Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1>CN1CCCC1=O.O>[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:2]2[CH:3]=[C:4]([N:21]([CH:31]3[CH2:33][CH2:32]3)[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:37][CH2:36]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Temperature: 120 °C

Procedure:
6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (9 g, 18.6 mmol) was combined with trans-1,4-diaminocyclohexane (31.9 g, 279 mmol) in N-methyl-2-pyrrolidinone (50 mL) and heated at 80° C. for 16 hours and at 120° C. for 6 hrs. The reaction was cooled to room temperature, and water (200 mL) was added, and the solid collected via Buchner filtration. The crude product was purified with silica gel chromatography using a stepwise gradient of 10% methanol/chloroform to 25% methanol/chloroform/1% triethylamine to isolated foamy solid. The solid was suspended in water (400 mL) and collected with Buchner filtration (2×50 mL water wash) and dried for 16 hrs under reduced pressure to afford 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (10.2 g, 18.18 mmol, 98% yield) as a off white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.77 minutes. [M+H]=561.16.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].I[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Reactant: IC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ice-cooled methyl 6-bromo-1H-indazole-4-carboxylate (2 g, 7.84 mmol) in 30 mL of DMF was treated with NaH (60%, 345 mg, 8.63 mmol) and the mixture was stirred for 1 hr at 0° C. Iodocyclopentane (2.31 g, 11.8 mmol) was then added and the mixture was stirred at 100° C. overnight. After cooling to RT, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4, filtered and evaporated. Hexanes was added to the brown oil and it was purified using silica gel chromatography (eluent: Hex/EtOAc, gradient 0 to 25%). The less polar product was evaporated to give an orange oil, and was dried on hivac overnight. The product was confirmed to be the alkylated 1-isomer as suggested by 2D HNMR, and was collected as 807 mg (32%). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1H) 8.37 (s, 1H) 7.81 (d, J=1.52 Hz, 1H) 5.26 (quin, J=7.07 Hz, 1H) 3.95 (s, 3H) 2.08-2.17 (m, 2H) 1.93-2.01 (m, 2H) 1.82-1.92 (m, 2H) 1.64-1.73 (m, 2H); LCMS (ES+): m/z=323.3/325.3
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([O:48]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:47])=O)=[CH:42][CH:43]=3)[N:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1.C(O)(C(F)(F)F)=O>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([NH:6][C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:47])=[O:48])=[CH:42][CH:43]=3)[N:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (0.112 g, 0.445 mmol) in tetrahydrofuran (1.780 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (0.490 ml, 0.490 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 4-(4-chloro-2-methoxyphenyl)quinazoline-7-sulfonate (Intermediate AAAAAA; 0.230 g, 0.445 mmol) in THF (1.5 mL) was added drop wise, and the reaction was stirred for two hours. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on an 12-g Redi-Sep Gold column with 0-50% EtOAc/Heptane. The material was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated and purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 4-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.48 (s, 1H), 8.49 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.97 (dd, J=1.8, 8.7 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.39 (d, J=1.7 Hz, 1H), 7.25 (dd, J=1.8, 8.1 Hz, 1H), 3.72 (s, 3H). m/z (ESI) 434.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5](C)C)[CH3:3].[CH2:8](Cl)[CH:9]=[C:10]([CH3:12])C>CC(C)=O>[CH3:5][CH2:4][C:2](=[O:1])[CH:3]=[CH:8][CH2:9][CH2:10][CH3:12]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)=CCCl
Solvent: CC(C)=O
Product: CCCC=CC(=O)CC

Procedure:
Acetone under the reaction conditions forms mesityl oxide, and this then reacts with the prenyl chloride to produce the above isomers; in the same manner, acetone reacts with prenyl chloride to produce methyl heptenone.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydro-quinolin-2(1H)-one (1.50 g) in N,N-dimethylformamide (10 ml), potassium carbonate (1.85 g) and methyl iodide (0.63 ml) were added and stirred overnight at room temperature. Insoluble materials were filtered off and the filtrate was concentrated. The resulting residue was diluted with ethyl acetate and then washed sequentially with water, saturated aqueous sodium thiosulfate:brine (1:1) and brine, followed by distilling off the solvent under reduced pressure. The resulting residue was diluted with n-hexane, and the crystal was collected by filtration to give 7-methoxy-3,4-dihydroquinolin-2(1H)-one (1.38 g) as a colorless crystal. To a solution of 7-methoxy-3,4-dihydroquinolin-2(1H)-one thus obtained (1.38 g) in tetrahydrofuran (30 ml), lithium aluminum hydride (592 mg) was added under ice cooling, heated under reflux for 4.5 hours, and then stirred overnight at room temperature. The reaction mixture was diluted with 28% aqueous ammonia under ice cooling and filtered to remove insoluble materials. The filtrate was evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 9:1) to give the titled compound, i.e., 7-methoxy-1,2,3,4-tetrahydroquinoline (1.18 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[CH2:36]([NH:43][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a mixture of 2-bromo-4-methylthiazole-5-carboxylic acid (10.00 g, 45.03 mmol) and 1-(3-dimethyl)aminopropyl)-3-ethylcarbodiimide hydrochloride (12.09 g, 63.04 mmol) in tetrahydrofuran (170 mL) under nitrogen atmosphere was added N,N-diisopropylethylamine (17.46 g, 135.0 mmol). After the mixture was stirred at ambient temperature for 30 minutes, 1-hydroxybenzotriazole (8.52 g, 63.04 mmol) and benzylamine (6.76 g, 6.88 mL, 63.04 mmol) were added. The mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (500 mL), washed with water (2×100 mL) and brine (2×100 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate:petroleum ether, 2:1) to afford the title compound (11.91 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 9.92 (t, J=6.0 Hz, 1H), 7.34-7.25 (m, 5H), 4.46 (d, J=6.0 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 298.1 (M+1), 300.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[N+:27]([O-:29])=[O:28])[CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1c1ccc(C)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of Example 12C (625 mg, 4.03 mmol) in acetonitrile (5 mL) was added 1-fluoro-4-methyl-2-nitrobenzene (1.00 g, 4.03 mmol) and potassium carbonate (1.11 g, 805 mmol). The reaction was heated in an oil bath at 60° C. overnight. The solution was concentrated onto silica gel and purified via flash chromatography (0-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.55-7.60 (m, 1H), 7.22-7.43 (m, 7H), 3.55-3.65 (m, 1H), 3.41-3.59 (m, 2H), 3.36 (s, 3H), 3.09-3.21 (m, 1H), 2.77-2.88 (m, 1H), 2.22-2.62 (m, 7H); MS (APCI+) m/z 384 (M+H)+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH:26][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 57.4 %

Procedure:
A solution of 10.75 g (38.56 mmol) of trityl chloride is added, at 0° C., to a solution of 6 g (38.56 mmol) of L-serine methyl ester hydrochloride and 7.8 g (77.12 mmol) of triethylamine in absolute THF and this solution is left to stir at 0° C. for 4 h and then at room temperature for 2 days. The solvent is removed in vacuo and the residue is partitioned between dichloromethane and a 10% aqueous solution of citric acid. The phases are separated and the organic phase is washed with water and dried over sodium sulfate. Following filtration, the solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate=6/4. 8 g (58%) of (34.3) are obtained after concentrating the product fractions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([I:9])=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cn1
Temperature: 80 °C
Yield: 66.8 %

Procedure:
4-Chloropyridin-2-amine (0.142 g, 1.10 mmol) and N-iodosuccinimide (0.273 g, 1.22 mmol) were combined in 1.5 mL of acetic acid. The solution was sonicated briefly and then heated to 80° C. After 1 hour the solution was cooled to room temperature and then concentrated under vacuum. After adjusting the pH to ˜8/9 with aqueous ammonia, a light brown solid was collected by filtration. The solid was purified on a 12 g Combiflash column eluting with a gradient of DCM to 5% methanol/0.25% NH4OH (˜28% in water)/DCM. The fractions containing the product were combined and concentrated under vacuum to give 4-chloro-5-iodopyridin-2-amine (187 mg, 67%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.20 (1 H, s), 6.69 (1 H, s), 6.40 (2 H, s); LCMS-ESI (POS), M/Z, M+1: Found 254.9.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.[C:9]1([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CCCC)CCCC)CCC.[OH-].[Na+]>[CH2:7]([C:5]1[N:6]=[C:2]2[N:1]=[C:16]([OH:17])[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:21]([OH:22])[N:3]2[N:4]=1)[CH3:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CCc1nc(N)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: CCc1nc2nc(O)c(-c3ccccc3)c(O)n2n1
Reaction time: 0.5 h

Procedure:
A solution of 5.00 g 3-amino-5-ethyl-1,2,4-triazole and 15.00 g diethyl phenylmalonate in 18 mL N,N-dibutylbutan-1-amine was stirred at 185° C. over night. The solution was diluted with 5N NaOH solution, the resulting mixture was stirred for 30 min. The aqueous layer was washed with diethylether, acidified at 0° C. with concentrated HCl until precipitation of the product was complete. The precipitate was collected by filtration to yield the product, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([CH3:28])[CH2:27][O:26][CH2:25][CH2:24][NH:23]1.Cl.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:23]3[CH2:24][CH2:25][O:26][CH2:27][C:22]3([CH3:28])[CH3:21])[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CC1(C)COCCN1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cn1c(CCN2CCOCC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (119 mg, 0.40 mmol) in DCE (10 mL) was added 3,3-dimethylmorpholine.HCl (61 mg, 0.40 mmol), triethylamine (0.06 mL, 0.40 mmol) and powdered 4 Å molecular sieves. After stirring at room temperature for 4 h, sodium triacetoxyborohydride (171 mg, 0.80 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-7% MeOH in DCM) to give the title compound as a pale yellow oil (44 mg, 28%). LCMS (Method H): RT=2.45 min, [M+H]+ 395.5
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:19][CH3:20])[CH3:18])=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:19]([N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][O:13][C:12]1[CH:21]=[CH:22][C:9]([C:3]2([CH2:2][N:1]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[CH:10][CH:11]=1)[CH3:20]
Reactant: CCN(C)CCCOc1ccc(C2(CN)CCOCC2)cc1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C)CCCOc1ccc(C2(CN3CCOCC3)CCOCC2)cc1
Temperature: 60 °C
Yield: 56 %

Procedure:
To a stirred solution of 3-{4-[4-(aminomethyl)tetrahydro-2H-pyran-4-yl]phenoxy}-N-ethyl-N-methylpropan-1-amine (500 mg, 1.6 mmol) and bis(2-bromoethyl)ether (345 mg, 1.5 mmol) in anhydrous acetonitrile (50 mL) was added potassium carbonate (450 mg, 3.3 mmol). The mixture was heated to 60° C. overnight then concentrated in vacuo. The crude product was partitioned between dichloromethane (50 ml) and water (50 ml), the aqueous phase was extracted with dichloromethane (25 ml) and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude material was carried out with flash chromatography (silica gel, dichloromethane/methanol/aqueous ammonia 100:0:0 to 96:4:0.4) to afford the title compound as a clear colourless oil (315 mg, 0.84 mmol, 52%). 1H NMR (400 MHz CDCl3) δ 1.05 (t, 3H), 1.82-1.93 (m, 2H), 1.92-2.00 (m, 2H), 2.08-2.20 (m, 6H), 2.25 (s, 3H), 2.39 (s, 2H), 2.40-2.50 (q, 2H), 2.50-2.59 (m, 2H), 3.48-3.60 (m, 6H), 3.70-3.80 (m, 2H), 4.00 (t, 2H), 6.86 (d, 2H), 7.20 (d, 2H). LRMS APCI+ m/z 377 [MH]+. HRMS ESI+ m/z 377.2792 [MH]+.−
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29].C([O-])(=O)C.[K+].[CH:36]([NH2:38])=O.C(OC(=O)C)(=O)C>[Cu]I.C(OCCCC)(=O)C>[C:36]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29])#[N:38]
Reactant: NC=O
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
2-Bromo-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino) azobenzene (2.4 parts), copper (I) iodide (0.95 parts), anhydrous potassium acetate (1.5 parts), formamide (1.8 parts), acetic anhydride (2.0 parts) and n-butyl acetate (44 parts) are mixed together and heated, with stirring, to 110° C. during 15 minutes. The temperature is maintained at 110° C. for 2 hours when reaction is complete. The mixture is cooled to room temperature and poured into petroleum ether (boiling range 60-80° C.) (400 parts). The precipitate is collected, washed with petroleum ether (100 parts) and dried. 2-Cyano-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene is obtained in 95% yield.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=1.[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:15][CH:13]([C:10]2[CH:11]=[N:12][C:7]([O:6][CH2:5][CH2:4][C:3]([F:2])([F:16])[F:17])=[CH:8][CH:9]=2)[CH3:14])=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: CC(N)c1ccc(OCCC(F)(F)F)nc1
Reactant: Nc1nccc(C(=O)O)n1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCCC(F)(F)F)nc1
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (100 mg, a white solid) from 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (120 mg, 0.4 mmol, Amine-21, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (62 mg, 0.4 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4].S(Cl)([Cl:19])=O>CN(C)C=O.ClCCl>[Cl:19][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O
Yield: 99.9 %

Procedure:
To 14.2 g of N-(1-hydroxy-2,2,2-trichloroethyl)-2-hydroxybenzamide were added 100 ml of dichloromethane, 0.1 g of N,N-dimethylformamide and 7.2 g of thionyl chloride, and the reaction was effected while stirring under reflux for three hours. Excess thionyl chloride was distilled off together with the solvent under reduced pressure to obtain 15.1 g of N-(1,2,2,2-tetrachloroethyl)-2-hydroxybenzamide.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[Si:10]([CH3:13])([CH3:12])[CH3:11].[Li]CCCC.CON(C)[C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23]>C1COCC1.CCCCCC>[F:8][C:7]1[C:2]([F:1])=[C:3]([Si:10]([CH3:12])([CH3:11])[CH3:13])[CH:4]=[C:5]([CH3:9])[C:6]=1[C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(F)c(F)c([Si](C)(C)C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc([Si](C)(C)C)c(F)c(F)c1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (2,3-difluoro-5-methylphenyl)trimethylsilane (10 g, 0.05 mol) in anhydrous THF (100 mL) at −78° C., under nitrogen, was added dropwise a solution of 2.5 M n-BuLi in hexane (20 mL). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (13.6 g, 0.05 mol) in anhydrous THF (60 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-(2,3-difluoro-6-methyl-4-(trimethylsilyl)benzoyl)piperidine-1-carboxylate, which was purified by column chromatography on silica gel elating with hexane (2 g, 10%). 1H NMR δ 6.90 (m, 2H), 4.00 (m, 4H), 2.20 (s, 3H), 1.47 (s, 9H), 1.30 (m, 4H), 0.35 (s, 9H).