Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:8][CH:7]=[CH:6][C:5]=1[OH:20])[CH2:2][CH3:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>OP(O)(O)=O.O.CCOCC>[C:14]1([C:12]2[C:8]3[CH:7]=[CH:6][C:5]([OH:20])=[C:4]([CH2:1][CH2:2][CH3:3])[C:9]=3[O:10][CH:11]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCc1c(O)cccc1OCC(=O)c1ccccc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOCC
Solvent: O
Product: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 2-propyl-3-(2-phenyl-2-oxoethoxy)phenol (9.30 g) in o-phosphoric acid(85%) (93 mL) at room temperature was added over a 45 minutes period phosphorus pentoxide(46.50 g). During this period the reaction mixture was heated several times with a heat gun. After stirring the mixture for 30 minutes the reaction was checked by TLC(to take a little of sample with a capillary and dissolve sample in water and add several drops of ether; elution: 50% methylene chloride in hexane). The reaction mixture was heated again with heat gun if the reaction was not complete. The reaction mixture continued to be stirred for 20 minutes, then was poured into a beaker containing ice. The reaction flask was then rinsed with water and ether, and the washings were added to the beaker. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. Column Chromatography (silica gel 60, 50% methylene chloride in hexane) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCN(C[C@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 219 was synthesized using 9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=76-77° C.; 400 MHz 1H NMR (CDCl3) δ: 8.08 (dd, J=8.6, 5.9 Hz, 1H), 7.37 (dd, J=9.4, 2.7 Hz, 1H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 3H), 7.14 (td, J=8.2, 2.7 Hz, 1H), 4.04-3.95 (m, 1H), 2.98-2.82 (m, 2H), 2.93 (s, 2H), 2.79-2.66 (m, 3H), 2.54-2.37 (m, 3H), 2.16-2.08 (m, 2H), 1.97-1.80 (m, 2H); LCMS: 454 [M+H].
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:16]>CN(C)C=O.O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: C=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(COC1CCN(C(C)=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
N-Acetyl-4-hydroxypiperidine (13.6 g.) in dimethylformamide (50 ml.) was added dropwise to a stirred suspension of sodium hydride (10 g. 50% dispersion in mineral oil) in dimethylformamide (50 ml.) under nitrogen. The mixture was stirred at room temperature for 3 hours then α-(bromomethyl)styrene (20 g.) in dimethylformamide (50 ml.) was added dropwise. The mixture was stirred at room temperature for 4 hours, then diluted with water and extracted with chloroform (3×200 ml.). The combined chloroform extracts were dried (Na2SO4), evaporated in vacuo, and distilled to give N-acetyl-4-(2-phenylallyloxy)piperidine (25 g.), b.p. 170°-180° C./0.3 mm. with an n.m.r. spectrum in accordance with this structure.
Reaction SMILES: [CH2:1]1[CH:6]=[CH:5][O:4][CH:3]([CH:7]=O)[CH2:2]1.[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>C(O)C>[CH3:10][C:9]([N:13]=[CH:7][CH:3]1[CH2:2][CH2:1][CH:6]=[CH:5][O:4]1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)N
Reactant: O=CC1CCC=CO1
Solvent: CCO
Product: CC(C)(C)N=CC1CCC=CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 323.0 g of acrolein dimer in 230 ml of anhydrous ethanol was added dropwise to a solution of 251 ml of t-butylamine in 250 ml of anhydrous ethanol at 25° C. over 2 hours. The reaction mixture was stirred at room temperature overnight. The solvents were stripped off on a rotary evaporator to leave 295.5 g of a yellow oil. This oil was vacuum distilled at 8 mm Hg to give 223 g of a colorless oil at 63°-67° C. and four fractions of colorless oil were collected as follows: 2.82 g at 45°-63° C., 181.27 g at 63°-66° C., 42.42 g at 66°-67° C. and 37.09 g at 67°-70° C., and were a mixture of isomers of the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:34])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([Br:33])[C:21]4[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CCO.Cl>C1COCC1>[Br:33][C:20]1[C:21]2[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=2[CH:32]=[C:18]([C:15]2[CH:16]=[N:17][C:12]([N:9]3[CH2:8][CH2:7][C:6]([CH3:34])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)=[N:13][CH:14]=2)[CH:19]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(Br)c2s1
Temperature: 70 °C
Reaction time: 6 h
Yield: 33.7 %

Procedure:
1-{5-[7-Bromo-2-(3-ethyl-ureido)-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid ethyl ester (50 mg) was dissolved in THF (1 mL) and 1 M aq NaOH (1 mL) added. The mixture was heated to 70° C. overnight. LCMS showed approx 50% conversion to product. EtOH (0.5 mL) was added and heating continued for a further 6 h. The mixture was acidified to pH 3 with 1 M HCl (aq) and concentrated under reduced pressure. The mixture was suspended in ˜10% MeOH in DCM and filtered through a syringe filter. The filtrate was concentrated in vacuo to give the desired product as an off-white solid (16 mg) which was used in the next step with no further purification. m/z: 519/521 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH:29]=C)[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl.C[OH:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH2:29][OH:40])[C:14]3=[O:31])=[CH:11][CH:12]=2)=[CH:32][CH:33]=1
Reactant: C=CC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1[C@@H](CCO)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (56 mg, 0.119 mmol) is dissolved in 3 mL of a 2:1 mixture of CH2Cl2-MeOH and is cooled to −78° C. Ozone is bubbled through the solution until a blue color persisted and then nitrogen is bubbled through until it is clear. NaBH4 (2.5 eq) is added and the reaction mixture is allowed to warm to room temperature. The mixture is stirred for 2 h, and then most of the solvent is removed by evaporation in vacuo. Water is added (10 mL) and the aqueous layer is extracted with ethyl acetate (5×10 mL). The combined extracts are washed with brine (10 mL), dried over Na2SO4, filtered and evaporated. The residue is purified on silica gel (0-55% ethyl acetate in hexane) to give (3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(2-hydroxyethyl)pyrrolidin-2-one (51 mg, 89%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.51-7.46 (m, 1H), 7.44-7.37 (m, 2H), 7.36-7.30 (m, 3H), 7.21-7.16 (m, 2H), 6.87-6.78 (m, 4H), 5.21 (dd, J=10.5, 2.0 Hz, 1H), 3.85-3.68 (m, 2H), 2.97-2.85 (m, 1H), 2.45-2.32 (m, 1H), 2.26-2.15 (m, 2H), 2.10-1.98 (m, 1H), 1.80-1.69 (m, 1H). HPLC-MS calculated for C25H21ClF3NO3 (M+H+) 476.12, found 476.10.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([NH:33][C:34]([CH3:41])([CH2:39][OH:40])[C:35]([O:37][CH3:38])=[O:36])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:23]([O:30][C:31]([NH:33][C:34]([CH3:41])([CH:39]=[O:40])[C:35]([O:37][CH3:38])=[O:36])=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(C)(CO)NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)(C=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of 97.7 mg (0.23 mmol) of Dess Martin periodinane reagent (Aldrich) in 1 ml of DCM is slowly added dropwise to a solution of 56 mg (0.21 mmol) of methyl 2-benzyloxycarbonylamino-3-hydroxy-2-methylpropionate in 1 ml of DCM, and the mixture is left to stir at room temperature for 30 min. 5 ml of diethyl ether and a mixture of 4 ml of saturated NaHCO3 and 0.36 g of Na2S2O3.5H2O are then added to the solution. It is stirred for 15 min until the solid has dissolved, and then the ether phase is washed with saturated NaHCO3 and water, dried over MgSO4 and concentrated in vacuo. The crude product is purified by chromatography on 4 g of SiO2 with EtOAc/heptane (gradient 0-50%). 40 mg of the desired aldehyde are obtained.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH2:28][C:29]([NH2:31])=[O:30].[Na].CC(C)=O>C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:28][C:29]([NH2:31])=[O:30])=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: NC(N)=O
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NC(N)=O)cc1

Procedure:
The 12.6 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride in methylene chloride is added to 5 g. of sodium urea in 30 ml. of acetone and the mixture is stirred at 20° C. for 18 hours. Dilute alkali is added and the solid washed with alkaline aqueous acetone. Recrystallization from ethanol gives pure white crystals of product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:7][C:8]([C:11]([OH:13])=O)=[N:9][N:10]=1.[NH2:14][C:15]([CH3:32])([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([CH3:30])[CH:23]=2)=[N:18]1>>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C:15]([NH:14][C:11]([C:8]3[NH:9][N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[O:13])([CH3:31])[CH3:32])[N:18]=2)=[CH:23][C:24]=1[CH3:30])#[N:27]
Reactant: O=C(O)C1=NN=C(c2ccco2)C1
Reactant: Cc1cc(-c2ccn(CC(C)(C)N)n2)ccc1C#N
Product: Cc1cc(-c2ccn(CC(C)(C)NC(=O)c3cc(-c4ccco4)n[nH]3)n2)ccc1C#N

Procedure:
The title compound was prepared using the method of Example 54 but starting from 5-(2-furyl)-4H-pyrazole-3-carboxylic acid (56 mg; 0.32 mmol) and 4-(1-(2-amino-2-methylpropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (80 mg; 0.32 mmol). Crude product was purified by chromatography (CombiFlash, silica-C18 column, eluent: 0-100% ACN/water) to obtain 16 mg of the product which was further purified by preparative HPLC (Waters Deltaprep 4000, SymmPrep 56.2, 25-80% ACN/AcONH4) to obtain 5.3 mg of he title compound. 1H-NMR (400 MHz; d1-CDCl3): δ 1.52 (s, 6H), 2.54 (s, 3H), 4.50 (s, 2H), 6.52 (dd, 1H), 6.57 (d, 1H), 6.64 (d, 1H), 6.90 (s, 1H), 7.44 (d, 1H), 7.48 (d, 1H), 7.59 (d, 1H), 7.70 (dd, 1H), 7.75 (d, 1H), 10.31 (broad s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.S(Cl)([Cl:16])(=O)=O>C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[C:3]=1[Cl:16]
Reactant: Cc1nc2cc(Cl)c(N)cc2o1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1nc2cc(Cl)c(N)c(Cl)c2o1

Procedure:
6-Amino-5-chloro-2-methylbenzoxazole (10 g, 54.76 mMole) was dissolved in ethyl acetate (150 mL). At room temperature and with good stirring, sulfuryl chloride (8.8 mL, 109.52 mMole) was added drop by drop over a 20-minute period. As the addition proceeds, additional ethyl acetate (350 mL) was added to keep the mixture stirring. After 1 hour the precipitate was filtered off, washed with ether and air-dried. Yield 10.5 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O:22]CC)=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.O.[Li+:26].[OH-]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+:26]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.239 g, 0.719 mmol) in THF (3 mL) was added H2O followed by LiOH (0.0344 g, 1.44 mmol) and the reaction was stirred at ambient temperature overnight. The reaction was transferred to a sealed tube and heated to 100° C. for 8 hours. The reaction mixture was concentrated providing 0.230 g of the crude desired product as a pale yellow foam, which was used directly in the subsequent step.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[N:24]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][N:21]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:24]3[C:20]([CH3:19])=[N:21][CH:22]=[N:23]3)=[CH:33][CH:32]=2)[CH2:2][CH2:3]1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4ncnc4C)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.77 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:33]1([CH2:39][C:40](Cl)=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:40](=[O:41])[CH2:39][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(Cl)CC1CCCCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)CC5CCCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 47.5 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and cyclohexyl acetyl chloride (39 mL, 0.690 mmol) gave 2-{5-[4-(2-cyclohexyl acetyl)-piperazin-1-yl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (61 mg, 47%). MS(ESI) m/z 559.4 (M+H)+
Reaction SMILES: C(O)C.[OH-].[K+].[NH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([OH:25])=[C:17]([C:26](OC2C=CC=CC=2)=[O:27])[CH:16]=1)([O-:14])=[O:13]>O>[C:9]([CH2:8][CH2:7][NH:6][C:26]([C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[OH:25])=[O:27])([OH:11])=[O:10]
Reactant: O=C(Oc1ccccc1)c1cc([N+](=O)[O-])c2ccccc2c1O
Reactant: NCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCNC(=O)c1cc([N+](=O)[O-])c2ccccc2c1O
Yield: 70 %

Procedure:
1,500 ml of ethanol was added to a solution of 56.8 g of potassium hydroxide dissolved in 100 cc of water. 47 g of β-alanine was dissolved into this mixture, and then 132 g of 4-nitro-2-phenoxycarbonyl-1-naphthol was suspended, followed by reflux for 4 hours. After the reaction was completed, the solution was cooled, followed, by filtration of crystal. The obtained crystal was dissolved in 4,000 ml of water. After the insolubles were filtered off, the aqueous solution was neutralized with hydrochloric acid to give yellow crystals. Recrystallization from 5,000 ml of ethanol gave the desired product at a yield of 70%.
Reaction SMILES: [CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][CH:8]1[OH:36])=[O:6])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.O>ClCCl>[CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][C:8]1=[O:36])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)C1c2cc(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc2CC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)C1C(=O)Cc2cc(Cl)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)cc21
Reaction time: 10 h

Procedure:
A solution of 5-chloro-2-hydroxy-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indane carboxylic acid isopropylamide (230 mg, 0.35 mmol) in dichloromethane is treated with pyridinium chlorochromate (29 mg, 1.0 mmol), stirred for 10 hours, and treated with water. Organic layer is separated, dried over sodium sulfate, filtered, and evaporated. Purification by chromatography using ethyl acetate/hexane as eluent gives 5-chloro-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indan-2-one carboxylic acid isopropylamide as solid; LC/MS: 540/542 (M+1)+; m.p.: 198-199° C.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:30][OH:31]>>[CH3:13][C:12]1[C:7]([NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[CH2:30][OH:31])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: N[C@H]1CCCC[C@H]1CO
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(N[C@H]2CCCC[C@H]2CO)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using rac-[(1R,2S)-2-aminocyclohexyl]methanol instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, methanol-d6) δ ppm 1.35 (bs, 2H), 1.50 (bs, 6H), 1.89 (bs, 3H), 2.20 (bs, 3H), 3.40-3.48 (m, 1H), 3.60-3.68 (m, 1H), 4.10-4.18 (m, 1H), 4.64 (bs, 2H), 7.26 (t, J=5.64 Hz, 1H), 7.40 (d, J=8.06 Hz, 1H), 7.75 (d, J=7.79 Hz, 1H), 8.46 (d, J=4.83, 1H); MS (ESI) m/z 342.8 (M+1)+.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:9]2[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[CH3:29])=[N:4][N:3]=[N:2]1.[OH-:30].[Na+].OO>CS(C)=O.O>[NH:4]1[C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[C:9]2[C:21]2[CH:28]=[CH:27][C:24]([C:25]([NH2:26])=[O:30])=[CH:23][C:22]=2[CH3:29])=[N:1][N:2]=[N:3]1
Reactant: [OH-]
Reactant: COc1ccc(-c2ccn(CCc3nnn[nH]3)c2-c2ccc(C#N)cc2C)cc1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2ccn(CCc3nnn[nH]3)c2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.2 %

Procedure:
To a solution of 4-(1-(2-(1H-tetrazol-5-yl)ethyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzonitrile (9J, R=2-(1H-tetrazol-5-yl)ethyl) (250 mg, 0.65 mmol) in DMSO (5 mL) was added a solution of NaOH (52 mg, 1.3 mmol) in a mixture of water (0.5 mL) and H2O2 (74 mg, 0.65 mmol). After being stirred at room temperature for 4 hours, the mixture was purified by preparative HPLC to give 24 mg of 4-(1-(2-(1H-tetrazol-5-yl)ethyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide (9K, R=2-(1H-tetrazol-5-yl)ethyl) (yield 9% in two steps) as a grey solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)=O)[CH3:2].C([O-])(=O)C.[NH4+].[BH3-]C#[N:28].[Na+]>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[NH2:28])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCN(CC)CC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: CCN(CC)CC(N)c1cc(OC)c(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 21 react 2-diethylamino-1-(3,4,5-trimethoxyphenyl)ethanone with ammonium acetate and NaCNBH3 to obtain the title compound.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[N:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C>ClCCl>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Nc1cnc2cccnc2c1O
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1cnc2cccnc2c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
A solution of valeryl chloride (4.4 mL, 37 mmol) in dichloromethane (25 mL) was added dropwise to a stirred suspension of 3-amino[1,5]naphthyridin-4-ol (5.0 g, 31 mmol) and triethylamine (6.6 mL, 47 mmol) in dichloromethane (100 mL), and the reaction was stirred for three days at room temperature. An analysis by LC/MS indicated the reaction was complete after 1.5 hours. The volatiles were removed under reduced pressure, and the residue was stirred with water (100 mL) for 15 minutes. The resulting solid was isolated by filtration and washed with water (100 mL) and diethyl ether (4×50 mL) to provide 5.35 g of N-(4-hydroxy[1,5]naphthyridin-3-yl)pentanamide.