Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[OH:25])[S:17][C:13]=3[CH:12]=2)[CH:2]=1.[CH3:28][S:29](O)(=[O:31])=[O:30]>CCO>[CH3:28][S:29]([O:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:16]1[S:17][C:13]2[CH:12]=[C:11]([CH2:10][N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)[CH:27]=[CH:26][C:14]=2[N:15]=1)(=[O:31])=[O:30]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Reactant: CS(=O)(=O)O
Solvent: CCO
Product: CS(=O)(=O)O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 55 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a suspension of (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (1.84 g, 4.88 mmol) in EtOH (100 mL) was added methanesulfonic acid (478 mg, 4.98 mmol) at rt. The reaction mixture was stirred at 55° C. for 2 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was diluted with 15 mL of water and freeze dried overnight to give (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol methanesulfonate as a tan solid (2.32 g, 100%). 1H NMR (300 MHz, MeOH-d4) δ 8.80 (s, 1H), 8.50 (dd, J=1.1, 4.7 Hz, 1H), 8.15 (dd, J=1.1, 8.1 Hz, 1H), 7.82 (s, 1H), 7.36-7.59 (m, 3H), 5.68 (s, 2H), 3.40-3.65 (m, 2H), 2.71 (s, 3H), 2.06 (d, J=12.2 Hz, 2H), 1.79 (d, J=6.6 Hz, 2H), 1.24-1.55 (m, 4H). LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:27]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 50 g (0.41 mole) of p-hydroxybenzaldehyde, 22.2 g (0.41 mole) of sodium methoxide and 500 ml of dried dimethylformamide was added 114 g (0.41 mole) of 1-bromotetradecane. The mixture was refluxed for 3 hours, then allowed to stand at room temperature overnight after which it was poured into ice-water and extracted with diethyl ether. The ether layer was washed with water, 5% potassium hydroxide, and saline, and dried over sodium sulfate, filtered and evaporated. The residue is recrystallized from hexane to give 4-tetradecycloxybenzaldehyde.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]([OH:13])=[O:12])[NH:8][C:7]=2[CH:14]=1>Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]([OH:13])=[O:12])[NH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2nc(C(=O)O)[nH]c2c1
Agent: Br
Product: O=C(O)c1nc2ccc(O)cc2[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of 26.0 g (105 mmol) of 6-methoxy-1H-benzoimidazole-2-carboxylic acid butilamide and 780 ml of 48% aqueus hydrobromic acid is stirred at 110° C. for 8 h, then refluxed for 12 h. The mixture is cooled to room temperature, the precipitated product is filtered off, washed with water until pH neutral and dried to yield 14.3 g (76.2%) of the title compound. Mp.: 206-207° C. (water).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:6])[CH2:4][CH3:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:19]1([NH:25][C:26]2[CH:35]=[C:34]3[C:29]([C:30](=[O:46])[C:31]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:32][N:33]3[CH:36]([CH2:39]O)[CH2:37][OH:38])=[CH:28][C:27]=2[F:47])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC=CC=1>[CH:19]1([NH:25][C:26]2[CH:35]=[C:34]3[C:29]([C:30](=[O:46])[C:31]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:32][N:33]3[CH:36]3[CH2:37][O:38][C:3]([CH2:4][CH3:5])([CH2:2][CH3:1])[O:6][CH2:39]3)=[CH:28][C:27]=2[F:47])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCC(=O)CC
Reactant: CCOC(=O)c1cn(C(CO)CO)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(C2COC(CC)(CC)OC2)c2cc(NC3CCCCC3)c(F)cc2c1=O

Procedure:
3-Pentanone and p-toluenesulfonic acid monohydrate were added to a benzene solution of ethyl 7-(cyclohexylamino)-6-fluoro-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate, for stirring under reflux under heating for 34 hours, to obtain ethyl 7-(cyclohexylamino)-1-(2,2-diethyl-1,3-dioxan-5-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.C([BH3-])#N.[Na+]>>[F:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH:3][O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: CON=CCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCCc1ccc(F)cc1

Procedure:
Reduction of 4-fluorophenylacetaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (62% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 2.64 (2H, d, J=7.1 Hz, CH2), 2.97 (2H, d, J=7.1 Hz, CH2), 3.53 (3H, s, OCH3), 5.24 (broad, NH), 6.9 (4H, m, aromatics).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:24][N:25]([CH:34]=[O:35])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]([N:16]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[F:41][C:42]1[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=1>CN(C)C=O>[CH:7]1([CH2:12][C@H:13]([CH2:24][N:25]([CH:34]=[O:35])[O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:48][C:45]3[CH:44]=[CH:43][C:42]([F:41])=[CH:47][N:46]=3)=[O:23])[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ccc(F)cn1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
1-Methylimidazole (59.6 μl, 0.747 mmol) was added into the solution of (55)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (150 mg, 0.374 mmol) in N,N-dimethylformamide (DMF) (2.7 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (30.4 μl, 0.392 mmol) was added dropwise at 0° C. To the reaction mixture was added 5-fluoro-2-pyridinamine (46.1 mg, 0.411 mmol). After stirring for 2 h 10 min at ambient temperature, the reaction solution was purified by RP-HPLC to yield (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-(5-fluoro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (104 mg, 0.210 mmol, 56% yield). MS (ES+) m/z 496.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 66.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.063 g, 0.122 mmol) obtained in step 2 and ethanesulfonamide (0.066 g, 0.610 mmol), the title compound (0.049 g, 66%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
The mixture of ethyl 3-chloro-4-[2-(2-methylphenyl)-benzoylamino]benzoate (4.0 g), 1N sodium hydroxide aqueous solution (15 ml) and ethanol (30 ml) was stirred for 5 hours at ambient temperature. Ethanol was removed in vacuo and the residue was washed with diethyl ether and the aqueous layer was acidified with 1N hydrochloric acid and diluted with ethyl acetate. The solution was washed with brine and dried over magnesium sulfate. Filtering and the removal of solvent afforded crude 3-chloro-4 [2-(2-methylphenyl)benzoylamino]benzoic acid (3.1 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:25])[C:17]([CH2:23][CH3:24])=[C:18]([C:21]#[N:22])[C:19]=1I)=[O:14])[CH3:11].C(Cl)Cl.C(N(CC)CC)C>C(#N)C.O>[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:25])[C:17]([CH2:23][CH3:24])=[C:18]([C:21]#[N:22])[C:19]=1[B:4]1[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Reactant: CC1(C)OBOC1(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(B2OC(C)(C)C(C)(C)O2)c(C#N)c(CC)n1C
Reaction time: 3 h

Procedure:
Add 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.87 mL, 6.0 mmol) to 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.0 g, 3.0 mmol, prepared in prepared in Preparation 38), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complex with methylene chloride (1:1) (0.122 g, 0.15 mmol), and triethylamine (1.25 mL, 9.0 mmol) in acetonitrile and heat to reflux. After 3 hours, cool and pour into water. Extract with ethyl acetate. Wash the combined organics with water and brine, dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography (silica gel), eluting with ethyl acetate:hexanes to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 4.33 (q, 2H), 3.84 (s, 3H), 2.80 (q, 2H), 1.40 (s, 12H), 1.46 (t, 3H), 1.22 (t, 3H).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([O-:11])=[O:10])(=O)C.[Na+:12].[OH-].[Na+].CCO>O>[NH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([O-:11])=[O:10].[Na+:12]
Reactant: CC(=O)NCCOCC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCCOCC(=O)[O-]
Temperature: 100 °C

Procedure:
52 g of sodium 5-acetylamino-3-oxapentanoate were dissolved in 200 ml of water. 11.4 g of NaOH were added at 20° C., and the reaction mixture was then heated at 100° C. for 8 h until precursor was no longer detectable. Then 200 ml of EtOH were added and the pH was adjusted to about 6, resulting in pure crystals of sodium 5-amino-3-oxapentanoate. The crude product resulting after removal of the solvent by distillation as a mixture with sodium acetate weighing 63.3 g (corresponding to 100% of theory) could be employed without prior precipitation for the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:24]([NH:27][C:28]([C@@H:30]4[CH2:34][CH2:33][CH2:32][NH:31]4)=[O:29])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:40](O)(=[O:43])[CH:41]=[CH2:42].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:24]([NH:27][C:28]([C@@H:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:40](=[O:43])[CH:41]=[CH2:42])=[O:29])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: C=CC(=O)O
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)N1CCC[C@H]1C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Yield: 9 %

Procedure:
302 mg of (2S)-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-amide as a starting material was dissolved in 10 ml of THF, and cooled to 0° C. The solution was reacted with 0.15 ml of acrylic acid, 0.18 ml of pyridine and 0.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 30 mins and at room temperature for 2 hours. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (31 mg, 9%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7]O)[NH2:6].C(N(CC)CC)C.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[C:17]([N@@:6]1[CH2:7][CH:5]1[C:4]([O:3][CH3:2])=[O:9])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)[C@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1C[N@]1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
200 g of D-serine methyl ester hydrochloride was added to 1.8 L of chloroform, and the reaction solution was cooled to 0° C., to which 448 mL of triethylamine was then slowly added. 358.4 g of trityl chloride was slowly added to the reaction mixture which was then stirred for 1 hour. The reaction mixture was warmed to room temperature, and 1 L of chloroform was added thereto, followed by washing with 2.5 L of water. The organic layer was dried over magnesium sulfate and cooled to 0° C., to which 484 mL of triethylamine and 15.7 g of 4-methylaminopyridine were then sequentially and slowly added. The reaction mixture was stirred for 5 min and 139 mL of methane sulfonyl chloride was slowly added thereto. The reaction mixture was warmed to room temperature, stirred for another 4 hours and then refluxed for 12 hours. The reaction mixture was cooled to room temperature, and washed with 4 L of water and then 3 L of brine. The organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. 3 L of ethanol was added to the resulting residue which was then stirred. The resulting solids were filtered to afford 329 g of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.Br[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:18]=[O:19].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CO.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.C(OCC)(=O)C>[CH:25]1([CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: O=Cc1ccc(OCC2CCCCC2)c(Br)c1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc(OCC2CCCCC2)c(-c2ccc3ccccc3c2)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 32.2 %

Procedure:
A solution of 2-naphthaleneboronic acid (535 mg) in methanol (5.0 ml), Intermediate 25 (1.16 g), and 2 M aqueous sodium carbonate (0.9 ml) were added with toluene (10.0 ml) and tetrakistriphenylphosphinepalladium(0) [hereinafter abbreviated as “(Ph3P)4Pd”] (116 mg, Nakarai Tecs), and stirred at 80° C. for 17 hours. The reaction mixture was added with ethyl acetate (100 ml), and washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=10:1) to obtain the title compound (Compound No. C-1, 345 mg).
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O>N1C=CC=CC=1>[CH:1]1([O:7][CH2:8][CH2:9][O:10][S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOC1C=CCCC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOC2C=CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-(cyclohex-2-enyloxy)ethanol (intermediate BU) (0.3 g) in anhydrous pyridine was added TsCl (1.3 eq). The mixture was stirred at room temperature for 16 h, after which TLC showed the reaction was complete. The mixture was poured into water, extracted with EA, washed with water and brine, and dried with anhydrous Na2SO4. Solvent was removed and the residue purified by column chromatography to obtain intermediate BV (0.3 g).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13](/[CH:14]=[CH:15]/[C:16](OCC)=[O:17])=[C:12]([CH3:21])[N:11]=[C:10]([NH:22][CH2:23][CH3:24])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CC(O)=O>[CH:1]1([N:7]2[C:8]3[N:9]=[C:10]([NH:22][CH2:23][CH3:24])[N:11]=[C:12]([CH3:21])[C:13]=3[CH:14]=[CH:15][C:16]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNc1nc(C)c(/C=C/C(=O)OCC)c(NC2CCCCC2)n1
Solvent: CC(=O)O
Product: CCNc1nc(C)c2ccc(=O)n(C3CCCCC3)c2n1
Temperature: 186 °C
Yield: 37.8 %

Procedure:
(E)-ethyl 3-(4-(cyclohexylamino)-2-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (200 mg, 0.6 mmol) was dissolved in AcOH (2 mL). This solution was heated in a sealed tube at 186° C. for 17 h. Standard workup and purification by column chromatography gave 65 mg (38% yield) of 8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].FC(F)(F)S(O[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=O)=O.N1C(C)=CC=CC=1C>ClCCl>[Si:23]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CON(C)C(=O)[C@H](CCCO)CCC(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)CCC(C)C

Procedure:
A solution of Example 8F (2.58 g, 11.1 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (2.8 mL, 12 mmol), and 2,6-lutidine (1.5 mL, 13 mmol) in dichloromethane (100 mL) at 0° C. was stirred for 2 hours, diluted with dichloromethane, washed sequentially with 10% KHSO4, aqueous NaHCO3, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 346 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([C:8]([OH:10])=[O:9])[NH2:7])[CH2:4][CH2:3][CH2:2]1.Cl[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]>[OH-].[Na+].O1CCOCC1>[CH:15]([O:14][C:12]([NH:7][C@@H:6]([C:8]([OH:10])=[O:9])[CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)OC(=O)Cl
Reactant: N[C@H](CC1CCC1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)OC(=O)N[C@H](CC1CCC1)C(=O)O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
0.57 g (4 mmol) of 3-cyclobutyl-D-alanine is dissolved in 8 ml 1:1 mixture of 1M NaOH solution and dioxane. The mixture is cooled to 0° C. and simultaneously 4 ml of 1M NaOH solution and 4 ml of isopropyl chloroformate (conc. 1M in toluene) solution are added with vigorous stirring. The reaction mixture is stirred for 1 hour at this temperature and for 5 hours at room temperature.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[C:13]([C:22]#[N:23])=[CH:12]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C>C(O)C>[CH:4]1([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[C:13]([C:22]([NH:2][OH:3])=[NH:23])=[CH:12]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1cccc2c(C#N)cn(CC3CCCCC3)c12
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2c(C(=N)NO)cn(CC3CCCCC3)c12
Temperature: 25 °C
Yield: 33.8 %

Procedure:
Hydroxylamine hydrochloride (966 mg, 13.9 mmol) was added to a mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbonitrile (2.48 g, 9.24 mmol), triethylamine (1.41 g, 13.9 mmol), and ethanol (50 ml), then the resulting mixture was stirred at reflux for 20 h. After being cooled to room temperature, the reaction mixture was concentrated in vacuo. The obtained residue was mixed with water (150 ml), adjusted to pH 10 by the addition of aqueous sodium hydroxide and extracted with dichloromethane (4×100 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 10% (v/v) acetone in dichloromethane to give 1-(cyclohexyl)methyl-N-hydroxy-7-methoxy-1H-indole-3-carboxamidine (940 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([CH3:20])=[CH:22][CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: Cc1ccc(CN)cc1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccc(C)cc1
Yield: 83 %

Procedure:
The compound prepared in Example 3 was reacted reacted with 4-methyl-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32]>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[N+:31]([O-:33])=[O:32])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a solution of 4-(benzyloxy)phenol (2.00 g, 10 mmol) in N,n-dimethylformamide (20 ml) was added potassium tert-butoxide (1.12 g, 10 mmol), followed by stirring for 10 minutes. To the reaction solution was added 4-chloro-3-nitroanisole (1.88 g, 10 mmol), followed by stirring at 150° C. for 6 hours. After allowing to stand overnight, the reaction solution was poured into water and extracted with ethyl acetate. After drying subsequent to washing with water and a saturated aqueous sodium chloride solution, the solvent was evaporated under reduced pressure. The resulting crude crystals were recrystallized from ethanol to give 4-[4-(benzyloxy)phenoxy]-3-nitroanisole (2.13 g).