Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:33][CH2:32][CH2:31][C@@H:30]2[C:34]2[CH:35]=[C:36]([C:51]([OH:53])=O)[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][C:39]3=[O:50])[CH:25]=[C:26]([F:28])[CH:27]=1.CCN(C(C)C)C(C)C.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>>[F:28][C:26]1[CH:25]=[C:24]([N:29]2[CH2:33][CH2:32][CH2:31][C@@H:30]2[C:34]2[CH:35]=[C:36]([C:51]([N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)=[O:53])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:40][C:39]3=[O:50])[CH:23]=[C:22]([F:21])[CH:27]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Reaction time: 1.5 h
Yield: 44 %

Procedure:
TSTU (106 mg, 0.33 mmol) was added in one portion to a stirred solution of 8-[(2R)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (144 mg, 0.30 mmol, >98% enantiomeric purity, made from the second eluting ester enantiomer from chiral separation of tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate—see below) and DIPEA (0.057 mL, 0.33 mmol) at room temperature and the resulting mixture was stirred for 1.5 h. Morpholine (0.052 mL, 0.60 mmol) was then added to the reaction mixture and stirring was continued over the week-end. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one (69 mg, 44%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:12])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=[CH:20][C:21](=[O:23])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CS(O)(=O)=O.O>C(#N)C>[C:1]1([C:7]2[NH:8][C:9](=[O:12])[O:10][C:11]=2[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][C:21](=[O:23])[CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)co1
Reactant: CC(=O)C=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC#N
Product: CC(=O)CC(c1ccccc1)c1oc(=O)[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of 4-phenyl-2-oxo-4-oxazoline (1.61 g) and benzalacetone (1.46 g) in acetonitrile (20 ml) was added dropwise methanesulfonic acid (0.96 g). After stirring the obtained mixture at room temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4), and the solvent was evaporated. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:1). The solvent was evaporated. Crystallization from isopropyl ether gave 4-(4-phenyl-2-oxo-4-oxazolin-5-yl)-4-phenyl-2-butanone (2.65 g; yield 86.3%). Recrystallization from ethanol gave colorless crystals.
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:27])[F:28])(=[O:18])=[O:19])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3ccccc3C(F)(F)F)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
Ethyl 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carboxylate (3.7 g) was dissolved in a mixed solvent of tetrahydrofuran (25 mL)-methanol (25 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (1.5 g) in water (20 mL)) was added to this solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with ethyl acetate-hexane to give the title compound (2.7 g, yield: 63%) as colorless crystals. MS: 399(MH+). melting point: 211-212° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[NH2:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[C:28]#[C:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[NH2:20]
Reactant: C#Cc1cccc(N)c1
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2cc(C(F)(F)F)ccc2F)c1
Temperature: 70 °C
Yield: 70 %

Procedure:
A multinecked flash as described in Example 1 was charged with 4.93 g (0.020 mol) of 3-bromo-4-fluorobenzotrifluoride, 75 ml of dried, degassed triethylamine, 2.34 g (0.020 mol) of 3-aminophenylacetylene, 0.06 g (0.08 mmol) of bis(triphenylphosphine) palladium II chloride, 0.118 g (0.45 mmol) of triphenylphosphine, and 0.06 g (0.31 mmol) of cuprous iodide. The reaction mixture was heated at 70° C. for 40 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble hydrobromide salt followed by concentration of the filtrate gave the crude product (5.5 g, 89%) as an orange liquid. Short path distillation of the crude product under reduced pressure gave 4.05 g (0.014 mol, 70% yield) of the product as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:52](Cl)(=[O:54])=[O:53])[CH:47]=[CH:48][C:49]=1[O:50][CH3:51]>C(#N)C>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:53])=[O:54])[CH:47]=[CH:48][C:49]=1[O:50][CH3:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1OC
Yield: 46.1 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0315 g, 0.0682 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.409 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (0.0480 g, 0.205 mmol) to obtain 4-(3,4-dimethoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0208 g, yield 46%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:15])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: NCCCO
Reactant: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)NCCCO
Temperature: 25 °C

Procedure:
2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylic acid (30a) (100 mg, 0.338 mmol) was dissolved in DMF (5 mL). 3-aminopropan-1-ol (1.691 mmol, 5 equiv.) and DIPEA (1.353 mmol, 4 equiv.) were added to the reaction mixture and stirred at room temperature. HATU (1.014 mmol, 3 equiv.) was added to the reaction mixture and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to remove excess of DMF. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash column chromatography through silica gel and MeOH:CHCl3 as eluent to afford the title compound, 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide (31).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[OH-:19].[Na+]>CN(C=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:4]2[C:3](=[O:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:14]=1
Reactant: [OH-]
Reactant: Clc1c(-c2cccnc2)cnc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2cccnc2)c[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2N Hydrochloric acid (10 ml) was added to a DMF solution (5 ml) of 4-chloro-(3-pyridin-3-yl)quinoline (0.51 g), and the mixture was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, 2N sodium hydroxide aqueous solution (10 ml) was added dropwise under ice cooling. The mixture was stirred. The precipitated insoluble matter was separated, washed with water and ether, and dried to give the title compound (0.35 g) as a pale whitish purple powder.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.C(N(CC)C(C)C)(C)C.[CH2:40]([NH:47][CH2:48][C:49]#[C:50][CH3:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([N:47]([CH2:48][C:49]#[C:50][CH3:51])[C:8](/[N:9]=[C:10]1\[S:11][C:12]([CH3:29])=[CH:13][N:14]\1[C:15]1[CH:28]=[CH:27][C:18]2[O:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[O:22][C:17]=2[CH:16]=1)=[O:30])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CC#CCNCc1ccccc1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCN(Cc1ccccc1)C(=O)/N=c1\sc(C)cn1-c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide (Example 81A, 0.75 mL of 0.14 M in acetonitrile, 58 mg, 0.1 mmol) was added to a 20 mL vial followed by N,N-diisopropylethylamine (0.75 mL of 0.14 M in acetonitrile, 18 mg, 0.13 mmol). Subsequently, N-benzylbut-2-yn-1-amine (0.57 mL of 0.2 M in acetonitrile, 0.11 mmol) was added. The resulting mixture was shaken at room temperature overnight. It was then concentrated in vacuo and the residue was taken up in 1:1 MeOH/DMSO and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method). 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.75 (3 H) 2.24 (3 H) 4.05 (2 H) 4.55 (2 H) 7.01-7.10 (1 H) 7.17-7.29 (4 H) 7.29-7.35 (1 H) 7.40-7.54 (1 H) 7.58-7.63 (1 H) 7.66-7.94 (1 H); MS (ESI+) m/z 506 (M+H)+.
Reaction SMILES: [Br:1]Cl.C(=O)=O.[CH2:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8].C1(C=CC=C(O)C=1)O>S(=O)=O>[CH2:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8].[Br:1][C:13]1[CH:14]=[CH:15][C:10]([CH2:6][CH:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=1
Reactant: ClBr
Agent: O=C=O
Agent: O=S=O
Agent: Oc1cccc(O)c1
Solvent: CC(C)Cc1ccccc1
Product: CC(C)Cc1ccc(Br)cc1
Yield: 83 %

Procedure:
Bromine chloride (Dow, 1.12 g, 9.7 millimMoles) is condensed in a tube using Dry ice cooling, then it is diluted with 20 ml of liquid sulfur dioxide and the resultant solution is cooled to -72° C. Isobutylbenzene (1.57 ml, 10.0 milliMoles) is added, and the resultant mixture is stirred at -70° for 65 minutes before quenched with 1.2 grams (10.9 milliMoles) of resorcinol. Workup and analysis as above gives 8% isobutylbenzene, 6% ortho-, and 83% para-bromoiso-butylbenzene. This result indicates that the bromination with bromine chloride is faster than that with molecular bromine, and the extent of ortho-bromination is somewhat higher.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][NH:5][C:4]1=[O:7])[CH3:2].[C:8]([O-:11])(=[O:10])[CH3:9].[Na+].C(O)(=O)C.C(OO)(=O)C>C(Cl)Cl>[C:8]([O:11][CH:6]1[NH:5][C:4](=[O:7])[CH:3]1[CH2:1][CH3:2])(=[O:10])[CH3:9]
Reactant: CC(=O)[O-]
Reactant: CCC1CNC1=O
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1C(=O)NC1OC(C)=O
Temperature: -5 °C
Yield: 74.5 %

Procedure:
1.0 g of 3-ethylazetidine-2-one and 0.83 of anhydrous sodium acetate were suspended in 20 ml of methylene chloride and cooled to -5° C., to which 0.35 g of ruthenium acetylacetonate complex was added. 3.8 ml of acetic acid solution containing 40% peracetic acid was dropped thereto carefully so as to maintain the temperature not higher than 0° C., followed by the procedures in Example 2 to obtain 1.17 g of the title compound (yield: 74.5%).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:18]I.Cl>CN(C)C=O>[CH3:18][O:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(O)c2ccccc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC(NC(N)=O)c2ccccc21
Reaction time: 8 h

Procedure:
A 2.0 g sample of 1,2,3,4-tetrahydro-4-hydroxy-1-naphthylurea (cis/trans) is stirred in 10 ml of dry dimethylformamide and one equivalent of sodium hydride in mineral oil added at 0° C under a nitrogen atmosphere. After the addition is completed, 1.2 equivalents of methyl iodide is added and the reaction mixture stirred overnight. The mixture is carefully poured on ice, neutralized with hydrochloric acid and the title compound collected by filtration. Evaporation of the filtrate to dryness and washing the residue with water affords additional title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[OH:18][C@@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)=[O:25])[CH2:20]1.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=[C:2]([N:22]2[CH2:23][C@@H:19]([OH:18])[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)=[O:25])[N:7]=1
Reactant: O=C(Nc1cnccn1)[C@@H]1C[C@H](O)CN1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1cnccn1)[C@@H]1C[C@H](O)CN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1

Procedure:
Compound 85B was prepared from 1A and 85A as described for 1C. LC/MS [M+H]+: 443/445; Ret time (Method F): 2.18 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:30]=[C:17]4[C:18]([C:22]5[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=5)=[CH:19][CH:20]=[CH:21][N:16]4[N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[C:17]3[N:16]([N:15]=[C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([CH:4]5[CH2:5][CH2:6][N:1]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:2][CH2:3]5)=[CH:12][CH:11]=4)[N:30]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:29][CH:28]=1)#[N:27]
Reactant: CN(C)C(=O)CCl
Reactant: N#Cc1ccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)cc1
Product: CN(C)C(=O)CN1CCC(c2ccc(Nc3nc4c(-c5ccc(C#N)cc5)cccn4n3)cc2)CC1

Procedure:
2-(4-{4-[8-(4-Cyano-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from 4-[2-(4-piperidin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridine-8-yl]benzonitrile (0.111 g, 0.281 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.043 mL, 0.422 mmol) in a manner analogous to Example 313 to give product (0.060 g, 44%). MP=245-246° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.71 (s, 1H), 8.87 (d, 1H), 8.40 (d, 2H), 8.00 (m, 3H), 7.62 (d, 2H), 7.15 (m, 3H), 3.12 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.80 (s, 3H), 2.40 (m, 1H), 2.12 (m, 2H), 1.65 (m, 4H). MS=480 (MH)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 100 °C
Yield: 86 %

Procedure:
To a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (5 g, 24 mmol) in DMSO (50 ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (4.78 g, 23.9 mmol, 1 eq.) and potassium carbonate (9.9 g, 72 mmol, 3 eq.). The resulting mixture was stirred with heating overnight at 100° C. (oil bath) and then diluted with water (300 ml). The solids were collected by filtration to afford tert-butyl 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate as a yellow powder (8 g, 86%); (ES, m/z): [M+H]+ 390.0; 1H NMR (300 MHz, DMSO-d6): δ 8.06 (d, J=9.3 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 6.89 (dd, J=2.4, 9.3 Hz, 1H), 3.87 (d, J=13.5 Hz, 2H), 3.68 (m, 1H), 2.95 (m, 2H), 2.54 (s, 0.6H), 1.89 (m, 2H), 1.39 (s, 9H), 1.28 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH2:23])[N:18]=1)[C:11]([NH2:13])=[NH:12].[CH3:24][O:25][C:26](OC)=[N:27][C:28]#[N:29]>CO>[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:26](=[N:27][C:28]#[N:29])[O:25][CH3:24])[N:18]=1)[C:11]([NH2:13])=[NH:12]
Reactant: COC(=NC#N)OC
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Yield: 69 %

Procedure:
Triethylamine (2.02 g.) was added to a suspension of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole dihydrochloride (3.04 g.) in methanol (30 ml.) stirred at room temperature. Dimethyl (N-cyanoimido)carbonate (1.14 g.) was added and the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was extracted with ethyl acetate (35 ml.) and the solution was washed with water (25 ml., 10 ml.) then dried (magnesium sulphate) and evaporated under reduced pressure to give 2-guanidino-4-[2-(3-cyano-2-methylisoureido)ethylthiomethyl]thiazole (2.16 g.). The n.m.r. spectrum in CDCl3 /d6 dimethyl sulphoxide using tetramethylsilane as internal standard had the following resonances (δ): 7.7 (1H, very broad); 6.7 (4H, broad); 6.4 (1H, singlet); 3.8 (3H, singlet); 3.6 (2H, singlet); 3.4 (obscured by H2O); 2.7 (2H, broad triplet).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Br.[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][NH:33][CH2:34]2)([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][N:33]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:34]2)([O-:29])=[O:28]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc2c1=O
Yield: 15.7 %

Procedure:
213 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 47 mg of the target compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([N:2]1[CH:3]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:21]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:1]1)(=[O:40])=[O:39]
Reactant: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.128 mmol) in dichloromethane (1 ml) was added triethylamine (23 μl, 0.166 mmol) followed by methanesulfonyl chloride (12 μl, 0.154 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The product was purified by preparatory HPLC to yield the desired product. RT: 2.41 min, MI: 468, Method: 2; 1H NMR (DMSO, 300 MHz): 9.56 (s, 1H), 9.47 (s, 1H), 8.94 (s, 1H), 8.18 (s, 2H), 7.69-7.54 (m, 3H), 6.93 (d, 2H), 4.06 (t, 2H), 3.72 (s, 3H), 2.92 (t, 2H), 2.67 (s, 4H), 1.74 (s, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].CN(C)CCN(C)C.ICCCCI>C1COCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Agent: ICCCCI
Solvent: O
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm3) of anhydrous THF under N2 was added n-butyllithium (1.6 M in hexanes, 19.7 cm3, 31.5 mmol) drop-wise. To the resulting milky solution was added N,N,N′,N′-tetramethylethylenediamine (4.75 cm3, 31.5 mmol). After 30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm3) was added and the reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was poured into water, extracted with EtOAc (×2), the combined organic layers were washed with dilute HCl (pH 1) and water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:4) to afford the subtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: 1H NMR (CDCl3) δ 1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J=7.5, 1.0 Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H).