Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=2)=[O:21])=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].CO.C(OCC)(=O)C>[C:43]([C:40]1[CH:39]=[CH:38][C:37]([CH:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=2)=[O:21])=[CH:42][CH:41]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)c1ccc(C(Cc2ccc(OCCOCc3ccccc3)cc2)C(=O)Nc2ccc(OCC3CCCCC3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(Cc2ccc(OCCO)cc2)C(=O)Nc2ccc(OCC3CCCCC3)cc2)cc1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of 3-[4-(2-Benzyloxyethoxy)-phenyl]-2-(4-tert-butylphenyl)-N-(4-cyclohexylmethoxyphenyl)-propionamide (200 mg, 0.32 mmol) and 10% Pd/C (20 mg) in a solution of methanol/ethyl acetate (60 mL, 4:1) was stirred under an atmosphere of H2 overnight. The mixture was filtered through celite and concentrated under vacuum. The crude was purified by chromatography on silica gel (ISCO cartridge, 40 g), eluting with dichloromethane over 20 minutes to afford 2-(4-tert-Butylphenyl)-N-(4-cyclohexylmethoxyphenyl)-3-[4-(2-hydroxy ethoxy)-phenyl]-propionamide (126 mg, 74%). LC-MS m/z/z=530 [C34H43NO4+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2N)CC1

Procedure:
tert-Butyl 4-{[2-(2-nitrophenyl)ethyl]amino}piperidine-1-carboxylate and 10% palladium on carbon (1.9 g) were stirred in ethanol (250 mL) overnight under one atmosphere hydrogen. Catalyst was filtered from the solution and solvent removed in vacuo to provide the title compound (17.2 g). MS 320 (M+1)
Reaction SMILES: [CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10]C)=O)[CH:4]=[O:5])=[CH2:2].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C[O-].[Na+]>CO>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:8](=[O:10])[CH2:7][CH2:6][N:3]([CH:1]=[CH2:2])[CH:4]=[O:5]
Reactant: NCCCCCO
Reactant: C=CN(C=O)CCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CN(C=O)CCC(=O)NCCCCCO

Procedure:
The apparatus of Example 2 was charged with 15.7 grams (0.1 mol) of methyl 3-(N-vinylformamido)propionate, 10.3 grams (0.1 mol) of 5-amino-1-pentanol and 0.12 gram of 25% sodium methoxide in methanol solution. The mixture was stirred at 90° C. for 3 hours after which the methanol coproduct was removed by distillation at reduced pressure. NMR analysis of the remaining amber liquid indicated about 69% conversion to the desired product.
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[CH3:25][C:26]1[C:30]([C:31](=[O:33])[CH3:32])=[C:29]([CH3:34])[NH:28][C:27]=1[C:35](O)=[O:36]>>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([C:4]([OH:3])=[O:24])[NH:6][C:35]([C:27]2[NH:28][C:29]([CH3:34])=[C:30]([C:31](=[O:33])[CH3:32])[C:26]=2[CH3:25])=[O:36])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Reactant: CC(=O)c1c(C)[nH]c(C(=O)O)c1C
Agent: Cl
Product: CC(=O)c1c(C)[nH]c(C(=O)N[C@@H](Cc2ccc(OCc3c(Cl)cccc3Cl)cc2)C(=O)O)c1C

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 3,5-dimethyl-4-acetylpyrrole-2-carboxylic acid. Freeze drying afforded the title compound as a light cream amorphous solid (550 mg). δH (DMSO-d6) 11.56, (1H, s), 7.61 (1H, d, J 7.8 Hz), 7.51 (2H, d, J 8.0 Hz), 7.41 (1H, t, J 8.0 Hz), 7.21 (2H, d, J 85 Hz), 6.96 (2H, d, J 8.5 Hz), 5.16 (2H, s), 4.69-4.55 (1H, m), 3.12 (1H, dd, J 13.7, 4.7 Hz), 2.99 (1H, dd, J 13.7, 9.1 Hz), 2.43 (3H, s), 2.38 (3H, s), 2.31 (3H, s); m/z (ESI, 60V) 503 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13]>C(OCC)(=O)C.C(O)C.CC[O-].[Na+]>[O:15]=[C:14]([CH3:16])[CH2:12][CH2:13][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)CCN1C(=O)c2ccccc2C1=O
Yield: 92.1 %

Procedure:
Prepare a suspension of phthalimide (5 g, 34 mmol) in ethyl acetate (40 mL). Add methyl vinyl ketone (2.8 mL, 34 mmol) followed by NaOEt (116 mg, 1.7 mmol) in ethanol (10 mL). Stir the reaction at room temperature for 2 hours, then heat to reflux and stir for 3 hours. Concentrate the reaction in vacuo to a solid. Recrystallize the solid from ethanol to afford 2-(3-oxobutyl)isoindole-1,3-dione (6.8 g). 1H NMR (CDCl3) δ 7.82-7.88 (m, 2H), 7.69-7.77 (m, 2H), 3.97 (t, J=7 Hz, 2H), 2.88 (t, J=7 Hz, 2H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1>>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C:9]([NH:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:11])=[S:10]
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Nc1nc2ccccc2s1
Product: Cc1ccc(Cl)cc1NC(=S)Nc1nc2ccccc2s1
Yield: 31.1 %

Procedure:
Prepared using Method A from 5.0 g (27.2 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 3.90 g (26 mmol) of 2-aminobenzothiazole to give 2.7 g of title compound as a white fluffy solid (30% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1
Reactant: COC=Cc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 65 %

Procedure:
A stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.79 g, 8.13 mmol) in THF (50 mL) at 0° C. was treated dropwise with n-BuLi (1.6-M in hexanes, 5.08 mL, 8.13 mmol), stirred for 1 h, treated with a solution of 6-(triphenylmethoxy)methylpyridine-2-carboxaldehyde (1.54 g, 4.06 mmol) in THF (15 mL) and allowed to warm to room temperature overnight. The reaction was treated with saturated NH4Cl solution (5 mL), diluted with water (50 mL), extracted with EtOAc (2×50 mL) and the combined organic phase diluted with iso-hexane (50 mL), dried (MgSO4), filtered through silica and concentrated in vacuo to give 2-(2-methoxyethenyl)-6-(triphenylmethoxy)methylpyridine (1.58 g) as a yellow oil. A solution of this crude alkene and 10% Pd/C (216 mg, 0.203 mmol) in EtOAc (50 mL) was stirred under a hydrogen atmosphere for 16 h, filtered through Celite and concentrated in vacuo to give the title compound (1.08 g, 65%) as a yellow oil; NMR 5H (400 MHz, CDCl3) 7.67-7.64 (1H, m), 7.52-7.49 (6H, m), 7.32-7.21 (10H, m), 7.09-7.07 (1H, m), 4.34 (2H, s), 3.69 (2H, t, J 6.5 Hz), 3.32 (3H, s) and 2.98 (2H, t, J 6.5 Hz); M/Z 410 (M+H)+.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: COCCN1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COCCN1CCN(c2c(C(C)Nc3ncnc4[nH]cnc34)cc(Cl)c3cccnc23)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.0274 g, 0.138 mmol), 1-{5-chloro-8-[4-(2-methoxyethyl)piperazin-1-yl]quinolin-7-yl]ethanamine (0.024 g, 0.069 mmol), and N,N-diisopropylethylamine (0.02396 mL, 0.1376 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the desired product as a tris-TFA salt. LCMS calculated for C23H28ClN8O(M+H)+: m/z=467.2; found: 467.1. 1H NMR (DMSO-d6, 400 MHz) δ 9.70 (1H, br s), 8.98 (1H, s), 8.50 (1H, d, J=8.0 Hz), 8.21 (2H, m), 8.02 (1H, s), 7.66 (1H, dd, J=8.4 and 4.4 Hz), 6.41 (1H, m), 4.42˜3.02 (12H, m), 3.33 (3H, s), 1.55 (3H, d, J=6.4 Hz) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:21])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCN(C)CC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)C2CCN(C)CC2)c1C
Temperature: 80 °C
Yield: 80 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((1-methylpiperidin-4-yl)amino)benzoate (0.6 g, 1.76 mmol) in acetonitrile (15 mL), cesium carbonate (1.14 g, 3.52 mmol) and methyl iodide (1.2 g, 8.8 mmol) were added; resulting reaction mass was heated at 80° C. for 7 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford the desired compound (0.5 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][Br:10]
Reactant: Cc1c(Br)cccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1c(Br)cccc1Br
Temperature: 85 °C
Reaction time: 16 h
Yield: 106.8 %

Procedure:
A mixture of 2,6-dibromotoluene (22.9 g, 92 mmol), N-bromosuccinimide (NBS) (15 g, 84 mmol), CCl4 (250 mL) and benzoyl peroxide (0.03 eq) was stirred at 85° C. (hot oil bath temperature) for 16 h, cooled to RT, filtered, washed with aq. NaHSO3, dried (Na2SO4), filtered, and evaporated to give 29.5 g (yield of 98%) of title product as a white solid. This solid contained 10% unreacted starting material but was successfully used without further purification. 1H NMR (300 MHz, CDCl3) δ 4.81 (s, 2H), 7.01 (t, 1H), 7.53 (d, 2H).
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][CH:9]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[C:10](=[O:28])[NH:11][CH:12]([CH:15]([OH:27])[C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][N:17]=2)[CH2:13][CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]1([CH2:4][S:5]([CH2:8][CH:9]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[C:10](=[O:28])[NH:11][CH:12]([C:15]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][N:17]=2)=[O:27])[CH2:13][CH3:14])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C(CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1)C(O)c1noc(-c2ccccc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(NC(=O)C(CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1)C(=O)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of morpholine-4-carboxylic acid (2-cyclopropylmethanesulfonyl-1-{1-[hydroxy-(5-phenyl-1,2,4-oxadiazol-3-yl)-methyl]-propylcarbamoyl}-ethyl)-amide (183 mg, 0.34 mmol) in methylene chloride (10 mL), Dess-Martin Periodinane (200 mg, 0.47 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was washed with a solution of Na2S2O3 in water (0.26M), saturated bicarbonate, and water, dried over Na2SO4 and concentrated under reduced pressure. The residue was subjected to flash chromatography eluting with a mixture of ethyl acetate and heptane to give morpholine-4-carboxylic acid {2-cyclopropylmethanesulfonyl-1-[1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propylcarbamoyl]-ethyl}-amide, a mixture of diastereomers, (45 mg) as an off white solid. 1H NMR (CDCl3): 8.22 (d, J=7 Hz, 2H), 7.83, 7.75 (2×d, J=7 Hz, 1H), 7.65 (m, 1H), 7.60-7.51 (m, 2H), 6.10-6.07 (2×d, J=7 Hz, 1H), 5.36 (m, 1H), 5.00-4.86 (m, 1H), 3.79 (m, 1H), 3.74-3.66 (m, 4H), 3.48 (m, 1H), 3.47-3.37 (m, 4H), 3.20-3.07 (m, 2H), 2.24-2.06 (m, 1H), 2.00-1.82 (m, 1H), 1.22 (m, 1H), 1.01 (t, J=7 Hz, 3H), 0.80-0.68 (m, 2H), 0.56-0.38 (m, 2H). MS: 534 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7](Cl)=[O:8])=[CH:4][S:5][CH:6]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cscc1Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1cscc1Cl
Reaction time: 12 h

Procedure:
4-Chlorothiophene-3-carbonyl chloride (13.5 g, 0.075 mol) are dissolved in 30 ml of dioxane and the solution is added dropwise at room temperature to a solution of aniline (7.7 g, 0.083 mol) in pyridine (160 ml). Stirring is carried out for 12 hours at room temperature, after which the mixture is evaporated to dryness and the residue is taken up in dichloromethane. The organic phase is extracted with aqueous citric acid solution, sodium bicarbonate solution and water, dried and evaporated to dryness. Yield: 16.7 g, 94%; mp. 119° to 121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@@H:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CC[C@H](N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 179. Product was isolated as tan solid (36 mg, 33%). LCMS (m/e) 539 (M+H), 1H NMR (CDCl3, 400 MHz) δ 8.02 (d, 1H, J=8.3 Hz), 7.81 (s, 1H), 6.88 (d, 1H, J=8.3 Hz), 6.31 (m, 1H), 6.25 (m, 1H), 5.85 (s, 1H), 5.55 (s, 1H), 4.19 (t, 1H, J=7.3 Hz), 3.01 (s, 4H), 3.72 (s, 3H), 3.49 (m, 2H), 3.07-3.15 (m, 4H), 2.91 (m, 2H), 2.76 (m, 1H), 2.38-2.47 (m, 3H), 2.18 (d, 1H, J=9.6 Hz), 1.61 (d, 1H, J=9.3 Hz), 1.48 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH:38][CH:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)NC5CCN(C)CC5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 1-methylpiperidin-4-amine. LCMS (M+H)+=544.1/546.1.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[C:21]([O:25][C:26]([NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([O:25][C:26](=[O:27])[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[CH:5]=[C:4]([Cl:11])[N:3]=2)[CH2:31][CH2:30]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCn1c(Cl)nc(Cl)cc1=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)cc1=O
Yield: 35.9 %

Procedure:
A solution of 2,6-dichloro-3-ethyl-3H-pyrimidin-4-one (320 mg, 1.64 mmol), DIEA (423 mg, 3.28 mmol) and (tert-butoxy)-N-(4-piperidyl)carboxamide (328 mg, 1.64 mmol) in DMF (10 mL) was heated to 120° C. for 1 h. The solvent was concentrated in vacuo and the residue was purified by silica chromatography (1:5, EA:PE) to give 210 mg (36%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.25-1.32 (m 2H), 1.35 (t, J=7.2 Hz, 3H), 1.96-2.02 (m, 2H), 2.98-3.06 (m, 2H), 3.70 (br, 1H), 4.30 (q, J=5.2 Hz, 2H), 4.44 (br, 1H), 4.57-4.61 (m, 2H), 5.95 (s, 1H). [M+H] Calc'd for C16H25ClN4O3, 357, 359. Found, 357, 359.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:42][CH2:43][C:44]1[N:49]([CH2:50][C:51](O)=[O:52])[C:48]2[N:54]=[CH:55][CH:56]=[CH:57][C:47]=2[C:46](=[O:58])[N:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:42][CH2:43][C:44]1[N:49]([CH2:50][C:51]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH:13]2[CH2:14][CH2:15][N:10]([C:2]([CH3:1])([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])[CH2:11][CH2:12]2)=[O:52])[C:48]2[N:54]=[CH:55][CH:56]=[CH:57][C:47]=2[C:46](=[O:58])[N:45]=1
Reactant: CC(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
A mixture of 1-methylethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}-amino)-1-piperidinyl]propanoate (Int. B3) (420 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)-ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (300 mg, 1 equiv), HATU (396 mg, 1.2 equiv), DIPEA (0.22 ml, 1.5 equiv) and DMF (3.0 ml) was stirred at room temperature for 30 min. The crude reaction mixture was applied directly to reverse-phase HPLC (Preparative Method A) to obtain 1-methylethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate (171 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH:37]=[CH2:38]>C(#N)C.O>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[N:27]([CH2:38][CH:37]=[CH2:36])[CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:29]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C=CCN1C2CCC1CC(=C1c3ccccc3Oc3cc(C(=O)N(CC)CC)ccc31)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.3 %

Procedure:
To a sample of compound 10a (0.37 g, 0.95 mmol) in 6 mL acetonitrile was added potassium carbonate (0.53 g, 3.81 mmol) and allyl bromide (80 μL, 0.95 mmol). The mixture was stirred at room temperature for 20 h. The reaction was diluted with water and extracted with CH2Cl2. The combined organic extracts were dried over magnesium sulfate and concentrated. The product was purified by flash column chromatography on silica gel, eluting with 10% 0.5 M NH3 in methanol/CH2Cl2 to yield 0.11 g (0.25 mmol) of Compound 14a. The product was converted into its HCl salt using ethereal hydrogen chloride. MS m/z=429.0 (M+1); 1H NMR 300 MHz (CDCl3) δ 1.1-1.4 (m, 6H), 1.7 (m, 2H), 2.3 (m, 2H), 3.1 (m, 2H), 3.4 (m, 2H), 3.6 (m, 4H), 4.0 (m, 2H), 4.4 (m, 2H), 4.7 (m, 2H), 5.5-5.9 (m, 4H), 6.3 (m, 2H), 7.1-7.4 (m, 7H).
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:4]2=[CH:3][C:2]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27]([N:9]2[CH2:8][CH2:7][CH2:6][N:5]3[N:1]=[C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:4]3[CH2:10]2)=[O:28])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: CCOC(=O)c1cc2n(n1)CCCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cc2n(n1)CCCN(C(=O)c1ccc(-c3ccccn3)s1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (0.033 g, 0.16 mmol) and 5-(2-pyridyl)thiophene-2-carboxylic acid (0.036 g, 0.18 mmol) in methylene chloride (1 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.07 g, 0.184 mmol) and N-methylmorpholine (0.053 mL, 0.48 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with methylene chloride (3 mL) and washed with saturated aqueous NaHCO3 (2 mL). The aqueous layer was extracted with additional methylene chloride (3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford Intermediate 31.