Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([O:42][C:43]3[C:48]([C:49]([NH:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([C:59]([CH3:64])([CH3:63])[C:60]([OH:62])=O)=[CH:55][CH:54]=4)=[O:50])=[CH:47][CH:46]=[CH:45][N:44]=3)=[CH:41][C:36]=2[O:35][CH2:34]1>O1CCCC1>[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([O:42][C:43]3[N:44]=[CH:45][CH:46]=[CH:47][C:48]=3[C:49]([NH:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([C:59]([C:60](=[O:62])[NH2:3])([CH3:63])[CH3:64])=[CH:55][CH:54]=3)=[O:50])=[CH:41][C:36]=2[O:35][CH2:34]1
Reactant: CC(C)(C(=O)O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C(N)=O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.71 g), 1-hydoxybenzo-triazole hydrate (1.24 g), and were combined and suspended in anhydrous tetrahydrofuran (45 mL). N,N-Diisopropylethylamine (5.93 mL) was added to the suspension, which was stirred for 0.5 h. 2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic acid (0.340 g) was added to the suspension, and the reaction mixture stirred at ambient temperature overnight. Anhydrous ammonia gas was bubbled into the solution for 20 min, generating a white precipitate, and then the reaction mixture was concentrated in vacuo. Water was added to the reaction mixture, and it was extracted with dichloromethane (7×30 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate) and further purified by silica gel chromatography (ethyl acetate:hexanes 17:3) to yield the title compound (0.150 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[S:31]1[C:35]([C:36]([NH:38][NH2:39])=O)=[CH:34][N:33]=[CH:32]1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:36]([C:35]3[S:31][CH:32]=[N:33][CH:34]=3)=[N:38][N:39]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1cncs1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2cncs2)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (263 mg, 0.903 mmol) was suspended in dichloromethane (DCM) (2 mL) before treating with triethyloxonium tetrafluoroborate (189 mg, 0.994 mmol) and stirring for 45 mins at RT under argon before adding 1,3-thiazole-5-carbohydrazide (I109)(155 mg, 1.084 mmol) and stirring for 18 hours (overnight). The DCM was removed and the residue was suspended in 1-butanol (2.0 mL) and heated at 110° C. for 3 hours. The reaction was cooled to RT, diluted with DCM (30 ml) and washed with saturated sodium bicarbonate solution (20 ml). The aqueous layers were extracted with DCM (2×20 ml), combined, washed with brine (20 ml), dried (MgSO4), filtered and evaporated to afford a yellow gum of crude product which was purified by MDAP. Desired fractions were isolated and solvent evaporated to afford a colourless gum which solidified when triturated with Et2O to afford a pale yellow solid of desired product in 100 mg.
Reaction SMILES: [O-2].[Mg+2].[OH:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH:9]([OH:16])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][OH:15].[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[C:35](Cl)(=[O:53])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>O1CCOCC1.O>[OH:3][CH2:4][CH2:5][CH2:6][N:7]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:8][CH:9]([OH:16])[CH2:10][N:11]([CH2:12][CH2:13][CH2:14][OH:15])[C:35](=[O:53])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: OCCCNCC(O)CNCCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCO)CC(O)CN(CCCO)C(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Yield: 76.7 %

Procedure:
Into other 500 ml rounded-flask, 4.0 g of magnesium oxide and 80 g of distilled water were placed. While stirring resultant mixture, 10.4 g of N,N'-bis(3-hydroxypropyl)-2-hydroxy-1,3-propanediamine was added, and then was added 250 ml of 1,4-dioxane. 13.4 g of palmitoyl chloride was added portionwise to the resulting mixture over 1 hour under violent stirring at a room temperature. After stirring for 2 hours at 10° C., 14.7 g of oleoyl chloride was gradually added dropwise over 1 hour. After stirring again for 2 hours, the mixture was filtered, and then the filtrate was mixed with 200 ml of chloroform and washed twice with 200 ml of distilled water. The organic phase was cooled to produce solid material, which was recovered by filtration. The solid material was dried and recrystallized from acetone to give 26.5 g of the title compound as white powder, which was identified by IR and NMR. The results are shown in Table 4.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[ClH:49]>CO>[ClH:49].[CH3:1][C:2]1[C:10]2[N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: Cc1cccc2[nH]c(/C=C/c3ccccc3)nc12
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cccc2c1nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from (E)-4-methyl-2-styryl-1H-benzimidazole and 2-fluoropyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from 2-propanol/isopropyl ether to give the titled compound. MW: 347.85; mp: 218.0-225.0° C.; 1H-NMR (DMSO) δ: 8.85-8.80 (1H, m), 8.45 (1H, d, J=16.1 Hz), 8.27 (1H, ddd, J=7.7,7.7, 1.5 Hz), 7.86 (1H, d, J=7.7 Hz), 7.77 (1H, dd, J=7.7, 4.5 Hz), 7.70-7.65 (2H, m), 7.48-7.42 (3H, m), 7.41-7.33 (3H, m), 7.17 (1H, d, J=16.1 Hz), 2.76 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OCc1ccccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccccn4)c(C)c3C)c2cc1OC
Yield: 70.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-pyridylmethanol (25 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 63%).
Reaction SMILES: [NH:1]1[C:4](=[O:5])[CH:3]2[CH2:6][CH2:7][C:8]3[C:13]([CH:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[ClH:14].[CH3:15][OH:16]>>[ClH:14].[NH2:1][CH:2]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:3]1[C:4]([O:16][CH3:15])=[O:5]
Reactant: CO
Reactant: O=C1NC2c3ccccc3CCC12
Agent: Cl
Product: COC(=O)C1CCc2ccccc2C1N
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To 2.36 g of 2a,3,4,8b-tetrahydronaphtho[1,2-b]azet-2(1H)-one was added 50 ml of a 10% hydrogen chloride/methanol solution, followed by stirring at 90° C. for 6 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure. To the obtained residue were added methanol and diethyl ether, and the insoluble material was collected by filtration and dried to obtain 3.08 g of methyl rac-(1S,2S)-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylate hydrochloride.
Reaction SMILES: [NH2:1][CH:2]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH:25]2[CH2:27][CH2:26]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1)=[O:4].CI.[CH3:39]N(C=O)C.[H-].[Na+]>C(OCC)(=O)C>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH:2]([NH:1][CH3:39])[C:3]([N:5]2[CH2:6][CH2:7][CH:8]([N:11]([CH:25]3[CH2:26][CH2:27]3)[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=3)(=[O:13])=[O:14])[CH2:9][CH2:10]2)=[O:4])=[CH:34][CH:33]=1)#[N:36]
Reactant: N#Cc1ccc(CC(N)C(=O)N2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CNC(Cc1ccc(C#N)cc1)C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
A mixture of N-{1-[2-amino-3-(4-cyanophenyl)propionyl]piperidin-4-yl}-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide (see Example 13, 300 mg, 0.58 mmol), MeI (830 mg, 5.9 mmol), and DMF (5 mL) was treated with NaH (67 mg, 60% mineral oil, 1.8 mmol) at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with water (5 mL) and brine (5 mL). The organic layer was evaporated and the residue was purified by column (silica gel, EtOAc/hexane 1/1) to give the title compound N-{1-[3-(4-cyanophenyl)-2-methylamino-propionyl]piperidin-4-yl}-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide (26) as free base, which was dissolved in 1,4-dioxane (4 mL), and treated with HCl solution (4N in 1,4-dioxane, 1 mL). The resulting mixture was triturated with ethyl ether (10 mL), and the precipitated material was collected by filtration, washed with ethyl ether (2×5 mL), and dried under vacuum for 12 hours to afford the title compound 26 as a HCl-salt (white solid, 0.2 g, yield 65%). 1H NMR (HCl-salt, CD3OD): δ 8.12-8.19 (m, 2H), 8.03 (d, 1H, J=9.2 Hz), 7.86 (dd, 1H, J=7.7 & 7.8 Hz), 7.77 (dd, 2H, J=4.3 & 8.1 Hz), 7.49 (dd, 2H, J=1.9 & 8.3 Hz), 4.76-4.79 (m, 1H), 4.52-4.59 (m, 1H), 3.96-4.06 (m, 1H), 3.6-3.7 (m, 1H), 3.34-3.38 (m, 1H), 3.06-3.14 (m, 2H), 2.68-2.72 (m, 3H, NCH3), 2.34-2.65 (m, 2H), 1.52-2.02 (m, 4H), 0.62-0.92 (m, 4H). LC: 100%. MS (e/z): 535 (m+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH2:19][N:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:21])(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:29]/[C:30](/[CH3:36])=[CH:31]\[C:32]([O:34][CH3:35])=[O:33]>>[CH3:15][C:13]1[NH:29][C:30]([CH3:36])=[C:31]([C:32]([O:34][CH3:35])=[O:33])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=2[Cl:1])[C:12]=1[C:11]([O:17][CH2:18][CH2:19][N:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:21])=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN(C)Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc(Cl)c1Cl
Yield: 59.6 %

Procedure:
To a solution of 350 mg of 2,3-dichlorobenzaldehyde in 2 ml of 2-prapanol were added 510 mg of 2-(N-benzyl-N-methylamino)ethyl acetoacetate and 250 mg of methyl 3-aminocrotonate. The mixture was refluxed for 12 hours. The solvent was distilled off in vacuo, and then the residue was chromatographed over silica gel with a mixture of chloroform and ethyl acetate as eluting solvents to yield 600 mg of the desired compound. The physical properties are as follows.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Br:10][C:11]1[CH:12]=[C:13]([S:17]([Cl:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>CCOCC>[ClH:20].[Br:10][C:11]1[CH:12]=[C:13]([S:17]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: NCCN1CCOCC1
Solvent: CCOCC
Product: Cl
Product: O=S(=O)(NCCN1CCOCC1)c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
4-(2-Aminoethyl)morpholine (2.54 g) was added, dropwise to a stirred solution of 3-bromobenzenesulphonyl chloride (5.0 g) in ether (50 ml) at 5° C. The resulting suspension was stirred for 30 minutes and filtered to afford the sub-titled compound as a solid (4.45 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:22])[C:10]([C:13]([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)([CH3:15])[CH3:14])=[N:11][N:12]=1.C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:22])[C:10]([C:13]([N:16]([CH3:25])[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)([CH3:15])[CH3:14])=[N:11][N:12]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)NC1CCCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C1CCCC1)C(C)(C)c1nnc(-c2ccccc2Cl)n1C
Product: Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 286.8 %

Procedure:
To an acetonitrile (10 ml) solution of N-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}cyclopentanamine (120 mg) were added 36% formaldehyde solution (92 μl) and sodium triacetoxyborohydride (239 mg), followed by stirring at room temperature for 6 hours. After chloroform, a 1M aqueous sodium hydroxide solution, and distilled water were added to the reaction solution, the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=25:1). 4M hydrogen chloride-ethyl acetate (0.38 ml) was added to an ethyl acetate (15 ml) solution of the resulting product and, after stirring at room temperature for 30 minutes, the precipitated solid was collected by filtration to obtain 146 mg of N-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}-N-methylcyclopentanamine dihydrochloride (colorless solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[S:13][C:14]3[N:15]=[C:16]([NH2:27])[N:17]=[C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:19]=3[N:20]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](O)=[O:36])=[CH:31][CH:30]=1>>[NH2:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:35](=[O:36])[CH2:34][O:33][C:32]3[CH:38]=[CH:39][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH2:25][CH2:26]2)[C:19]2[N:20]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:13][C:14]=2[N:15]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCCCc3ccc(F)cc3)sc2n1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(CCCCc3ccc(F)cc3)sc2n1
Yield: 23 %

Procedure:
This compound was prepared from 2-(4-(4-fluorophenyl)butyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 23%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>CO.C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: Cn1c(C2CCNCC2)nc(-c2ccncc2)cc1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(c2nc(-c3ccncc3)cc(=O)n2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 3-methyl-2-piperidin-4-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.74 mmol) in methanol/acetic acid was added sodium triacetoxyborohydride (1.1 mmol) and 0.5 mL of 37% aqueous formaldehyde. The reaction was stirred at room temperature for 30 min. The solvent was removed under vacuum and the residue partitioned between dichloromethane and 1N NaOH. The product was purified on silica. M+1=284.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].F[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]>C(O)C>[CH:1]([NH:4][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropyl amine (3 mL) is added to a solution of 1-fluoro-2-nitrobenzene (500 mg, 3.55 mmol) in ethanol. The reaction may be stirred at room temperature overnight and concentrated. The residue may be purified, for example by Biotage column chromatography to give N-isopropyl-2-nitroaniline (590 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[N:13]=[C:12](Cl)[N:11]=2)=[C:4]([CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.N1C=CC=C[CH:32]=1>C1COCC1>[CH3:32][C:29]1[CH:30]=[C:23]([NH:22][C:12]2[N:11]=[C:10]([NH:9][C:5]3[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[CH3:21])[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[N:13]=2)[CH:24]=[CH:25][C:26]=1[C:27]#[N:28]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(Br)cc(C)c1Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reactant: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C)c([N+](=O)[O-])c(Nc3c(C)cc(Br)cc3C)n2)ccc1C#N
Reaction time: 48 h
Yield: 61.9 %

Procedure:
To a solution of N-(4-bromo-2,6-dimethylphenyl)-2-chloro-6-methyl-5-nitropyrimidin-4-amine (18.5 g, 49.8 mmol) and 4-aminobenzonitrile (5.9 g, 49.8 mmol) in THF (250 ml) at ambient temperature was added pyridine (4.0 ml, 49.8 mmol). The reaction mixture was heated to reflux and stirred for 2 days under argon. Upon completion half of the solvent was removed in vacuo. The solids were dissolved in methanol and 250 ml brine was added. The aqueous layer was extracted with ethyl acetate (3×125 ml) and the collected organic fractions were dried with MgSO4, filtered and reduced in vacuo. The resulting solids were slurried in methanol and Et2O and filtered. The filtrand was washed 3× with cold Et2O and dried overnight under vacuum to give 14.4 g (64%) of methyl 4-(4-(4-bromo-2,6-dimethylphenylamino)-6-methyl-5-nitropyrimidin-2-ylamino)benzonitrile as a brown powder. m/z=453 [M+1].
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:7]=1)/[CH:2]=[CH:3]/[CH3:4].C(N(CC)CC)C.[C:29](Cl)(=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:31]([O:30][C:29]([N:19]1[CH2:20][CH2:21][N:16]([C:8]2[N:7]=[C:6]([O:5][CH2:1]/[CH:2]=[CH:3]/[CH3:4])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:17][CH2:18]1)=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C/C=C/COc1nc(N2CCNCC2)nc2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C/COc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12

Procedure:
To a solution of 4-[trans-(2-buten-1-yl)oxy]-2-(1-piperazinyl) quinazoline (1.20 g) in dry methylene chloride (12 ml) is added triethylamine (1.77 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (0.73 ml) in dry methylene chloride (5 ml). The mixture is stirred under ice-cooling for 3 hours. The reaction mixture is diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (elutant, chloroform) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[trans-(2-buten-1-yl)oxy]quinazoline (1.57 g) as crystals.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH:16]([C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([C:29](=O)[CH2:30][CH3:31])[CH:27]=2)[O:22][C:21]([CH3:36])([CH3:35])[CH:20]=1)([CH3:18])[CH3:17]>>[F:7]/[C:6](=[C:29](/[C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:33][CH3:34])[O:22][C:21]([CH3:36])([CH3:35])[CH:20]=[C:19]2[CH:16]([CH3:17])[CH3:18])\[CH2:30][CH3:31])/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCC(=O)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Product: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (605 mg, 2.50 mmol) and 1-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-propan-1-one (Compound 58, 148 mg, 0.50 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([O:20][CH3:21])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:21][O:20][CH:6]1[CH2:7][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:9][CH2:10][CH:4]([NH2:1])[CH2:5]1
Reactant: COC1CC(N=[N+]=[N-])CCN(c2c([N+](=O)[O-])cnn2C)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC1CC(N)CCN(c2c([N+](=O)[O-])cnn2C)C1
Temperature: 65 °C

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol, Intermediate 18 (0.85 g, 3.0 mmol) in DMF (5 mL) cooled to 0° C. under nitrogen, was added sodium hydride (60% in mineral oil, 133 mg, 3.3 mmol) and the resulting mixture was stirred for 10 min. Iodomethane (0.37 mL, 6.0 mmol) was added and the mixture stirred at room temperature for 16 hr. Water (200 mL) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave 5-azido-3-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as an oil (0.76 g). This azide (0.76 g, 2.6 mmol) in THF (15 mL) and water (3 mL) was treated with triphenylphosphine (0.71 g, 2.7 mmol). The mixture was heated at 65° C. for 16 hr and the solvents were removed under reduced pressure to afford 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine. This amine was suspended in DCM (40 mL) and di-tert-butyl dicarbonate (1.13 g, 5.2 mmol) and DIPEA (1.36 mL, 7.8 mmol) were added. After stirring at room temperature for 16 hr the solvent was removed under reduced pressure and the residue dissolved in DCM (40 mL). Water (20 ml) was added and the organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave tert-butyl 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (0.84 g, 74% over three steps) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=4.3 Hz, 1H), 5.39 (d, J=7.9 Hz, 1H), 4.21-3.94 (m, 1H), 3.84 (s, 3H), 3.56-3.42 (m, 2H), 3.35-3.03 (m, 6H), 2.28-1.89 (m, 4H), 1.46 (s, 9H).