Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (386 mg, 2 mmol), aniline (182 μL, 2 mmol) and DIEA (419 μL, 2.4 mmol) in 3 mL dioxane was stirred in microwave at 180° C. for 10 min. After removal of the solvent, the residue was dissolved in 3 mL DCM, subjected to silica gel column purification to give 308 mg (yield 61.7%) (6-chloro-3-nitro-pyridin-2-yl)-phenyl-amine. Calculated mass=249. Observed mass=250.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([CH3:24])=[CH:17][CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[CH:15][C:16]([CH3:24])=[CH:17][CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C=CC(C)=CC=CC(=O)OC)cc1
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc(C=CC(C)=CC=CC(=O)O)cc1

Procedure:
In a manner similar to Example 6, alkaline hydrolysis of methyl 7-(4-hexyloxyphenyl)-5-methyl-hepta-2,4,6-trienoate afforded, after trituration from ethyl acetate, the acid as yellow powder, m.p. 181°-185° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[NH:13])[CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]([C:21]([N:23]=[C:24]=[S:25])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:1]([O:8][C:9](=[NH:13])[C:10]([C:11]#[N:12])=[C:24]([SH:25])[NH:23][C:21]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)Oc1ccccc1
Reactant: N#CCC(=N)OCc1ccccc1
Solvent: CC#N
Product: N#CC(C(=N)OCc1ccccc1)=C(S)NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a stirred 0° C. solution of 2-cyano-acetimidic acid benzyl ester (327 g, 1.88 mol) in acetonitrile (1 L) was added a 0° C. solution of phenoxycarbonylisothiocyanate (353 g, 1.97 mol) in acetonitrile (1 L). The reaction was allowed to warm to ambient temperature and was stirred overnight. The mixture was then placed in the refrigerator and kept still at 5° C. for 48 hours. The solid product was filtered, compressed, and washed with 20° C. acetonitrile (3×200 mL). Air was then drawn though the relatively stable solid followed by further drying under high vacuum to yield a yellow solid (282 g, 798 mmol, 42%). 1H NMR (400 MHz, DMSO) δ 5.39 (s, 2H), 7.11-7.19 (m, 2H), 7.20-7.24 (m, 1H), 7.36-7.46 (m, 7H), 10.23 (broad s, 1H), 10.67 (s, 1H), 12.19 (broad s, 1H) ppm; MS (APCl, m/z): 354 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH2:19][CH2:20][CH:21]=C)=[N:14]1.I([O-])(=O)(=O)=[O:24].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH2:19][CH2:20][CH:21]=[O:24])=[N:14]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C#CCOc1cc(-n2nc(CCC=C)[nH]c2=O)c(Cl)cc1Cl
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOc1cc(-n2nc(CCC=O)[nH]c2=O)c(Cl)cc1Cl
Yield: 92.2 %

Procedure:
To a solution of 500 mg (1.48 mmol) of 2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-2,4-dihydro-5-(3-butenyl)-3H-1,2,4-triazol-3-one in a mixture of 10 mL of tetrahydrofuran and 10 mL of water was added 696 mg (3.25 mmol) of sodium periodate and 167 mL of 0.18M aqueous solution of osmium tetroxide at room temperature. The mixture was stirred at the room temperature for 2h, and then diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel, eluting with a 96:4 v:v mixture of dichloromethane and methanol to give 464 mg of the title product of Step 1 as a white foam. 1H NMR (CDCI3, 400 MHz) δ 11.5 (broad s,1H), 9.8 (s,1H), 7.55 (s,1H), 7.2 (s,1H), 4.8 (s,2H), 2.9 (m,4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[C:8]([OH:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:14]([O-])([OH:16])=[O:15]>C[N+]([O-])=O>[Cl:12][C:9]1[C:10]([CH3:11])=[C:2]([Cl:1])[C:3]([C:4]([OH:6])=[O:5])=[C:7]([N+:14]([O-:16])=[O:15])[C:8]=1[OH:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(Cl)c(O)cc(C(=O)O)c1Cl
Solvent: C[N+](=O)[O-]
Product: Cc1c(Cl)c(O)c([N+](=O)[O-])c(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
2,4-Dichloro-5-hydroxy-3-methylbenzoic acid (90 mg, 0.41 mmol) was mixed with CH3NO2 (9 mL) and heated to 40 --C. To the solution was added HNO3 (20 μL, 90%, 0.43 mmol) and the reaction mixture was stirred at room temperature for 4 h. Evaporation of the solvent followed by vacuum-drying over KOH gave 112 mg of a crude product. Purification by flash column chromatography (SiO2, EtOAc-HOAc 30:1) afforded 79 mg of the title compound. Mp: 199° C. (dec); 1H NMR (DMSO-d6): δ 2.45 (s, 3H); 13C NMR (DMSO-d6): δ 164.27, 147.05, 139.61, 136.27, 128.35, 126.46, 118.87, 18.62; MS (EI, 70 eV): m/z (rel.int.) 267/265 (M+, 66/100), 249/248 (67/85), 205/203 (28/54).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccn1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccccn1)c1ccccc1

Procedure:
The title product was prepared from 2-hydroxypyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (57%, colorless oil). HPLC-MS: m/z=229.1 (M+23); Rt: 2.80 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:19]=1)=[O:5])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:13]=[N:12][C:11]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:38][CH:37]=3)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(C2CCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Product: CCOC(=O)c1cn(C2CCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 14 h
Yield: 34.6 %

Procedure:
8-Cyclopentyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (45 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (23 mg, 0.12 mmol) were combined in i-PrOH (1 mL) and heated to 80° C. After 14 h, the solution was concentrated and purified by preparative HPLC (30 mL/min 0-100% H2O/MeCN gradient over 10 min) to provide 19.8 mg of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. The ester was dissolved in MeOH (2 mL) and cooled to −78° C. in a high pressure vessel. Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After 14 h, the solution was cooled to −78° C., the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated to provide 5.4 mg of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. 1H-NMR (400 MHz, CDCl3:) δ ppm 9.30 (s, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 7.53 (d, 2H, J=8.9 Hz), 6.94 (d, 2H, J=9.0 Hz), 5.23-5.52 (m, 4H), 4.38 (q, 2H, J=7.1 Hz), 3.34-3.36 (m, 4H), 3.00-3.01 (m, 4H), 2.60 (s, 3H), 2.21-2.28 (m, 2H), 1.80-1.93 (m, 6H), 1.40 (t, 3H, J=7.1 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H32N6O3: 476.25, found: (M+H) 477.3.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[NH:23][C:22]2=[O:31]>>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[NH:23][C:22]2=[O:31]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: O=C1NC2(CCNCC2)c2c(Br)cccc21
Product: O=C1NC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 28 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 7-bromospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 2 tR=2.206, min, m/z=481; 1H NMR (CDCl3) 1.43 (d, 2H), 2.68 (t, 2H), 2.80-2.92 (m, 3H), 3.15 (t, 2H), 3.32 (t, 1H), 3.92 (d, 1H), 4.85 (d, 1H), 7.25 (m, 2H), 7.40 (m, 2H), 7.56 (d, 1H), 7.65 (d, 1H), 7.79 (d, 1H), 9.20 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][N:21]=1>CS(C)=O>[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([O:18][C:20]4[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][N:21]=4)[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.331 g, 8.28 mmol, 60% disp. in mineral oil) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.5 g, 6.9 mmol) in dimethyl sulfoxide (15 ml). After 0.5 hours, 6-chloro-N-methyl-nicotinamide (D10) (2.34 g, 13.8 mmol) was added and the reaction mixture was heated to 100° C. for 18 hours. The reaction was allowed to cool to room temperature and then partitioned between ethyl acetate and water. The ethyl acetate layer was separated and the water layer washed with further volumes of ethyl acetate. The combined organic layers were then washed with water, brine, dried (Na2SO4) and then filtered. The mixture was concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.5:4.5:95 then 1:9:90) to afford the title compound (E121) which then was recrystallised from toluene. 1H NMR (DMSO-d6) δ 8.56 (1H, dd, J=2.4, 0.4 Hz), 8.48 (1H, br m), 8.20 (1H, dd, J=8.4, 2.4 Hz), 7.16 (1H, d, J=8.0 Hz), 7.03 (1H, dd, J=8.4, 0.4 Hz), 6.91 (1H, d, J=2.4 Hz), 6.86 (1H, dd, J=8.0, 2.4 Hz), 2.87-2.77 (8H, m), 2.36 (4H, m), 2.00 (2H, m), 1.78 (2H, m), 1.58 (2H, m); MS (ES+) m/e 352 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[N:13]=[N:14][N:15]=[C:8]1[CH2:7][CH2:6]2.C1N2CN3CN(C2)CN1C3.[C:26](O)(C(F)(F)F)=[O:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:26]=[O:27])[N:9]1[N:13]=[N:14][N:15]=[C:8]1[CH2:7][CH2:6]2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(c1)CCc1nnnn1-2
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(cc1C=O)-n1nnnc1CC2
Yield: 50 %

Procedure:
To a stirred solution of Compound 1 (160 mg, 0.79 mmol) in TFA (16 ml) was added hexamethylenetetramine (1.1 g, 7.9 mmol), and refluxed for 3 days. The solvent was evaporated, and the residue was diluted with AcOEt. This organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 2 (90 mg, 0.39 mmol, 50%) as a white solid.
Reaction SMILES: C([N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)C.Cl.[OH-].[K+]>O>[CH2:11]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCN(C(C)=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCNc1ccccc1
Temperature: 105 °C
Reaction time: 96 h
Yield: 99.5 %

Procedure:
To N-acetyl-N-octylaniline (48.4 g, 196 mmol) there was added 4N hydrochloric acid (100 mL) and the mixture heated to 100-110° C. and stirred at this temperature for 4 days. The reaction mixture was cooled to ambient temperature, diluted with water (100 mL), and hexanes (200 mL). The pH of the reaction mixture was brought to pH 14 by addition of 45% potassium hydroxide with cooling by an ice bath. The layers were separated and the aqueous layer washed with hexanes (100 mL). The combined organic layers were dried over sodium sulfate and concentrated by rotary evaporation to give the desired product as a light brown oil (40 g, 195 mmol, 99%). The product was identified by NMR spectroscopy and mass spectrometry and in general was used without further purification. Analytically pure product was obtained by distillation at reduced pressure: by 145-150° C. (0.5 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[N:12]([Si](C)(C)C)=[N+:13]=[N-:14].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:10])[NH:14][N:13]=[N:12]2)=[C:4]([F:11])[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]nnn1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
A stirred solution of 17.1 grams (0.10 mole) of 4-chloro-2-fluorophenyl isocyanate and 20.0 grams (0.17 mole) of azidotrimethylsilane was heated under reflux for 16 hours. The reaction mixture was cooled to ambient temperature and 60 ml of toluene and 100 ml of water were added. The mixture was allowed to stand for two hours and the resultant solid collected by filtration. The filter cake was washed with petroleum ether to yield 14.5 grams of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one; m.p. 185°-187° C. The reaction was repeated several times.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.[C:22]([CH:24]([C:32]#[N:33])[C:25]([CH3:31])([CH3:30])[C:26](OC)=[O:27])#[N:23].CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[NH2:23][C:22]1[C:24]2[C:25]([CH3:31])([CH3:30])[C:26](=[O:27])[NH:33][C:32]=2[N:17]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][C:11]([CH3:14])=[N:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[N:6]=2)[N:16]=1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3ccccc3F)c2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1

Procedure:
200 mg (0.70 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were admixed with 3 ml of tert-butanol, 146 mg (0.70 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 1.5 ml of tert-butanol and 94 mg (0.84 mmol) of potassium tert-butoxide, and the mixture was heated under reflux for 48 h. Water was added and the precipitate was filtered off. The filtrate was extracted with dichloromethane, and the organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was stirred with water/ethanol. The solid was filtered off and dried under high vacuum. 102 mg (34% of theory) of the target compound were obtained.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[CH:39]1([NH:42][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH2:41][CH2:40]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: O=C(NC1CC1)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 73.7 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 42 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1([CH2:18][CH3:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)C.[OH-].[Li+]>C(O)C>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH2:18][CH3:19])([C:4]([OH:20])=[O:3])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Yield: 45.3 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-ethylisonipecotic acid ethyl ester (570 mg) in ethanol (10 ml) was added a 1M lithium hydroxide solution (8 ml), and the mixture was refluxed under heating for 20 hours. Then, the reaction mixture was concentrated, and water was added to the residue. The aqueous layer was washed with ether acidified with 1N hydrochloric acid, and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (233 mg, yield 45%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4](Cl)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)nc(N)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1nc(N2CCOCC2)nc(N)c1[N+](=O)[O-]
Temperature: 82 °C
Reaction time: 16 h

Procedure:
To pressure vessel, a mixture of commercially available 4-amino-2-chloro-6-methyl-5-nitropyrimidine (2.00 g, 10.6 mmol) and morpholine (1.85 mL, 21.2 mmol) in absolute ethanol (40 mL) was stirred at 82° C. for 16 hours. Absolute ethanol was evaporated in vacuo and the crude product was dissolved in a mixture of THF:EtOAc and this then subjected on top of a silica gel pad. Elution with EtOAc gave, after evaporation, the title compound as a yellow solid (2.47 g, 97%): IR (KBr, cm−1) 3468, 3307, 1615, 1560, 1247; 1H NMR (400 MHz, DMSO) δ 7.96 (s, 2H), 3.77 (br s, 4H), 3.62–3.60 (m, 4H), 2.53 (s, 3H); LCMS (+ESI, M+H+) m/z 240; HPLC: 100% (220 m).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[Li+].[Cl-].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc(C#N)c(F)c1

Procedure:
To a solution of 4-bromo-2-fluorobenzonitrile (5.0 g, 13 mmol) in 100 ml of toluene was added LiCl (1.7 g, 39 mmol), Pd(PPh3)4 (400 mg), Allyl tributyltin (5.2 g, 16 mmol), and then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-fluorobenzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([CH:30]=[O:31])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: COCCOCCn1c2ccccc2c2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 2a (1.5 g, 4.3 mmol) in dried THF (45 mL) was added n-BuLi (3.5 mL 5.2 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and then added with dried DMF (3 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight before quenched with aqueous ammonia chloride solution. Water was added and extracted with ethyl acetate three times. The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solvent, the residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:2) as eluent to afford 3a (0.76 g) as yellow solid in 60% yield. 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.58 (d, J=0.8 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.98 (dd, J=8.8 Hz, 0.8 Hz, 1H), 7.51 (m, 3H), 7.30 (m, 1H), 4.53 (t, J=6.0 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 3.49 (m, 2H), 3.38 (m, 2H), 3.26 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 191.8, 144.3, 141.1, 128.5, 127.1, 126.6, 123.7, 123.0, 122.9, 120.6, 120.4, 109.4, 109.3, 71.8, 70.8, 69.1, 59.0, 43.4. MS (FAB) m/z Calcd for C18H19NO3 297.1 Found 297.3 [M]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:7]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:6]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CO>[C:33]([NH:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:7]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:6]=1)(=[O:35])[CH3:34]
Reactant: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C)Cc1ccccc1

Procedure:
A solution of 2-(((S)-2-amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (25 mg, 0.058 mmol) and acetic anhydride (200 ml) in methanol (2 ml) was kept at room temperature for 1 h. Evaporation followed by chromatography of the resultant product on a column of silica gel (10% methanol/dichloromethane) provided the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]#[C:13][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:12]([C:11]1[S:10][C:9]([NH2:18])=[N:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)#[CH:13]
Reactant: C[Si](C)(C)C#Cc1sc(N)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1sc(N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To the above prepared 4-phenyl-5-trimethylsilanylethynyl-thiazol-2-ylamine (1.070 g, 3.927 mmol), dissolved in 14 mL of MeOH, was added K2CO3 (0.814 g, 1.5 eq.)) and the mixture was stirred for 2 h at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness, followed by flash chromatography (SiO2, hexane/ethyl acetate=7/3), gave 0.667 g of the title compound as dark brown viscous oil.