Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][O:13][N:14]=[CH:15][C:16]1[N:17]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1.[OH-].[NH4+:34].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:12][O:13][N:14]=[CH:15][C:16]1[N:17]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:34])[C:19]=2[N:28]=1
Reactant: [NH4+]
Reactant: CON=Cc1nc2cnc3ccccc3c2n1CC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CON=Cc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
mCPBA (1.75 g of 77% pure material, 7.79 mmol) was added in portions over a period of five minutes to a solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde O-methyloxime (1.1 g, 3.9 mmol) in chloroform (40 mL), and the reaction was stirred at room temperature for one hour. Ammonium hydroxide (20 mL) was added, and the resulting mixture was stirred for five minutes before the addition of p-toluenesulfonyl chloride (0.891 g, 4.68 mmol) in portions. The reaction mixture was stirred at room temperature for 1.5 hours. The aqueous layer was then separated and extracted with dichloromethane (3×30 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.2 g of crude product as a brown foamy solid. The crude product was dissolved in dichloromethane (15 mL) and purified by chromatography using a HORIZON HPFC system (FLASH 40M silica cartridge available from Biotage, Inc., eluting with 2% to 7% methanol in ethyl acetate). The resulting product (580 mg) was recrystallized from acetonitrile (10 mL), and the crystals were isolated by filtration, washed with diethyl ether, and dried overnight in a vacuum oven at 65° C. to provide 236 mg of 4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde O-methyloxime as a brown solid, mp 181-183° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl.[OH:23][C@H:24]1[CH2:28][NH:27][C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1>ClCCl.CCOC(C)=O>[OH:23][C@H:24]1[CH2:28][N:27]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([F:21])([F:20])[F:8])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Triethylamine (TEA) (15.34 ml, 110.1 mmol) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (8.97 g, 36.7 mmol) were added to a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2) (6.59 g, 36.7 mmol) in dichloromethane (150 ml) in an ice bath. The mixture was warmed to room temperature and stirred overnight at RT., concentrated reaction in vacuo, dissolved in EtOAc and washed with 0.1M aqueous HCl, sat. sodium bicarbonate solution and brine. The organic layers were dried with sodium sulfate and concentrated in vacuo to yield (2S,4R)-methyl 4-hydroxy-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxylate) (3) (9.55 g, 73%) as a white semi-solid, which was used without further purification in the next step. MS m/z 376.1 (M+Na)+; retention time=1.691 min, method [1].
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([Mg]Cl)[CH:18]([CH3:20])[CH3:19].Cl>C(OCC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]([OH:11])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)C[Mg]Cl
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C(O)CC(C)C)cc1OC1CCCC1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a magnetically-stirred solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (25.0 mmol, 5.50 g) of Example 1A, in anhydrous ethyl ether (250 mL) at 0° C. is added isobutylmagnesium chloride (30 mmol, 15 mL; 2.0M solution in ethyl ether) dropwise over 20 minutes. The reaction mixture is allowed to stir while slowly warming to room temperature over 1 hour and is then poured into 1N HCl (250 mL) and partitioned with ethyl ether (200 mL). The aqueous phase is extracted with ethyl ether (200 mL) and the combined organics are washed with aqueous saturated NaHCO3 (200 mL), aqueous saturated NaCl (200 mL), and dried (MgSO4). Concentration in vacuo affords a yellow oil which is purified by flash chromatography (SiO2 : 1) methylene chloride, 2) 2% ethyl acetate/methylene chloride, 3) 5% ethyl acetate/methylene chloride) to give the title compound as a white solid (21.5 mmol, 5.98 g; 86 %).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH-].[Li+].C1COCC1.CO>O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(Nc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(Nc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
To ethyl 2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetate (0.6 g, 1.51 mmol) was added a solution of lithium hydroxide (0.317 g, 7.22 mmol) in water (4 mL) followed by THF (4 mL) and methanol (0.5 mL) and stirred for 12 hours at 25° C. Organic solvents were evaporated from the reaction mixture and aqueous layer was acidified 1N HCl, extracted with ethyl acetate (3×15 mL), organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and washed concentrated under reduced pressure to provide 2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetic acid (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15]C.Cl[C:33]1C=C(Cl)C=CC=1C1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C.IC(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:30])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH:28]([CH3:29])[CH3:33])=[N:13][C:14]=1[CH3:15]
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Solvent: CC(C)I
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 2-iodopropane, and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.50-7.46, 7.34-7.26, 5.76, 5.43, 4.47, 3.72, 3.14-3.11, 2.41, 2.26, 1.20, 1.12; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1441. Anal. Calcd for C24H25Cl2N3O: C, 65.16; H, 5.70; N, 9.50. Found: C, 65.33; H, 5.83; N, 9.34.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([O:20][CH3:21])[C:10]2([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])[C:30](O)=[O:31])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([O:20][CH3:21])[C:10]2([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]2)=[CH:3][C:2]=1[NH:1][C:30](=[O:31])[C@H:29]([C:26]1[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=1)[C@@H:33]([CH3:38])[C:34]([F:35])([F:36])[F:37]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: COC(c1ccc(Cl)c(N)c1)C1(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.641 mmol) of (+/−)-tert-butyl 1-[(3-amino-4-chlorophenyl)(methoxy)methyl]cyclopropanecarboxylate and 188 mg (0.706 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 2.3 ml of DMF and 0.7 ml of pyridine, and 293 mg (0.770 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight. Another 0.6 eq. of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid was then added, and the reaction mixture was stirred at 45° C. for 14 h. After cooling, the mixture was diluted with ethyl acetate and the solution was washed with 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 30:1). This gave 168 mg of the target compound (39.9% of theory).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1.O>O1CCOCC1>[Cl:8][C:5]1[N:4]=[N:3][C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
Under an argon atmosphere a solution of 1.08 g (7.05 mmol) 3,6-dichloro-pyridazin, 10 mL 2 M Na2CO3 solution and 80 mg (0.14 mmol) chlorine(di-2-norbornylphosphino)(2′-dimethylamino-1-1′-biphenyl-2-yl)palladium(II) in 150 mL 1,4-dioxane is heated to 110° C. At this temperature a solution of 1.13 g (7.05 mmol) 4-chlorophenyl-boric acid in 50 mL 1,4-dioxane is added dropwise within 2 h and the reaction mixture is heated for another hour. After cooling it is combined with 100 mL water, extracted with 100 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 8:2).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:8]([CH3:10])[CH3:9].[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:22][C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:22][C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[C:17]([CH:21]=1)[C:18]([O:20][CH:8]([CH3:10])[CH3:9])=[O:19]
Reactant: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
Cesium carbonate (105 mg, 0.19 mmol) and 2-iodopropane (18 mg, 0.11 mmol) were added to a solution of the intermediate 5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino] benzoic acid (30 mg, 0.10 mmol) in DMF (4 mL). The mixture was stirred at rt for 16 h. The reaction was quenched with water (5 mL) and then extracted with dichloromethane (3×5 mL). The combined organic layers were washed with water (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. HPLC purification of the residue (YMC propack C18 column, 150×20 mm ID, 30%-80% acetonitrile in water gradient) afforded the desired product as a white solid (20 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.65 (d, 1H), 6.96-7.56 (m, 9H), 6.29 (dd, 1H), 5.06 (q, 1H), 3.69 (s, 3H), 1.24 (d, 6H); ES-MS m/z 352.1 (MH+); HPLC RT (min) 3.53.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH2:22]2)[CH2:13][C@H:9]1[C:10]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:12])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: C1CNCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N2CCNCC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
(4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]-L-proline (0.92 g, 2.41 mmol) obtained in Step C of Example 1, was dissolved in DMF (10 mL) and DIPEA (1.05 mL, 6.01 mmol) was added thereto. Piperazine (0.25 g, 2.89 mmol) and HBTU (0.91 g, 2.41 mmol) were also added thereto in order. After the reaction solution was stirred at room temperature for 2 hours, the solution was concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution. The extracted organic solution was dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography (eluent: MC/MeOH=10/1) to give the title compound (1.01 g, 93%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14]1.Cl[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=1>>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([N:16]4[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]4[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:7][CH:6]=[CH:5][N:4]3[N:8]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: CN1CCNC(c2ccccc2)C1
Reactant: Nc1nc2c(Cl)nccn2n1
Reactant: COc1cc(Cl)cc(OC)c1
Product: COc1cc(Nc2nc3c(N4CCN(C)CC4c4ccccc4)nccn3n2)cc(OC)c1

Procedure:
8-Chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-methyl-3-phenyl-piperazine are coupled according general procedure 3. The intermediate is isolated and Buchwald Hartwig Amination following general procedure 2 with 1-chloro-3,5-dimethoxy-benzene gives the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O.O>CN1CCCC1=O>[C:12]1([N:18]2[C:6](=[O:8])[C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:11][C:19]2=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
42.5 g of 4-chloroanthranilic acid were dissolved in 250 ml of N-methylpyrrolidone and 29.5 g of phenyl isocyanate were added dropwise at room temperature in 30 minutes. The mixture was further stirred for 5 hours at 80° C. and then 24.5 g of concentrated sulphuric acid were added dropwise in the course of 1 hour. The mixture was then further stirred at 80° C. for 3 hours, then cooled to room temperature, 500 ml of water were added, the product precipitated out was filtered off by suction, washed with water and dried in a vacuum drying cabinet. In this manner 57.4 g (85% of theory) of pure 3-phenyl-7-chloro-quinazoline-2,4-dione were obtained having a melting point of above 300° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 165 °C
Yield: 100.2 %

Procedure:
A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 77; 0.30 g, 1.07 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.23 g, 1.61 mmol), and DIEA (0.23 ml, 1.34 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 165° C. for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a yellow solid (0.41 g, 99%). NMR (400 MHz) 12.22 (s, 1H), 10.98 (s, 1H), 8.70 (d, J=7.2 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 6.22 (d, J=9.2 Hz, 1H), 6.17 (s, 1H), 5.27 (m, 1H), 1.89 (m, 1H), 1.52 (d, J=6.4 Hz, 3H), 0.95 (m, 2H), 0.64 (m 2H). MS: Calcd.: 382; Found: [M+H]+ 383.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(OCC)C.C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][N:19]([C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:18]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:17]=1
Reactant: CCCCCCCCCCCBr
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC1C=C(Cl)C=CN1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.2 %

Procedure:
To a stirred mixture of magnesium turnings (0.584, 24 mmol) in 40 ml of anhydrous diethyl ether was added 1-bromoundecane (5.36 mL, 24 mmol). After a self sustained reflux period of 10 minutes, the solution was refluxed an additional 45 min and then allowed to cool to room temperature. The newly formed Grignard was canulated in a stirred solution of 4-chloropyridine hydrochloride (1.5 g, 10 mmol) in 80 ml of THF at −78° C. After 20 minutes, phenyl chloroformate (1.26 ml, 10 mmol) was added dropwise. Stirring was continued for 30 min. longer at −78° C. The cooling bath was removed and the reaction mixture was allowed to stir for 30 minutes longer while slowly warming to room temperature. 20% NH4Cl (30 ml) and ether (40 ml) were added and the layers separated, and the aqueous layer was extracted with two 25 ml portions of ether. The combined organic extracts were washed successively with 25 ml portions of saturated CuSO4, water, saturated NaHCO3, and brine. The organic phase was dried with MgSO4, the solvent was evaporated, to yield the crude product as a yellow oil. Purification by column chromatography with 5% EtOAc in hexanes afforded 3.4 g (88%) of the product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) 67.45-7.10 (m, 5H), 6.94-6.86 (pair of d, 1H), 5.68 (d, 1H), 5.41-5.29 (dd, 1H), 5.02-4.85 (m, 1H), 1.83-1.40 (m, 2H), 1.24 (br s, 18H), 0.88 (t, 3H); FT-IR (neat) 2954, 2923, 2852, 1735, 1635, 1592, 1495, 1471, 1332, 1202, 1050 cm−1.
Reaction SMILES: [Na].Br[C:3]1[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=[C:5]([Cl:20])[C:4]=1[CH3:21].[CH2:22]([O:24][CH:25]([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)[CH3:26])[CH3:23]>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:5]1[C:4]([CH3:21])=[C:3]([C:30]2[CH:29]=[N:28][N:27]([CH:25]([O:24][CH2:22][CH3:23])[CH3:26])[CH:31]=2)[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cc(F)cc(F)c1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Temperature: 90 °C
Yield: 40.1 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water (2 mL) was added a solution of 1-(6-bromo-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.20 g, 0.56 mmol) in toluene (2 mL) followed by 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.18 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.056 mmol). The mixture was bubbled with N2 for 5 min and then heated at 90° C. overnight. The organic layer was concentrated and flashed on silica gel (eluting with 0-20% of ethyl acetate in hexanes) to afford the desired product (94 mg, 40%). LCMS calculated for C22H22ClF2N2O2 (M+H)+: m/z=419.1. found: 419.1.
Reaction SMILES: Cl[N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH3:16][N:17]([CH3:27])[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCOCC1>[CH3:27][N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([N:2]2[NH:6][CH:5]=[C:4]([C:7]3[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=3)[S:3]2)[CH2:25][CH2:26]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(Cl)S1
Solvent: C1COCCO1
Product: CN(C)CCCN1CCN(N2NC=C(c3ncc([N+](=O)[O-])n3C)S2)CC1

Procedure:
A solution of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole in 200 ml. of dioxane is treated with 5.1 g. of 1-(3-dimethylaminopropyl)piperazine, and the mixture stirred at room temperature for 18 hours. The precipitate is collected, dissolved in 100 ml. of water, made alkaline with sodium hydroxide solution, and then extracted with 500 ml. of chloroform. The chloroform extract is dried and the solvent removed under reduced pressure. The yellow residue is recrystallized from 100 ml. of ethanol to give 2.9 g. of product, melting at 174°-175° C.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH:26]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])=[CH2:27]>>[CH3:32][N:28]([CH2:26][CH2:27][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:29](=[O:31])[CH3:30]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CN(C)C(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CC(=O)N(C)CCP(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 94 %

Procedure:
A 100 ml 3-necked round bottomed flask was heated to 100° C. under a nitrogen atmosphere and 7.14 g diphenyl-phosphine (38.4 mmole), 0.15 g 2,2'-azobis (2-methylpropionitrile), and 3.77 g N-vinyl-N-methyl acetamide (38.1 mmole) from Polysciences were added in the stated sequence. The reaction was maintained at 100° C. for 45 minutes under a nitrogen atmosphere and then evacuated (1 mm) for 24 hours at 100° C. A viscuous oil resulted whose infrared spectrum displayed a strong γ (CO) band at 1645 cm-1 and a small γ (P-H) band at 2300 cm-1 due to a small amount of diphenylphosphine impurity. The elemental analysis was the following: calculated (found); C, 71.58 (69.89); H, 7.02 (7.15); N, 4.91 (4.57); P, 10.87 (10.97). The yield was 94%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: COCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-methoxyethylamine (0.58 ml) in dichloromethane (10 ml) was added triethylamine (1.0 ml) and methanesulphonyl chloride (0.51 ml). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo to give a crude product which was purified by flash chromatography to give N-(2-Methoxy-ethyl)-methanesulfonamide (0.74 g).