Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH2:22][NH:39][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:27]([F:28])([F:30])[F:29])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: NCCc1ccccc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(CNCCc2ccccc2)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and phenethylamine according to the procedure of Example 66. MS (ES) m/z 511.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][CH:20]([CH3:39])[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38])O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH3:38])[CH:20]([CH3:39])[CH3:19])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C(C)C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl)-propan-1-ol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-ethoxy-3-(2-methyl-4-{2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-propionic acid ethyl ester as a mixture of two diastereomeric racemates as light yellow liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Yield: 69.2 %

Procedure:
5-Bromo-2-hydroxy-benzoic acid (5 g, 23.04 mmol) was reacted with 4-trifluoromethyl phenyl boronic acid (6.56 g, 34.5 mmol) as desribed in general procedure D. The crude product was then was then purified by silica gel column chromatography (ethyl acetate:hexanes from 20:80 to 60:40) to afford 4.5 g of the 4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid as a white solid.
Reaction SMILES: [OH:1][C:2]1([CH2:19][OH:20])[C:6](=[O:7])[O:5][C@H:4]2[C:8]3[C@@:13]([CH3:16])([CH2:14][CH2:15][C:3]12[OH:18])[CH2:12][CH2:11][CH2:10][C:9]=3[CH3:17].[C:21](OC(=O)C)(=[O:23])[CH3:22].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:21]([O:20][CH2:19][C:2]1([OH:1])[C:6](=[O:7])[O:5][C@H:4]2[C:8]3[C@@:13]([CH3:16])([CH2:14][CH2:15][C:3]12[OH:18])[CH2:12][CH2:11][CH2:10][C:9]=3[CH3:17])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(CO)C3(O)CC[C@@]2(C)CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC1(O)C(=O)O[C@H]2C3=C(C)CCC[C@]3(C)CCC21O
Reaction time: 0.5 h

Procedure:
Compound of example 2 (150 mg, 0.531 mmole) was dissolved in dichloromethane (10 mL). Acetic anhydride (54.25 mg, 0.531 mmole), pyridine (84 mg, 1.062 mmole) and 4-(dimethylamino)-pyridine (DMAP) (2 mg) were added to this solution and reaction mixture was stirred for 30 minutes. Reaction mixture was extracted with dichloromethane (3×100 mL). The dichloromethane layer was washed with water and brine and was dried over sodium sulfate. The solvent was removed and crude product was purified by crystallization using ethyl acetate/petroleum ether to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:34][C:11]3[C:12](=[O:33])[N:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]([OH:30])[CH2:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[C:17]([O:31][CH3:32])[CH:16]=4)[CH2:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[NH:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:36]([C:40](O)=[O:41])[CH:37]([CH3:39])[CH3:38].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:46]([O:45][C:43]([NH:35][C@@H:36]([CH:37]([CH3:39])[CH3:38])[C:40]([O:30][C@H:23]([CH2:24][S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]2[CH2:14][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[S:34][C:11]=3[C:12]2=[O:33])=[CH:16][C:17]=1[O:31][CH3:32])=[O:41])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCS(=O)(=O)C[C@@H](O)COc1ccc(N2Cc3cc(-c4ccc(Cl)cc4)sc3C2=O)cc1OC
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)C[C@H](COc1ccc(N2Cc3cc(-c4ccc(Cl)cc4)sc3C2=O)cc1OC)OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 79 %

Procedure:
To a suspension of (S)-2-(4-chlorophenyl)-5-(4-(3-(ethylsulfonyl)-2-hydroxypropoxy)-3-methoxyphenyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one) (46.0 mg, 0.088 mmol), DMAP (5.47 mg, 0.045 mmol) and BOC-Val-OH (22.96 mg, 0.106 mmol) in CH2Cl2 (0.401 mL) at RT was added DIC (0.022 mL, 0.141 mmol) dropwise over a period of 1 h. After stirring for an additional 2H, the reaction mixture was filtered and the filtrate was washed with cold 1N HCl (3×10 mL) and cold 10% NaHCO3 (3×10 mL) prior to drying over anhydrous Na2SO4 and concentrating under vacuum. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to 0:100) to afford 50.4 mg (79% yield) of the title compound as a yellow solid: HPLC retention time: 4.153 min., LCMS (ES): m/z 721 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[NH:6]2.CCN(P1(N(C)CCCN1C)=N[C:36](C)([CH3:38])[CH3:37])CC.IC(C)C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH:36]([CH3:38])[CH3:37]
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)[nH]c2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
200 mg (0.531 mmol) of the compound from example 33 and 145 mg (0.531 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 90 mg (0.531 mmol) of 2-iodopropane ml of dimethylformamide was added dropwise at 0° C. within 10 min The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 117 mg of the title compound were obtained (50% of theory).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[C:29]([O:38][CH3:39])=[N:30][CH:31]=[C:32]([CH:37]=2)[C:33](OC)=[O:34])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1>[CH:22]1([O:27][C:28]2[CH:37]=[C:32]([C:33](=[O:34])[CH2:20][C:19]3[C:18]([Cl:21])=[CH:17][N:16]=[CH:15][C:14]=3[Cl:13])[CH:31]=[N:30][C:29]=2[O:38][CH3:39])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ncc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
n-Butyl lithium (4.9 mL of a 2.5M solution in hexanes) is added dropwise to a stirred solution of diisopropylamine (1.7 mL) in dry tetrahydrofuran (20 mL) at −78° C. under a nitrogen atmosphere. After 30 minutes. a solution of 3,5-dichloro-4-methylpyridine (1.95 g) in dry tetrahydrofuran (10 mL) is added dropwise and the solution stirred at −78° C. for a further 30 minutes. A solution of methyl 5-cyclopentyloxy-6-methoxynicotinoate (1.5 g) in dry tetrahydrofuran (15 mL) is added and the red mixture stirred and allowed to warm to room temperature during 4 hours. After stirring overnight at room temperature the mixture is treated with saturated aqueous ammonium chloride. The tetrahydrofuran layer is separated and the aqueous phase is extracted with ethyl acetate. The combined organic layers are washed with saline and dried over anhydrous magnesium sulphate. Concentration gives a light brown oil which is triturated with a mixture of n-pentane and methyl t-butyl ether to give 1-(5-cyclopentyloxy-6-methoxypyridin-3-yl)-2-(3,5-dichloropyrid-4-yl)ethanone (1 g) in the form of a beige solid, m.p. 118-9° C. [Elemental analysis: C, 56.8; H, 4.82; Cl, 18.5; N, 7.40% calculated: C, 56.7; H, 4.76; Cl, 18.6; N, 7.35%.]
Reaction SMILES: [CH3:1][P:2]([O-:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6].[C:9](#[N:13])/[CH:10]=[CH:11]/[CH3:12].[H-].[Na+].C(O)(=O)C>C(O)C>[C:9]([CH2:10][CH:11]([P:2]([CH3:1])(=[O:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH3:12])#[N:13]
Reactant: CC(C)COP(C)[O-]
Reactant: C/C=C/C#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)COP(C)(=O)C(C)CC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 50.0 g of isobutyl P-methylphosphonite and 22.8 g of crotononitrile in 50 ml of dry ethanol is added to a stirred mixture of 0.8 g of sodium hydride (50% dispersion in oil) in 25 ml of ethanol at 0° C. , under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled to give isobutyl P-(3-cyanoprop-2-yl)-P-(methyl)phosphinate, b.p. 110°/0.125 mbar, 31P-NMR spectrum: δ=+55.9 and +55.5 ppm (CDCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21]2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]([C:30]2[N:34](C3CCCCO3)[N:33]=[CH:32][CH:31]=2)=[CH:5][N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:21][CH2:22]2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:6]([C:30]2[NH:34][N:33]=[CH:32][CH:31]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(-c2ccnn2C2CCCCO2)cc1NC(=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(-c2ccn[nH]2)cc1NC(=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a 20 ml vial was added (2S)—N-(2-methoxy-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)-3-phenyl-2-(1-(pyridin-2-yl)cyclopropylamino)propanamide 14.1.D (200 mg, 0.37 mmole), 8 ml of DCM and 2 ml of TFA. The reaction was stirred at room temperature for 2 hours then refluxed for 2 seconds at which time the solvent was removed with a stream of nitrogen. The crude was purified by reverse phase preparative HPLC to give (2S)—N-(2-methoxy-5-(1H-pyrazol-5-yl)pyridin-3-yl)-3-phenyl-2-(1-(pyridin-2-yl)cyclopropylamino)propanamide 14.1. (74 mg, 44% yield) LCMS ESI (pos.) m/e: 455.2 (M+1): 1H NMR (400 MHz, MeOH-d) δ ppm 8.59 (d, J=5.48 Hz, 1H), 8.56 (d, J=2.35 Hz, 1H,) 8.28 (d, J=2.35 Hz, 1H), 8.03-8.08 (m, 1H), 7.71 (d, J=2.35 Hz, 1H), 7.53-7.57 (m, 1H), 7.36 (d, J=8.22 Hz, 1H), 7.23-7.32 (m, 5H), 6.61 (d, J=2.35 Hz, 1H), 4.33 (t, J=7.63 Hz, 1H), 3.89 (s, 3H), 3.20 (d, J=7.83 Hz, 2H), 1.62-1.70 (m, 2H), 1.50-1.57 (m, 1H), 1.32 (ddd, J=10.17, 4.11, 2.15 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:12]=1[F:20].[NH2:21][C:22]1[C:23]([N:31]2[CH2:36][C@H:35]([CH3:37])[C@@H:34]([O:38][Si](C(C)(C)C)(C)C)[C@H:33]([NH:46]C(=O)OC(C)(C)C)[CH2:32]2)=[C:24]2[CH2:30][CH2:29][O:28][C:25]2=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>>[NH2:46][C@H:33]1[C@H:34]([OH:38])[C@@H:35]([CH3:37])[CH2:36][N:31]([C:23]2[C:22]([NH:21][C:17]([C:15]3[CH:14]=[CH:13][C:12]([F:20])=[C:11]([C:3]4[C:4]([F:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])[N:16]=3)=[O:19])=[CH:27][N:26]=[C:25]3[O:28][CH2:29][CH2:30][C:24]=23)[CH2:32]1
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@@H](N)[C@H](O)[C@@H](C)C3)CCO4)ccc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
To a mixture of 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (176 mg, 0.372 mmol), tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (152 mg, 0.317 mmol), and HATU (374 mg, 0.983 mmol) in DMF (3.0 mL) DIPEA (238 mg, 1.84 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (54 mg, 32%). LCMS calc. for C26H27F3N5O4 (M+H)+: m/z=530.2. found 530.0. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.70 (s, 1H), 8.34 (dd, J=8.7, 4.0 Hz, 1H), 8.18 (t, J=8.8 Hz, 1H), 7.39-7.32 (m, 1H), 7.24-7.17 (m, 1H), 4.53-4.44 (m, 2H), 4.41 (d, J=3.8 Hz, 1H), 3.89 (s, 3H), 3.36 (t, J=8.5 Hz, 2H), 3.10-3.04 (m, 1H), 3.00-2.93 (m, 1H), 2.63 (t, J=10.8 Hz, 1H), 2.58-2.51 (m, 2H), 2.46-2.38 (m, 1H), 1.66 (br, 2H), 1.48-1.36 (m, 1H), 0.69 (d, J=6.5 Hz, 3H) ppm.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCCCCCCCCCBr)OCc1ccccc1

Procedure:
30 g (113.1 mmol) of 11-bromoundecanoic acid, 18.35 g (169.7 mmol) of benzyl alcohol and 0.5 g of p-toluenesulfonic acid are heated in 200 ml of toluene for 12 hours in a water separator. It is allowed to reach room temperature, and the organic phase is washed twice with 100 ml of 5% aqueous potassium carbonate solution each. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/acetone=30:1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:16])(=O)=O.O.[OH-].[Na+]>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([Cl:16])[CH:10]=[C:11]([CH3:12])[C:2]=1[NH2:1]
Reactant: COC(=O)c1cccc(C)c1N
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(C)c1N
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
The solution prepared in Step A (195 g, 475 mmol) was diluted with acetonitrile (50 mL), and heated to 50° C. Then a solution of sulfuryl chloride (70.6 g, 523 mmol) in acetonitrile (100 mL) was added over 3.25 h at 50-55° C. Immediately after completion of the addition, the mixture was cooled to 5° C., water (150 g) was added, and the pH of the solution was adjusted to 6.0 by slow addition of 50% aqueous sodium hydroxide (103 g). After stirring for 10 minutes at this temperature, the organic layer was separated, and the aqueous layer was extracted with acetonitrile (50 mL). The organic layers were combined, dried (MgSO4), and partially evaporated to a weight of 193.7 g. Quantitative HPLC of this solution showed 41.5 wt % of the title compound (80.4 g, 84.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[S:13]
Reactant: NCCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c(N=C=S)c1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)c(NC(=S)NCCCO)c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a stirred solution of 24 parts of 1-chloro-2-isothiocyanato-4-nitrobenzene in 200 parts of ethanol 95% are added dropwise 9 parts of 3-amino-1-propanol at a temperature below 20° C. Upon completion, stirring is continued for 30 minutes at room temperature. The reaction mixture is evaporated. The residue is crystallized from acetonitrile. The product is filtered off and dried, yielding 23 parts (72%) of N-(2-chloro-5-nitrophenyl)-N'-(3-hydroxypropyl)thiourea; mp. 126.8° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[O:17]1CCC[CH2:18]1.C([Li])CCC.CN(C)C=O>C(OCC)C>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:18][OH:17])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a mixture of 2-bromo-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (11 g) and tetrahydrofuran (450 mL) was added n-butyllithium (1.6 M hexane solution, 25.3 mL) at −78° C., and the reaction mixture was stirred for 1 hr. Then, N,N-dimethylformamide (3.17 mL) was added at −78° C., and the temperature of the mixture was raised to room temperature and stirred for 16 hr. The reaction mixture was diluted with diethyl ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (200 mL), sodium borohydride (1.95 g) was added at 0° C., and the reaction mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the obtained residue was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (7.53 g, 64%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:28]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][C:10]([NH:9][CH2:8][CH2:7][O:6][C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:11])[CH2:18][CH2:17]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cccc(OCCNC(=O)CC2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCCNC(=O)CC2CCN(Cc3ccccc3)CC2)c1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
430 mg (1.58 mmol) of N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide was dissolved in 10 ml of dimethylformamide. 540 mg (3.93 mmol) of potassium carbonate and 0.16 ml (1.31 mmol) of benzyl bromide were added to the solution, and they were stirred at 50° C. for 13 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, crude 1-benzyl-N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide was obtained. The crude product was stirred in 10 ml of dioxane containing 4 N hydrogen chloride. 3.5 ml of ethanol containing 30% (w/v) of hydrogen chloride was added to the resultant mixture. After the stirring at room temperature for 3 days, the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of 10% (w/v) solution of ammonia in ethanol, and the obtained solution was stirred at room temperature for 2 days. The solvent was evaporated, and the residue was treated by the reversed-phase high-performance liquid chromatography with silica gel, containing octadodecyl group chemically bonded thereto, as the filler. After the elution with a mixed solvent of water and acetonitrile containing 0.1% (v/v) of trifluoroacetic acid, the fraction of the intended product was freeze-dried to obtain the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[NH2:30][NH2:31]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: O=C(CCc1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CCO
Product: O=c1c2c(CCc3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 72.8 %

Procedure:
To a suspension of 4-hydroxy-3-(1-oxo-3-phenylpropyl)-1-phenyl-1,8-naphthyridin-2 (1H)-one (110 mg, 0.30 mmol, prepared in Synthetic Example 6) in ethanol (6 ml) was added hydrazine monohydrate (80%, 44 μl, 1.1 mmol, 3.7 eq.), and the mixture was treated in the same manner as in Example 1 to give 5-phenyl-3-(2-phenylethyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (80 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:13]([OH:15])[CH3:14]>CCOCC>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:15][CH2:13][CH3:14])=[O:5]
Reactant: CCO
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Solvent: CCOCC
Product: CCOC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 17 °C
Reaction time: 17 h
Yield: 90.8 %

Procedure:
A 25-mL round-bottom flask was equipped with a magnetic stir bar, thermometer, nitrogen inlet, addition funnel, and a reflux condenser. The flask was charged with 2,4-dichloro-5-fluorobenzoyl chloride (5.38 g, 23.65 mmol) and ethyl ether (5.0 g). The resulting colorless solution was cooled to 17° C. using a cool water bath. Ethanol (3.20 g, 69.47 mmol; absolute grade) was added dropwise from the addition funnel over ten minutes. Once the addition was complete, the solution was warmed to room temperature and stirred overnight (17 hours). Additional ether (20 mL) was added to the reaction mixture, which was then transferred to a separatory funnel. The reaction mixture was washed twice with 2% sodium hydroxide solution (10 mL), then with water (10 mL). The upper organic layer was separated and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried in a vacuum oven to give 5.09 g of ethyl 2,4-dichloro-5-fluorobenzoate as a pale yellow oil.