Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[H][H].C1(C)C=C(C)C=C(C)C=1[CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>O1CCCC1>[C:6]([CH:5]([C:3]#[N:4])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CCCCc2c(C)cc(C)cc2C)cc1
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CCCCc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A mixture of 10.30 g (1.1 eq) of 80% sodium hydride in mineral oil is washed twice with anhydrous tetrahydrofuran (to remove the mineral oil) and 400 mL of tetrahydrofuran are then added. This is cooled to 0° C. and a solution of 35.29 g (1.0 eq) of ethyl cyanoacetate in anhydrous tetrahydrofuran is added dropwise under nitrogen. The mixture is stirred vigorously at ambient temperatures until the evolution of hydrogen ceases and an anhydrous solution of 89.33 g (1.0 eq) of methyl 4-(4-mesitylbutyl)benzoate is then added in a dropwise fashion. The mixture is stirred at ambient temperatures for 12 hours, then at reflux temperatures for 6 hours, and then cooled. The solvent is removed under reduced pressure and diethyl ether is added. The organic phase is separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed with 1:4 ethyl acetate:hexane and the homogeneous fractions are combined and concentrated to yield methyl 4-(5-carboethoxy-5-cyanopentyl)benzoate as a liquid, IR (film) vmax 2915, 2860, 2255, 1730, 1609, 1571, 1432, 1413, 1368, 1320, 1178, 1105, 1019, 962, 853, 759, and 602 cm-1 ; 1H NMR (CDCl3) delta 7.95 (d, J=8.1 Hz, 2H, Ar), 7.24 (d, J=8.1 Hz, 2H, Ar), 4.25 (q, J=7.2 Hz, 2H, CH2CH3), 3.90 (s, 3H, CO2CH3), 3.46 (t, J=6.8 Hz, 1H, CHCN), 2.69 (t, J=7.5 Hz, 2H, benzyl), 1.93-2.00 (m, 2H, CH2CH), 1.54-1.72 (m, 4H, 2° aliphatic), 1.30 (t, J=7.3 Hz, 3H, CH2CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15].C1(C2C3C(=C(Cl)C=CC=3)CCN=2)C=CC=CC=1>>[C:12]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)Cl
Reactant: NCCc1ccccc1CO
Agent: Clc1cccc2c1CCN=C2c1ccccc1
Product: CCCC(=O)NCCc1ccccc1CO

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and butyryl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-butyrylamino-2-(2-hydroxymethylphenyl)ethane as an oil. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-n-propylisoquinoline-5-acetonitrile.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:15]=2[C:16]#[N:17])[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.C1COCC1.CCOC(C)=O.[Fe]>[NH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH2:12][C@H:8]2[CH2:9][CH2:10][CH2:11][N:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:7]2)[C:15]=1[C:16]#[N:17]
Reactant: CCCC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-((1-butyrylpiperidin-3-yl)methoxy)-6-nitrobenzonitrile (Example 1c, 9.92 g, 32.92 mmol) in acetic acid (60 mL) and THF (60 mL), was added iron powder (5.5 g. 98.76 mmol) at room temperature. The reaction mixture was heated to 70° C. and stirred for 1 hour then cooled to room temperature, diluted with EtOAc, filtered through Celite. The filtrate was concentrated under reduced pressure and then re-dissolved in EtOAc, washed with NaHCO3, water and brine, dried over MgSO4, filtered and evaporated. The residue was crystallized from DCM/EtOAc, to give the title compound as off white solid (9.92 g, 93% for 2 steps). MS 302 (MH+).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:53]=[CH:52][C:29]3[N:30]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:32][C:28]=3[CH:27]=2)=[CH:22][C:21]=1[CH:54]=O.[CH3:56][Si:57]([CH3:71])([CH3:70])[CH2:58][CH2:59][O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH2:69])[CH2:65][CH2:64]1)=[O:62].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C.ClCCl>[CH3:56][Si:57]([CH3:71])([CH3:70])[CH2:58][CH2:59][O:60][C:61]([N:63]1[CH2:64][CH2:65][CH:66]([NH:69][CH2:54][C:21]2[CH:22]=[C:23]([C:26]3[CH:53]=[CH:52][C:29]4[N:30]([C:33]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:31]=[N:32][C:28]=4[CH:27]=3)[CH:24]=[CH:25][C:20]=2[F:19])[CH2:67][CH2:68]1)=[O:62]
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(N)CC1
Reactant: O=Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)N1CCC(NCc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
Sodium triacetoxyborohydride (890 mg, 4.2 mmol) and acetic acid (126 mg, 4.2 mmol) were added to a solution of 5-(4-fluoro-3-formylphenyl)-1-trityl-1H-benzotriazole (1.0 mg, 2.1 mmol) and 4-amino-piperidine-1-carboxylic acid 2-trimethylsilanyl-ethyl ester (760 mg, 3.1 mmol) in dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane, and neutralized with careful addition of 1 M sodium carbonate solution. The layers were separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography provided 980 mg of product. LC/MS: Retention time, 3.27 and 3.34 min; (M+H)=712.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>O1CCCC1.CN(C)C=O>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]1)=[O:32]
Reactant: CCN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccco4)cc23)CC1
Yield: 73.1 %

Procedure:
To a solution of 0.780 gm (3.2 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)-1H-indole in 10 mL tetrahydrofuran and 10 mL dimethylformamide were added 0.536 mL (3.85 mMol) triethylamine followed by the dropwise addition of 0.348 mL (3.5 mMol) 2-furoyl chloride. After 18 hours the reaction mixture was cooled in an ice bath. The reaction mixture was the partitioned between 100 mL ethyl acetate and 100 mL 2N sodium hydroxide. The phases were separated and the aqueous extracted again with ethyl acetate. Organic extracts were combined and washed sequentially with 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (2 mm silica), eluting with 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give 0.789 gm (73.1%) of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[C:24]4=[CH:27][S:28][CH:29]=[C:23]4[NH:22][C:21]3=[O:30])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:38]([O:42][CH3:43])(=[O:41])[CH:39]=[CH2:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[C:24]4=[CH:27][S:28][CH:29]=[C:23]4[N:22]([CH2:40][CH2:39][C:38]([O:42][CH3:43])=[O:41])[C:21]3=[O:30])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2cscc2c(=O)n1CCCCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: C=CC(=O)OC
Product: COC(=O)CCn1c(=O)n(CCCCCN2CCC(=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Yield: 57 %

Procedure:
The title compound was prepared by starting with 3-[5-[4-(bis(4-fluorophenyl)methylene]piperidin-1-yl]pentyl]thieno[3,4-d]pyrimidine-2,4-dione. This material (11.0 g, 21 mmol) was reacted with methyl acrylate as described in Example 1 to produce 8.06 g (57%) of methyl 3-[3-[5-[4-[bis(4-fluorophenyl)methylene]piperidin-1-yl]pentyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate as a yellow oil. A portion of this material was converted to its crystalline oxalate salt by dissolving in acetone and treating with 1.1 equivalents of oxalic acid. There was obtained a cream-colored solid, mp 129°-136° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][C:37]([CH3:41])([CH3:40])[CH2:38][NH2:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:39][CH2:38][C:37]([CH3:41])([CH3:40])[CH3:36])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCC(C)(C)C)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzoic acid (30 mg, 0.062 mmol) in dichloromethane (2.0 mL) and DMF (0.5 mL) were added (2,2-dimethylpropyl)amine (10.9 μL, 0.093 mmol), HBTU (25.6 mg, 0.068 mmol) and triethylamine (35.0 μL, 0.25 mmol). The reaction mixture was stirred at room temperature for 16 hours then was applied to HPLC to afford the titled compound 14.9 mg (44%). LC-MS m/z 552 (M+H)+; 1H-NMR (MeOD) 0.99 (s, 9H), 2.33 (s, 3H), 2.76 (s, 6H), 3.15 (s, 2H), 3.24 (s, 2H), 3.54 (m, 2H), 4.16 (m, 2H), 7.18 (m, 2H), 7.51 (m, 2H), 7.72 (s, 1H), 7.89 (m, 1H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2([CH:26]([F:28])[F:27])[CH2:25][CH2:24]2)[CH2:10][CH2:9]1)=[O:7])C.Cl>C(O)C.O>[F:27][CH:26]([F:28])[C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)C1(CCCCCCCCCCCCC2(C(F)F)CC2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(CCCCCCCCCCCCC2(C(F)F)CC2)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a solution of potassium hydroxide (0.63 g, 11.2 mol) in 90% ethanol (5 mL) was added product of Example 38 (0.5 g, 1.3 mmol) at 40° C. and the reaction mass was stirred at 40° C. over a period of 16 h. The crude product obtained upon evaporation of the solvent was diluted with water (5 mL), acidified to pH=2 (1N HCl) and extracted with ethyl acetate (100 mL×3). The crude product obtained upon evaporation of the solvent was purified by silica gel column (5% ethyl acetate in petroleum ether) to give product as white solid 0.32 g (69.5%). mp: 54.0° C.-54.8° C.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16](N=C=O)[CH:15]=1>C1(C)C=CC=CC=1>[N-:27]=[C:28]=[O:29].[N-:27]=[C:28]=[O:29].[C:19]1([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: [N-]=C=O
Product: c1ccc(Cc2ccccc2)cc1
Reaction time: 4 h

Procedure:
1.5 g of tributyl phosphine were added at room temperature to a solution of 1,000 g (4.0 mols) of diphenylmethane-4,4'-diisocyanate (MDI) in 2,000 g of toluene. After a short time, the dimeric MDI separated out of the solution and the temperature gradually rose to from 30° to 35° C. The reaction mixture was stirred for an additional 4 hours and the dimerization catalyst was then stopped by adding 1.5 g of toluene sulfonic acid methyl ester. The solid MDI "dimer" which formed was filtered by suction. After drying for about 5 hours at from 70° to 80° C., about 800 g of MDI "dimer" were obtained in the form of a fine powder. This powder was insoluble in practically all solvents. The decomposition point was above 250° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.O>CN(C=O)C.CCOC(C)=O>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: BrCc1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Methyl 3-(4-hydroxyphenyl)propanoate (0.5 g, 2.77 mmol) in dry DMF (10 ml) is added potassium carbonate (0.76 g, 5.55 mmol) followed by 4-(bromomethyl)pyridine hydrobromide (0.7 g, 2.77 mmol). The reaction mixture is stirred at room temperature overnight then poured into water (80 ml) and extracted with EtOAc (40 ml). The organic phase is washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield a dark brown oil. Chromatography (SiO2, EtOAc) yields 3-[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid methyl ester as a colourless oil; [M+H]+ 272.0
Reaction SMILES: [P:1]([Cl:14])(Cl)(=[O:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[CH2:15]([OH:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCCCCCCCCC.CN1C=CN=C1>ClCCl.CCCCCC>[P:1]([Cl:14])(=[O:12])([O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[O:31][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Cl)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCO
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCOP(=O)(Cl)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
p-Nitrophenyl phosphorodichloridate (75 g, 0.29 mol) in anhydrous dichloromethane (300 mL) was added to a 1 L, three necked, round-bottomed flask with stir bar that had been purged with N2. A solution of hexadecanol (71.03 g, 0.29 mol) and N-methylimidazole (23.35 mL, 0.29 mol) in anhydrous dichloromethane (250 mL) was added dropwise over a period of 2 hours. The reaction mixture was stirred for an additional 1 hour before pouring into a 1 L separatory funnel. N-methylimidazole hydrochloride salts separated at the bottom as an oil and were removed from the funnel. Dichloromethane was removed from the mixture at less than 30° C. under vacuum to give an amber oil which was taken up in hexane (400 mL) and placed in a freezer overnight. The reaction mixture was then thawed and the soluble portion was filtered to remove the crystals of p-nitrophenyl phosphorodichloridate. The solvent was removed from the filtrate via rotary evaporation at less than 35° C. to give n-hexyl p-nitrophenyl phosphorochloridate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[N:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([NH:28][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:19])([F:29])[F:30])=[O:18])[CH2:14][CH2:15]2)[N:3]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)O)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a suspension of 1-[4-chloro-6-(methylamino)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (885 mg, 3.25 mmol, 1.00 equiv) in DMF (32 ml) at room temperature, {[2-(trifluoromethyl)phenyl]methyl}amine (456 μL, 3.25 mmol, 1.00 equiv), EDCI (748 mg, 3.90 mmol, 1.20 equiv), HOBT (527 mg, 3.90 mmol, 1.00 equiv), and diisopropylethylamine (DIEA, 2.80 ml, 16.3 mmol, 5.00 equiv) were added. Stirring was continued overnight at room temperature. The reaction mixture was partitioned between 1:1 water and ethyl acetate (200 ml). The product was extracted three times with ethyl acetate (50 ml). The ethyl acetate extracts were combined and washed successively with saturated ammonium chloride (100 ml), water (100 ml), and saturated sodium chloride (100 ml). The ethyl acetate solution was dried with Na2SO4, filtered, and concentrated under reduced pressure to yield 1.23 g (88%) of the title compound. MS ES+): m/e 428.7 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH3:11][O:12][CH2:13][CH2:14]CBr.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:12][CH:13]([CH3:14])[CH2:17][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COCCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(C)COc1ccccc1[N+](=O)[O-]

Procedure:
2-Nitrophenol, 3-bromopropyl methyl ether, anhydrous potassium carbonate and acetone were reacted according to the procedure outlined in Example 1 to yield 2-methoxypropoxynitrobenzene, which was reduced to the corresponding aniline. The aniline was isolated by vacuum distillation.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:29](OCC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].[OH2:34].[NH2:35][NH2:36]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:29](=[O:34])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1)[CH3:3]
Reactant: NN
Reactant: O
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C)cc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: CO
Product: Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(CN(C)C)cc2)cc1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 11 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine monohydrate (1 mL) and methanol (3 mL) was stirred at 10° C. for 2.5 h. The mixture was purified by prep-HPLC to obtain the title compound as a white solid (14 mg, yield 11%). LC-MS (ESI) m/z: 411 (M+1)+; 1H-NMR (400 MHz, CD3O) δ (ppm): 2.18 (s, 3H), 2.31 (s, 6H), 3.57 (s, 2H), 4.25-4.27 (d, J=8.4 Hz, 1H), 4.72-4.74 (d, J=8.4 Hz, 1H), 6.95-7.02 (m, 4H), 7.19-7.29 (m, 5H), 7.55-7.57 (m, 1H), 7.62-7.64 (t, J=8 Hz, 1H).
Reaction SMILES: [O:1]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=O.[C:26]([NH:29][NH2:30])([NH2:28])=[NH:27].[ClH:31]>CO.Cl.Cl.NNC(N)=N>[ClH:31].[ClH:31].[C:26]([NH:29][N:30]=[CH:19][C:18]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[N:30][NH:29][C:26](=[NH:27])[NH2:28])[CH:17]=1)(=[NH:28])[NH2:27]
Reactant: COc1ccc(C=O)cc1OCCCOc1cc(C=O)ccc1OC
Reactant: N=C(N)NN
Agent: Cl
Solvent: CO
Product: COc1ccc(C=NNC(=N)N)cc1OCCCOc1cc(C=NNC(=N)N)ccc1OC
Yield: 86.5 %

Procedure:
3,3'-(trimethylenedioxy)di-p-anisaldehyde (1.032 g), aminoguanidine hydrochloride (0.829 g), and aminoguanidine dihydrochloride (0.02 g) were heated in 95% methanol (10.5 mL) for 16 hr. Cooling and filtration gave 1.372 g of 3,3'-(trimethylenedioxy) di-p-anisaldehyde bis(amidinohydrazone) dihydrochloride, mp 233°-5° C.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1C=CC=[CH:8][CH:7]=1)([O-:3])=[O:2].Cl.CO[NH2:15].[C:16](=[O:19])([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1.O>[N+:1]([CH2:4][CH:5]([NH2:15])[C:6]1[O:19][CH:16]=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: O=C([O-])O
Reactant: CON
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(C[N+](=O)[O-])c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.1 %

Procedure:
To a solution of nitrostyrene 23 (14.9 g, 0.1 mol) in tetrahydrofuran (100 mL) was added solid O-methylhydroxylamine hydrochloride (9.2 g, 0.11 mol) and sodium hydrogen carbonate (9.24 g, 0.11 mol). The reaction mixture was diluted with water (25 mL) and stirred at room temperature overnight under argon. The reaction mixture was mixed with ethyl acetate (150 mL) and washed with water (1×50 mL). The aqueous layer was back washed with ethyl acetate (1×50 mL). The combined organic layers were washed with brine (1×75 mL), filtered through 1PS filter paper and stripped to give 18.6 g (95% yield) of 34I as brown oil. Hplc analysis showed a purity of 98%. NMR (CDCl3) δ 7.5(S, 5H), 6.1(S br, 1H), 4.5–5.1(m, 3H), 3.5(S, 3H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].[NH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1>CC(C)=O>[F:5][C:4]([F:7])([F:6])[C:3]1[N:9]=[C:10]2[N:14]([CH:2]=1)[CH:13]=[CH:12][S:11]2
Reactant: Nc1nccs1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CC(C)=O
Product: FC(F)(F)c1cn2ccsc2n1
Temperature: 25 °C

Procedure:
3-Bromo-1,1,1-trifluoroacetone (11.0 mmol) is added to a solution of 2-aminothiazole (10.0 mmol) in acetone (20 mL) and the mixture is stirred at reflux for 20 h. The obtained precipitate is filtered off, treated with hydrobromic acid (2.0 M, 40 mL), stirred at reflux for 1 h and cooled to RT. The mixture is made basic by addition of ammonium hydroxide solution (15%) and the resulting free base is crystallized from EtOH to give the desired product. LC-MS: tR=0.78 min; [M+H]+=192.95.