Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:36][CH3:37])[C:19]([Cl:38])=[CH:18][N:17]=1>>[Cl:38][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:36][CH3:37])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CC1(C)CCCOc2c(N)cccc21
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in the analogous manner to Example 179. Product was isolated as a tan solid (12 mg, 10%). LCMS (m/e) 523 (M+H); 1H NMR δ 8.28 (d, 1H, J=7.8 Hz), 8.21 (d, 1H, J=9.1 Hz), 8.03 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 6.89-6.97 (m, 2H), 6.58 (s, 2H), 4.01 (m, 2H), 3.90 (s, 3H), 3.22 (m, 4H), 2.61 (m, 4H), 2.38 (s, 3H), 2.07 (m, 2H), 1.69 (m, 2H), 1.39 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][C:6]#[N:7].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](N)[CH2:25][NH2:26].ClC1C=CC=CC=1Cl>C(Cl)Cl>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][C:6]1[NH:26][CH2:25][CH2:24][N:7]=1
Reactant: N#CCNc1ccc(Cl)cc1Cl
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Clc1ccccc1Cl
Product: Clc1ccc(NCC2=NCCN2)c(Cl)c1
Reaction time: 1.17 h
Yield: 84.1 %

Procedure:
A mixture of 21.5 grams (g) of 2,4-dichloroanilinoacetonitrile, 23.3 g of ethylenediamine p-toluenesulfonate and 75 milliliters (ml) of 1,2-dichlorobenzene was heated with stirring in a round-bottomed three-necked flask at from about 140°-170° C. for about 70 minutes under a small flow of nitrogen. The reaction mixture was cooled and then diluted with methylene chloride. The mixture was cooled and then filtered, which gave 35.1 g of 2-((2,4-dichloroanilino)methyl)-2-imidazoline p-toluenesulfonate as white crystals. The p-toluenesulfonate salt was slurried in water and CH2Cl2 and then basified. The CH2Cl2 layer was separated and the remaining aqueous portion extracted with CH2Cl2 and then CHCl3. The extracts were combined, treated with diatomaceous earth and activated charcoal, and then filtered. Concentrating the filtrate to dryness, left 17.0 g of crystals. Recrystallization from ethylene dichloride gave 14.0 g of purified 2-((2,4-dichloroanilino)methyl)-2-imidazoline as white crystals, having a melting point (m.p.) of 154°-156° C.
Reaction SMILES: Cl.O.[O:3]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]3[C:14](=[CH:15][C:4]1=2)[C:13](=O)[CH2:12][CH2:11][CH2:10]3>[Zn].C1(C)C=CC=CC=1>[O:3]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]3[C:14](=[CH:15][C:4]1=2)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: O=C1CCCc2cc3c(cc21)OCC3
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: c1c2c(cc3c1CCO3)CCCC2

Procedure:
An amalgam of zinc and mercuric chloride (72 g Zn and 7.1 g HgCl2) is added to a mixture containing 120 ml of concentrated hydrochloric acid, 57 ml of water, 30 g of the compound of Example 1 and 71 ml of toluene, with stirring.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[CH:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[N:7]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:30])=O>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[CH:5]=[C:4]([Cl:30])[N:3]=1
Reactant: N#Cc1cccc(-c2cc(=O)[nH]c(N)n2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: N#Cc1cccc(-c2cc(Cl)nc(N)n2)c1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
2.00 g (9.42 mmol) of 3-(2-amino-6-oxo-1,6-dihydropyrimidin-4-yl)benzonitrile (from example LV) are suspended in 10 ml of phosphoryl chloride. Over a period of one hour, 180 mg (1.23 mmol) of N,N-diethylaniline are added dropwise, and over a period of a further hour, the mixture is heated to 115° C. The mixture is then heated at RF for one hour. The mixture is allowed to cool to RT and poured into ice water. The mixture is extracted twice with ethyl acetate and the solvent is removed under reduced pressure. The residue is suspended in water. With ice-cooling, the solution is neutralized by addition of conc. sodium hydroxide solution. Saturated sodium carbonate solution is added, and the mixture is stirred at RT overnight. The precipitate is filtered off with suction and washed with water. This gives the title compound.
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:39])=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([NH:30][C:31]([C:33]3[N:34]=[N:35][N:36]([OH:38])[CH:37]=3)=[O:32])[CH2:24][C@@H:25]([OH:29])[C:26]([OH:28])=[O:27])=[CH:18][CH:17]=2)[CH:15]=1.CC(C)=O.CCN(CC)CC>>[C:1]([O:6][CH2:7][O:38][N:36]1[CH:37]=[C:33]([C:31]([NH:30][C@H:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([C:14]3[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=3[F:39])=[CH:17][CH:18]=2)[CH2:24][C@@H:25]([OH:29])[C:26]([OH:28])=[O:27])=[O:32])[N:34]=[N:35]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Reactant: CCCC(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCC(=O)OCOn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Chloromethyl butyrate (13.7 mg, 100 μmol) was added to a solution of (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (30.0 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol). Et3N (18.6 μL, 134 μmol) was added and the resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (6.0 mg). MS m/z [M+H]+ calc'd for C25H26ClFN4O7, 549.15. found 549.1.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:16]>C(#N)C>[Br:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(Br)ccc2c(O)ccnc12
Solvent: CC#N
Product: Cc1c(Br)ccc2c(Cl)ccnc12
Temperature: 90 °C

Procedure:
To a flask charged with 7-bromo-8-methylquinolin-4-ol (1.00 g, 4.20 mmol) was added Acetonitrile (21.00 ml) and POCl3 (0.411 ml, 4.41 mmol) and the resulting suspension heated to 90° C. for 1.5 hrs affording a brown solution and near complete conversion to desired product. The mixture was added to a cooled solution of sat. aq. NaHCO3 affording a tan precipitate which was collected via vacuum filtration and washed with water and dried under high vacuum affording product as a tan solid. m/z (ESI) 258.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]([O:47][C:48](=[O:60])[C@H:49]([OH:59])[C@H:50]([NH2:58])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:46]>C(Cl)Cl>[CH2:45]([O:47][C:48](=[O:60])[C@H:49]([OH:59])[C@H:50]([NH:58][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Br:1])[CH:3]=1)[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:46]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1
Reaction time: 1 h

Procedure:
3-Bromo-4-fluorobenzoic acid (109 mg, 497 μmol, 1.0 eq.), DIPEA (273 μL, 3.2 eq.), HATU (189 mg, 497 μmol, 1.0 eq.), and (2R,3R)-3-amino-2-hydroxy-4-phenyl-butyric acid ethyl ester (129 mg, 497 μmol, 1.0 eq.) were combined in DCM (2 mL) and stirred for 1 hour. The crude reaction was then chromatographed (0-80% EtOAc/hexanes gradient) to yield (2R,3R)-3-(3-bromo-4-fluoro-benzoylamino)-2-hydroxy-4-phenyl-butyric acid ethyl ester.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1>>[NH2:37][C@@H:34]1[CH2:35][CH2:36][N:32]([CH2:29][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:8]4[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=4[CH3:13])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:31])[CH:15]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=2)[CH2:33]1
Reactant: N[C@@H]1CCNC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CC[C@@H](N)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using the product of Example 75 step i) and (R)-pyrrolidin-3-ylamine.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH2:4][CH2:3]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[Cl:34].C(N(CC)CC)C>C1COCC1>[Cl:34][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:25]=1[F:24])[C:29]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([F:1])[CH2:3][CH2:4]2)=[C:12]([C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH:13]=1)=[O:30]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCC(F)CC1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(F)c(Cl)c2)ccc1OCCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.8 %

Procedure:
A mixture of 4-[2-(4-fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (80 mg, 0.25 mmol), 4-fluoro-3-chlorobenzoyl chloride (48 mg, 0.25 mmol), and triethylamine (0.3 mL) in THF (3 mL) was stirred at r.t. for 10 min. The solvent was concentrated in vacuo and the crude was purified by HPLC to give the title compound (58 mg, 50%) as a white solid as TFA salt. 1H NMR (acetone-d6, 400 MHz) δ 2.02-2.24 (m, 4H), 3.08-3.18 (m, 2H), 3.32-3.42 (m, 2H), 3.63 (t, J=4.55 Hz, 2H), 3.80 (s, 3H), 4.59 (t, J=4.55 Hz, 2H), 4.91-5.03 (m, 1H), 6.30 (d, J=1.77 Hz, 1H), 7.23 (d, J=8.84 Hz, 1H), 7.43-7.51 (m, 2H), 7.81 (t, J=2.27 Hz, 1H), 7.91-7.97 (m, 1H), 8.02-8.08 (m, 1H), 8.18 (dd, J=2.53, 7.33 Hz, 1H), 9.71 (s, 1H). Exact mass calculated for C24H25ClF2N4O2 503.1, found 504.1/506.1 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>C(O)C>[CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[N:24][OH:25])[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCN(CC=C)CC(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCN(CC=C)CC(=NO)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
2-(Diallylamino)-1-(4-fluorophenyl)ethanone (13.38 g, 57.36 mmol) is dissolved in ethanol (250 mL) and sodium acetate (5.7 g) is added followed by hydroxylamine hydrochloride (5.23 g, 74.6 mmol). The reaction is warmed to 70° C. for 2.5 hours then stirred at room temperature for 16 hours. The mixture is concentrated and the resulting residue is purified by silica gel flash chromatography eluting with ethyl acetate/hexanes (gradient 0-100%). The isolated material is repurified a second time to give the title compound (7.76 g, 54.5%). ES/MS (m/e): 249 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[C:19](F)(F)S(OC)(=O)=O>ClCCl>[CH3:19][N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2)c1=O
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cn(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 21.1 %

Procedure:
To a solution of ethyl 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (1000 mg, 5.0 mmol) in dichloromethane (10 mL) was added methyl trifluoromethanesulfonate (1200 mg, 7.3 mmol). The red solution was stirred at room temperature. After 14 h, the mixture was partitioned between dichloromethane and NaHCO3 (sat). The aqueous was extracted with dichloromethane (2×). The combined organic was dried over Na2SO4, concentrated and purified on silica. The product was triturated with EtOAc-hexane-CHCl3 to give the pure product as crystals (260 mg, 21%). Calc'd for C12H12N2O3, 232.08; MS (ESI pos. ion) m/z: 233 (MH+). 1H NMR (400 MHz, CHLOROFORM-d): 1.36 (t, J=7.04 Hz, 3H), 3.39 (s, 3H), 4.32 (q, J=7.17 Hz, 2H), 7.32 (d, J=7.43 Hz, 2H), 7.42 (t, J=7.34 Hz, 1H), 7.50 (t, J=7.73 Hz, 2H), 7.99 (s, 1H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])([CH3:3])[CH3:2].CO>[C].[Pd].C(OCC)(=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:8]([O:7][CH2:6][CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])=[C:9]([CH:15]=1)[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(C)NCCOc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)NCCOc1ccc(N)cc1NS(C)(=O)=O
Yield: 93.1 %

Procedure:
2′-[2-(Isopropylamino)ethoxy]-5′-nitromethanesulfonanilide (26.1 g) was dissolved into mixed solvents of methanol (200 ml) and ethyl acetate (200 ml) and subjected to hydrogenation reaction with 10% palladium carbon catalyst at ambient pressure. After completion of hydrogenation reaction, catalyst was removed by filtration. Filtrate was concentrated to dryness under vacuum to obtain 5′-amino-2′-[2-(isopropylamino)ethoxy]methanesulfonanilide (22 g) as brownish solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:17][CH:13]1[CH2:16][CH2:15][CH2:14]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: NC1CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2cnccc2nc1NC1CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A mixture of 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol), cyclobutanamine (47.0 μL, 0.550 mmol) and DIPEA (260 μL, 1.500 mmol) was stirred at 0° C. for 15 min then at rt for 30 min. Saturated aqueous NH4Cl was added to the mixture and the product was extracted with EtOAc. The combined organic layers were filtered through a pad of silica (EtOAc wash) and the filtrate was concentrated to afford 3-chloro-N-cyclobutylpyrido[3,4-b]pyrazin-2-amine (116.1 mg, 99%) as a yellow solid, which was used without further purification. ESI-MS m/z [M+H]+ 235.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])[C:2]1C=CC=CC=1>C(O)C.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])[CH3:2]
Reactant: NC(=O)c1cc(OCc2ccccc2)ccc1NCCN1CCN(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc(NCCN2CCN(c3ccccc3)CC2)c(C(N)=O)c1
Yield: 45.4 %

Procedure:
5-Benzyloxy-2-(2-[4-phenyl-1-piperazinyl]ethylamino)benzamide (1.8 g) in 35 ml ethanol was hydrogenated using 1 g 5% Pd-C catalyst. The mixture was heated to boiling and filtered. The filtrate was cooled and the solid filtered and washed to give 0.7 g product, m.142-3.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.I[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH2:15][CH2:16][OH:17])[CH:1]=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: OCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(OC)c1OCCO
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Syringaldehyde (1.0 g,5.49 mmole), 2-iodo-1-ethanol (1.90 g,10.98 mmole) and potassium carbonate (1.90 g, 13.77 mmole) were added to 15 ml dry DMF and stirred for 24 hours at 80° C. under an argon atmosphere. The reaction mixture was added to 100 ml H2O and acidified with 10% HCl. The product was extracted into CHCl3, dried over MgSO4, and concentrated to an oil in vacuo. The remaining oil was purified by flash column chromatography using 1:1 hex/ethyl acetate as eluent (1.009 g, 81%). NMR: (CDCl3) 3.23,t,1H; 3.73,m,2H; 3.93,s,6H; 4.20,t,2H; 7.13,s,2H; 9.87,s,1H M.S. (CI): 227 (100%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[ClH:22].O1CCOCC1>>[ClH:22].[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(C2CCCN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1CCC(C2CCCN2)CC1
Yield: 100 %

Procedure:
To a mixture of tert-butyl 2-(piperidin-4-yl)pyrrolidine-1-carboxylate (400 mg, 1.57 mmol) in dry DMF (2.0 mL) at 0° C., was added NaH (132 mg, 3.30 mmol, 60% in mineral oil) in small portion. The reaction mixture was then warmed to room temperature with stirring for another 1 h. 2-iodopropane (2.0 mL) was added. The resulting mixture was stirred at room temperature for 24 h and then poured into the ice-water (20 mL). The resultant mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel chromatography eluting with a 5-10% gradient of MeOH in DCM to afford tert-butyl 2-(1-isopropylpiperidin-4-yl)pyrrolidine-1-carboxylate (302 mg, 65% yield). A solution of tert-butyl 2-(1-isopropylpiperidin-4-yl)pyrrolidine-1-carboxylate (302 mg, 1.02 mmol) in sat. HCl/dioxane (5 mL) was stirred at room temperature for 8 h. After removal of the solvent, 1-isopropyl-4-(pyrrolidin-2-yl)piperidine hydrochloride (232 mg, 100% yield) as yellow solid was obtained. LCMS (ESI) m/z: 197.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:20]=[C:21]4[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]4[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Product: CN1c2cc(OCc3ccc(Oc4ccc(Cl)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((6-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and 7-chloro-1,2,2-trimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1.C(Cl)CCCCCC[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH2:3]([OH:11])[CH2:4][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)CCCCCCCCCCCl
Product: CC(C)CCCCCCCCCCO

Procedure:
This compound was prepared from 4-hydroxybenzoic acid methylester and isotridecylchloride, initially obtained from isotridecanol (an oxalcohol prepared from tetrapropylene) using known techniques. The product recovered exhibited a refractive index of
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36][CH2:37][O:38][CH3:39])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2[CH:32]=O)[CH3:21].O>CN(C)C=O>[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36][CH2:37][O:38][CH3:39])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2/[CH:32]=[CH:11]/[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH3:21]
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: CCOP(=O)(CC(=O)N1CCCCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c(/C=C/C(=O)N3CCCCC3)cc(OC)c(OCOC)c12
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
0.15 g of 60% sodium hydride was suspended in 20 ml of N,N-dimethylformamide, to which 1.15 g of N-(diethoxyphosphoryl)acetylpiperidine was gradually added at room temperature. After stirring for 10 minutes, a solution of 800 mg of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde in N,N-dimethylformamide (10 ml) was gradually added. After stirring for 20 minutes, water was added, followed by extraction with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the resultant residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain 1.1 g of the titled compound as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11]>ClCCl.[O-2].[Mn+4].[O-2]>[CH:2]1([OH:1])[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:9][CH2:10][O:11]1
Reactant: OCCc1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: OC1OCCc2ccccc21
Reaction time: 18 h
Yield: 53.3 %

Procedure:
Manganese(IV) oxide (1.43 g) was added to a solution of 2-(2-hydroxymethyl-phenyl)-ethanol (0.5 g) in dichloromethane (25 mL) and stirred for 18 hours under nitrogen. The reaction was filtered through celite, the filter pad washed with dichloromethane (2×20 mL), and the combined filtrates evaporated. Purification on silica, eluting with a gradient of iso-hexane:ethyl acetate [1:0 to 4:1], afforded the subtitle compound as a yellow oil (263 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[S:21].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[C:25]2/[C:23](=[O:24])[NH:22][C:20](=[S:21])[S:19]/2)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(/C=C2\SC(=S)NC2=O)ccc1OCc1ccccc1

Procedure:
4-Benzyloxy-3-methoxy-benzaldehyde (29 g) was dissolved in acetic acid (16 g) and then rhodanine (16 g) and sodium acetate (36 g) added into. The solution was refluxed for one hour. The reaction solution was poured into water. The solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:14](=[O:15])[C:13]([F:20])([F:19])[F:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1cc(N)cc(OC)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Yield: 97.4 %

Procedure:
To 3,5-dimethoxyaniline (20 g, 131 mmol) dissolved in anhydrous tetrahydrofuran (90 mL) was added 4-(dimethylamino)pyridine (1.6 g, 13.1 mmol) and ethyl trifluoroacetate (47 mL, 392 mmol). After refluxing 48 hours, the cooled reaction mixture was concentrated and partitioned between ethyl acetate (300 mL) and 2N hydrochloric acid (100 mL). The ethyl acetate layer was washed with water (100 mL), dried using anhydrous sodium sulfate, and concentrated to yield N-(3,5-Dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (31.8 g, 98%) as pale yellow solid.