Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][CH3:36]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:12]([CH2:33][CH2:34][CH2:35][CH3:36])[C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: CCCCBr
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)c2cc(/C=C/C(=O)OC)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 4 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (Intermediate 5 STEP B, 500 mg, 1.24 mmol) was dissolved in dry DMF (4.5 ml) and added dropwise to a stirred suspension of NaH (60% oil dispersion, 59.6 mg, 1.49 mmol) in dry DMF (4.5 ml) cooled at 4° C. The mixture was stirred for 10 min at 0° C. and then 1-bromobutane (0.205 ml, 1.86 mmol) was added dropwise. The resulting yellow solution was stirred overnight at RT and then partitioned between EtOAc and saturated solution of NH4Cl. The organic layer was rinsed twice with water, dried over Na2SO4 and concentrated to dryness. The crude mixture was purified by column chromatography (eluent:petroleum ether:AcOEt 75:25) to give (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester as white foam (225 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]2[N:21]=[CH:22][CH:23]=[C:4]2[N:3]=1.[CH:24]([O:27][C:28]1[CH:34]=[C:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:32]([CH3:41])=[CH:31][C:29]=1[NH2:30])([CH3:26])[CH3:25].Cl>C(O)(C)C.O1CCOCC1>[CH:24]([O:27][C:28]1[CH:34]=[C:33]([CH:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]2)[C:32]([CH3:41])=[CH:31][C:29]=1[NH:30][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]2[N:21]=[CH:22][CH:23]=[C:4]2[N:3]=1)([CH3:26])[CH3:25]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)nc2ccnn12
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1cc(Nc2cc(Nc3ccccc3S(=O)(=O)C(C)C)n3nccc3n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-N-(2-(isopropylsulfonyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.1 mmol) and 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (0.1 mmol) in 2 mL of isopropanol, was added 25 uL of HCl in dioxane (2 N). The suspension was stirred at 150° C. for 3 hours. After work-up and prep-HPLC, product was obtained. 1H NMR (CDCl3, 400 MHz) δ 7.88-7.95 (m, 3H), 7.73-7.75 (d, 1H), 7.61-7.64 (m, 1H), 7.23-7.26 (m, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 6.17-6.18 (d, 1H), 6.09 (s, 1H), 4.46-4.54 (m. 1H), 3.30-3.34 (m, 2H), 3.12-3.21 (m, 1H), 2.79-2.83 (m, 3H), 2.27 (s, 3H), 1.77-1.79 (m, 4H), 1.15-1.28 (m, 12H); MS (ES+): 563.28 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1cccnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)c1cccnc1
Temperature: 67 °C

Procedure:
A mixture of rac-6-chloro-3-pyridin-3-yl-1,3-dihydro-indol-2-one (0.081 g, 0.33 mmol) (from Example 39b supra), 3-chlorobenzyl bromide (0.080 g, 0.39 mmol) (Aldrich), potassium iodide (0.065 g, 0.39 mmol) and potassium carbonate (0.098 g, 0.72 mmol) in acetone (3 mL) was heated at 67° C. for 2 hours in a capped pressure tube. After cooling, the mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-pyridin-3-yl-1,3-dihydro-indol-2-one as an off-white solid. (Yield, 0.05 g, 42%).
Reaction SMILES: C([N+:8]1[CH:17]=[CH:16][C:15]2[C:14]3[N:18]([CH3:33])[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]=3[CH2:12][CH2:11][C:10]=2[CH:9]=1)C1C=CC=CC=1.[Br-].CC(C)([O-])C.[K+]>CS(C)=O.C1COCC1>[CH2:24]([O:23][C:21]([C:20]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:9]=[N:8][CH:17]=[CH:16][C:15]=3[C:14]=2[N:18]([CH3:33])[C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])=[O:22])[CH3:25]
Reactant: CCOC(=O)c1c2c(n(C)c1-c1ccccc1C)-c1cc[n+](Cc3ccccc3)cc1CC2
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(=O)c1c2c(n(C)c1-c1ccccc1C)-c1ccncc1CC2

Procedure:
To a solution of 7-benzyl-3-ethoxycarbonyl-1-methyl-2-o-tolyl-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinolin-7-ium; bromide XXIIIA (1.64 mmol) in dry DMSO (1 mL), 1M potassium tert-butoxide (11.5 mmol) in THF was added. The solution was bubbled with dry air overnight. Volatiles were removed, the residue was suspended in DCM, washed with water, dried (Na2SO4), filtered and the solvent evaporated. Chromatography on silica gel (eluant: DCM/MeOH 20:1) afforded the title compound. ESI (+) MS: m/z 347 (MH+). 1H NMR: 1.1 (t, J=7.1, 3H), 2.15 (s, 3H), 2.9 (m, 2H), 3.02 (m, 2H), 4.05 (q, J=7.1, 2H), 4.2 (s, 3H), 7.2-7.4 (m, 4H), 7.48 (d, J=5.1, 1H), 8.36 (d, J=5.1, 1H), 8.4 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.BrC1C=C([F:31])C=CC=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:31])[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1cccc(Br)c1
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Product: O=C(O)Cc1c(C(=O)c2cccc(F)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 3-bromofluorobenzene.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.[Br:20][C:21]1[C:22]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[N:23][NH:24][C:25]=1[CH:26]=[O:27].O>CN(C)C=O>[Br:20][C:21]1[C:22]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[N:23][N:24]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:25]=1[CH:26]=[O:27]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=Cc1[nH]nc(-c2cccs2)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(Br)c(-c2cccs2)nn1CC(F)(F)F
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 32.3 %

Procedure:
Cesium carbonate (1.56 g, 4.78 mmol) and 2,2,2-triflouroethyl trifluoromethanesulfonate (0.92 mL, 6.38 mmol) were added to a solution of 4-bromo-3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (34c) (0.82 g, 3.19 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 100° C. for 50 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×40 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 100/0 to 94/6), to provide 4-bromo-3-(thiophen-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carbaldehyde (34d) (350 mg, 1.03 mmol, 32%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-])(=[O:3])[CH3:2].[CH3:11][N:12](C)C(Cl)=O.C([Si](C)(C)C)#N.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: CC(=O)c1cccc[n+]1[O-]
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-acetylpyridine-N-oxide (0.098 mol) in 200 ml of methylene chloride was added dimethylcarbamyl chloride (0.1 mol) and the reaction mixture was allowed to react at room temperature under nitrogen for 24 hours. Additional dimethylcarbamyl chloride (0.1 mol) was added followed by cyanotrimethylsilane (0.22 mol), and the resulting mixture was allowed to react at 20° C. for 2 days. An additional 4 ml (0.03 mol) of cyanotrimethylsilane was then added, and the mixture was stirred at room temperature for another 24 hours. A solution of 200 ml of 10% K2CO3 was added to the reaction mixture and the resulting mixture was stirred for 45 minutes. The aqueous layer was extracted with 100 ml methylene chloride twice, the organic layers were combined and dried (K2CO3). After stripping the solvent, 16.9 g of crude product was isolated. The crude product obtained was chromatographed over Florisil® to isolate the desired products and the by-products with elution by the series of solvents: 2-acetyl-6-cyanopyridine (3a) (2g, 50% CH2Cl2 /hexane), 2-cyano-6-(1-cyano-1-trimethysilyloxy)ethylpyridine (3b) (0.81 g, CH2Cl2), 2-cyano-6-(1-cyano-1-dimethylcarbamoyloxy)ethylpyridine (3c) (1.67 g, 25:72 EtOAc/CH2Cl2), 2-(1-cyano-1-hydroxy)ethylpyridine (3d) (0.42 g, 50:50 EtOAc/CH2Cl2), and 2-(1-cyano-1-dimethylcarbamoyloxy)ethylpyridine-1-N-oxide (3e) (1.8 g, EtOAc). The products exhibited the following properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[C:21]([O:28][CH3:29])[CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:34]1C=C(S(Cl)(=O)=O)C=C[C:39]=1Cl>>[CH2:34]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:30]=[CH:31][CH:32]=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])[CH:14]=2)=[CH:20][C:21]=1[O:28][CH3:29])[CH3:39]
Reactant: COc1cc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1OC

Procedure:
4-[3-(3,4-Dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid, MS (ISP): m/e=495.2 (M+H+), was prepared in analogy to example 17, steps A to D. Step C was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,4-dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][CH2:15][C:16]([OH:18])=[O:17].Cl>CC(C)=O.[OH-].[Na+].O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: NCC(=O)O
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Ex-26A: To a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.3 mmol) in acetone (7.5 mL) was added a solution of glycine (0.42 g, 5.7 mmol) in 5% aqueous sodium hydroxide (2.5 mL) and the reaction was stirred for 30 min at room temperature. The mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting solid was dried in vacuo to afford 0.55 g (94%) of (4-acetylbenzenesulfonylamino)acetic acid as a white solid, mp 213–215° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.28 (t, 1H, J=5.4 Hz), 8.12 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.4 Hz), 3.64 (d, 2H, J=5.1 Hz), 2.64 (s, 3H). Anal. Calcd. for C10H11NO5S: C, 46.69; H, 4.31; N, 5.44; S, 12.46; Found: C, 46.76; H, 4.43; N, 5.39; S, 12.16.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=[CH:23][C:14]=1[C:12]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:13]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccc2c(n1)CCCC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccc3c(n2)CCCC3)sc2ccccc12
Yield: 29.9 %

Procedure:
A mixture of methyl thiosalicylate (0.43 g, 2.5 mmol), 2-cyano-5,6,7,8-tetrahydroquinoline (0.40 g, 2.5 mmol), triethylamine (0.50 ml, 3.8 mmol) and toluene (2.0 ml) was refluxed for 17 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.22 g, 30%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[S:32][C:31]([CH3:36])=[N:30][C:29]=3[C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:20][C:19]=1[CH3:41]>ClCCl>[CH3:41][C:19]1[CH:20]=[C:21]([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[S:32][C:31]([CH3:36])=[N:30][C:29]=3[C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:13]([CH:10]1[CH2:12][CH2:11]1)=[O:14]
Reactant: Cc1nc2c(s1)CCN(C(=O)c1ccc(CN)c(C)c1)c1ccccc1-2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(s1)CCN(C(=O)c1ccc(CNC(=O)C3CC3)c(C)c1)c1ccccc1-2
Temperature: 25 °C
Reaction time: 20 h
Yield: 46 %

Procedure:
DIEA (0.02 ml, 0.115 mmol) and cyclopropanecarbonyl chloride (0.008 ml, 0.088 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulen-6-yl)-methanone from E124.2 (20 mg, 0.055 mmol) in dichloromethane (5 ml) at 0° C. The mixture was stirred for 20 h at room temperature then concentrated in vacuo and purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% di-chloromethane) to give a white powder identified as the title compound (11 mg, 46%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH:52]([CH3:54])[CH3:53])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:40]=1[NH2:55].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:55][C:40]3[CH:41]=[CH:42][C:43]([CH:45]4[CH2:46][CH2:47][N:48]([CH2:51][CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50]4)=[CH:44][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(C2CCN(CC(C)C)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(C4CCN(CC(C)C)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 120 °C
Yield: 51.1 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[1-(2-methylpropyl)-4-piperidinyl]aniline (Example 160, step C) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.092 mmol, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.37 (d, J=6.78 Hz, 1H), 8.50 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.04 (d, J=2.01 Hz, 1H), 7.67-7.75 (m, 2H), 7.64 (d, J=8.06 Hz, 1H), 7.41-7.46 (m, 1H), 7.32-7.40 (m, 1H), 7.25 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.15 Hz, 2H), 6.94-6.98 (m, 2H), 6.78 (dd, J=8.24, 1.46 Hz, 1H), 6.59 (d, J=5.31 Hz, 1H), 4.25 (q, J=6.84 Hz, 2H), 3.82 (s, 3H), 2.90 (d, J=10.44 Hz, 2H), 2.42-2.46 (m, 1H), 2.02 (d, J=7.14 Hz, 2H), 1.91 (t, J=10.44 Hz, 2H), 1.65-1.75 (m, 5H), 1.41 (t, J=6.87 Hz, 3H), 0.84 (d, J=6.41 Hz, 6H). MS (ESI): 732 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[F:39][C:40]1([F:47])[CH2:42][C:41]1([CH3:46])[C:43](Cl)=[O:44]>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:43]([C:41]3([CH3:46])[CH2:42][C:40]3([F:47])[F:39])=[O:44])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1(C(=O)Cl)CC1(F)F
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3(C)CC3(F)F)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, a solution of 2,2-difluoro-1-methylcyclopropanecarbonyl chloride (25 mg, 165 μmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions. Once analysis of the reaction by HPLC showed substantial conversion (3 h), the reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (26.8 mg, 76% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:30])[C@H:25]([C@@H:27]([CH3:29])[OH:28])[NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[CH:27]([OH:28])[CH3:29])[CH3:22]
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(NC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH:11]3[CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[CH2:9]2)=[CH:5][CH:4]=1)[CH3:2].CCN(C(C)C)C(C)C.[S:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[CH:42]=[C:41]1[C:49](Cl)=[O:50].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH:11]3[CH2:14][N:15]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:49]([C:41]3[S:40][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[CH:42]=3)=[O:50])[CH2:9]2)=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCc1ccc(CN2CC3C(CNc4ccc(N5CCOCC5)c(F)c4)C3C2)cc1
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCc1ccc(CN2CC3C(C2)C3CN(C(=O)c2cc3ccccc3s2)c2ccc(N3CCOCC3)c(F)c2)cc1
Reaction time: 1 h

Procedure:
To a stirring solution of [3-(4-Ethyl-benzyl)-3-aza-bicyclo[3.1.0]hex-6-ylmethyl]-(3-fluoro-4-morpholin-4-yl-phenyl)-amine prepared above (50 mg, 0.12 mmol) in 2 mL of DCE at room temperature was added DIEA (0.03 mL, 0.18 mmol) and 2-benzthiophenecarbonylchloride (0.02 mL, 0.18 mmol). After 1 hour, saturated NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude material was taken up in 50% EtOAc/hexanes and the white solids were filtered off. The remaining filtrate was concentrated under reduce pressure to yield 58 mg of the desired product. 400 MHz 1H NMR (CDCl3) δ 7.60-7.68 (m, 2H), 7.24-7.31 (m, 2H),7.08-7.18 (m, 5H), 6.99-7.02 (m, 2H), 6.86-6.91 (m, 1H), 3.82-3.88 (m, 4H), 3.68 (d, J=7.47 Hz, 2H), 3.50 (brs, 2H), 3.10-3.12 (m, 4H), 2.88 (brd, J=7.47 Hz, 2H), 2.49 (q, 2H), 2.28, (brs, 2H), 1.49 (brs, 1H), 1.22-1.24 (m, 2H), 1.19 (t, 3H); MS (M+1) 570.2.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[C:25](=[O:36])[NH:26][C:27]1[CH:28]=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][C:11]2[CH:12]=[N:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[O:21])=[CH:18][C:17]=1[C:25]([NH:26][C:27]1[CH:28]=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1)=[O:36]
Reactant: O=C(Cl)c1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Reactant: Nc1ccc(Oc2ccccc2)nc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccccc2)nc1)c1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
6-Phenoxy-pyridin-3-ylamine (0.078 g, 0.42 mmol) was added to a solution of 4-chloro-3-(1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl)-benzoyl chloride in DCM (5 ml) and the reaction stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the crude product triturated with acetonitrile:water (1:1, 10 ml). The solid was filtered to afford 4-Chloro-N1-(6-phenoxy-pyridin-3-yl)-N3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-isophthalamide as the hydrochloride salt, 0.086 g, (37% yield) over two steps.