Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl.[CH3:18][N:19]([CH2:21][C:22](Cl)=[O:23])[CH3:20].C(N(CC)CC)C>ClCCl>[CH3:18][N:19]([CH3:20])[CH2:21][C:22]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1)=[O:23]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.490 g, 2.20 mmol), dimethylamino-acetyl chloride hydrochloride (0.4181 g, 2.646 mmol), and Triethylamine (0.7683 mL, 5.512 mmol) in dichloromethane (11 mL) and the reaction was stirred overnight at room temperature. The reaction mixture was next partitioned between water and ethyl acetate, and the layers separated. The aqueous phase was extracted twice with EtOAc and the combined organic extract was washed with water, dried (MgSO4), filtered, and concentrated, and the product, 2-dimethylamino-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone, was isolated by flash chromatography (SiO2, MeOH/dichloromethane 0-10%) as an oil (600 mg, 90%). LC/MS (ESI+): 308.04 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:19]([O:23]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]2[N:56]=[C:57]([NH2:60])[S:58][CH:59]=2)[CH:50]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:19](=[O:23])[NH:60][C:57]1[S:58][CH:59]=[C:55]([C:51]2[CH:50]=[N:49][CH:54]=[CH:53][CH:52]=2)[N:56]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nc(-c2cccnc2)cs1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(-c2cccnc2)cs1)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyrrolidine-1-carboxylic acid benzyl ester, (224 mg, 0.9 mmol) was combined with 376 mg (1.0 mmol) of HATU. This mixture was dissolved in 15 ml of DMF. To this solution was added DIEA (1.8 mmol, 0.3 mL). This solution was stirred at room temperature for 1.5 hours. To this solution was then added 4-pyridin-3-yl-thiazol-2-ylamine (100 mg, 0.56 mg). Reaction mixture was stirred at room temperature overnight and then purified using reverse phase HPLC. MS: 409.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) (HCl salt) 12.62 (s, 1H), 9.28 (s, 1H), 8.78 (s, 1H), 8.03 (m, 2H), 7.38 (m, 3H), 7.04 (d, 2H), 5.00 (m, 2H), 4.53 (m, 1H), 3.62 (m, 2H), 2.22 (m, 1H), 1.89 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.[C@@H:15]12[CH2:21][CH2:20][C@@H:19]1[CH2:18][NH:17][CH2:16]2.[I-].[Na+]>>[C@@H:15]12[CH2:21][CH2:20][C@@H:19]1[CH2:18][N:17]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1)[CH2:16]2
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: C1C[C@H]2CNC[C@@H]12
Agent: [I-]
Agent: [Na+]
Product: NC(=O)c1ccc(OCCCN2C[C@H]3CC[C@H]3C2)cc1
Reaction time: 16 h

Procedure:
To the reaction mixture of Step 1, at ambient temperature, there are added 0.004 mol of (1R,5S)-3-azabicyclo[3.2.0]heptane, the synthesis of which is described in the publication J. Med. Chem. 1967, 10, 621-623, and 0.002 mol of sodium iodide. Heating at reflux is then resumed for 16 hours. The precipitate is filtered off and rinsed with acetonitrile. The filtrate is concentrated to dryness. The residue is taken up in dichloromethane. The resulting solution is extracted with sodium hydroxide solution and then with water, before being dried over magnesium sulphate and concentrated to dryness. The residue is purified by a preparative chromatography technique on a Lichroprep RP-18 phase.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:19]O>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc2cccnc2c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2cccnc2c1

Procedure:
To a solution of example 11A (1.98 g, 10.59 mmol) in 40 mL of anhydrous methanol was slowly added SOCl2 (1.5 mL, 31.7 mmol), and a drop of dimethylformamide as catalyst. The mixture was refluxed for 5 hrs and then concentrated under reduced pressure. The residue was dissolved in water (10 mL) and neutralized with aqueous sodium bicarbonate to pH 8. The product was extracted with methylene chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure to afford 2.13 g of the title compound. MS (ESI+) m/z 202 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=O.[C:14]1([C@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH3-]C#N.[Na+]>CO>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[O:10][CH3:11])[CH2:5][NH:22][C@@H:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:21])=[CH:3][CH:2]=1.[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH2:5][NH:22][C@@H:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:21]
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1cc(C=O)cc(Br)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CN[C@H](C)c2ccccc2)cc(Br)c1OC
Product: COc1ccc(-c2cc(CN[C@H](C)c3ccccc3)cc(OC)c2OC)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromo-4,5-dimethoxybenzaldehyde 111 (5.0 g, 0.020 mol, Aldrich), (R)-1-phenylethanamine (2.6 mL, 0.020 mol, Aldrich) and ACQH (5.0 mL) in 70 mL of MeOH was stirred at room temp. for 2 hours. The solution was then cooled to 0° C. and NaBH3CN solid was added in portions. The reaction solution was then warmed up to room temp and continued to stir overnight. The mixture was concentrated in vacuo and re-dissolved in 150 mL of EtOAc. The organic solution was washed with 50 mL of saturated. NaHCO3 followed by 50 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was passed through a short silica gel pad (eluted with 50% EtOAc/hex). The eluant was concentrated in vacuo to give a light yellow oil, which solidified upon standing to give desired product (R)—N-(3-bromo-4,5-dimethoxybenzyl)-1-phenylethanamine 112 as white waxy solid (5.1 g, 73%). MS (ESI, pos. ion) m/z: 350.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 7.4-7.5 (m, 5H); 6.9 (s, 1H); 7.0 (s, 1H), 3.9 (s, 3H); 3.8 (s, 3H); 3.7-3.9 (m, 3H); 1.7 (d, J=7.0 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[N:3]=1.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[OH-].[Na+]>ClC(Cl)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)[N:3]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCCNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CN1CCCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To a mixture of 3-iodo-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.4 g, 0.00116 mol) and sodium triacetoxyborohydride (0.34 g, 0.00162 mol) in dichloroethane (30 mL) was added formaldehyde solution (37% in water, 0.035 mL, 00.00128 mol, 1.1 eq.) at room temperature. The mixture was stirred at room temperature under an atmosphere of nitrogen for 18 hours. Additional formaldehyde solution (37% in water, 0.035 mL, 0.00128 mol, 1.1 eq.) was added, and the mixture was stirred at room temperature for 2 hours. A 5 N aqueous solution of sodium hydroxide (5 mL) was added to the mixture. The solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure, and the mixture was lyophilized to yield 3-iodo-1-(1-methyl-3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.41 g, 0.0011 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 6.0 min. MS: MH+ 359
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1.[Br:22][C:23]1[CH:24]=[C:25]([C:29]([NH2:32])([CH3:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:15]([NH:32][C:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Br:22])[CH:24]=1)([CH3:30])[CH3:31])=[O:16])[CH2:2]2
Reactant: CC(C)(N)c1cccc(Br)c1
Reactant: NC1CN2CCC1CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(NC(=O)NC1CN2CCC1CC2)c1cccc(Br)c1
Yield: 57.4 %

Procedure:
Using general procedure C, quinuclidin-3-amine (100 mg, 0.792 mmol), CDI (128 mg, 0.789 mmol) and 2-(3-bromophenyl)propan-2-amine (170 mg, 0.791 mmol) gave the title compound as a white solid (166 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.30 (t, J=7.2 Hz, 2H), 7.15 (t, J=7.9 Hz, 1H), 5.54 (d, J=22.7 Hz, 1H), 5.16 (d, J=29.7 Hz, 1H), 3.60 (s, 1H), 3.14 (ddd, J=13.3, 9.4, 1.6 Hz, 1H), 2.61 (d, J=52.6 Hz, 4H), 2.18 (dd, J=14.1, 2.8 Hz, 1H), 1.66 (d, J=3.0 Hz, 2H), 1.51 (d, J=7.6 Hz, 6H), 1.28 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.1, 150.4, 130.3, 130.0, 128.6, 124.0, 123.0, 57.0, 54.6, 47.6, 47.2, 46.8, 30.5, 30.3, 26.3, 26.2, 20.2 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.66 min; (M+1) 367.8.
Reaction SMILES: C1(P([C:14]2[CH:19]=[CH:18]C=CC=2)C2C=CC=CN=2)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=[O:27])=CC=1.[C:31]([OH:35])(=[O:34])[CH2:32][CH3:33]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N)CCC>[C:31]([O:35][C:14](=[O:27])[CH2:19][CH3:18])(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN
Product: CCC(=O)OC(=O)CC
Temperature: 110 °C

Procedure:
A 250 ml stainless steel, magnetically stirred autoclave was filled with 0.1 mmol palladium(II) acetate, 5 mmol bisphenyl(2-pyridyl)phosphine, 4 mmol p-toluenesulfonic acid, 50 ml propionic acid and 10 ml n-butylamine. Air was then evacuated from the autoclave. The autoclave was then pressurized with 30 bar carbon monoxide and 20 bar ethene, sealed and heated to 110° C. After 11/2 hours reaction time, a sample of the contents of the autoclave was withdrawn and analyzed by gas-liquid chromatography. The analysis revealed that N-butyl propionamide had been formed with a selectivity (based on amine) of >95%, together with propionic anhydride. The mean conversion rate was calculated to be 1,500 moles ethene/gram atom Pd/hour.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:6]2[N:5]=[CH:4][CH:3]=1.[CH3:16][NH:17][CH2:18][CH3:19].[OH-].[Na+].Cl>CC#N.CCO.O>[CH2:18]([N:17]([CH3:16])[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[N:5]=[CH:4][CH:3]=1)[CH3:19]
Reactant: CCOC(=O)c1cnn2c(Cl)ccnc12
Reactant: CCNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CCN(C)c1ccnc2c(C(=O)O)cnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 7-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (68 mg, 0.30 mmol) in CH3CN (1 mL) was added N-methylethanamine (18 mg, 0.30 mmol) and the mixture was stirred at ambient temperature for 16 h. The mixture was evaporated and the residue was purified by column chromatography (0-10% MeOH in dichloromethane) to give a solid. The solid was taken up in EtOH (0.5 mL) and water (0.1 mL) before NaOH (12 mg, 0.30 mmol) was added. The mixture was stirred at 50° C. for 4 h. The pH of the mixture was adjusted to 4 with conc. HCl, and the solvents were removed. The residue was co-evaporated with MeOH (3×) to provide 7-(ethyl(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. ESI-MS m/z calc. 220.1, found 221.5 (M+1)+; Retention time: 0.29 minutes (3 min run).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=2)[CH2:4][C:3]1([CH3:21])[CH3:20].ClC(OCC)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:31][CH:30]=1>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[C:3]([CH3:20])([CH3:21])[CH2:4][CH:5]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:33][CH:34]=3)=[O:19])=[N:15][CH:16]=2)[CH2:6][C:7]1([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CN1C(C)(C)CC(Oc2ccc(C(=O)O)nc2)CC1(C)C
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(C)(C)CC(Oc2ccc(C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc3)nc2)CC1(C)C
Temperature: 50 °C
Yield: 120.5 %

Procedure:
To a stirred solution of 5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinic acid (250 mg, 0.86 mmol) in DCM/THF (6 mL, 2:1, v/v) at rt was added TEA (144 μL, 1.03 mmol) and ethyl chloroformate (82 μL, 0.86 mmol). The resulting mixture was stirred at rt for 20 min before tert-butyl 4-aminophenylcarbamate (178 mg, 0.86 mmol) was added. The resulting mixture was heated at 50° C. for 1 h. LC-MS indicated the reaction was complete. Solvents were then removed under reduced pressure and the residue was partitioned between EtOAc (30 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give crude tert-butyl 4-(5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamido)phenylcarbamate (500 mg) as an off-white foam. LC-MS (ESI) m/z 483 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1)=[O:14]>CCCCCC.C1COCC1>[OH:14][CH:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1
Reactant: Brc1ccccn1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(O)c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17.1 %

Procedure:
Butyllithium, 1.6M in hexane (146 ml) was added dropwise at −78° C. under N2 flow to a solution of 2-bromopyridine (0.1348 mol) in THF (300 ml). The mixture was stirred at −78° C. for 20 minutes. A solution of N-(4-formylphenyl) acetamide (0.1226 mol) in THF (300 ml) was added at −60° C./−70° C. The mixture was stirred at −60° C./−70° C. for 1 hour, then poured out into ice water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (27 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether and 2-propanone. The precipitate was filtered off and dried, yielding 5.09 g (17%) (±)-N-[4-[hydroxy(2-pyridinyl)methyl]phenyl]-acetamide (compound 688).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]/[CH2:4]O.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:27])(=O)=O>CN(C=O)C>[Cl:27][CH2:4]/[CH:3]=[C:2](/[CH3:1])\[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C\CCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a stirred solution of 10.0 g (64.83 mmol) of (Z)-3,7-dimethyl-2,6-octadien-1-ol and 9.42 mL (71.31 mmol) of 2,4,6-collidine under argon at room temperature was added dropwise 2.74 g (64.83 mmol) of lithium chloride in 30 mL of DMF. The mixture was cooled to 0° C. and treated with 5.52 mL (71.31 mmol) of methanesulfonyl chloride dropwise over 10 minutes. The reaction was stirred at 0° C. for 4 hours (solid present), then was poured into 300 mL of ice/water. The aqueous solution was washed three times with 200 mL portions of hexane. The organic layers were combined and washed with 5% KHSO4, water, saturated NaHCO3, brine, dried (MgSO4) and evaporated to provide 9.48 g (85%) of title chloride as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4](=O)[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.CCN(CC)CC.Cl.[NH2:33][OH:34]>O1CCOCC1>[C:15]([O:14][C:13]([NH:12][CH:3]([C:4](=[N:33][OH:34])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:1])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccncc1)C(=O)N1CCCC1
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCCC1)C(=NO)c1ccncc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a stirred solution of tert-butyl (±)-1,3-dioxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate TTA 08120 (0.20 g, 0.60 mmol) in 10 mL of dioxane were added Et3N (125 μl, 0.90 mmol) and hydroxylamine hydrochloride (65 mg, 0.90 mmol). The mixture was stirred 2 h at 110° C. in a sealed tube then dioxane was evaporated. The obtained residue was purified by column chromatography (SiO2, CH2Cl2:MeOH=9:1 to 97:3) to give (±)-2-tert-butyloxycarbonylamino-3-(hydroxyimino)-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-1-one TTA 08160 (100 mg, 48% yield) as an oil.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:23][C:24]([C:26]2([NH:41]C(=O)OC(C)(C)C)[CH2:31][CH2:30][N:29]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>>[NH2:41][C:26]1([C:24]([NH:23][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[O:25])[CH2:27][CH2:28][N:29]([C:32]2[C:33]3[CH:40]=[CH:39][NH:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCNS(C)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
HCl (4M) in 1,4-Dioxane (1.615 mL, 6.46 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-(methylsulfonamido)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 117) (261 mg, 0.43 mmol), The resulting suspension was stirred at 20° C. for 1 hour. No reaction. TFA (1 mL) was then added to the reaction and stirred for 16 hours. The reaction was vacuumed to dryness and was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3/MeOH and pure fractions were evaporated to dryness to afford crude material. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing [AP-HPLC Buffer]) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-(methylsulfonamido)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (142 mg, 65.2%) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[C:5](=[O:17])[N:4]([CH3:18])[CH:3]=1.[C:19]([C:23]1[CH:47]=[CH:46][C:26]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[C:31]=2[CH3:45])=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:19]([C:23]1[CH:47]=[CH:46][C:26]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=4)[C:5](=[O:17])[N:4]([CH3:18])[CH:3]=3)[C:31]=2[CH3:45])=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cn1cc(Br)nc(Nc2ccc(C=O)cc2)c1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C=O)cc2)n1
Temperature: 95 °C
Yield: 111.8 %

Procedure:
A mixture of 4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzaldehyde (3) (2.0 g; 6.51 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (3.28 g; 7.8 mmol), tetrakis(triphenylphosphine)palladium (0.75 g; 0.65 mmol), 1N sodium carbonate (16.0 mL), and 1,2-dimethoxyethane (50 mL) was heated at 95° C. in a sealed pressure vessel for 12 hr. The mixture was cooled to room temperature, treated with water (70 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (2×75 mL) and brine (1×75 mL), dried over solid sodium sulfate, and evaporated under reduced pressure. The resulting residue was triturated with diethyl ether/dichloromethane to give 4-tert-butyl-N-{3-[6-(4-formyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide (4) as a light gray solid (3.6 g), MS 495.35 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10](#[N:16])[CH:11]([CH2:13][C:14]#[N:15])[OH:12]>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:13]([C:14]#[N:15])[CH:11]([OH:12])[C:10]#[N:16]
Reactant: O=Cc1ccccc1F
Reactant: N#CCC(O)C#N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1ccccc1F)C(O)C#N

Procedure:
2-Fluorobenzaldehyde (15.8 ml) was dissolved in ethanol (100 ml) and to the stirred solution was added malonitrile (9.9 g). The solution was heated to reflux, the heating discontinued and piperidine (4 drops) was added. Once the vigorous reaction had diminished, the solution was heated for 15 minutes and then chilled. Crystals of product were filtered off and washed with ethanol, m.p. 122° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([CH3:16])[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]([CH:23](OC)OC)[CH3:22].N1CC[CH2:30][CH2:29]1.CCOC(C)=O.CCCCCC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11](/[CH:16]=[CH:20]/[N:21]2[CH2:23][CH2:30][CH2:29][CH2:22]2)[C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1c(Br)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(OCc2ccccc2)ccc(Br)c1/C=C/N1CCCC1

Procedure:
1-Benzyloxy-4-bromo-3-methyl-2-nitro-benzene (20 g, 62.1 mmol; Intermediate 81) was dissolved in DMF. DMFDMA (9.93 ml, 74.5 mmol) and pyrrolidine (6.22 ml, 74.5 mmol) was added. The solution was heated at 110° under nitrogen. TLC (EtOAc/Hexane 1/3) indicated that the starting material was consumed after 2 h. The heating was turned off. The reaction mixture was allowed to adopt room temperature, and was left over night. The solution was evaporated and the residue solidified on standing in the refrigerator. 50 mL of methanol was added and the mixture was heated. The solid was partly dissolved. The mixture was allowed to adopt room temperature, and was then filtered. The solid was washed with methanol and dried. Obtained 17 g.