Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][N:12]([CH2:20][CH2:21][CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:15]([O:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH:22]([O:27][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([CH3:10])[N:9]=1)[C:23]([F:26])([F:25])[F:24])[CH3:11])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: CN(CCC(O)C(F)(F)F)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(OC(CCN(C)C(=O)OC(C)(C)C)C(F)(F)F)n1
Reaction time: 96 h
Yield: 31.2 %

Procedure:
A mixture of 2-chloro-6-methylnicotinonitrile (0.215 g, 1.41 mmol) and tert-butyl N-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)carbamate (0.345 g, 1.34 mmol) in DMF (6 mL) was treated with caesium carbonate (0.875 g, 2.69 mmol) at ambient temperature. After stirring for 4 days, the mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were washed (water, brine), dried, and evaporated to an orange oil/solid mixture. The crude material was purified by silica gel chromatography, eluting with 100% dichloromethane and 5% methanol/95% dichloromethane (v/v) to give the product as a yellow oil (0.156 g, 31%).
Reaction SMILES: [CH2:1]([N:4]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][N:20]([C@@H:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]3[CH2:35][C:36]([O:38]CC3C=CC=CC=3)=[O:37])[CH2:19]2)[CH2:13][CH2:12]1)[C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].[H][H]>CO.[Pd]>[CH2:1]([N:4]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][N:20]([C@@H:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]3[CH2:35][C:36]([OH:38])=[O:37])[CH2:19]2)[CH2:13][CH2:12]1)[C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccccc3)C[C@@H]2c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2ccccc2)CC1
Yield: 40.1 %

Procedure:
A solution of 2-(R)-(3-(S)-((4-(N-(prop-1-yl)-N-(pyrimid-2-yl)amino)-piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexylacetic acid, benzyl ester (0.026 ml, 0.24 mmol) from Step A), in 3.0 mL of MeOH was hydrogenated using 10% palladium on carbon (28 mg, 0.026 mmol) under one atmosphere of hydrogen gas. After TLC indicated the absence of the starting benzylester, the reaction was filtered through a 0.45 micron nylon membrane polypropylene filter and concentrated under reduced pressure to give 50 mg (74%) of the title compound as a white solid. HPLC (Zorbax SB-C8 column, 4.6 mm×7.5 cm, Gradient: 90 H2O:10 CH3CN to 0 H2O:100 CH3CN over 7.5 minutes then hold at 100 CH3CN:0 H2O for 45 seconds, 2.25 mL/min, 220 nm): Retention Time: 3.28 minutes. ESI-MS: 520 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH:29]([NH2:31])[CH3:30].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>[Cl-].[Na+].O.CN(C=O)C>[CH3:30][CH:29]([NH:31][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: CC(N)Cc1ccccn1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (300 mg, 0.81 mmol), 1-(pyridin-2-yl)propan-2-amine (165 mg, 1.21 mmol) and DIPEA (312 mg, 2.42 mmol) were combined with DMF (5 mL) to give a yellow solution. HATU (306 mg, 0.81 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with brine and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% methanol in dichloromethane) to afford 360 mg (86%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide as a yellow oil. MS: (M+H)+=491.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1.[I:14]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([Br:11])=[CH:9][C:10]=1[I:14]
Reactant: COC(=O)Nc1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)Nc1cc(C)c(Br)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a solution of 5.00 g (4-bromo-3-methyl-phenyl)-carbamic acid methyl ester in 50 ml acetonitrile were added at 0° C. 4.84 g N-iodosuccinimide and 0.18-ml trifluoromethanesulfonic acid. The mixture was stirred 18 h at room temperature. The solid was collected by filtration, washed with cold acetonitrile and dried to constant weight to yield 5.80 g (4-bromo-2-iodo-5-methyl-phenyl)-carbamic acid methyl ester as white crystals melting at 140–141° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)Oc1cccc(N)c1
Reactant: CCCC=O
Product: CCCCNc1cccc(OC(C)C)c1
Yield: 88.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3-isopropoxyaniline (485 μL, 3.31 mmol) and butyraldehyde (310 μL, 3.47 mmol) were converted to the title compound (610 mg, 84%). 1H NMR (CDCl3) δ 7.15-6.96 (m, 1H), 6.37-6.01 (m, 2H), 4.60-4.39 (m, 1H), 3.75 (br s, 1H), 3.10 (t, J=7.0 Hz, 2H), 1.68-1.52 (m, 2H), 1.50-1.38 (m, 2H), 1.34 (s, 3H), 1.33 (s, 3H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[CH:2]([CH3:18])[CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:18][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:22][CH:21]=1
Reactant: CC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(N(CCCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-[(2-bromo-propyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02180, 146 mg, 0.50 mmol), 4-hydroxy-thiophenol (240 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMF (10 mL) was stirred for 48 hours at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.31) to give an yellow oil, which was crystallised from methanol. Yield: 211 mg (60%). 1H-NMR (400 MHz, d6-DMSO) δ=1.64 (tt, J=7.0, 7.0 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 3.92 (t, J=7.0 Hz, 2H), 6.57 (d, J=9.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 7.20 (d, J=9.0 Hz, 2H), 7.71 (d, J=9.0 Hz, 2H), 8.96 (s, 2H), 9.59 (s, 1H, —OH). LRMS (FAB+): 352.1 (100, [M+H]+).
Reaction SMILES: Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=2[CH2:10][CH2:11][N:12]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]3[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=3[CH2:10][CH2:11][N:12]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:37][CH:38]=2)=[CH:42][CH:41]=1
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(Br)cc1)Cc1ccc(C(=O)OC)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(-c2ccc(Cl)cc2)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
300.0 mg (0.51 mmol) of methyl 4-{[{2-[(4-bromobenzyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 4 are initially charged in 3 ml of dimethoxyethane and admixed successively with 101.7 mg (0.62 mmol) of 4-chlorophenylboronic acid and 0.57 ml of 2M sodium carbonate solution. 10.0 mg of dichlorobis(triphenylphosphine)palladium(II) are added, and the mixture is then heated at reflux temperature for 18 hours. The reaction solution is cooled, admixed with 20 ml of ethyl acetate and washed successively with 5% strength sodium hydrogen phosphate solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and the solvent is distilled off under reduced pressure. The crude product is chromatographed over silica gel using the mobile phase cyclohexane/ethyl acetate=10:1.
Reaction SMILES: C(N1C[C@H](O)C[C@H]1C(O)=O)(OC(C)(C)C)=O.C(O[Na])(C)(C)C.Cl[C:24]1[C:33](C(F)(F)C=C)=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.[Si](C=[N+]=[N-])(C)(C)C>CN(C=O)C.C1COCC1.C(Cl)Cl.CO>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:32]=[CH:33][CH:24]=1
Reactant: C=CC(F)(F)c1nc2ccccc2nc1Cl
Agent: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)O[Na]
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 283.8 %

Procedure:
To a solution of N-Boc-trans-4-hydroxy-L-proline 2-11 (2.404 g, 10.396 mmol) in DMF (14 ml) and THF (60 ml) at 0° C. was added t-BuONa (3.0 g, 31.189 mmol) portionwise. The reaction mixture was allowed to warm up to rt. After stirring for 1 h, the mixture was cooled down to 0° C. and 2-chloro-3-(1,1-difluoroallyl)quinoxaline 2-10 (2.45 g, ˜10.396 mmol) was added and warmed up to rt. After stirring for 4 h, the reaction mixture was quenched with 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (3×), and the organic layer was combined, washed with water, brine, dried and concentrated in vacuo. To the residue in DCM (50 ml) and MeOH (10 ml) was added TMSCHN2 (10.4 ml, 20.792 mmol, 2.0 M in Hexane). The solution was stirred at rt for 30 min then concentrated in vacuo. The residue was purified by flash chromatography on CombiFlash with Hexane to 30% ethyl acetate in hexane to afford desired product 1-1 (3.84 g, 82%). MS (ESI): m/z=450.24 [M+H].
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[CH2:25][CH2:24][CH2:23][NH:22][C:21]=4[N:20]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)C.C1COCC1.CO.O.O.[OH-].[Li+].Cl>C(OCC)(=O)C>[C:29]1([CH:6]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[CH2:25][CH2:24][CH2:23][NH:22][C:21]=5[N:20]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:5][C:4]([OH:35])=[O:3])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CC(c1ccccc1)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Reaction time: 20 h
Yield: 66.1 %

Procedure:
A solution of 3-phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic acid ethyl ester (2.14 g, 4.49 mmol) in a 2:1:0.2 THF/MeOH/H2O (67 mL) was treated with lithium hydroxide monohydrate (0.38 g, 9.00 mmol) at room temperature. The reaction was stirred for 20 h. The mixture was diluted with ethyl acetate, acidified to pH 4 (0.5 N HCl), washed with water and brine, dried and concentrated to afford a crude mixture (2.02 g), which was purified by column chromatography with silica gel (39:1 to 29:1 dichloromethane/MeOH) to give the title compound (1.31 g, 66% yield). 1H NMR (CDCl3) δ 10.5 (s, 1H), 7.44 (d, 1H, J=3.1 Hz), 7.20-7.00 (m, 7H), 6.76 (m, 1H), 6.53 (dd, 1H, J=2.3, 6.6 Hz), 6.41 (s, 1H), 6.19 (d, 1H, J=7.3 Hz), 6.07 (dd, 1H, J=4.3, 7.1 Hz), 3.68 (m, 1H), 3.52 (m, 1H), 3.33 (m, 3H), 3.25-3.09 (m, 2H), 2.58 (m, 3H), 1.77 (m, 3H). Mass Spectrum (LCMS, ESI) calculated for C27H28N3O3 442.2 (M+H); found 442.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH4+:16].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([NH2:16])=[O:7])[CH2:3]1
Reactant: CC1(C)CC(C(=O)O)C1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)CC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A solution of 3,3-dimethylcyclobutane carboxylic acid (0.5 g, 3.90 mmol) and oxalyl chloride (0.512 mL, 5.85 mmol) in DCM (10 mL) was treated with DMF (1 drop) and stirred at RT for 2 h. The mixture was concentrated to dryness, treated with DCM (5 mL) and concentrated to dryness a second time. The crude acid chloride was dissolved in THF (5 mL), added drop-wise to a solution of NH4OH (˜15M, 3.80 mL, ˜57 mmol) in THF (5 mL), stirred for 30 min, diluted with brine and extracted with EtOAc (3×). The combined organics were dried over MgSO4 and evaporated to afford 3,3-dimethylcyclobutanecarboxamide (448 mg, 90%). 1H NMR (400 MHz, DMSO-d6): δ 7.07 (s, 1H), 6.64 (s, 1H), 2.86 (m, 1H), 1.86 (m, 2H), 1.75 (m, 2H), 1.10 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>>[CH:18]([NH:21][C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23])([CH3:20])[CH3:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 71.2 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.077 mL (0.78 mMol) isopropyl isocyanate, 0.146 gm (71%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol. m.p.=217-219° C. (dec.) MS(m/e): 315(M+) Calculated for C17H25N5O: Theory: C, 64.74; H, 7.99; N, 22.20; Found: C, 64.84; H, 8.06; N, 22.44.
Reaction SMILES: [CH2:1]([PH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:17]([N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:22](=[O:25])CCl)[CH:18]([CH3:20])[CH3:19].[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH2:1]([P:9](=[O:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:22](=[O:25])[N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[PH](=O)c1ccccc1
Reactant: CC(C)CN(CC(C)C)C(=O)CCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCP(=O)(C(=O)N(CC(C)C)CC(C)C)c1ccccc1

Procedure:
Octylphenyl N,N-diisobutylcarbamoyl phosphine oxide was prepared by reacting octylphenyl phosphine oxide with N,N-diisobutylchloroacetamide under basic conditions using phase transfer conditions. The octyl phenyl phosphine oxide (357.5 grams) was added over a two hour period to a solution of 308.5 grams of N,N-diisobutylchloroacetamide in 600 ml. of CH2Cl2 and 300 ml. of a 50% NaOH solution containing 3.5 grams of "Adogen 464." A stirring rate of 250 rpm and a temperature of 35° C. to 40° C. was used. The reaction was continued until all the octyl phenyl phosphine oxide was consumed as determined by a GC analysis of the mixture. The reaction mixture was diluted with water. The organic layer was separated, dried over anhydrous MgSO4 and stripped of solvent to give a crude product.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:33])[CH2:17][C:18]4[CH:32]=[CH:31][C:21]5[N:22](C6CCCCO6)[CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[NH:22]1[C:21]2[CH:31]=[CH:32][C:18]([CH2:17][N:16]([CH3:33])[C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)=[CH:19][C:20]=2[N:24]=[CH:23]1
Reactant: CN(Cc1ccc2c(c1)ncn2C1CCCCO1)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CN(Cc1ccc2[nH]cnc2c1)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 80 °C

Procedure:
A tube was charged with a solution of 70 (444 mg, 1.0 mmol) in MeOH (5 mL) and water (1 mL) then TsOH.H2O (190 mg, 1.0 mmol) was added. The tube was sealed and heated at 80° C. overnight. The solvent was evaporated in vacuo and the residue was purified by preparative HPLC to afford 240 mg (66%) of I-12 as a white solid.
Reaction SMILES: C([O:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7])(=O)C.[NH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([Cl:35])[C:19]=2[N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]2)[NH:14][CH:13]=1.C(N(CC)CC)C.[Li+].[OH-]>ClCCl.CN1C(=O)CCC1.O.CC#N.O.C1COCC1>[Cl:35][C:18]1[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:22]2)=[C:20]2[C:12]([NH:11][C:6](=[O:7])[C:5]([OH:4])([CH3:10])[CH3:9])=[CH:13][NH:14][C:15]2=[N:16][CH:17]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C(C)(C)O)c23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
A solution of 1-chloro-2-methyl-1-oxopropan-2-yl acetate (540 mg, 0.469 mL, 3.28 mmol) in anhydrous dichloromethane (2 mL) was added dropwise to a solution of (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (200 mg, 547 mmol; Example 91, Step A) and triethylamine (387 mg, 0.533 mL, 3.83 mmol) in NMP (15 mL) cooled on an ice-bath. The mixture was stirred at ambient temperature for 2 hours. THF (10 mL) was added. The mixture treated with an aqueous solution of 2N LiOH (10 mL) and stirred overnight. The mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-75% CH3CN/water, 25CV) to give (R)-tert-butyl 1-(5-chloro-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (221 mg, 89% yield) as a solid. LCMS (APCI+) m/z 452, 454 (M+H)+, Retention time=3.44 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[NH:5][CH2:4][NH:3]1>[Co]=O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[N:5]=[CH:4][NH:3]1
Reactant: CC1CC(C)(C)NCN1
Agent: O=[Co]
Product: CC1CC(C)(C)NC=N1
Yield: 10 %

Procedure:
Heating a mixture of 12.6 g of 4,4,6-trimethyl hexahydropyrimidine and 0.5 g. of cobalt oxide on kieselguhr for 9 hrs. at 185°-190° C. yielded 10% of 4,4,6-trimethyl-3,4,5,6-tetrahydropyrimidine.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[F:15][C:16]([F:26])([F:25])[C:17]1[N:18]=[C:19]([C:22]([NH2:24])=O)[S:20][CH:21]=1.N1C=CC=CC=1>C(#N)C.CCOC(C)=O>[F:26][C:16]([F:15])([F:25])[C:17]1[N:18]=[C:19]([C:22]#[N:24])[S:20][CH:21]=1
Reactant: NC(=O)c1nc(C(F)(F)F)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1nc(C(F)(F)F)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of anhydrous DMF (18.5 mL, 1.3 eq.) in acetonitrile (460 mL) was added a 2M solution of oxalyl chloride in DCM (118 mL, 1.3 eq.) dropwise at 0° C. After the mixture was stirred for 30 min at 0° C., a solution of compound 285a (35.5 g, 1.0 eq.) and pyridine (14.5 mL, 1.0 eq.) in acetonitrile (180 mL) was added. The reaction mixture was stirred at room temperature for 3 hrs. The mixture was concentrated in vacuo. The residue obtained was dissolved in EtOAc (400 mL) and washed with H2O (4×300 mL). Organics were dried over MgSO4, filtered, and concentrated in vacuo to yield compound 285b as a brown oil in 87% yield. 1H NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[CH:27]=[C:28]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38]([OH:40])=O)[CH:29]=[CH:30][CH:31]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:38]([C:33]1[N:34]=[C:35]([CH3:37])[S:36][C:32]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)=[O:40]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2cccc(F)c2)s1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-(3-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) 348 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.O>ClCCl.C(OCC)(=O)C>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(NC(c1ccccc1)c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of aminodiphenylmethane (0.4 g) in dichloromethane (5 ml) were added in turn pyridine (0.21 ml) and 4-fluorobenzoyl chloride (0.23 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour, which was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give (4-fluorobenzoylamino)-diphenylmethane (0.49 g).