Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH2:22][CH3:23])[C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[F:27][C:28]([F:36])([F:35])[C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH2:22][CH3:23])[C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:32]([C:29]3([C:28]([F:36])([F:35])[F:27])[CH2:31][CH2:30]3)=[O:33])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc(N)c1
Product: CC[C@H]1C(=O)N(C)C(N)=N[C@]1(C)c1cccc(NC(=O)C2(C(F)(F)F)CC2)c1

Procedure:
The coupling of give [(4S,5R)-4-(3-amino-phenyl)-5-ethyl-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@@H:13]([NH:15][C:16]2[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.CC(C)([O-])C.[Na+].[CH3:29][NH2:30].C1COCC1>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH:30][CH3:29])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1
Reactant: CN
Reactant: Clc1nccnc1N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNc1nccnc1N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
To a glass microwave reaction vessel was added cis-N1-(benzo[d]thiazol-2-yl)-N3-(3-chloropyrazin-2-yl)cyclobutane-1,3-diamine (Intermediate 81, 0.1952 g, 0.588 mmol), sodium tert-butoxide (0.226 g, 2.353 mmol, Sigma-Aldrich Chemical Company, Inc.), and BrettPhos precatalyst (7.05 mg, 8.82 mol, Strem Chemicals, Inc.), and methanamine solution, 2.0 M in THF (1.471 ml, 2.94 mmol, Sigma-Aldrich Chemical Company, Inc.) in dioxane (1.177 ml) to stir at 50° C. for 3 h. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 1% to 8% MeOH in CH2Cl2, to provide the title compound (110 mg, 0.337 mmol, 57.3% yield). LCMS showed product peak at 1.26 min (m+1=327.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.95 (m, 2 H) 2.80-2.91 (m, 5 H) 4.00-4.18 (m, 2 H) 6.31 (br. s., 1 H) 6.38 (d, J=6.06 Hz, 1 H) 7.03 (td, J=7.63, 1.17 Hz, 1 H) 7.20 (d, J=3.13 Hz, 1 H) 7.21-7.28 (m, 2 H) 7.41 (d, J=7.43 Hz, 1 H) 7.69 (dd, J=7.82, 0.78 Hz, 1 H) 8.36 (d, J=6.85 Hz, 1 H)
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].C([O-])(=[O:19])C.[Na+].C(=O)(O)[O-].[Na+].Cl>CS(C)=O.O>[CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[NH:7][C:6]1=[O:19])[C:2]#[C:3][CH3:4]
Reactant: CC(=O)[O-]
Reactant: CC#CCn1c(Cl)nc2nc(Cl)nc(Cl)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC#CCn1c(=O)[nH]c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
7-(2-Butynyl)-2,6,8-trichloro-7H-purine (1.0 g) was dissolved in dimethylsulfoxide (20 mL), and then sodium acetate (595 mg) and sodium bicarbonate (366 mg) were added to the mixture. This reaction solution was stirred at room temperature for 12 hours, and then 1 N of aqueous hydrochloric acid solution (5.0 mL) and 80 mL of water were added. This reaction solution was stirred at room temperature for one hour, and then a white precipitate was collected by filtration. The white solid obtained was washed with water and t-butyl methyl ether to give the title compound (800 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([O:12][CH3:13])=[C:6]([CH:8](O)[CH2:9][CH3:10])[CH:7]=1.CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([O:12][CH3:13])=[C:6]([CH:8]([F:22])[CH2:9][CH3:10])[CH:7]=1
Reactant: CCC(O)c1cc(Br)cc(OC)c1OC
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCC(F)c1cc(Br)cc(OC)c1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
To a stirred solution of 1-(5-bromo-2,3-dimethoxyphenyl)propan-1-ol (400 mg, 1.45 mmol) in DCM (10 mL) at −78° C. was added DAST (0.58 mL, 4.36 mmol) and stirred the reaction for 10 min at −78° C., then warmed to 0° C. for 2 h. The reaction was quenched with water and saturated aqueous NH4Cl (100 mL), extracted with EtOAc, dried over NasSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using 30% EtOAc in hexanes as an eluent to furnish 5-bromo-1-(1-fluoropropyl)-2,3-dimethoxybenzene (80%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10](F)[C:11]=2[O:13][CH3:14])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.COB(OC)OC.C(#N)C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:11]=2[O:13][CH3:14])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(OC)c21
Reactant: C1CNCCN1
Agent: COB(OC)OC
Solvent: CC#N
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(OC)c21
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A mixture of 2.83 g of 1-ethyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (10 mmol), 1.72 g of anhydrous piperazine (20 mmol), 1.04 g of trimethoxyborane (10 mmol) and 15 ml of acetonitrile was refluxed with heating for 4.5 hours. The reaction solution was cooled to room temperature, 30 ml of water was added therein, and separated crystals were filtered and dried to obtain 2.00 g of the objective compound.
Reaction SMILES: CS(O)(=O)=O.[N:6]1([C:12]2[C:13](=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1)=[O:29]>C(#N)C>[CH3:39][O:38][C:32]1[CH:31]=[C:30]([C:28](=[O:29])[CH2:27][N:9]2[CH2:8][CH2:7][N:6]([C:12]3[C:13](=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:10]2)[CH:35]=[CH:34][C:33]=1[O:36][CH3:37]
Reactant: O=c1cccccc1N1CCNCC1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)CN2CCN(c3cccccc3=O)CC2)cc1OC
Temperature: 85 °C
Reaction time: 1.25 h
Yield: 32.5 %

Procedure:
To a suspension of 2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one methane sulfonate (19.64 g, described in Example 2) in acetonitrile, (150 ml) was added potassium carbonate (20.8 g). The resulting suspension was refluxed for about 20 min. A solution of 2-bromo-1-(3,4-dimethoxyphenyl)-1-ethanone (17.8 g) in acetonitrile (100 ml) was added dropwise. The mixture was stirred at 85° C. for 1.25 hr. The mixture was filtered and the filtrate was evaporated. The filtered solid and oily residue was taken up in chloroform-water, and the chloroform layer was dried and evaporated to yield crude product (24.17 g). Chromatographic purification on silica gel (1000 gel) using ethyl acetate gave 2-[4-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (8.2 g), mp 132°-135° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:27]4[CH2:28][CH2:29][CH:25]([CH2:24][NH:23][CH3:22])[CH2:26]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CNCC1CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Yield: 49.3 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-methylaminomethylpyrrolidine (90 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 75 minutes. After cooling, the resulting precipitate was collected by filtration and recrystallized from a solution of dichloromethane-methanol (1:1) to give the title compound (130 mg) as white powdery crystals, mp 226.5°-230° C.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.O>[CH2:27]([O:8][C:9]1[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH2:12][C:11]1[CH:15]=[CH:16][CH:17]=[CH:9][CH:10]=1)=[O:13])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)O)c1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1F
Reaction time: 48 h
Yield: 147.4 %

Procedure:
To a mixture of 3-tert-butyldimethylsilyloxy-2-fluorobenzoic acid (7.74 g, 29 mmol), potassium carbonate (24.0 g, 174 mmol) and sodium iodide (25.9 g, 174 mmol) in DMF (180 ml) was added benzyl chloride (8.33 ml, 72.4 mmol) dropwise over 5 min. After stirring for 2 days the reaction mixture was poured into water (400 ml) and extracted with diethyl ether (3×200 ml). The combined extracts were washed with brine (100 ml), dried (MgSO4) and concentrated under reduced pressure. The crude product obtained was recrystallized from 2-propanol to afford title compound (7.19 g, 74%) as white flakes.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C-:20]#[N:21].[Li+]>CN(C=O)C>[C:20]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:21]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1Cl
Reactant: [C-]#N
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Temperature: 0 °C
Yield: 60.4 %

Procedure:
A solution of 6.4 g of 5-chloro-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester and 2 g of lithium cyanide dissolved in 30 ml of DMF was reacted at approximately 110° C. for 23 hours. One additional gram of lithium cyanide was added to the reaction mixture which was heated for an additional 7 hours. The mixture was poured into ice water and the precipitated solid was collected by filtration and recrystallized from 3A alcohol (charcoal) to provide 3.75 g of 5-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 61%. mp=79°-81° C.
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][CH2:49][CH2:50][CH2:51][F:52])=[N:40]2>>[F:17][C:18]1[CH:19]=[C:20]([C@H:26]([NH:27][C:45]([C:43]2[CH:42]=[C:41]3[C:36]([CH:37]=[N:38][C:39]([NH:48][CH2:49][CH2:50][CH2:51][F:52])=[N:40]3)=[C:35]([F:34])[CH:44]=2)=[O:46])[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: O=C(O)c1cc(F)c2cnc(NCCCF)nc2c1
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(NCCCF)nc3c2)c2cnn(C)c2)cc1F

Procedure:
5-Fluoro-2-(3-fluoro-propylamino)-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-methoxy-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide (I-59) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87b.
Reaction SMILES: Br[C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[CH3:20][O-:21].[Na+]>CO>[CH3:20][O:21][C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1
Reactant: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)ncnc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Yield: 54.8 %

Procedure:
To a solution of 8-bromo-2'-deoxyadenosine (1.85 g, 5.61 mmol) in methanol (100 ml) was added sodium methoxide (0.908 g, 16.8 mmol), and the mixture was refluxed for 20 h. The solvent was evaporated and the residue chromatographed on silica gel (5% methanol/chloroform) to give 0.865 g (55%) of 2'-deoxy-8-methoxyadenosine: 1H NMR (Me2SO-d6) δ2.11 (m, 2H), 3.53 (m, 2H), 3.81 (m, 1H), 4.10 (s, 3H), 4.38 (m, 1H), 5.24 (m, 2H), 6.18 (t, 1H, J=6.8 Hz), 6.89 (br.s, 2H), 8.02 (s, 1H); UV (H2O) λmax 261 nm. 2'Deoxy-8-methoxyadenosine was converted to 2',3'-dideoxy-8-methoxydenosine (IX) by using in sequence Procedures A (64%), D (83%), and E and F (79%): mp 197°-799° C.; 13C NMR (Me2SO-d6) δ27.0, 28.9, 57.2, 64.0, 81.1, 83.3, 114.8, 148.8, 150.7, 153.9, 154.3; 1H NMR (Me2SO-d6) δ2.16 (m, 4H), 3.51 (m, 2H), 4.10 (br.s, 4H), 5.01 (m, 1H), 6.08 (m, 1H), 6.85 (br.s, 2H), 8.03 (s, 1H); UV (H2O) λmax 260 nm (ε11040); FAB HRMS obsd (M+ +H) 266.1273, calcd for C11H15N5O3 266.1253.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.[C:13]([Cu])#[N:14].[C-]#N.[Na+].OP([O-])(O)=O.[K+]>CN1C(=O)CCC1.CCOCC>[CH3:11][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=1)[NH:4][N:3]=[C:2]2[C:13]#[N:14]
Reactant: Cc1cc(C)c2[nH]nc(I)c2c1
Reactant: N#C[Cu]
Agent: O=P([O-])(O)O
Agent: [C-]#N
Agent: [K+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c2[nH]nc(C#N)c2c1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
Iodide 3 (20 g, 74.0 mmol) was dissolved in anhydrous NMP (300 mL). To this solution were added CuCN (19.9 g, 222 mmol, 3 eq) and NaCN (7.25 g, 148 mmol, 2 eq) and the mixture was heated at 130 ° C. for 18 h under an inert atmosphere. This solution was then poured into 0.25 M KH2PO4 (1.5 L) and Et2O (750 mL) and Celite (˜100g) were added. The suspension was stirred vigorously for 0.5 h then filtered through a sintered glass funnel. The phases were separated and the aqueous layer extracted with Et2O (3×200 mL). The combined organic extracts were washed with H2O (2×200 mL), brine (1×200 mL), dried (MgSO4), filtered and concentrated provide 8.3g (65% yield) of 5,7-dimethyl-1H-indazole-3-carbonitrile 4. The nitrile was used as is for the next reaction. RP-HPLC Method: 2-100% B in 2 minutes.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7]([Cl:20])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SCC(Cc1ccccc1C)C(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)SCC(Cc1ccccc1C)C(=O)Cl
Reaction time: 18 h

Procedure:
To 2-acetylthiomethyl-3-(2-methylphenyl)propionic acid (1.80 g, 7.0 mmol) in toluene (50 ml) add thionyl chloride (1.25 g, 10.5 mmol). Stir 18 hr, concentrate, dilute with toluene, concentrate, and repeat to obtain 2-acetylthiomethyl-3-(2-methylphenyl)propionyl chloride, a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[Cl:13][CH2:14][C:15]([C:7]1[C:6]([CH3:8])=[CH:5][C:4]([NH:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[CH3:1])=[O:16]
Reactant: CC(=O)Nc1cc(C)cc(C)c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(C)c(C(=O)CCl)c(C)c1
Yield: 57.9 %

Procedure:
To a solution of N-(3,5-dimethylphenyl)acetamide (4.0 g, 24.5 mmol) and ClCH2COCl (4.2 g, 37 mmol) in CS2 (30 mL), AlCl3 (10.0 g, 74.9 mmol) was added in portions. The resulting mixture was refluxed overnight. The reaction mixture was then cooled down to room temperature before the CS2 layer was decanted. The resulting complex was decomposed by pouring onto a mixture of ice (500 g) and concentrated HCl (30 mL). The solid was collected by suction, washed with 1N HCl and water, and recrystallized in EtOH to afford N-(4-(2-chloroacetyl)-3,5-dimethylphenyl)acetamide as a brown powder (3.4 g, 57.9%), which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(#N)C.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCNCC1
Yield: 88 %

Procedure:
1.15 g of the N-hydroxysuccinimide ester of N-(tert-butoxycarbonyl)-L-alanine are dissolved in 100 ml of DMF and the solution is added dropwise over 6 hours to a mixture of 3.4 g (10 equivalents) of piperazine in 200 ml of DMF. The mixture is concentrated and the residue is taken up in water and extracted three times with 200 ml of dichloromethane each time. The organic phase is dried and the solvent is removed under reduced pressure. The target compound is obtained in a yield of 88%. [TLC: acetonitrile/water/glacial acetic acid 5:1:0.2 Rf =0.42].
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([OH:29])=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([O:29][CH: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])[C:4]([OH:3])=[O:19])=[CH:23][C:22]=2[O:21]1
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(Oc1ccc2c(c1)OCO2)C(=O)O
Temperature: 90 °C
Reaction time: 6 h
Yield: 109.9 %

Procedure:
33.5 g of 2-bromotetradecanoic acid ethyl ester and 13.8 g of 3,4-methylenedioxyphenol were dissolved in 100 ml of dimethylformamide, to which was added 13.8 g of anhydrous potassium carbonate while introducing a nitrogen gas and the mixture was stirred at 90° C. for 6 hours. The reaction solution was poured into 300 ml of cold water and extracted with 300 ml of ethyl acetate. The ethyl acetate layer was washed with 300 ml of water and the ethyl acetate was distilled off under reduced pressure. To the residue was added 120 ml of a 10% methanol solution of potassium hydroxide and the mixture was refluxed for 30 minutes. The reaction mixture was poured into 300 ml of a cold 7% aqueous hydrochloric acid solution and extracted with 300 ml of ethyl acetate. The ethyl acetate layer was washed with 300 ml of water and dried with anhydrous sodium sulfate. After removing the sodium sulfate by filtration, the ethyl acetate was distilled off under reduced pressure and to the resulting residue was added 70 ml of acetonitrile to crystallize. The crystals thus deposited were collected by filtration to obtain 40 g of 2-(3,4-methylenedioxyphenoxy)tetradecanoic acid having a melting point of 70° to 72° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:4]([NH2:16])[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: Cc1ccc(Sc2ccc(C)cc2N)cc1

Procedure:
The product from Example 47a was reduced with SnCl2 following the procedure from Example 1f giving the title compound.
Reaction SMILES: [OH:1][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])[CH:3]=1.[H-].[Na+].[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)CCCCCCc1ccccc1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCCCCc1ccccc1)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 176 mg, 4.4 mmol, 1.1 eq.), and the mixture was stirred at a room temperature for 40 minutes. Then, 7-phenylheptanoyl chloride (4.8 mmol, 1.2 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 1.5 hours. Thereafter, the water was added to the reaction solution, and the precipitate was separated by filtration and dried to give 1-phenyl-4-(7-phenylheptanoyloxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (1.52 g, yield 89%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:32])[CH:19]([CH:20]=[C:21]([O:26][CH2:27][CH3:28])[C:22]([F:25])([F:24])[F:23])[CH:18]1[C:29](Cl)=[O:30].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][O:12][C:29]([CH:18]1[CH:19]([CH:20]=[C:21]([O:26][CH2:27][CH3:28])[C:22]([F:25])([F:23])[F:24])[C:17]1([CH3:16])[CH3:32])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=CC1C(C(=O)Cl)C1(C)C)C(F)(F)F
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=CC1C(C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C)C(F)(F)F
Reaction time: 3 h
Yield: 87.6 %

Procedure:
5.2 g (0.026 mol) of 3-phenoxy-benzyl alcohol and 7 g (0.026 mol) of 2,2-dimethyl-3-(3,3,3-trifluoro-2-ethoxy-prop-1-enyl)-cyclopropanecarboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.5 g of pyridine, dissolved in 20 ml of anhydrous toluene, were added dropwise at 20°-25° C., while stirring. Stirring was then continued at 25°-35° C. for 3 hours. The reaction mixture was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a water-pump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 9.9 g (87.7% of theory) of 2,2-dimethyl-3-(3,3,3-trifluoro-2-ethoxy-prop-1-enyl)-cyclopropanecarboxylic acid 3-phenoxybenzyl ester were obtained as a yellow oil with the refractive index nD25 : 1.5130.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[CH3:11][O:12][C:13]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:14]=1[NH:15][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(NC(=O)c2ccc(F)cc2)c(OC)c1

Procedure:
The protocol is identical to that described for Example 1.1, with 4-fluorobenzoyl chloride replacing 2,6-difluorobenzoyl chloride and 2,4-dimethoxyaniline replacing 3,5-dimethoxyaniline.