Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24]Cl)[CH2:19][CH2:18]3)[C:10]3=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[C:27]=1[Br:28].[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([CH:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][N:29]4[CH2:34][CH2:33][S:32][CH2:31][CH2:30]4)[CH2:21][CH2:22]3)[C:10]3=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[C:27]=1[Br:28]
Reactant: O=C(CCl)N1CCC(C2c3ccc(Cl)c(Br)c3CCc3cc(Br)cnc32)CC1
Reactant: C1CSCCN1
Solvent: O
Solvent: ClCCl
Product: O=C(CN1CCSCC1)N1CCC(C2c3ccc(Cl)c(Br)c3CCc3cc(Br)cnc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ~0.11 g of 4-[8-Chloro-3,7-dibromo-5,6-dihydro-11H-benzo[5,6 ]cyclohepta[1,2-b]pyridin-11-yl]-1-(chloroacetyl)piperidine in 5 ml of CH2Cl2 is added 0.12 ml of thiomorpholine and the mixture is stirred at ambient temperature for 24 h, and diluted with 20 ml of distilled water. The layers are separated and the aqueous layer is back extracted with 10 ml of CH2Cl2. The combined organic layer is washed once with saturated brine, dried over Mg2SO4, filtered and evaporated to a brown residue. Flash chromatography over 20 g silica gel with 200 ml of 3% MeOH/CH2Cl2 gives 0.12 g of the title compound, yield in two steps is 93.8%. MS: 614.5 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: C1CCCNCC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CN2CCCCCC2)c1
Yield: 70.1 %

Procedure:
To a solution of 3-nitrobenzyl bromide (10.5 g, 48.7 mmol) in methylene chloride is added azepane (5.5 mL, 48.7 mmol) and 20.0 mL (146.1 mmol) of triethylamine, and the reaction solution is heated at 60□C under N2 for 20 minutes. After evaporating to dryness, the resulting brown residue is dissolved in methylene chloride and washed twice with saturated Na2CO3 solution, and once with brine solution. After drying over Mg2SO4, the organic solution is filtered and concentrated to give 8.0 g (70.1% yield) of brown oil.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)COc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc([C@@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)cc1OCC(=O)O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A mixture of 3-(3-ethoxycarbonylmethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester (118 mg, 0.25 mmol), potassium carbonate (68 mg, 0.49 mmol), methanol (10 mL) and water (2 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 110 mg (97%) of (S)-3-(3-carboxymethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:17][N:18]2[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]2)[S:11][C:12]=1[C:13]([O:15]C)=[O:14].O.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:17][N:18]2[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]2)[S:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1sc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1sc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
3.60 g (8.91 mmol) of methyl 4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}-1,3-thiazole-5-carboxylate were dissolved in 18 ml of dioxane and 6 ml of water and 45% strength aqueous sodium hydroxide solution (10.06 mmol) was added dropwise at 0° C. The reaction was stirred for a further hour and warmed to RT. The ethanol was then removed under reduced pressure, and ice-water (10 ml) was added to the residue. The aqueous phase was extracted with ethyl acetate. The organic phase was discarded. Then the aqueous phase was adjusted to a pH of 3 using hydrochloric acid, and again extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over sodium sulphate. (logP: 2.63; MH+: 390; 1H-NMR (400 MHz, DMSO, ppm): 6.65 (s, 2H), 7.36-7.55 (m, 4H).
Reaction SMILES: [CH2:1]([NH2:5])[C:2]([OH:4])=[O:3].C([O-])(O)=O.[Na+].[CH2:11]([C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([NH:29][CH3:30])=[C:20]2[S:25](Cl)(=[O:27])=[O:26])[CH2:12][CH2:13][CH3:14]>O.CC(C)=O>[CH2:11]([C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([NH:29][CH3:30])=[C:20]2[S:25]([NH:5][CH2:1][C:2]([OH:4])=[O:3])(=[O:27])=[O:26])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1cccc2c(S(=O)(=O)Cl)c(NC)ccc12
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCc1cccc2c(S(=O)(=O)NCC(=O)O)c(NC)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two mmoles of L-glycine and 3 mmoles of NaHCO3 were dissolved in 5 ml of water. A solution containing 1 mmol of 3 in acetone was slowly added. More acetone was added until the solution was clear. The mixture was stirred overnight at room temperature, and protected from light. Acetone was removed by flash evaporation and the remaining water solution was acidified to pH=4.5 to 5 by adding 2M citric acid. Then, NaCl was added until saturation and the solution was extracted with three portions of ethyl acetate (20 ml each). The extracts were combined, dried over MgSO4 and solution filtered Solvent was removed and residue purified by liquid chromatography on silica gel. A gradient of 0 to 5% methanol in dichloromethane was used as eluent. Fractions containing desired products were combined and solvents removed. The residue was triturated in 1:1 ether: petroleum ether. Precipitate was filtered out and dried in vacuum overnight thus affording 5-Butylmethylamino-naphtalene-1-sulfonyl-glycine (NST703).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]([CH:16]1[CH2:21][NH:20][C:19]2[CH:22]=[C:23]([O:26][C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:25][C:18]=2[O:17]1)=[O:15].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]([CH:16]1[O:17][C:18]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:22][C:19]=2[NH:20][CH2:21]1)=[O:15]
Reactant: C#CCO
Reactant: Cc1ccc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(C#CCO)c1
Temperature: 75 °C
Yield: 72.8 %

Procedure:
Prop-2-yn-1-ol (195 mg, 202 μL, 3.48 mmol), N-(2-bromo-4-methyl-phenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (300 mg, 0.69 mmol), PdCl2(PPh3)2 (122 mg, 0.17 mmol), CuI (19.88 mg, 0.10 mmol), and triethylamine (970 μL, 6.96 mmol) were combined in DMF (5 mL) and heated at 75° C. for 18 h. Purification by silica gel chromatography (0-50% ethyl acetate/hexanes) provided N-(2-(3-hydroxyprop-1-ynyl)-4-methylphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (204 mg, 72% yield). LC/MS m/z 407.4 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:39][CH:36]([CH3:38])[CH3:37])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: CC(C)N
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNC(C)C)CCC2)c1=O

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268 g) and isopropylamine using a similar method to that described for example 167f.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].C[O-].[Na+].Cl>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC#N
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 95.8 %

Procedure:
In a 200 mL-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 9.2 g (31.6 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 7.5 mL (143 mmol) of acetonitrile, 45 mL of toluene (dielectric constant at 25° C.: 2.38), and 1.99 g (36.8 mmol) of sodium methoxide. The content was reacted at 50° C. for 8 hours. The resulting mixture was chilled in an ice bath. To the chilled mixture were slowly added under stirring 40 mL of toluene and 34.0 mL (34.0 mmol) of hydrochloric acid (1 mol/L), successively. The separated organic portion was taken out. After washing with 30 mL of saturated aqueous sodium chloride solution, the organic portion was dried over anhydrous magnesium sulfate. The organic portion was then filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 9.52 g (yield: 96%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced. The organic portion was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane (15/85, vol. ratio) to obtain 9.29 g (yield 88%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile as a yellow crystalline product (purity: 94%, measured by high performance liquid chromatography).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][C:25]([CH:22]5[CH2:24][CH2:23]5)=[O:26])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Product: O=C(Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2)C1CC1
Yield: 37.2 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (200 mg, 0.72 mmol) and and cyclopropane carboxylic acid (80 mg, 0.93 mmol) according to the procedure described for example 93. Obtained the title compound as a white solid (93 mg, 37%),
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 95.1 %

Procedure:
A mixture of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid tert-butyl ester (13.3 g, 41.5 mmol) cyclohexene (45 mL), ethanol (300 mL) and 10% Pd/C (0.4 g) was stirred at 80° C. for 7 hours. Additional 10% Pd/C was added (0.9 g) and the mixture stirred at 80° C. for additional 4 hours. The reaction mixture was filtered over a celite pad washing thoroughly with ethanol and the filtrate was evaporated to dryness affording the title compound as a pale yellow solid (11.5 g, 95% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([Cl:30])=[N:18][C:17]=3[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:34]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[N:20][C:19]([Cl:30])=[N:18][C:17]=3[CH:16]=2)([O:14][CH3:34])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (335 mg) in DMF (3 ml) was added sodium hydride (60% w/w suspension in mineral oil, 41 mg) at 0° C. After 30 min, iodomethane (56 ul) was added and the reaction mixture was warmed slowly to room temperature overnight. Ethyl acetate/brine extraction and purification on silica afforded 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (219 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16](C)([CH3:18])[CH3:17]>ClCCl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:15](=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
EX-5A) A solution of 2-amino pyridine (20.42 , 217.0 mmol) in dichloromethane 500 mL was cooled to 0° C. and treated with triethyl amine (36.29 mL, 260.4 mmol) and pivaloyl chloride (28.06 mL, 227.8 mmol). After 15 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was poured onto ice, and the organic layer was washed with saturated NaHCO3 (aq), and dried over Na2SO4. The volatile components were removed, and a brown oil was isolated. Crystallization with hexanes afforded 31 g of N-(pyrid-2-yl)-2,2-dimethylacetamide (EX-5A) as white crystals in 80% yield. Reference: Turner, J. A. J. Org. Chem, 1983, 48, 3401.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20](O)=[O:21])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.B.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:19][CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1(CC(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-ethoxycarbonyl-piperidin-4-ylacetic acid (2.34 g) in tetrahydrofuran (60 ml) was added a 1M borane tetrahydrofuran solution (7.42 ml) at −78° C., and the mixture was allowed to warm to room temperature in 15 hours in stirring. After completion of the reaction, water and potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour. Water was added and the mixture was washed with hexane. The aqueous layer was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (1.92 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([F:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([F:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(C)cc(F)c3)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(C)cc(F)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Yield: 71.1 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea (197 mg, 0.319 mmol) and anisole (172 mg, 1.594 mmol) was stirred in TFA (4 mL) at RT for 3 h. The mixture was concentrated to near-dryness, treated with EtOAc and satd. NaHCO3 and the resulting solid collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea (113 mg, 71% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.18 (br s, 1H), 8.80 (br s, 1H), 8.41 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.73 (s, 1H), 7.52 (d, J=10.8 Hz, 1H), 7.22 (d, J=11.5 Hz, 1H), 7.03 (br s, 1H), 6.92 (s, 1H), 6.67-6.59 (m, 1H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.86 (s, 3H), 2.25 (s, 3H), 1.21 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 498.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:22]([C:2]1[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1)=[O:25]
Reactant: Cc1cc(Oc2ccc(C#N)cc2)nc2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2ccc(C#N)cc2)nc2cc(-c3ccccc3C=O)ccc12

Procedure:
Prepared analogously to Example 27e from 4-[(7-bromo-4-methyl-quinolin-2-yl)oxy]-benzonitrile, 2-formylbenzeneboric acid, sodium carbonate and tetrakis-(triphenylphosphine)-palladium (0) in toluene/water.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:24])[N:3]=1.B([C:28]1[CH:39]=[CH:38][C:31]([CH2:32][C@@H:33]([C:35]([OH:37])=[O:36])[NH2:34])=[CH:30][CH:29]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:34][CH:33]([CH2:32][C:31]1[CH:38]=[CH:39][C:28]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:24])[N:3]=2)=[CH:29][CH:30]=1)[C:35]([OH:37])=[O:36]
Reactant: Nc1nc(Cl)cc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)n1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1nc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)cc(-c2ccc(CC(N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 11.2 %

Procedure:
In a microwave vial, 4-chloro-2-amino-6-[1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml of acetonitrile, 0.7 ml of water. 0.3 ml of 1N aqueous sodium carbonate was added to above solution followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 5.6 mg of 2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-trifluoromethylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ 7.96 (m, 3H), 7.80 (d, J=8.06 Hz, 1H), 7.74 (t, J=7.91 Hz 1H), 7.63 (t, J=8.06 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.21 (m, 1H), 6.69 (s, 1H), 3.87 (m, 1H), 3.34 (m, 1H), 3.08 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH2:11][CH2:10]1
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1ccccc1N1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)CCCCCBr)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
To a stirred mixture of 1-(2-methoxyphenyl)piperazine (21.34 mmol) and pyridine (25.6 mmol) in 60 mL of dry dichloromethane was added dropwise a solution of 6-bromohexanoyl chloride (23.52 mmol) in 20 mL of dichloromethane at 0° C. under nitrogen. After addition, the mixture was allowed to warm to room temperature and stirred for 1-2 hours. The mixture was quenched with 10% potassium carbonate in water, and extracted with dichloromethane. The organic phase was washed with brine and water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 5% methanol, 0.5% ammonium hydroxide in ethyl acetate to give 1-(2-methoxyphenyl)-4-(6-bromohexanoyl)piperazine (6.00 g, 76%).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH2:16][CH2:17][NH2:18])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>C(Cl)Cl>[C:30]([O:29][C:27]([NH:18][CH2:17][CH2:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][C:5]3[NH:1][N:2]=[N:3][N:4]=3)[CH:8]=2)[NH:12][CH:11]=1)=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCc1c[nH]c2ccc(Cc3nnn[nH]3)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(Cc3nnn[nH]3)cc12
Reaction time: 16 h
Yield: 64.3 %

Procedure:
To a stirred suspension of 2-(5-tetrazol-5-ylmethyl-1H-indol-3-yl)ethylamine (1.76 g, 7.27 mmol) in dry CH2Cl2 (40 ml) was added triethylamine (1.5 g, 14.9 mmol) and (BOC)2O (1.9 g, 7.3 mmol) and the mixture stirred for 16 h. The solvent was removed under vacuum and the residue chromatographed on silica-gel eluting with EtOH/Et2O/H2O/NH3 (20:60:8:1) to give the title product (1.6 g, 64%); δ (360 MHz, CD3OD) 1.41 (9H, s, 3 of CH3); 2.87 (2H, t, J=7.4 Hz, CH2); 3.30 (2H, t, J=7.4 Hz, CH2); 4.32 (2H, s, CH2); 6.99 (1H, d, J=8.3 Hz, Ar--H); 7.04 (1H, s, Ar--H); 7.26 (1H, d, J=8.3 Hz, Ar--H); 7.49 (1H, s, Ar--H).