Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][NH2:12])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.C(O[CH:16]=[C:17]([C:20](=[O:22])[CH3:21])[C:18]#[N:19])C>C(O)C>[C:20]([C:17]1[CH:16]=[N:12][N:11]([C:3]2[C:2]([Cl:1])=[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][N:5]3[N:4]=2)[C:18]=1[NH2:19])(=[O:22])[CH3:21]
Reactant: NNc1nn2c(c1Cl)CCCC2
Reactant: CCOC=C(C#N)C(C)=O
Solvent: CCO
Product: CC(=O)c1cnn(-c2nn3c(c2Cl)CCCC3)c1N

Procedure:
0.56 g (3 mmol) 3-Chloro-2-hydrazino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine was dissolved in 5 ml ethanol and treated with 0.42 g (3 mmol) 2-ethoxymethylen-3-oxobutyronitrile. After heating under reflux for 3 hours, the mixture was concentrated and the residue purified by silica gel chromatography (hexane/ethyl acetate 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[C:36]([C:37]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:38])=[C:35]([CH3:45])[O:34][N:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:42]3[CH2:43][CH2:44][N:39]([C:37]([C:36]4[C:32]([CH3:31])=[N:33][O:34][C:35]=4[CH3:45])=[O:38])[CH2:40][CH2:41]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1C(=O)N1CCNCC1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)c2c(C)noc2C)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1-yl]-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. LR-MS: 652.2 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@H:16]([C:24]([NH2:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([C@@H:16]1[NH:15][C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[NH:26][C:24]1=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2

Procedure:
N-tert-Butyloxycarbonylpiperidone (6.0 g, 29.8 mmol) was added to a solution of (S)-phenylalaninamide (4.9 g, 29.8 mmol) in dry EtOH (20 ml) and the mixture was heated for 2.5 h under reflux. The solvent was distilled off and the tert-butyl 3-(S)-benzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (10.8 g) was used without further workup.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][NH:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:37]([CH2:38][CH2:39][OH:40])[CH3:36])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1
Reactant: CNCCO
Product: CN(CCO)c1cc(-c2ccc(F)cc2)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 140 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
A mixture of 0.10 g (0.20 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 0.45 g (6.0 mmol) 2-(methylamino)ethanol was stirred 6 h at 140° C. After cooling to room temperature the reaction mixture was partitioned between water and tert-butyl methyl ether and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with a saturated aqueous solution of ammonium chloride and water, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 87 mg (78%) of the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21].[OH-].[K+]>CS(C)=O>[CH3:17][O:18][CH2:19][CH2:20][O:21][C:2]1[C:3]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: COCCO
Reactant: Nc1cc(Cl)c(-n2cccc2)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCCOc1cc(N)c([N+](=O)[O-])cc1-n1cccc1

Procedure:
The title compound was prepared from 5-chloro-2-nitro-4-pyrrol-1-yl-phenylamine (Example F3) (1.01 g, 4 mmol), 2-methoxyethanol (1.58 mL, 20 mmol) and KOH (316 mg, 4.8 mmol) in DMSO (5 mL) according to the general procedure E. Obtained as an orange solid (870 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH:4]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C(#N)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[N:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH:4]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cc(CBr)n(-c2ccccc2Cl)n1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(COc2ccc(Br)cc2)n(-c2ccccc2Cl)n1

Procedure:
Into a 25 mL flask was weighed 1.52 g (4.48 mmol) of 5-bromomethyl-1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole, 854 mg of 4-bromophenol, 584 mg of sodium carbonate, then 5 mL of DMF, and 5 mL of acetonitrile were added. The resulting suspension was stirred and heated at 80-850C for 20 h then was washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 80 g Silica gel, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless solid, yield: 1.917 g (99%); 1H NMR (400 MHz, DMSO-d6): δ 7.82 (m, 2H), 7.70 (dt, J=1.5, 7.5 Hz, 1H), 7.62 (dt, J=1.5, 7.5 Hz, 1H), 7.49 (d, J=9 Hz, 2H), 7.27 (s, 1H), 6.92 (d, J=9 Hz, 2H), 5.12 (s, 2H); MS (ES): 431 [M+H]+.
Reaction SMILES: FC(F)(F)CO.Cl.O1CCOCC1.[CH3:14][O:15][C:16]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:17]=1[NH2:18].[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH3:52])[CH:44]=2)[C:40]([Cl:53])=[CH:39][N:38]=1>>[ClH:36].[Cl:53][C:40]1[C:41]([C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH3:52])[CH:44]=2)=[N:42][C:37]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[CH:22][C:16]=2[O:15][CH3:14])=[N:38][CH:39]=1
Reactant: Cn1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
2,2,2-Trifluoroethanol (1.5 ml) was added to a 10 mL vial charged with 4 N HCl in dioxane (0.135 ml, 0.54 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.082 g, 0.27 mmol), and 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole (INTERMEDIATE 49, 0.075 g, 0.27 mmol). The reaction was stirred at RT for 5 min and then microwaved at 150° C. for 50 min. Concentration in vacuo gave a crude residue, and it was purified by silica gel chromatography (10% methanol andl% ammonium hydroxide in DCM) to give the product (0.105 g, 66.8%). The product was stirred in 20 mL of 0.5 N HCl in methanol for 1 min and then concentrated under reduced pressure to give the title product. (yellow solid).
Reaction SMILES: [NH3:1].C([O:4][C:5]([CH:7]([NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)=O)C>C(O)C>[C:5]([CH:7]([NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)(=[O:4])[NH2:1]
Reactant: CCOC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Reactant: N
Solvent: CCO
Product: NC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
20 ml of a 10% solution of ammonia in ethanol was added to 200 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was stirred at room temperature for 3 days. The crystal thus precipitated was recovered by filtration. Thus, 60 mg of the title compound was obtained.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CI.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[C:26]([OH:27])[C:21]3=[CH:20][N:19]=2)=[O:17])=[CH:12][C:11]=1[O:28][CH3:29].C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:1])[C:21]3=[CH:20][N:19]=2)=[O:17])=[CH:12][C:11]=1[O:28][CH3:29]
Reactant: COc1cc(C(=O)c2ncc3c(O)cccn23)ccc1N
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2ncc3c(OC)cccn23)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.79 g (2.43 mmol) of cesium carbonate and then 0.05 ml (0.84 mmol) of methyl iodide are added to 0.22 g (0.76 mmol) of (4-amino-3-methoxyphenyl)(8-hydroxyimidazo[1,5-a]pyridin-3-yl)methanone obtained in example 147 in 5 ml of DMF. The reaction medium is stirred at ambient temperature for 4 hours. After addition of a saturated sodium hydrogencarbonate solution, the reaction medium is extracted with ethyl acetate. The organic phase obtained is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, elution being carried out with dichloromethane. 0.2 g of an orange-yellow solid is collected. Melting point: 229° C.; 1H NMR (CDCl3): 3.86 (3H, s), 4.01 (3H, s), 5.80 (2H, m), 6.69 (1H, m), 6.69-6.72 (1H, m), 7.03-7.09 (1H, t), 7.78 (1H, s), 7.92 (1H, s), 8.24 (1H, m), 9.25-9.28 (1H, m)
Reaction SMILES: Cl.[CH:2]([C:5](C(C)C)([CH:8]([CH3:10])C)[CH2:6][NH2:7])([CH3:4])[CH3:3].[N:14](C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=C=O>CN(C)C=O.O1CCCC1>[CH2:6]1[C:5]2[CH:8]=[CH:10][N:14]=[CH:4][C:2]=2[CH2:3][NH:7]1
Reactant: CC(C)C(CN)(C(C)C)C(C)C
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1cc2c(cn1)CNC2
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
HCl (1.55 g, 8.03 mmol) was suspended in dimethylformamide (30 ml) and treated with triisopropylethylamine (4.21 ml, 24.08 mmol). After stirring for 20 minutes, the mixture was cooled to −15° C. 2-(4-Isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.028 g, 8.03 mmol) was dissolved in 10 ml tetrahydrofuran and added via syringe over 10 minutes. The mixture was allowed to warm to room temperature, and it was stirred for 3 hours and concentrated under a stream of nitrogen to minimal volume. The residue was diluted with cold water to give a turbid mixture which was filtered with water washes to provide the title compound after drying.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:24]([OH:39])[C:25]([N:27]2[CH2:38][CH2:37][CH2:36][C@H:28]2[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=1)=[O:4].[NH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[O:55]1[CH2:56][CH2:57][N:52]([CH2:51][CH2:50][NH:49][CH2:2][C:3]([NH:5][C:6]2[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:24]([OH:39])[C:25]([N:27]3[CH2:38][CH2:37][CH2:36][C@H:28]3[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:53][CH2:54]1
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CBr)cc1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CNCCN2CCOCC2)cc1

Procedure:
Following a procedure similar to that described in Example 38, but using 100 mg (0.137 mmol) of 1-{(2S,3S)-3-[N2 -(4-bromoacetamidophenoxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-N-t-butyl-L-prolinamide and 1 ml of 4-(2-aminoethyl)morpholine, 17 mg of the title compound were obtained as a colorless powder, melting at 123°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28](/[C:42](/[NH:45]O)=[N:43]/[H])[CH:29]=[C:30]2[C:34]=1[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:43]=[C:42]([C:28]3[CH:29]=[C:30]4[C:34](=[C:26]([F:25])[CH:27]=3)[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]4)[N:45]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1cc(F)c2[nH]c(CCC(=O)OCC)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (368 mg) in tetrahydrofuran (30 mL) stirred at room temperature was added EDC (654 mg) and HOBT (522 mg). The reaction mixture was stirred at room temperature for 0.5 h. Then ethyl 3-{7-fluoro-5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D163) (500 mg) was added. The reaction mixture was stirred at room temperature for an hour, and then TBAF (1.78 g) was added. The reaction mixture was sealed and heated in Biotage Initiator using initial high to 120° C. for 0.5 h. After cooling the reaction, the solvent was removed. The residue was diluted with EtOAc (30 mL), and the organic phase was washed with water (25 mL×4), dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D166) (600 mg) as a yellow solid. MS (ES): C23H22ClFN4O4 requires 472; found 473.2 (M+H+).
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O[CH2:20][C@@H:21]([O:31][CH2:32][P:33]([OH:36])([OH:35])=[O:34])[CH2:22][N:23]1[CH:30]=[N:29][C:27]([NH2:28])=[N:26][C:24]1=[O:25].[CH2:37](Br)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>CO>[CH3:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][P:33]1([O:34][CH2:20][C@H:21]([CH2:22][N:23]2[C:24](=[O:25])[N:26]=[C:27]([NH2:28])[N:29]=[CH:30]2)[O:31][CH2:32]1)=[O:35]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Nc1ncn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOP1(=O)CO[C@@H](Cn2cnc(N)nc2=O)CO1
Reaction time: 0.08 h

Procedure:
1 M Methanolic tetrabutylammonium hydroxide (0.61 ml; 0.61 mmol) was added to a solution of cyclic HPMP-5-azaC (161 mg, 0.61 mmol) in absolute methanol (50 ml), the mixture stirred for 5 min, then evaporated and the residue coevaporated with toluene (20 ml), followed by dry dioxane (20 ml). The residue was dissolved in dioxane (10 ml) and stirred with octadecyl bromide (500 mg, 1.5 mmol) at 95° C. for 3 h. The reaction mixture was evaporated, the residue chromatographed on a column of silica gel (30 ml) in system chloroform-methanol (85:15). Yield: 250 mg, 80%, white solid. ESI MS: 1051.0 (2M+Na)+ (41), 537.3 (M+Na)+ (64), 515.3 (23) (MH)+. HRMS (ESI): For C25H48N4O5P (MH+) calculated: 515.3362. Found: 515.3382. 1H NMR (DMSO-d6): 8.11 s, 1H (H-6); 7.46 brs, 1H and 7.45 brs, 1H (NH2); other signals not distinguished. 13C NMR (DMSO-d6): 166.50 (C-4); 159.62 (C-6); 153.95 (C-2); 73.19 d, J (P, C)=4.9 (C-2′); 72.04 d, J (P, C)=12.4 (C-3′); 65.19 d, J (P, C)=5.9 (OCH2); 62.70 d, J (P, C)=141.6 (P—C); 45.75 (C-1′); 31.44, 30.03, 29.18, 5 C, 29.09, 25.09, 23.24, 5 C, 22.24 and 19.37 (CH2); 13.65 (CH3).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:29][S:30](O)(=[O:32])=[O:31].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: CS(=O)(=O)O
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNS(C)(=O)=O)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol -3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.025 g, 0.065 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.065 mmol), DIEA (0.017 g, 0.13 mmol), DMAP (0.09 g, 0.072 mmol), and THF (5 ml). The resulting solution was shaken vigorously at 60° C. for 8 hrs. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.016 g, 53%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.39 (m, 2H), 7.14 (d, J=10.7 Hz, 1H), 7.01-6.97 (m, 2H), 5.16-5.09 (m, 1H), 4.15-4.06 (m, 2H), 2.99 (s, 3H), 1.88-1.83 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.95-0.93 (m, 2H), 0.66-0.64 (m, 2H). MS: Calcd.: 462. Found: [M+H]+ 463.
Reaction SMILES: FC([Si:5]([CH3:8])([CH3:7])[CH3:6])(F)F.[Si:9]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:49]=[CH2:50])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])[CH2:34][C@:18]12[CH3:19])[C:31]1[CH:30]=[CH:29][C:28]([O:47][CH3:48])=[CH:27][C:26]=1[CH2:25][CH2:24]3)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[Si:9]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:49]=[CH2:50])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([C:42]([F:45])([F:44])[F:43])([O:46][Si:5]([CH3:6])([CH3:7])[CH3:8])[C:42]([F:44])([F:43])[F:45])[CH2:34][C@:18]12[CH3:19])[C:31]1[CH:30]=[CH:29][C:28]([O:47][CH3:48])=[CH:27][C:26]=1[CH2:25][CH2:24]3)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCCC(=O)C(F)(F)F)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12
Reactant: C[Si](C)(C)C(F)(F)F
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCCC(O[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12

Procedure:
In the reaction with (trifluoromethyl)-trimethylsilane analogously to instructions 1.1, 135 mg of alcohol 16c yields 159 mg of trimethylsilyl ether 17c as a yellow, viscous mass (GC-MS: m/z theor.: 748, pract.: 748). The latter is, without the reaction being performed with tetrabutylammonium fluoride-trihydrate, used in the next stage.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]=[O:14].[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:6]1[N:2]([CH3:1])[C:3]([CH:13]=[O:14])=[N:4][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc(-c2ccccc2)nc1C=O
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(C=O)nc(-c2ccccc2)c1Cl
Temperature: 25 °C

Procedure:
To a solution of 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde 43 (0.299 g, 1.61 mmol) in CCl4 (6 mL) was added N-chlorosuccinimide (229 mg, 1.72 mmol). The reaction mixture was heated to reflux for 4 h, cooled to room temperature, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% to 20% EtOAc in hexanes) gave 5-chloro-1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde 44. Mass spectrum: calculated for C1H9ClN2O 220.0; found 221.3 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:3](C#N)=[N:4][C:5]([Br:9])=[CH:6][C:7]=1[Br:8].O.[C:13](=[O:16])(O)[O-:14].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:3]([C:13]([OH:14])=[O:16])=[N:4][C:5]([Br:9])=[CH:6][C:7]=1[Br:8]
Reactant: O=C([O-])O
Reactant: N#Cc1nc(Br)cc(Br)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Nc1c(Br)cc(Br)nc1C(=O)O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-amino-4,6-dibromo-pyridine-2-carbonitrile (158 mg) was dissolved in concentrated sulfuric acid (1.5 mL) and stirred for 1 h at 100° C. The reaction mixture was cooled to room temperature and water (1.5 mL) was slowly added. The reaction mixture was warmed again to 100° C. and stirred at this temperature for 2 h. Water was added after cooling to room temperature, the pH was adjusted to −10 by addition of solid sodium bicarbonate and the aqueous solution was washed 2× with MTB-ether. The aqueous layer was then adjusted to pH ˜2 by addition of 2 M hydrochloric acid and extracted 3× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum to afford 123 mg of the title compound of the formula
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[O:11][N:12]=[C:13]2[CH:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][C:14]=12>>[CH2:1]([N:8]([CH3:9])[C:19]([C:17]1[CH:16]=[CH:15][C:14]2=[N:10][O:11][N:12]=[C:13]2[CH:18]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: O=C(Cl)c1ccc2nonc2c1
Product: CN(Cc1ccccc1)C(=O)c1ccc2nonc2c1

Procedure:
Prepared from N-benzyl-N-methylamine and [2,1,3]-benzoxadiazole-5-carbonylchloride according to the procedure previously described. N-Benzyl-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide was isolated as a white solid. Mp=105-106° C., LC-MS, MH+=268; 1H NMR (300 MHz, CDCl3, 2 rotamers) δ 7.96-7.86 (m, 1H); 7.90 (d, 1H, J=9.6 Hz); 7.43-7.30 (m, 5H); 7.19-7.13 (m, 1H); 4.78+4.56 (s+s, 2H); 3.11 and 2.94 ppm (s+s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[NH:14][N:13]=2)=[C:2]([CH:7]=1)[NH2:1]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=[N+]([O-])c1cc(CCl)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1SCc1cc([N+](=O)[O-])[nH]n1
Yield: 49 %

Procedure:
(5-Nitro-1H-pyrazol-3-yl)methanol (524 mg, 3.66 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 3-(chloromethyl)-5-nitro-1H-pyrazole. Then following General Procedure A, the title compound (515 mg, 49%) was prepared from 2-amino-4-chlorobenzenethiol (161 mg, 1.01 mmol), crude 3-(chloromethyl)-5-nitro-1H-pyrazole, K2CO3 (468 mg, 3.39 mmol) in DMF (3 ml).