ml of a 2M lithium diisopropylamide solution, at −23° C. The mixture was kept at that temperature for 15 min. then, 1.19 ml of methyl iodide were added dropwise. The reaction mixture was kept at 0° C. for 4 hours then allowed to warm at room temperature for several days. The mixture was quenched with 100 ml of 1N hydrochloric acid solution. The mixture was extracted with three portions of 100 ml of ethyl acetate. The combined organic extracts were washed with 100 ml of a saturated aqueous sodium chloride solution. The organic phase was dried with MgSO4, and the solvent was evaporated. The yellow oil was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes). 1H NMR (CDCl3): 7.31 (d, J=2.2 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.15 (dd, J=8.3, 2.2 Hz, 1H), 1.67 (s, 4H), 1.58 (s, 6H), 1.27 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:32](O)(=[O:36])[CH2:33][CH2:34][CH3:35]>>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12](=[C:15]3[C:16]4[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=4[CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=4)[CH2:13][CH2:14]2)=[CH:30][CH:31]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Reactant: CCCC(=O)O
Product: CCCC(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 68.5 %

Procedure:
This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and butanoic acid. Yield 68.5%
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][CH2:10][C:11](OCC)(OCC)OCC>C(O)C>[Cl:9][CH2:10][C:11]1[S:8][C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[CH:5][N:4]=2
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1cccnc1S
Solvent: CCO
Product: ClCc1nc2cccnc2s1

Procedure:
3-Amino-2-pyridinethiol (5.0 g, 39.6 mmol) and 2-chloro-1,1,1-triethoxyethane (8.57 g, 43.5 mmol) were combined in absolute ethanol (40 mL) and refluxed for 2 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography (ethyl acetate:hexanes, 1:4) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 4.93 (s, 2H) 7.47 (dd, J=8.14, 4.75 Hz, 1H) 8.26 (dd, J=8.31, 1.53 Hz, 1H) 8.62 (dd, J=4.58, 1.53 Hz, 1H). (ESI) m/z 186 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[C:24]([O:23][C:22](=[O:28])[NH:21][N:15]1[CH2:20][CH2:19][N:18]([CH2:13][C:11]([OH:12])([CH3:14])[CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])[CH2:17][CH2:16]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: CC(O)(CN1CCN(NC(=O)OC(C)(C)C)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 72.6 %

Procedure:
Using 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (4.36 g, 20.0 mmol) and tert-butyl piperazin-1-ylcarbamate (4.44 g, 22.0 mmol) gave tert-butyl{4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-yl}carbamate (6.08 g, yield 72%) as a white powder in the same manner as in Example 365.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)O1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:28]4[CH:29]=[CH:30][C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[CH:32][CH:33]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C)OB(c2ccc(N3CCCCC3)cc2)OC1(C)C
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4ccc(N5CCCCC5)cc4)nc23)CCCCC1

Procedure:
(1-Methyl-cyclohexyl)-[2-(4-piperidin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidine following general procedures as described in these Examples. MP 234-236° C., M+H=403.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([CH:22]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1ccc2c(-c3ccccc3)n[nH]c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 6-bromo-3-phenyl-1H-indazole (109 mg, 0.40 mmol) in anhydrous THF (3 mL) was added n-butyl lithium solution (2M in hexanes, 0.47 mL, 0.94 mmol) dropwise at −78° C. under argon. The reaction mixture was stirred at −78° C. for 30 min and at −40° C. for 6 min before benzaldehyde (0.1 mL, 1 mmol) was added at −40° C. The reaction mixture was then stirred at rt for 1 hr. quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (10 mL). The ethyl acetate extract was dried (Na2SO4) and concentrated. Silica gel flash chromatography gave phenyl(3-phenyl-1H-indazol-6-yl)methanol (71 mg, 0.24 mmol, 59% yield) as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18](=[O:34])[NH:19][C@H:20]([CH2:32][OH:33])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[CH3:1][S:2]([O:33][CH2:32][C@@H:20]([NH:19][C:18]([O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:34])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
103 mg (0.90 mmol) of methanesulfonyl chloride and 0.21 ml (1.5 mmol) of triethylamine are added to a solution of 240 mg (0.75 mmol) of tert-butyl[(1S)-4-[(tert-butoxycarbonyl)amino]-1-(hydroxymethyl)butyl]carbamate (Example 83A) in 20 ml of dichloromethane, and the mixture is stirred at RT for 16 h. The mixture is diluted with dichloromethane and washed twice with 0.1N hydrochloric acid. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccccn1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.8 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)pyridin-2-yl-amine (255 mg, 1.09 mmol) in EtOAc (20 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (28 mg) and was stirred at RT under a hydrogen atmosphere for 18 h. The suspension was filtered through a phase separator and the filtrate concentrated in vacuo to afford the title compound as a black solid (241 mg, quantitative). 1H NMR (CDCl3, 400 MHz): δ 8.20-8.16 (1H, m), 7.51-7.44 (1H, m), 7.12-7.07 (1H, m), 6.78-6.72 (3H, m), 6.55 (1H, dt, J=8.39, 0.93 Hz), 6.22 (1H, s), 3.63 (2H, s).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].CCN(CC)CC.[Br:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[N:19][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][S:21]([C:17]1[CH:18]=[N:19][CH:20]=[C:15]([Br:14])[CH:16]=1)(=[O:23])=[O:22])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: CC(C)(N)CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of commercially available 2-amino-2-methyl-1-propanol (478 mg, 5 mmol) and Et3N (0.75 mL, 5 mmol) in THF (50 mL) at 0° C. was added portionwise added 5-bromo-pyridine-3-sulfonyl chloride [CAS-No. 65001-21-0] (according to J. Org. Chem. 1989, 54(2), 389) (1.28 g, 5 mmol) and the mixture was stirred at 23° C. for 1 h. The reaction is worked up by neutralization with 5% citric acid, extracted with EtOAc, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4, filtered and concentrated to give a light brown solid, which was purified by trituration with heptane/diethyl ether gave the title compound as a white solid (1.25 g, 82%). MS (ISP) 309.2 [(M+H)+], 311.1 [(M+2+H)+]; mp 112° C.
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19]Br)=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:23]>>[C:1]([C:9]1[C:18]([CH2:19][OH:23])=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(c1ccccc1)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Product: O=C(c1ccccc1)c1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Yield: 59 %

Procedure:
A stirred slurry of 10.0 g (0.028 mol.) of 2-benzoyl-3-bromomethylquinoxaline 1,4-dioxide in 1,000 ml. of water was heated under reflux for 18 hours. The hot reaction mixture was filtered, and the filtrate was allowed to cool to 25° C. The solid which precipitated was collected by filtration to provide a first crop of crude product. The aqueous filtrate was extracted with dichloromethane, which was then dried and evaporated in vacuo, to provide a second crop of crude product. The combined crude product was 7.0 g. (85% yield). It was recrystallized from ethanol to give 4.9 g. (59% yield) of 2-benzoyl-3-hydroxymethylquinoxaline 1,4-dioxide having m.p 178°-179° C.