Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=O)[CH3:3].[ClH:5].[NH2:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:18](Br)=[CH:17][N:16]=[C:15]3[NH:20][CH:21]=[C:22]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=4)[C:14]=23)[CH2:9]1>>[ClH:5].[Cl:5][C:18]1[C:13]([N:10]2[CH2:11][CH2:12][CH2:8][C@@H:7]([NH:6][CH:2]([CH3:3])[CH3:1])[CH2:9]2)=[C:14]2[C:22]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=3)=[CH:21][NH:20][C:15]2=[N:16][CH:17]=1
Reactant: CC(C)=O
Reactant: NC[C@@H]1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Agent: Cl
Product: CC(C)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Yield: 64 %

Procedure:
(R)—N-(5-Chloro-4-(3-(isopropylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (30 mg, 64% yield) was prepared as described in Example 6, using propan-2-one (104 mg, 1.80 mmol) and substituting (R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (43 mg, 0.089 mmol) for (S)—N-(4-(3-(aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride. 1H NMR (400 MHz, D2O) δ 9.20-9.19 (m, 1H), 8.88-8.83 (m, 2H), 8.17 (s, 1H), 8.05-7.80 (m, 1H), 7.44-7.43 (m, 1H), 3.86-3.73 (m, 1H), 3.50-3.44 (m, 1H), 3.41-3.31 (m, 2H), 3.18-3.10 (m, 1H), 3.06-2.98 (m, 1H), 2.04-1.95 (m, 1H), 1.69-1.61 (m, 1H), 1.58-1.47 (m, 1H), 1.35-1.25 (m, 1H), 1.14 (d, 3H), 1.10 (d, 3H); LCMS (APCI+) m/z 413.1 (M+H)+, Retention time=2.06 minutes (Method 2).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:29])[C@H:6]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16](N3CCNCC3)=[CH:15][CH:14]=2)=[CH:11][S:10][N:9]=1)#[N:2].[C:30](C1C=CC(B(O)O)=CC=1)(=[O:32])[CH3:31]>>[C:30]([C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:8]([NH:7][C@H:6]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:29])[CH2:25][CH:26]([CH3:27])[CH3:28])=[N:9][S:10][CH:11]=2)=[CH:18][CH:17]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)C[C@H](Nc1nscc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N
Product: CC(=O)c1ccc(-c2csnc2N[C@@H](CC(C)C)C(=O)NCC#N)cc1

Procedure:
N2-(4-bromoisothiazol-3-yl)-N1-(cyanomethyl)leucinamide (100 mg, 0.30 mmol, prepared as described in Example 13) was submitted to a Suzuki coupling with 4-acetylphenylboronic acid (99 mg, 0.60 mmoles) as described in Example 1 to afford N2-[4-(4-acetylphenyl)isothiazol-3-yl]-N1-(cyanomethyl)leucinamide which was purified by flash chromatography (30% to 55% EtOAc/hexanes).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)[CH2:8][CH2:7]1.[C@@H:22]12[C:31](=O)[O:30][C:28](=[O:29])[C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27]2.[ClH:33]>N1C=CC=CC=1.C(O)C>[ClH:33].[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]4[C:28](=[O:29])[C@H:23]5[C@H:22]([CH2:27][CH2:26][CH2:25][CH2:24]5)[C:31]4=[O:30])[CH2:7][CH2:8]3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 16.1 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (3.23 g, 21 mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the end of the reaction, pyridine was removed to dryness. The crude product was purified on a silica gel column. The material thus obtained weighed 3.18 g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), then was treated with HCl in ethanol (45 ml). Crystallization took place upon cooling. The crystals were collected, 3.2 g, m.p.=229°-231° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]([S:36]([CH3:39])(=[O:38])=[O:37])[C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][CH:22]=1.[N:40]1([CH2:46][CH2:47][CH2:48]O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[N:40]1([CH2:46][CH2:47][CH2:48][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]([S:36]([CH3:39])(=[O:38])=[O:37])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:23][CH:22]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CS(=O)(=O)n1c(-c2ccc(O)cc2)cc2ccccc21
Reactant: OCCCN1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)n1c(-c2ccc(OCCCN3CCCCC3)cc2)cc2ccccc21
Reaction time: 20 h
Yield: 47 %

Procedure:
A mixture of immobilized triphenylphosphine resin (330 mg, 1.0 meq (Fluka)), and the product of Step E (140 mg, 0.50 mmol) in tetrahydrofuran (6.0 mL) was treated with 3-(piperdin-1-yl)propanol (143 mg, 1.0 mmol) followed by diethylazidodicarboxylate (0.16 mL, 1.1 mmol). The reaction was shaken for 20 hr. and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography (methanol/ethyl acetate) to afford pure title compound (97 mg). MS (ESI) m/z 413 (MH+); 1H-NMR (CDCl3) δ 8.13 (d, 1H), 7.59 (d, 1H), 7.50 (d, 2H), 7.36 (m, 2H), 6.97 (d, 2H), 6.68 (s, 1H), 4.08 (t, 2H), 2.72 (s, 3H), 2.4 (m, 6H), 1.63 (m, 6H), 1.45 (m, 2H).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23]COC)[CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].Cl>O1CCOCC1>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([OH:23])=[C:16]([C:15]#[C:14][C:9]2[CH:8]=[C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH:12]=[CH:11][C:10]=2[CH3:13])[CH:21]=1
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCOC)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2O)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.5 %

Procedure:
3-{[5-Chloro-2-(methoxymethoxy)phenyl]ethynyl}-4-methylphenyl propyl sulfone (Intermediate 266; 1.09 g; 2.77 mmol) was treated with a 4 N solution hydrogen chloride in 1,4-dioxane (21 ml) and stirred at RT for 7 hours. The reaction mixture was concentrated to dryness under reduced pressure to afford the title compound as a beige solid (884 mg; 91%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:37][CH2:38][N:39]([CH3:41])[CH3:40]>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=577.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 1-chloro-2-dimethylaminoethane hydrochloride.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8](=[O:23])[N:9]3[C:14](=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[C:13]2[S:20][CH:21]=[CH:22][C:12]=2[CH:11]=[CH:10]3)=[CH:3][CH:2]=1.O=S(Cl)Cl.C(N(CC)CC)C.[CH3:41][O:42][CH2:43][CH2:44][NH:45][CH2:46][CH2:47][O:48][CH3:49]>C1(C)C=CC=CC=1.ClCCl>[CH3:41][O:42][CH2:43][CH2:44][N:45]([CH2:46][CH2:47][O:48][CH3:49])[C:17]([C:15]1[CH:16]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:2][CH:3]=2)[C:8](=[O:23])[N:9]2[C:14]=1[C:13]1[S:20][CH:21]=[CH:22][C:12]=1[CH:11]=[CH:10]2)=[O:19]
Reactant: O=C(O)c1cc(-c2ccc(-c3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: COCCNCCOC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C(=O)c1cc(-c2ccc(-c3ccccc3)cc2)c(=O)n2ccc3ccsc3c12

Procedure:
From 8-(biphenyl-4-yl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 in toluene. Then treatment with triethylamine and bis(2-methoxyethyl)amine in dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][CH2:12][CH2:13][OH:14].C([O-])(O)=O.[Na+].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: NCCO
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCCO)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 149.1 %

Procedure:
A mixture of 4-methoxybenzaldehyde (10 g, 74 mmol), 2-aminoethanol (4.9 g, 81 mmol) and NaHCO3 (9.3 g, 110 mmol) in MeOH (100 mL) was refluxed for 3 hours. The reaction mixture was cooled to 15° C. To the mixture was added portionwise NaBH4 (3.3 g, 88 mmol) at 15° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 2-[(4-methoxybenzyl)amino]ethanol (130a, 20 g) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([OH:11])[CH2:9][S:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)CSCc2ccncc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(O)CSCc2ccncc2)cc1

Procedure:
Under a nitrogen atmosphere, alpha-(4-picolylthio)p-methoxyacetophenone (1.99 g., 7.3 mmoles) was dissolved in 25 ml. of stirring ethanol. Sodium borohydride (0.45 g., 11.7 mmoles) was added portionwise and the mixture then refluxed gently for 30 minutes. The mixture was partially cooled and evaporated to dryness. Water (50 ml.) was added to the residue, which was then acidified with excess 1 N hydrochloric acid. The acid solution was made basic with solid sodium bicarbonate and product extracted into ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate and concentrated to an oil, which crystallized on standing. Trituration with diethyl ether and filtration gave purified 4-[2-(4-methoxyphenyl)2-hydroxyethylthiomethyl]pyridine [1.50 g.; m.p. 70°-72.5° C.; pnmr/CDCl3 /TMS/τ: 7.2 (d, 2H), 6.4 (s, 2H), 6.3 (1H, exchanges with D2O), 6.2 (d, 3H), 5.3 (t, 1H), 3.2 (broad doublet, 2H), 2.7 (d and s, 4H), 1.5 (d, 2H); ir (KBr): 3.25, 6.25, 6.65, 8.05, 8.6, 12.5μ].
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[N:3]1[C:4]=23.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])([O-])=O.[K+].[K+].C(=O)([O-])N>O1CCOCC1>[O:12]=[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:2](=[O:1])[N:3]3[C@H:14]([CH2:15][N:16]4[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]4)[CH2:13][N:5]1[C:4]=23
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: NC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Temperature: 120 °C
Yield: 27 %

Procedure:
A solution of 1,1-dimethylethyl (1-{[(2R)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl}-4-piperidinyl)carbamate (5.710 g, 14.19 mmol) in 1,4-dioxane (50 ml) at rt was treated with DDQ (4.83 g, 21.28 mmol) and then heated at 120° C. for 1 h. The reaction was then cooled to rt. The reaction mixture was treated with saturated aqueous K2CO3 (5%, 1000 ml) and extracted with DCM (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product as a brown solid. The reaction was repeated using a further portion of carbamate (2.889 g, 7.18 mmol) in 1,4-dioxane (50 ml) with DDQ (2.444 g, 10.77 mmol). The reaction was performed and worked up as above and the combined residues were chromatographed (0-100% EtOAc:40-60 Petroleum ether then 0-20% MeOH:EtOAc) to give the product as a brown solid (1.532 g, 18%).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1.O>O1CCCC1>[CH:1]1([CH2:4][O:5][C:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:12][S:11][N:10]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1cncc(-c2nsnc2OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a solution of cyclopropylcarbinol (360 mg, 5 mmol) and sodium hydride (110 mg, 5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 400 mg (69%) of the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]([NH:11][CH2:12][CH2:13][NH2:14])([CH3:10])[CH3:9].Cl[CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])=[O:19]>C(N(CC)CC)C>[CH:8]([NH:11][CH2:12][CH2:13][NH:14][CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])=[O:19])([CH3:10])[CH3:9]
Reactant: Cc1cccc(C)c1NC(=O)CCCl
Reactant: CC(C)NCCN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CCNCCNC(C)C
Yield: 63.2 %

Procedure:
Three hundred milliliters of a toluene solution of a mixture of N-isopropyl-1,2-ethylenediamine (20.0 g), 3-chloro-2',6'-dimethylpropionanilide (13.9 g) and triethylamine (10 ml) is treated as in Example 1 to provide a pale yellow powder. Recrystallization from n-hexane provides a colorless needle in an amount of 11.5 g (yield: 63.2%). m.p. 69.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]2[S:23][C:22]([C:24]3([O:28][CH2:29][O:30][CH3:31])[CH2:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=3[F:18])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:19]2[S:23][C:22]([C:24]3([O:28][CH2:29][O:30][CH3:31])[CH2:25][CH2:26][CH2:27]3)=[N:21][CH:20]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH:15][C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])=[CH:13][C:12]=3[F:18])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(N)cc5F)cc34)s2)CCC1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)cc5F)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-fluoroaniline (Example 60B) (68 mg, 0.148 mmol) and dimethyl glycine (15.3 mg, 0.148 mmol) in N,N-dimethylformamide (0.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (67.6 mg, 0.178 mmol) and 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol). The reaction was stirred for 16 hours at ambient temperature. The reaction was treated with more O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (67.6 mg, 0.178 mmol) and 4-(dimethylamino)pyridine (18.1 mg, 0.148 mmol), and the reaction was stirred another 16 hours at ambient temperature. The reaction was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution, and brine. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 1 to 5% methanol in dichloromethane, to give the title compound. MS ESI(+) m/z 544.1 [M+H]+.
Reaction SMILES: NC1N=C(OC2C3C(=CC=CC=3)C(NC(N[C:23]3[CH:28]=[C:27]([C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=3[O:36][CH3:37])=O)=CC=2)C=CN=1.F[B-](F)(F)F.[O:43]=[N+:44]=[O:45]>C(#N)C>[N+:44]([C:25]1[CH:26]=[C:27]([C:29]([F:34])([F:35])[C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:23][C:24]=1[O:36][CH3:37])([O-:45])=[O:43]
Reactant: O=[N+]=O
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1NC(=O)Nc1ccc(Oc2ccnc(N)n2)c2ccccc12
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
The above 4-pentafluoroethylanisole (1.131 g, 0.005 mol) was combined with 10 mL acetonitrile in a 3-neck micro flask. Nitronium tetrafluoroborate (0/797 g, 0.006 mol) was added in portions causing the clear solution to turn brown. The reaction was stirred overnight at room temperature, concentrated, and the product purified by Kugelrohr distillation. The desired 2-nitro-4-pentafluoroethylanisole (0.8 g, bp>80° C.) was obtained as a slightly yellow oil that formed a semi-solid after sitting 60 h.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[N:27]=[C:26]2[CH2:28][C:29]3([CH2:39][C:25]2=[CH:24][CH:23]=1)[C:37]1[C:32](=[N:33][CH:34]=[CH:35][CH:36]=1)[NH:31][C:30]3=[O:38].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([NH:21][C:22]2[N:27]=[C:26]3[CH2:28][C:29]4([CH2:39][C:25]3=[CH:24][CH:23]=2)[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[NH:31][C:30]4=[O:38])=[O:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cn1c(=O)n(-c2ccccn2)c2ccccc21)Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (16 mg, 0.060 mmol, described in Intermediate 7), (±)-2-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1W)-one (15 mg, 0.060 mmol, described in Intermediate 5), PyClu (26 mg, 0.072 mmol), and DIEA (0.053 mL, 0.30 mmol) in THF (1 mL) was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=504 (M+1). HRMS: m/z=504.1796; calculated m/z=504.1779 for C28H22N7O3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[NH:54]1[CH:58]=[CH:57][C:56]([C:59](O)=[O:60])=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:56]2[CH:57]=[CH:58][NH:54][N:55]=2)=[O:60])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1cc[nH]n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2cc[nH]n2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1H-pyrazole-3-carboxylic acid as the starting materials in 66% yield. LCMS for C27H27ClN9O2 (M+H)+: m/z=544.0.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][N:20]([C@@H:23]([CH3:34])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH2:21][CH3:22])[CH2:15][CH2:14]1)=[O:12])=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][N:20]([C@@H:23]([CH3:34])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH2:21][CH3:22])[CH2:15][CH2:14]1)=[O:12]
Reactant: CCN(CC1CCN(C(=O)CCNC(=O)OC(C)(C)C)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC1CCN(C(=O)CCN)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
To (S)-3-tert-Butoxycarbonylamino-1-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}methyl)piperidin-1-yl]-propan-1-one (0.76 grams, 1.60 mmol) was added 20% trifluroacetic acid (20 ml). The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The organic layer was washed with water, dried over potassium carbonate and concentrated to give (S)-3-amino-1-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}methyl)piperidin-1-yl]-propan-1-one as an oil (0.59 grams, 99%), M+H 373.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]#[N:25])[CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][O-:29].[Na+].O>CO>[CH3:28][O:29][C:24]([N:21]1[CH2:20][CH2:19][CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][CH:5]=3)[N:10]=2)[CH2:23][CH2:22]1)=[NH:25]
Reactant: N#CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=N)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of 4-[1-(4-trifluoromethylphenyl)-1H-indazol-3-yl]-piperidine-1-carbonitrile of Example 101 (20.0 g, 0.054 moles) and sodium methoxide (12.4 ml of 25% sodium methoxide in methanol 0.054 moles) in methanol (120 ml) was warmed to effect solution and then stirred at ambient temperature for 3 hours. The mixture was poured into H2O, extracted (CHCl3), dried (MgSO4), and concentrated to yield an oil. The oil was triturated with hexane which produced 19 g of a solid. The solid was recrystallized twice from toluene-hexane which yielded 14.2 g (65%) of 4-[1-[4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboximidic acid methyl ester, m.p. 113°-115° C.