Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][C:16]([C:17](=[O:19])[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:15]([Cl:26])[C:16]([C:17](=[O:19])[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)cc(C(N)=O)c2C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(c(C(N)=O)c(Cl)c2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
A solution of 8-carbamoyl-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (8.0 g, Reference Example 3) in dichloromethane (300 mL) was treated with N-chlorosuccinimide (3.12 g). After stirring at room temperature for a further 16 hours the reaction mixture was washed four times with water (50 mL) and then once with brine (50 mL). The organic phase was then dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of ethyl acetate and pentane (3:7, v/v) to give the title compound (4.3 g) as a white solid, m.p. 183–185° C. 1H NMR [(CD3)2SO]: δ 7.52–7.40 (m, 5H), 7.30 (bs, 1H), 6.80 (bs, 1H), 4.81 (s, 2H), 3.82 (t, 2H), 3.66 (t, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:9]([CH:10]([OH:26])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]([Cl:24])[C:12]=2[Cl:25])=[CH:8][CH:7]=[N:6]1)[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:24][C:13]1[C:12]([Cl:25])=[C:11]([C:10]([C:9]2[N:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]=[CH:7][CH:8]=2)=[O:26])[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOCn1nccc1C(O)c1ccc(OCC(=O)OCC)c(Cl)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOCn1nccc1C(=O)c1ccc(OCC(=O)OCC)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
770 mg of α-(1-ethoxymethyl-5-pyrazolyl)-2,3-dichloro-4-ethoxycarbonylmethoxybenzylalcohol and 1.66 g of manganese dioxide are suspended in 30 ml of methylene chloride, and the suspension is stirred at room temperature for 24 hours. The reaction mixture is filtered and the filtrate is evaporated to remove solvent. The residue is triturated with a mixture of isopropyl ether and hexane to give 703 mg of ethyl [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetate as crystals.
Reaction SMILES: C(CO[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=1)#N.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>O>[CH2:32]([N:34]([CH2:35][CH3:36])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:8][N:7]=1)[CH3:33]
Reactant: CCNCC
Reactant: N#CCOC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Heat at reflux for 6 hours a mixture of 0.1 mole of cyanomethyl-5-(triphenylmethyl)-picolinate and 0.5 moles of diethylamine. Cool the reaction mixture, pour into water and extract with chloroform. Dry the chloroform layer over anhydrous sodium sulfate and evaporate to obtain thereby the product of this example.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].CN(C)C=O>O>[O:23]=[C:21]1[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](=[O:28])[N:22]1[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCOP(=O)(Cc1ccccc1CBr)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccccc1CN1C(=O)c2ccccc2C1=O)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.1 %

Procedure:
A mixture of diethyl [2-(bromomethyl)benzyl]phosphonate (11.2 g), potassium phthalimide (6.46 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was ashed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave diethyl {2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzyl}phosphonate (11.3 g, 83%) as colorless prism crystals. melting point: 91-92° C.
Reaction SMILES: C.Cl[C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH:11]([OH:13])[CH3:12])[C:6]([N+:14]([O-:16])=[O:15])=[C:5]([NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:4]=1.C(O)C.C(N(CC)CC)C>[Pd].C(O)=O>[OH:13][CH:11]([CH3:12])[CH2:10][NH:9][C:7]1[CH:8]=[CH:3][CH:4]=[C:5]([NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(O)CNc1cc(Cl)cc(NCC(C)O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(O)CNc1cccc(NCC(C)O)c1[N+](=O)[O-]

Procedure:
340 mg of palladium at a concentration of 10% on active charcoal are added to 0.07 mole (21.3 g) of 4-chloro-2-(β-hydroxypropyl)amino-6-(β-hydroxypropyl)aminonitrobenzene in 30 ml of 96° ethanol and 29.2 ml of triethylamine, after which 5.8 ml of formic acid are run in dropwise.
Reaction SMILES: [CH2:1]([C:4]([CH:13]([C:26]1[CH:31]=[CH:30][C:29](OC)=[CH:28][CH:27]=1)[CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:25])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7]C)=O)[CH:2]=[CH2:3].C[O-].[Na+].CN(C)[CH:39]=[O:40].Cl>CO>[CH3:12][O:11][C:9]([C:4]1([CH2:1][CH:2]=[CH2:3])[CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:40][CH3:39])[CH2:14][C:15]2[C:20]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:25][C:5]1=[O:7])=[O:10]
Reactant: CN(C)C=O
Reactant: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1c(N)cccc1C(F)(F)F)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCC1(C(=O)OC)C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccccc1OC

Procedure:
α-(2-Propenyl)-[2-(2-amino-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (9.03 g; 19.4 mmole) and a 25% (by weight) sodium methoxide in methanol solution (20.5 ml; 89.5 mmole; d=0.945; 4.6 eq.) in methanol (100 ml) and dry dimethylformamide (100 ml) were refluxed (~95° C. for four hours. 1N Hydrochloric acid was added with stirring, producing a precipitate that was collected by suction-filtration, washed with water (three times) and dried in vacuo giving ~10 g of the title compound as a solid. The "crude" material was used "as is".
Reaction SMILES: [CH2:1](Br)[C:2]#[C:3][CH3:4].[F:6][CH:7]([F:18])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[O:8][CH:7]([F:6])[F:18])[CH:13]=[O:14])[C:2]#[C:3][CH3:4]
Reactant: CC#CCBr
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#CCOc1cc(C=O)ccc1OC(F)F
Yield: 95.9 %

Procedure:
But-2-ynyl bromide (0.29 mL, 3.4 mmol) was added to a suspension of 4-difluoromethoxy-3-hydroxybenzaldehyde (0.43 g, 2.3 mmol) and potassium carbonate (0.95 g, 6.9 mmol) in acetonitrile (5 mL). The suspension was heated to reflux for 16 h and then concentrated under reduced pressure. Water was added and the aqueous phase was extracted with EtOAc. The combined organic fractions were washed with water, brine, dried. The product was concentrated under reduced pressure providing 3-(but-2-ynyloxy)-4-difluoromethoxybenzaldehyde (0.53 g, 97%) as a yellow crystalline solid; mp 46-47° C.; δH (500 MHz, CDCl3) 1.86 (t, J=2.5 Hz, 3H, C≡CCH3), 4.81 (q, J=2.5 Hz, 2H, OCH2), 6.68 (t, J=72.0 Hz, 1H, CHF2), 7.33 (d, J5,6=8.0 Hz, 1H, H5), 7.50 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.63 (d, J2,6=2.0 Hz, 1H, H2), 9.96 (s, 1H, CHO); δC (125 MHz, CDCl3) 3.7, 57.5, 72.7, 85.3, 113.4, 115.6 (t, J=256 Hz), 121.8, 125.1, 134.4, 145.3, 149.7, 190.7; νmax 1123, 1268, 1435, 1505, 1597, 1698, 2858 cm−1.
Reaction SMILES: OC1C=CC([N+]([O-])=O)=C(C=1)C#N.[OH:13][C:14]1[CH:15]=[CH:16][C:17]([N+]([O-])=O)=[C:18]([CH:21]=1)[CH:19]=[O:20]>>[OH:13][C:14]1[CH:21]=[C:18]([CH:17]=[CH:16][CH:15]=1)[CH:19]=[O:20]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: N#Cc1cc(O)ccc1[N+](=O)[O-]
Product: O=Cc1cccc(O)c1
Yield: 34 %

Procedure:
For example, in Case No. 9 of the above table, the yield of the para nitro isomer (4-nitro isomer), i.e., 5-hydroxy-2-nitrobenzonitrile, is 32.5%, and in Case No. 10 the yield of the para nitro isomer, i.e., 5-hydroxy-2-nitrobenzaldehyde, is 38.47%. Studies have been done in order to separate a single objective nitrated product from such an isomeric mixture. For example, Hornig reported that 5-hydroxy-2-nitrobenzaldehyde in purified form was obtained in 34% yield by recrystallization from water after direct nitration of 3-hydroxybenzaldehyde in benzene. The present inventors followed this procedure, but could not achieve the objective of obtaining the pure product in such a high yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:13][C@H:10]([C:8]2[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]3[CH:21]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11][CH3:12])[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]propylamine (88 mg, 0.32 mmol), 4-amino-6-chloro-5-cyanopyrimidine (49 mg, 0.32 mmol) and DIPEA (0.11 mL, 0.64 mmol) in IPA (1 mL) was heated for 5.5 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% 2M NH3/MeOH in EtOAc) to afford 350 as a pale yellow solid (83 mg, 64%). LCMS (Method K): RT 3.67 min [M+H]+ 407.0. 1H NMR (CDCl3, 400 MHz): δ 8.68 (1H, d, J=2.7 Hz), 8.60 (1H, br s), 8.01 (1H, s), 7.70 (1H, dd, J=9.0, 4.9 Hz), 7.67 (1H, br s), 7.06 (1H, app. td, J=9.2, 2.4 Hz), 6.79 (1H, dd, J=8.3, 2.4 Hz), 6.00 (1H, d, J=8.0 Hz), 5.40 (2H, s), 5.31 (1H, dt, J=8.0, 7.3 Hz), 2.05 (1H, dqd, J=14.7, 7.4, 7.3 Hz), 1.97 (1H, dqd, J=14.7, 7.4, 7.3 Hz), 0.86 (3H, t, J=7.4 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(OCC1C=CC=CC=1)=O.O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:26][C:25]1[C:3]2[C:2](=[CH:24][CH:23]=[CH:22][C:4]=2[O:5][CH2:6][C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OC[C@H]1CCCN1C(=O)OCc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3)c2c1N

Procedure:
Prepared as in Example 2a from (R)-benzyl 2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate (Example 92c) and ethyl 3-oxobutanoate as brown solid. MS 330 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])[C:15](O)=[O:16].O.Cl>C1COCC1>[OH:16][CH2:15][CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([CH3:28])([CH3:27])[CH2:8][OH:7]
Reactant: CC(C)(CO)CCCCC(CCCCC(C)(C)CO)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)CCCCC(CO)CCCCC(C)(C)CO
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Under nitrogen atmosphere, to a solution of lithium aluminum hydride (1.09 g, 28.8 mmol) in anhydrous THF (100 mL) was added dropwise a solution of 8-hydroxy-2-(6-hydroxy-5,5-dimethylhexyl)-7,7-dimethyloctanoic acid (3.64 g, 11.5 mmol) in THF (40 mL) at room temperature. The reaction mixture was heated at reflux for 5 h and kept at room temperature overnight. Water (100 mL) was added carefully to the reaction mixture under cooling with a water bath. The pH was adjusted to 1 with 2 N hydrochloric acid. The product was extracted with diethyl ether (3×60 mL). The combined organic layers were washed with water (2×50 mL) and brine (50 mL). The ethereal solution was dried over sodium sulfate and concentrated in vacuo to furnish the crude product (3.2 g), which was purified by chromatography on silica (hexanes:ethyl acetate=50:50) to yield 7-hydroxymethyl-2,2,12,12-tetramethyltridecane-1,13-diol (3.0 g, 86%) as a yellow oil. 1H NMR (300 MHz, CD3OD/TMS): δ (ppm): 4.88 (s, 3H), 3.44 (d, 2H, J=4.8 Hz), 3.23 (s, 4H), 1.5-1.1 (m, 17H), 0.85 (s, 12H). 13C NMR (75 MHz, CD3OD/TMS): δ (ppm): 72.0, 65.7, 41.7, 40.0, 36.0, 32.2, 29.0, 25.4, 24.7, 24.6. HRMS (LSIMS, gly): Calcd. for C18H39O3 (MH+): 303.2899. found 303.2901. HPLC: 94.6% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: COC(=O)CBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(Br)ccc2o1
Reaction time: 15 h
Yield: 34.2 %

Procedure:
To a stirred solution of 5-bromo-2-hydroxybenzaldehyde (14a, 1.5 g, 7.46 mmol) in DMF (20 mL), was added methyl bromoacetate (8.21 mmol, 0.78 mL) and potassium carbonate (4.12 g, 29.84 mmol). The reaction mixture was heated at 80° and stirred for 15 hours, quenched with water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic phase was dried with sodium sulfate, concentrated and the residue was purified by flash chromatography on silica gel, eluent hexanes-EtOAc (9:1). This afforded 244a as a white solid (650 mg, 35% yield). 1H NMR: (DMSO) δ 8.01-8.00 (m, 1H), 7.73-7.70 (m, 2H), 7.66-7.63 (m, 1H), 3.89 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[O:35])/[CH:9]=[CH:10]/[C@@H:11]([NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:3])[CH3:2]>CCO.[Pd]>[CH:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[O:35])[CH2:9][CH2:10][C@@H:11]([NH:19][C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NCCNC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)NCCNC(=O)CC[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
To a solution of (E)-(S)-4-(3-biphenyl-4-yl-ureido)-5-phenyl-pent-2-enoic acid (2-isopropylamino-ethyl)-amide (Example 21) (0.03 g, 0.06 mmol) in EtOH (0.64 mL) was added Pd/C (10%, 0.011 g). The reaction vessel was sealed, flushed with N2 followed by evacuation (3×), and was then placed under H2 (1 atm), and the contents were stirred at rt for 3 h. The suspension was filtered through diatomaceous earth, which was washed with copious amounts of MeOH. The filtrate was concentrated under reduced pressure to afford 0.03 g (99%) of the desired product as a white solid. MS (electrospray): mass calculated for C29H36N4O2, 472.28; m/z found, 473.3 [M+H]+, 495.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.85 (br s, 1H), 7.50–7.09 (m, 14H), 6.84 (br s, 1H), 5.72 (br d, J=7.8 Hz, 1H), 4.12–4.00 (m, 1H), 3.32–3.23 (m, H), 3.20–3.12 (m, 1H), 2.80 (dd, J=13.6, 6.3 Hz, 1H), 2.70–2.56 (m, 5H), 2.20 (br t, J=6.8 Hz, 2H), 1.79–1.72 (m, 1H), 1.69–1.60 (m, 1H), 0.89 (d, J=6.3 Hz, 6H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]#[N:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl-].[NH4+].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[NH:31][N:30]=[N:29][N:26]=4)[CH2:21][CH2:20]3)=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C#N)CC3)cn2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4nnn[nH]4)CC3)cn2)cc1
Temperature: 100 °C

Procedure:
A solution of (4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbonitrile (241 mg, 0.65 mmol) in DMF (3 mL) was treated with ammonium chloride (52 mg, 0.97 mmol) and sodium azide (63 mg, 0.97 mmol) at room temperature. The mixture was heated at 100° C. for 19 h. After cooling down, the solid was removed by filtration and washed with DMF. The filtrate was concentrated and a small amount of MeOH and CH2Cl2 was added to the residue. After sonication, the resulting precipitate was collected and washed with THF including a small amount of water. 2-[4-(Methylsulfonyl)phenyl]-5-({[1-(1H-tetrazol-5-yl)-4-piperidinyl]methyl}oxy)pyridine was obtained as a light gray solid (170 mg, 60%) after drying in vacuo. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, 1H, J=2.9 Hz), 8.28 (d, 2H, J=8.6 Hz), 8.07 (d, 1H, J=8.8 Hz), 7.99 (d, 2H, J=8.6 Hz), 7.55 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 4.03 (d, 2H, J=6.3 Hz), 3.88 (d, 2H, J=12.7 Hz), 3.25 (s, 3H), 3.13-3.00 (m, 2H), 2.13-2.01 (m, 1H), 1.93-1.84 (m, 2H), 1.47-1.31 (m, 2H); LRMS (ESI), m/z 415 (M+H).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 14 h

Procedure:
In a DMF solution of 0.50 g of Boc-Pro-OH, 0.24 ml of tert-butylamine, 0.36 g of HOBt and 0.53 g of EDC hydrochloride were added under ice cooling and the mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 28 (Process 2) to give 373 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:26])[CH:3]=1.[O:27]1[CH2:31][CH:30]=[N:29][C:28]1=[O:32]>>[CH:23]1([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:5]4[C:6]([F:8])=[CH:7][C:2]([N:29]5[CH2:30][CH2:31][O:27][C:28]5=[O:32])=[CH:3][C:4]=4[F:26])=[O:10])[CH2:12][CH2:13]3)=[N:18][CH:19]=2)[CH2:25][CH2:24]1
Reactant: O=C1N=CCO1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Product: O=C(c1c(F)cc(N2CCOC2=O)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Yield: 68.2 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2,6-difluorophenyl)[4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl]methanone (422 mg) described in Preparation Example 189 and oxazolin-2-one (104 mg), the title compound (292 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1.CCN(CC)CC>CCO>[Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[N:4][C:5]([NH:29][C@H:26]2[CH2:27][CH2:28][C@@H:23]([CH3:22])[CH2:24][CH2:25]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2nc(Cl)ncc2Br)C1
Reactant: C[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 3-(5-bromo-2-chloropyrimidin-4-yloxy)azetidine-1-carboxylate (6 g, 16.4 mmol), cis-4-methylcyclohexanamine hydrochloride (2.4 5g, 16.4 mmol) and Et3N (7 mL, 49.2 mmol) in EtOH (20 mL) was executed in microwave reactor at 130° C. for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted by 10 to 20% ethyl acetate in DCM) to give the titled compound (6.5 g, 90% yield). MS (ESI) m/z: Calc. 440.1 (M+). Found: 442.1 (M++2).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][O:18][C:19]([O:21][CH3:22])=[O:20])=[NH:16])=[CH:10][CH:9]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][O:18][C:19]([O:21][CH3:22])=[O:20])=[NH:16])=[CH:12][CH:13]=1)([OH:7])=[O:5]
Reactant: COC(=O)ONC(=N)Nc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)ONC(=N)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
In 25 ml of trifluoroacetic acid was dissolved 9.2 g of N-(4-t-butoxycarbonylphenyl)-N'-methoxycarbonyloxyguanidine produced in Reference Example 31. The solution was stirred for two hours at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added 100 ml of water. To the mixture was added sodium hydrogencarbonate to adjust the pH to 6. The resulting crystalline precipitate was collected by filtration, followed by recrystallization from tetrahydrofuranethyl acetate to afford 4.53 g of the title compound as a colorless crystalline product.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][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][CH3:16].C(O[C:23](=[O:25])[CH3:24])(=O)C>C1CCCCC1>[C:1]([O:18][C:23](=[O:25])[CH2:24][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:17])[CH2:2][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][CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)O
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCC

Procedure:
Palmitic acid (512.04 g, 2.00 moles) and acetic anhydride (204.05 g, 2.00 moles) were charged to a two liter reaction flask fitted with an overhead stirrer, thermometer, condenser and nitrogen inlet. The mixture was heated gently with stirring to allow the solid palmitic acid to melt (61° C. to 64° C.). Heating was continued until the reflux temperature had been reached (147° C.), this temperature was maintained for a period of one hour. The resultant mixture was cooled to room temperature to allow a light yellow solid to form, this was slurried in cyclohexane (100 ml), filtered and recrystallised from petroleum ether 60-80. The recrystallised wet solid was placed in a vacuum oven at 40° C. until dry of residual acetic acid. The resultant white powdery solid was stored under vacuum in the presence of silica gel. The yield of palmitic anhydride was 458.49 g which represented a 92.8% chemical yield.