Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.N12CCCN=C1CCCCC2>ClCCl>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([NH:34][S:31]([C:28]1[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:32])=[O:33])=[O:18]
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NS(=O)(=O)c1ccc(Cl)nc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
1,1′-Carbonyl-diimidazole (4.22 g, 26 mmol) was added to a solution of 2,4-dichlorobenzoic acid (4.73 g, 24.8 mmol) in 100 ml dichloromethane the mixture was stirred for 30 minutes at room temperature and subsequently refluxed for 30 minutes. Then 6-chloro-pyridine-3-sulfonic acid amide (5.00 g, 26 mmol) and 1,8-diazabicylo[5.4.0]undec-7-en (3.96 g, 26 mmol) were added and the mixture was stirred at room temperature overnight. After evaporation to dryness the residue was taken up with 100 ml ethyl acetate and washed with 1 M HCl and 1 M NaOH and the organic phase was dried over sodium sulphate and concentrated in vacuo. Flash chromatography (SiO2, heptane-ethyl acetate gradient) yielded 6.72 g of the title compound as a white solid, m/z=365 (ES+), 363 (ES−).
Reaction SMILES: C(Cl)(=O)C.[CH3:5][Si:6]([CH2:9][OH:10])([CH3:8])[CH3:7].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]([OH:39])[CH2:19][NH:20][CH:21]([CH3:38])[CH2:22][C:23]2[CH:37]=[CH:36][C:26]3[O:27][C:28]([C:33]([OH:35])=[O:34])([C:30](O)=[O:31])[O:29][C:25]=3[CH:24]=2)[CH:15]=[CH:16][CH:17]=1>C(=O)(O)[O-].[Na+]>[CH3:5][Si:6]([CH:9]([O:10][C:30]([C:28]1([C:33]([OH:35])=[O:34])[O:27][C:26]2[CH:36]=[CH:37][C:23]([CH2:22][CH:21]([NH:20][CH2:19][CH:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=3)[OH:39])[CH3:38])=[CH:24][C:25]=2[O:29]1)=[O:31])[Si:6]([CH3:8])([CH3:7])[CH3:5])([CH3:8])[CH3:7]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: C[Si](C)(C)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)OC([Si](C)(C)C)[Si](C)(C)C)O2)NCC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Acetyl chloride (0.59 g, 7.5 mmol) was added to trimethylsilylmethanol (4.03 g, 37.5 mmol) with stirring at room temperature. After 0.5 h, 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid (1.05 g, 2.5 mmol) was added in portions. The resulting solution was stirred for 3 days, and then treated with 50 ml of 50% sodium bicarbonate solution, followed by extraction with ethyl acetate (50 ml). The organic extract was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was passed through a pad of silica gel, eluting with hexanes, and ether-hexanes/1:1 until no more trimethylsilylmethanol could be detected. The filter pad was then eluted with ethyl acetate, and the solvent was evaporated to give 1.14 g of the desired product as a colorless gum. Conversion to the HCl salt yielded 1.16 g of white foam; 1H NMR (CDCl3) δ 0.06 (s, 18H), 1.33 (d, J=6.5 Hz, 3H), 2.80 (m, 1H), 3.15 (m, 1H), 3.20 (m, 1H), 3.48 (m, 2H), 4.014 (s, 2H), 4.015 (s, 2H), 5.45 (bd, J=9.7 Hz, 1H), 5.60 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1763 cm-1 (C=O); MS (ES) m/z 594 (MH+); [α]D25 -23° (c, 1.0, CHCl3). Anal. Calcd. for C28H40ClNO7Si2 ·HCl: C, 53.32; H, 6.39; N, 2.22; Cl, 11.24; Si, 8.91. Found: C, 52.65; H, 6.70; N, 2.11; Cl, 11.47; Si, 9.00.
Reaction SMILES: C(OC(=O)[N:7]([S:11]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[OH:21])(=[O:13])=[O:12])[CH2:8][CH2:9]Cl)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(O)C.CCCCCCC>[Br:20][C:18]1[CH:17]=[CH:16][C:15]2[O:21][CH2:9][CH2:8][NH:7][S:11](=[O:13])(=[O:12])[C:14]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N(CCCl)S(=O)(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCCCCCC
Product: O=S1(=O)NCCOc2ccc(Br)cc21
Reaction time: 1 h

Procedure:
37 g (81 mmol) of the product obtained in Step D above are heated at reflux in the presence of 2.69 g (16 mmol) of KI and 33.6 g (240 mmol) of K2CO3 in 1.2 L of ethanol for about 18 hours. After cooling, the salts are filtered off and rinsed with acetone. After evaporation, the filtrate is taken up in water. The mixture is acidified with 1N HCl solution and then extracted 3 times with CH2Cl2. The organic phase is washed twice with brine, dried over MgSO4 and evaporated. The residue obtained (˜22 g) is then triturated in heptane, and then the mixture is allowed to separate in order to remove the heptane supernatant. The residue is again triturated in a heptane/isopropyl ether mixture to obtain a solid. After filtration, the product is rapidly dried and then ground in a mortar. The solid obtained is dissolved in heptane, stirred for about 1 hour and filtered to yield the expected product.
Reaction SMILES: C([O:8][C:9](=[O:46])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:45])[C@H:16]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34]C(OCC1C=CC=CC=1)=O)[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-])=O)(=[O:20])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd].O>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:46])=[O:8])=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])(=[O:20])=[O:19]
Reactant: [H][H]
Reactant: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NCCCC[C@H](NS(=O)(=O)c1ccccc1N)C(=O)N1CCC[C@H]1C(=O)O
Yield: 91.1 %

Procedure:
Nα -o-nitrobenzenesulfonyl-Nε -benzyloxycarbonyl-L-lysyl-L-proline benzylester (5.82 g, 8.9 mmole) was dissolved in methanol (40 ml), and hydrogen gas was Passed through the solution in the presence of 5% palladium-carbon as a catalyst for 6 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in water (25 ml). The solution was washed with three 25 ml portions of diethyl ether and the water layer as separated was freeze-dried to obtain Nα -o-aminobenzenesulfonyl-L-lysyl-L-proline (yield: 3.23 g, 90.9%).
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=3)[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:37][C:34]4[CH:35]=[CH:36][C:31]([CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:32][CH:33]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(-c5cccc(CN(C)S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(3-{2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (45.0 mg, 0.236 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.039 g, 36%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.5 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.96 (s, 1H), 7.59 (d, J=7.1 Hz, 1H), 7.55-7.50 (m, 3H), 7.42 (d, J=7.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 6.96 (t, J=7.0 Hz, 1H), 6.81 (s, 1H), 4.42 (s, 2H), 3.01-2.94 (m, 2H), 2.87 (s, 3H), 2.83 (s, 3H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.09-2.00 (m, 2H), 1.87-1.73 (m, 4H). MS=505 (MH)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[BH3-]C#N.[Na+]>C(Cl)Cl.C(OC)(C)(C)C.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1
Reactant: O=C1CCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Brc1ccc(NC2CCCC2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.5 %

Procedure:
To a solution of 6-bromopyrid-3-ylamine (2.0 g, 11.6 mmol) in CH2Cl2 (30 mL) was added cyclopentanone (1.3 mL) 15.5 mmol), followed by TiCl4 (1.4 mL, 12.7 mmol) in CH2Cl2 (20 mL) and after stirring for 3.5 h at room temperature, NaBH3CN (2.17 g, 34.5 mmol) was added portion-wise. The reaction was left to stir overnight at ambient temperature, diluted with t-BuOMe (200 mL), washed with water, brine and dried (Na2SO4). Solvent removal and purification by chromatography afforded the sub-title compound (880 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C1(N=C=NC2CCCCC2)CCCCC1.[C:25](=S)=[S:26]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:6]=[C:25]=[S:26]
Reactant: S=C=S
Reactant: NCc1cccc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: Fc1cccc(CN=C=S)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 3-fluorobenzylamine (6.26 g., 0.05 mole) in ether (10 ml.) was added dropwise to a solution of dicyclohexylcarbodiimide (10.3 g., 0.05 mole) and carbon disulfide (20 ml., 0.333 mole) in ether (60 ml.) at -5 °to -10° C. and the mixture was stirred for 17 hours at 25° C. The mixture was filtered, and the solvent was removed under vacuum. The resulting oil was dissolved in hexane-ethyl acetate (19:1), filtered and the solvent removed under vacuum. The oil was then dissolved in hexane-ethyl acetate (9:1) and purified by flash chromatography (silica) to give 3-fluorobenzylisothiocyanate as an oil (8.14 g., 97%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[N:11][N:10]([CH2:13][CH2:14]Br)[C:9](=[O:16])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:17][CH:18]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1)[CH2:19][NH:20][CH3:21].C(N(CC)CC)C>C(O)C>[OH:17][CH:18]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][CH:27]=1)[CH2:19][N:20]([CH3:21])[CH2:14][CH2:13][N:10]1[C:9](=[O:16])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[N:11]1
Reactant: O=c1cc(-c2ccccc2)cnn1CCBr
Reactant: CNCC(O)c1ccc(NS(C)(=O)=O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(CCn1ncc(-c2ccccc2)cc1=O)CC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
2-[5-Phenyl-2H-pyridazin-3-on-2-yl]ethyl bromide (0.28 g), 2-hydroxy-N-methyl-2-(4-methanesulphonamidophenyl)ethylamine (0.24 g) and triethylamine (0.22 g) were refluxed in ethanol (30 ml) for 4 hours. The solvent was removed and the residue taken up in methylene chloride, washed with water, evaporated and the residue chromatographed on silica [Merck `Kieselgel 60` (Trade Mark)], eluting with ethyl acetate. Collection and evaporation of appropriate fractions gave the title compound as a solid which was recrystallised from diisopropyl ether, yield 0.1 g, m.p. 108°.
Reaction SMILES: [H-].[Li+].[O:3]=[C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[CH:6][NH:5]1.I[CH3:15]>CN(C=O)C.CCOC(C)=O>[CH3:15][N:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]1=[O:3]
Reactant: COC(=O)c1ccc[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiH (10 mg, 1.3 mmol) was added to the solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (0.10 g, 0.65 mmol) in DMF (3 mL) at 0° C. After stirring for 30 minutes, iodomethane (0.08 mL, 1.30 mmol) was added to the reaction mixture at the temperature, and the reaction was warmed to room temperature. After stirring for 3 days, the reaction mixture was diluted with EtOAc, quenched with ice water, extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:23]1([C:28](N)=[NH:29])C=CC=N1.C(N(CC)C(C)C)C.O>CN(C=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:28]([NH2:29])=[NH:23])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N=C(N)n1cccn1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Agent: CCN(CC)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N=C(N)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 100 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine, 1H-pyrazol-1-carboxamidine hydrochloride and diethyl isopropylamine are dissolved in DMF, and the reaction mixture is heated to 100° C., then cooled and diluted by addition of water. The aqueous mixture is extracted with EtOAc, and the combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure to give N-(6-benzenesulfonyl-naphthalen-1-ylmethyl)-guanidine.
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[O:31]1[CH2:36][CH2:35][CH2:34][O:33][CH:32]1CO>>[Na:1].[O:31]1[CH2:36][CH2:35][CH2:34][O:33][CH:32]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:20])[C:13]=1[CH3:30]
Reactant: OCC1OCCCO1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: Cc1c(OCC2OCCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 10 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 1,3-dioxan-2-ylmethanol obtained in the step (32b) to obtain the title compound (148 mg, total yield:10%) as a light yellow solid.
Reaction SMILES: N1C=C[CH:4]=[CH:3][C:2]=1[C:7]([C:9]1C=CC=CN=1)=O.CO.[CH3:17][C:18]([OH:20])=[O:19].C(Cl)Cl>>[C:18]([OH:20])(=[O:19])/[CH:17]=[CH:4]/[CH2:3][CH2:2][CH2:7][CH3:9]
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCC/C=C/C(=O)O
Yield: 70 %

Procedure:
Prepared as above from 376.4 mg (0.86 mmol) of the (±)-pyridyl ketone and 790.6 mg (1.73 mmol) of the Wittig salt. Preparative HPLC with MeOH-AcOH-CH2Cl2 (4:1:95) gave in ~92% yield a mixture of Wittig product (E/Z=~96:4) from which 320.9 mg (70%) of (±)-(E)-heptenoic acid was isolated cleanly: mp 68-73° C.; 1H NMR (CDCl3) δ8.61 (br s, 1H), 8.49 (br s, 1H), 8.28 (s, 1H), 8.06 (d, J=8.1 Hz, 2H), 7.52 (br s, 1H), 7.46 (br d, J=8.0 Hz, 1H), 7.28 (d, 2H), 7.27 (buried, 1H), 6.21 (t, J=7.4 Hz, 1H), 4.04 (dt, J=13.3, 1.9 Hz, 1H), 3.69 (br s, 4H), 3.50 (m, 5H), 2.33 (dd, J=7.1, 6.7 Hz, 2H), 2.21 (ddd, J=7.2, 7.0, 6.7 Hz, 2H), 1.89-1.26 (m, 10H); FDMS 534 (M+1). Anal. (C30H35N3O6.0.25C2H4O2) C, H, N.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([CH2:24][C:25]([OH:27])=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O[N:29]=[C:30]([C:32]1[CH:33]=[CH:34][C:35]([CH3:50])=[C:36]([NH:38][C:39]([C:41]2[N:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]3=[N:43][CH:42]=2)=[O:40])[CH:37]=1)[NH2:31].O>CN1C(=O)CCC1>[N:43]1[CH:42]=[C:41]([C:39]([NH:38][C:36]2[CH:37]=[C:32]([C:30]3[N:29]=[C:25]([CH2:24][CH:22]4[CH2:21][N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:23]4)[O:27][N:31]=3)[CH:33]=[CH:34][C:35]=2[CH3:50])=[O:40])[N:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=12
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(CC3CN(C(=O)OC(C)(C)C)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 125 °C
Reaction time: 0.33 h

Procedure:
Carbonyl diimidazole (CDI) (52.0 mg, 0.32 mmol) was added to a stirred solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (69.0 mg, 0.32 mmol) in NMP (1.0 mL). After 20 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (49.5 mg, 0.16 mmol) was added in one portion and the resulting solution was stirred for 30 minutes before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction mixture was added dropwise to water (20 mL) with stirring. The precipitate was filterted and dried to give tert-butyl 3-((3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl)azetidine-1-carboxylate (54). MS m/z 489.2 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH3:14].O>C(O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
In 200 g of ethanol were dissolved 86.5 g (0.5 mol) of 4-bromophenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 75.4 g (0.55 mol) of n-butyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter was separated therefrom and concentrated by a rotary evaporator, yielding 90 g of 4-n-butoxyphenyl bromide. This was used in the subsequent reaction without further purification.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4](OCC)(=O)CC(OCC)=O.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=1)[C:21](Cl)=[O:22].Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:21]([C:20]1[CH:19]=[N:18][CH:17]=[C:16]([Br:15])[CH:24]=1)(=[O:22])[CH3:4]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.3 %

Procedure:
1.24 g of ground magnesium chloride was suspended in 13 ml of toluene and 6.2 ml of triethylamine and 2.93 g of diethyl malonate were added in turn. After stirring at room temperature for 1.5 hours, a suspension of 4.08 g of 5-bromonicotinoyl chloride obtained in the step 1 in 10 ml of toluene was added dropwise over 15 minutes, followed by stirring at room temperature for 2 hours. After neutralizing with 40 ml of 1N hydrochloric acid, the aqueous layer was separated. The aqueous layer was further subjected to extraction with diethyl ether and the organic layers were combined, and then the solvent was distilled off under reduced pressure. To the resulting oily product, dimethyl sulfoxide-water (17 ml-0.7 ml) was added, followed by stirring with heating at 150 to 160° C. for 2 hours. The reaction solution was air-cooled, and then water was added. Then, the deposited crystals were collected by filtration. The deposited crystals were dissolved in ethyl acetate, washed in turn with water and an aqueous saturated sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. 0.60 g of activated carbon (Kyoryoku Shirasagi MOIWY433) was added and, after standing for 10 minutes, activated carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.89 g of the objective compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15]([C:23]1[S:27][C:26](C=O)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[N+](C1C=C([N+]([O-])=O)C=CC=1S(O)(=O)=O)([O-])=O.C1(C)C=CC=CC=1>O>[CH2:15]([C:23]1[S:27][C:26](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH2:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: CCCCCCCCc1ccc(C=O)s1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)O)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCC1=CCC(=Nc2ccc(CCC(=O)OCC)cc2)S1

Procedure:
A solution of 8.6 g. ethyl 4-aminohydrocinnamate, 9.77 g. 5-octyl-2-thiophenecarboxaldehyde and a few crystals of 2,4-dinitrobenzenesulfonic acid in 250 ml. toluene is refluxed under a Dean-Stark trap for 17 hours, whereupon the theoretical amount (0.8 ml.) water has been collected. The toluene is evaporated to yield ethyl 3-[4-(5-octyl-2-thienylideneamino)phenyl]propionate as a crystalline mass.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CN(C)C=O.[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1OCCOCCOCCOCCOCCOC1.O>[CH2:8]([C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(=O)Cc1sccc1Br
Reactant: CCOC(=O)CS
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCc1c(C(=O)OCC)sc2ccsc12
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Compound 59 (35.4 g, 0.13 mol) and K2CO3 (27.6 g, 0.2 mol) were mixed with N,N-dimethylformamide (100 mL). A catalytic amount (˜25 mg) 18-crown-6 was added, and to this mixture, ethyl 2-mercaptoacetate (14.0 mL, 0.13 mol) was added dropwise at 60° C. The mixture was stirred overnight and poured into water (500 mL). The organic component was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (2×100 mL) and water (100 mL). Organic layer was then dried over MgSO4. After evaporation of the solvent, the crude compound 61 was obtained and purified by column chromatography (SiO2/5% ethyl acetate in hexanes) to yield pure compound 61 (32.1 g, 84.5%). GC/MS: 296 g/mol (M). 1H NMR (CD2Cl2) δ 7.56 (d, 1H), 7.24 (d, 1H), 4.34 (q, 2H), 3.15 (t, 2H), 1.71 (m, 2H), 1.32 (m, 6H), 0.88 (m, 6H). 13C NMR: 163.24, 143.31, 141.85, 141.09, 131.13, 128.44, 120.35, 61.25, 31.99, 29.72 (overlap), 22.98, 14.52, 14.23.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:29]([O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(O)CO>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:40][C:39]4[CH:38]=[CH:37][C:36]([O:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:42][CH:41]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: CCCCCCOc1ccc(N)cc1
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCOc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1
Temperature: 170 °C
Yield: 23.1 %

Procedure:
To a magnetically stirred solution of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.89 mmol) in ethylene glycol (3.0 mL) under nitrogen at room temperature was added N,N-diisopropylethylamine (0.12 g, 0.89 mmol) followed by 4-hexyloxyaniline (0.27 g, 1.4 mmol). The reaction mixture was heated to 170° C. for 5.5 h, cooled to room temperature and partitioned between water (20 mL) and chloroform (20 mL). The aqueous layer was extracted with chloroform (20 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude brown solid was purified by chromatography (silica gel, 2:1 hexanes/ethyl acetate) to afford N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-n-hexyloxyphenyl)-2,4-pyrimidindiamine (0.09 g, 23%) as a white solid: Rf0.53 (silica gel, 4:1 chloroform/ethyl acetate); mp 115–117° C.; 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J=3.2 Hz, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.29 (d, J=2.5 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 6.88–6.82 (m, 3H), 6.61 (s, 1H), 4.29 (d, J=3.1 Hz, 4H), 3.94 (t, J=6.6, 6.7 Hz, 2H), 1.77 (m, 2H), 1.47 (m, 2H), 1.35 (m, 4H), 0.92 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 155.1, 150.3, 143.6, 142.7, 140.3, 140,07 139.4, 133.0, 131.7, 121.9, 117.3, 115.0, 114.7, 110.8, 68.6, 64.6, 31.8, 29.5, 25.9, 22.8, 14.2; IR (ATR) 3357 cm−1; ESI MS m/z 439 [C24H27FN4O3+H]+; HPLC (Method B) 98.5% (AUC), tR=7.9 min. Anal. Calcd for C24H27FN4O3: C, 65.74; H, 6.21; N, 12.78. Found: C, 65.34; H, 6.19; N, 12.96.