Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:43][C@H:44]([C:47]([NH2:49])=[O:48])[CH2:45][OH:46])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(OCC)C.C(Cl)(Cl)[Cl:56]>N1CCCCC1>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:56].[NH2:43][C@H:44]([C:47]([NH2:49])=[O:48])[CH2:45][OH:46]
Reactant: NC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: ClC(Cl)Cl
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Solvent: C1CCNCC1
Solvent: CCOCC
Product: Cl
Product: NC(=O)[C@@H](N)CO
Reaction time: 1 h

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Fmoc-L-serineamide (1,430 mg, 2.07 mmols) were dissolved in 5 ml of chloroform and 2 ml of piperidine. The reaction was conducted for 1 hour, and the product was then purified using a silica-gel column (eluent, mixture of ethyl acetate and dichloromethane at a ratio by volume of 1:1). The thus-purified product was concentrated to dryness under reduced pressure, and then dissolved in 10 ml of a solution of 4-M hydrochloric acid and dioxane. The resulting mixture was reacted at 70 ° C. for 1 hour. One-hundred milliliters of diethyl ether were added thereto, and the resulting precipitate was collected by filtration. The thus-obtained powder was purified through medium-pressure liquid chromatography (ODS, mixture of water and acetonitrile at a ratio by volume of from 75:25), and was heat-dissolved in a mixture of chloroform and methanol at a ratio of 5:1 to produce 460 mg (0.992 mmols) of the final product in a yield of 48%.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:14]=2)[C:9](F)=[N:10][CH:11]=1.N#N.[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1C=CC=CC=1.C1COCC1.C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:15]2[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]3[C:9]([NH:49][C:46]4[CH:47]=[N:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=4)=[N:10][CH:11]=[C:6]([CH:7]=3)[CH:2]=[O:3])[N:14]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4OCCO4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 8 h
Yield: 61 %

Procedure:
A stock solution of 4-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 143, Step 1) (5.85 g, 11.30 mmol) in benzene (50 mL) contained in a 250 mL round-bottomed flask with stir bar was frozen and lyophilized overnight (pale yellow solid obtained). The flask was opened to N2 and THF (50 mL) was added followed by 6-methoxypyridin-3-amine (1.332 mL, 12.43 mmol). The solution was cooled in an ice bath and LiHMDS (44 mL of a 1.0 M solution in THF, 44 mmol) was added. The mixture was stirred for 40 min and then quenched with water (3 mL) and concentrated to dryness. The residue was taken up in a mixture of DCM and 2N aqueous HCl and stirred for 30 min. The product was extracted into DCM from 2N HCl, washed with saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give a brown solid. This was dissolved in DCM and purified by flash chrormatography (30% EtOAc, 10% DCM, 60% hexane) to give 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (3.98 g, 6.89 mmol, 61.0% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.09 (s, 1H); 9.90 (s, 1H); 9.14 (d, J=2.35 Hz, 1H); 8.77 (d, J=2.35 Hz, 1H); 8.31 (d, J=2.74 Hz, 1H); 7.87 (dd, J=8.80, 2.74 Hz, 1H); 7.28 (d, J=8.61 Hz, 2H); 7.21 (d, J=8.80 Hz, 2H); 6.87-6.94 (m, 2H); 6.78-6.87 (m, 3H); 4.83 (d, J=7.24 Hz, 4H); 3.85 (s, 3H); 3.74 (s, 3H); 3.69 (s, 3H); 2.58 (s, 3H). m/z (ESI, +ve ion) 578 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](O)=[O:23])[N:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]=1[C:33]([OH:35])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:38]([CH:42]([CH3:44])C)[CH:39]([CH3:41])C.CN(C(ON1N=N[C:55]2C=[CH:57][CH:58]=[N:59][C:54]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>CN(C=O)C>[CH2:15]([O:14][C:13]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([C:33]([N:59]([CH2:54][CH3:55])[CH2:58][CH3:57])=[O:35])[N:11]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:12]=1[C:22]([N:38]([CH2:39][CH3:41])[CH2:42][CH3:44])=[O:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(-n2c(C(=O)O)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(CC)CC)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of 4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylic acid (2) (400 mg, 0.85 mmol) and DIPEA (386 μL, 2.11 mmol) in DMF (4 mL) was added HATU (803 mg, 2.11 mmol) followed by diethylamine (219 μL, 2.11 mmol). The reaction mixture was stirred at RT for 1 h and then partitioned between Et2O (50 mL) and sat. NaOAc (aq.) (30 mL). The organic phase was washed succesively with sat. NaOAc (aq.) (20 mL), sat. NaHCO3 (aq.) (20 mL) and brine (2×20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the crude product. The residue was purified by silica gel chromatography (12 g, 30% EtOAc/isohexane) to afford 3,4-bis(benzyloxy)-N2,N2,N5,N5-tetraethyl-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxamide (UL1-046) (201 mg, 41%) as a yellow solid: m/z 584 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.47-7.22 (m, 10H), 7.09-6.99 (m, 2H), 6.94-6.76 (m, 2H), 4.97 (s, 4H), 3.74 (s, 3H), 3.29-3.03 (m, 8H), 0.98-0.71 (m, 12H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]([O:19][CH3:20])(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[SH:13].C([O-])([O-])=O.[K+].[K+]>[Cu]I.COCCOC>[CH3:8][C:6]1[CH:7]=[C:2]([S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]([O:19][CH3:20])=[O:18])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccccc1Sc1cc(C)cc(C)c1
Yield: 86.6 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-Xylene (144 μL, 1.0 mmol), Methyl thiosalicylate (138 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), and DME (1.0 mL) were used to obtain the methyl 2-(3,5-dimethylphenyl)sulfanylbenzoate (236 mg, 86% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=20/1). Rf=0.5 (hexane/ethyl acetate=10/1). 1H NMR (CDCl3, 300 MHz) δ 7.95 (dd, 1 H, J=1.8 Hz, 8.1 Hz), 7.19-7.25 (m, 1 H), 7.17 (s, 2 H), 7.08 (dt, 1 H, J=1.2 Hz, 7.8 Hz), 7.03 (s, 1 H), 6.81 (dd, 1 H, J=0.9 Hz, 8.1 Hz), 3.94 (s, 3 H), 2.32 (s, 6 H). 13C NMR (CDCl3, 75 MHz) δ 170.0, 144.0, 139.6, 133.4, 132.5, 131.2, 127.4, 126.5, 124.2, 117.1, 52.5, 21.6. IR (neat, cm−1) 2950, 2916, 1712, 1711. MS (EI) m/z (relative intensity) 272 (100), 197 (70). HRMS (EI), Cald. for C16H16O2S 272.0866; Found 272.0858.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].[Li]CCCC.[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH:19]1([C:23]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=3)[N:10]=[CH:11][N:12]=2)=[O:22])[CH2:20][CH2:21]1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(-n2cncn2)cc1
Agent: [Li]CCCC
Product: C=Cc1ccc(-n2ncnc2C(=O)C2CC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]-triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy N-methylcyclopropoxide in THF (0.82 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (420 mg, 30%): mp 90-91° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 6.75 (dd, J=16.3, 10.7 Hz, 1H), 5.81 (d, J=16.3 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 3.22 (m, 1H), 1.27 (m, 2H), 1.18 (m, 2H); ESIMS m/z 240.18 ([M+H]+); IR (thin film) 2922, 1630 cm−1.
Reaction SMILES: Cl[C:2]1C=C[C:5]([CH:8](CCCC)[C:9]([NH2:11])=O)=[CH:4][CH:3]=1.B#B.O1[CH2:22][CH2:21][CH2:20][CH2:19]1.[ClH:23].O1[CH2:28][CH2:27]CC1>>[Cl:23][C:19]1[CH:28]=[CH:27][C:22]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH2:9][NH2:11])=[CH:21][CH:20]=1
Reactant: Cl
Reactant: C1CCOC1
Reactant: CCCCC(C(N)=O)c1ccc(Cl)cc1
Agent: B#B
Product: NCCCCCCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
A solution of 16.4 g (0.073 mole) of 6-(p-chlorophenyl hexanamide (VI) in 30 ml. of dry tetrahydrofuran was added dropwise to a stirred solution of 170 ml of 1.0M diborane/tetrahydrofuran solution (Aldrich) at 0° C. under a nitrogen atmosphere. After addition, the mixture was stirred at 0° C. for 15 minutes, then warmed to reflux and kept there for 2.5 hours. The mixture was cooled to room temperature, and 85 ml of 6N hydrochloric acid was added cautiously to quench the reaction. The solvent was removed and the aqueous mixture was brought to pH 10 with 10% sodium hydroxide solution. The aqueous mixture was extracted three times with 60 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated leaving an oil. Distillation under reduced pressure afforded 10.4 g (67%) of VII as a colorless oil, bp. 108°-115° C. (0.3 torr).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1([CH2:12][OH:13])[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:1][N:2]([CH3:14])[C:3]1([CH2:12][O:13][C:20](=[O:21])[C:19]2[CH:18]=[C:17]([O:16][CH3:15])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=2)[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CN(C)C1(CO)CCCc2sccc21
Solvent: c1ccncc1
Product: COc1cc(C(=O)OCC2(N(C)C)CCCc3sccc32)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
15 ml of pyridine Containing 1.52 g of 4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiophene obtained in Example 1 was cooled with ice, and added with 1.82 g of 3,4,5-trimethoxybenzoylchloride. The reaction mixture was then stirred at room temperature for 14 hours. The solvent was removed under reduced pressure, and the residue was poured into water, followed by extracting with chloroform. The chloroform phase was washed with water and dried. The solvent was removed under reduced pressure, and the residue was crystallized from isopropyl ether to obtain 1.87 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][OH:22])[CH2:3]/[C:4](/[CH3:19])=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C(OCC)(=O)C>[C:26]([O:22][CH2:21][CH2:20][N:2]([CH3:1])[CH2:3]/[C:4](/[CH3:19])=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)CN(C)CCO
Reactant: C=C1CC(=O)O1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)OCCN(C)C/C(C)=C/c1ccc(Cc2cccnc2)cc1
Yield: 65.8 %

Procedure:
In 5 ml of ethyl acetate was dissolved 1.26 g of 2-[N-methyl-N-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyl]amino]ethanol, and to the resulting solution was dropwise added a mixture of 0.36 ml of diketene and 1 ml of ethyl acetate under reflux over one hour, after which the resulting mixture was subjected to reaction at the same temperature for 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 1.06 g (yield 65.8%) of colorless, oily 2-[N-methyl-N-[(E)-3-[4-(pyridine-3-ylmethyl)phenyl]-2-methylallyl]amino]ethyl acetoacetate.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>O1CCCC1.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CN1CCOCC1
Product: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.2 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(2-ethoxy-1 -methyl-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 89 ) (370 mg, 0.93 mmol) and N-methylmorpholine (170 μl, 1.54 mmol) in anhydrous tetrahydrofuran (15 ml) was cooled to 0° C., treated with isobutyl chloroformate (130 μl, 100 mmol) and stirred under a nitrogen atmosphere for 2.5 hours. O-(Trimethylsilyl)hydroxylamine (380 μl, 3.10 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (4 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane methanol) to afford the title compound as a colourless oil (330 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([N:7]([CH2:19][C:20](O)=[O:21])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:5][NH2:6].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][NH:6][C:20](=[O:21])[CH2:19][N:7]1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:23]
Reactant: COC(=O)C(CN)N(CC(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1CNC(=O)CN1S(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-amino-2-[carboxymethyl-(4-methoxybenzenesulfonyl)-amino]-propionic acid methyl ester trfluoracetic acid salt (2.11 grams, 6.1 mmol) in methylene chloride (5 ml) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.76 grams, 9.2 mmol) and triethyamine (3.4 ml, 24.4 mmol). The resulting mixture is stirred overnight, diluted with ethyl acetate and washed with 1N hydrochlori acid. The organic layer is dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with ethyl acetate) to provide 1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[H][H].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20]>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: ClCCCCCBr
Reactant: [H][H]
Reactant: N#Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCCCCl)cc1
Temperature: 25 °C

Procedure:
To a solution of 16.9 g (135 mmol) p-cyanophenol in 169 mL of dimethylformamide (DMF), cooled in an ice-bath is added in portions 6.5 g (135 mmol) sodium hydride (50% dispersion in oil). The reaction is stirred and allowed to warm-up to room temperature until no further hydrogen evolution is observed. The solution is then cooled in an ice-bath and a solution of 1-bromo-5-chloro-pentane 25 g (135 mmol) in 84 mL of dimethylformamide is added. The reaction is allowed to warm up to room temperature and stirred for 18 h. The reaction is then poured onto water and the resulting solid filtered off and dried to give 4-(5-chloropentoxy) benzonitrile, m.p. 52°-54° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14]O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:35][CH2:14][CH2:13][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(C(F)(F)F)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1cc(CCCBr)ccc1C(F)(F)F
Yield: 79 %

Procedure:
Compound 68-2 (2.83 g) was dissolved in methylene chloride (42 ml), triphenylphosphine (3.67 g) and N-bromosuccinimide (2.56 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.87 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4]Br.ClC1C(C)=C(C=CC=1)C[Br:16].[NH2:21][C:22]1[C:23]2[N:24]([C:28]([CH3:32])=[C:29]([CH3:31])[N:30]=2)[CH:25]=[CH:26][CH:27]=1>>[Br:16][C:2]1[C:3]([CH3:4])=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][NH:21][C:22]1[C:23]2[N:24]([C:28]([CH3:32])=[C:29]([CH3:31])[N:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(Cl)cccc1CBr
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: Cc1cccc(Cl)c1CBr
Product: Cc1nc2c(NCc3cccc(Br)c3C)cccn2c1C

Procedure:
Example 1.34 and 1.35 are prepared from a mixture of 2-chloro-6-methylbenzylbromide and 3-chloro-2-methylbenzylbromide. The yields are referred to 8-amino-2,3-dimethylimidazo[1,2-a]pyridine.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C(O)C>[Br:1][C:2]1[C:3]([N:9]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1nc(Br)cnc1Br
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: CN(C)C=Nc1nc(Br)cnc1Br
Yield: 99.3 %

Procedure:
A mixture of 3,6-dibromo-pyrazin-2-ylamine (15.37 g, 60.80 mmol) and N,N-dimethylformamide dimethyl acetal (10.1 mL, 76.00 mmol), suspended in ethanol (150 mL), is refluxed for 2 hours. The reaction mixture is evaporated in vacuo affording the title compound (18.6 g). 1H-NMR (400 MHz, CDCl3) δ (ppm) 3.20 (s, 3H), 3.21 (s, 3H), 7.93 (s, 1H), 8.48 (s, 1H). LCMS: Rt 3.81 min (99.1%), m/z (APCI) 307 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([O:37][C:38]2[CH:39]=[N:40][CH:41]=[N:42][CH:43]=2)[CH:36]=1)[C:30](OC)=[O:31].Cl>C1COCC1.CCOC(C)=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([O:37][C:38]2[CH:43]=[N:42][CH:41]=[N:40][CH:39]=2)[CH:36]=1)[C:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1)=[O:31]
Reactant: COC(=O)c1cc(Cl)cc(Oc2cncnc2)c1
Reactant: Nc1cc(F)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(F)ccn1)c1cc(Cl)cc(Oc2cncnc2)c1
Reaction time: 0.08 h
Yield: 38.5 %

Procedure:
2-Amino-4-fluoropyridine (254 mg, 2.27 mmol, 2.00 eq) was dissolved in THF (2.5 mL) in a flame-dried round bottom flask. A 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (4.76 mL, 2.27 mmol, 2.00 eq) was added dropwise and the reaction was stirred for 5 min. Compound 7 (300 mg, 1.13 mmol, 1.00 eq) was added as a solution in THF (2.5 mL) and the reaction was stirred for 30 min. The reaction was diluted with EtOAc, neutralized with 1N HCl and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 150 mg (38%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 11.12 (s, 1H), 9.07 (s, 1H), 8.75 (s, 2H), 8.39 (d, J=3.0 Hz, 1H), 8.16 (dd, J=5.0, 4.2 Hz, 1H), 7.88 (t, J=1.6 Hz, 1H), 7.80 (td, J=8.7, 31. Hz, 1H), 7.68 (t, J=2.0 Hz, 1H), 7.58 (t, J=2.1 Hz, 1H); [M+1]+: 345.2
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([NH2:4])=[O:3].Cl[C:10]([S:12]Cl)=[O:11]>C1(C)C=CC=CC=1>[O:11]=[C:10]1[S:12][N:4]=[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[O:3]1
Reactant: CCOC(=O)C(N)=O
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nsc(=O)o1
Yield: 64.2 %

Procedure:
A mixture of 99.7 g (0.85 mol) of ethyl oxamate and 552 g (4.23 mol) of chlorocarbonylsulfenyl chloride, prepared in accordance with British Pat. No. 1,079,348, in toluene was held at reflux for 5.25 hours and then was concentrated under vacuum. Benzene was added to the residue, and the solution was extracted twice with water, twice with 5% NaHCO3, again with water, and was dried (CaSO4) and concentrated under vacuum. The residual oil was filtered to remove sulfur and was crystallized twice from methylcyclohexane to give 95.61 g (64%) of white solid, mp 49°-50.5 C.