Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH2:15])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[O:17]1[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]1.ClC(Cl)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][CH2:23][CH:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCN)s1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ncc(CCNCC2CCOCC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask was charged with compound 14.1 (200 mg, 100 mol %), tetrahydro-pyran-4-carbaldehyde (100 mol %), and dichloroethane. To this was added NaBH(OAc)3 (150 mol %) and the resulting slurry was stirred at room temperature for 2 hours. The solvents were removed in vacuo and the residue was re-suspended in EtOAc and H2O. The organic layer was washed sequentially with saturated sodium bicarbonate, H2O, and brine. The organic layers were combined, dried over Na2SO4, and concentrated to give (5-{2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-thiazol-2-yl)-carbamic acid tert-butyl ester (compound 33.1) as an oil which was used in the next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:15])(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.[S-:16][C:17]#[N:18].[NH4+].[O:20]([C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.CN(C=O)C.CC(C)=O>[O:20]([C:27]1[CH:28]=[C:29]([NH:30][C:17]([NH:18][C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:15])=[S:16])[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N#C[S-]
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=C(O)c1cccnc1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC(=S)Nc1cccc(Oc2ccccc2)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (2.8 mL, 32 mmol) is added to a suspension of nicotinic acid (3.7 g, 30 mmol) in methylene chloride (35 ml) followed by 2 drops of DMF. The reaction is refluxed for 1.5 h and all the volatiles are removed on a rotovap. Alternatively, rather than convert nicotinic acid to the acid chloride, commercially available nicotinyl chloride hydrochloride may be used. The solid is resuspended in methylene chloride/acetone (1:1) (50 ml) and an acetone (10 ml) solution of ammonium thiocyanate (3.5 g, 45 mmol) is added. The reaction is stirred for 1 h at room temperature followed by the addition of 3-phenoxy aniline. The stirring is continued over night at room temperature. The solvent is evaporated and the residue suspended in water (100 ml) and extracted with methylene chloride (3×75 ml). The organic layers are combined, dried over sodium sulphate, filtered to remove any insoluble materials and evaporated. The residue is purified by column chromatography on silica gel and crystallized from methanol to give the desired product. MP: 144.5-145.5° C., 1H NMR (300 MHz, DMSO): δ 12.330 (s, 1H), 11.93 (s, 1H), 9.07 (s, 1H), 8.80 (m, 1H), 8.300 (d, 2H, J=8.1 Hz), 7.955 (s, 1H), 7.81 (d, 1H, J=9.0 Hz), 7.57 (m, 1H), 7.299 (d, 1H, J=9.0 Hz), 4.13 (t, 2H, J=6.2 Hz), 1.77-1.72 (m, 2H,), 1.44-1.34 (m, 4H), 0.92-0.87 (t, 3H, J=7.1). MS (APCI) m/z 350.1 [M+H]+.
Reaction SMILES: C1(CN)(CN)CCCCC1.[CH:11]1([CH2:19][NH2:20])CC[CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1.[C@H]1(CN)CC[C@H](CN)CC1.[C:31]([OH:40])(=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[NH2:18][CH2:17][CH2:14][CH2:13][CH2:12][CH2:11][CH2:19][NH2:20].[C:31]([OH:40])(=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: NCC1CCC(CN)CC1
Agent: NCC1(CN)CCCCC1
Agent: NC[C@H]1CC[C@H](CN)CC1
Agent: O=C(O)CCCCC(=O)O
Product: NCCCCCCN

Procedure:
Polyamides derived from cyclohexanebis (methylamine) are known in the prior art. In U.S. Pat. No. 3,012,994 polyamides derived from the condensation of 1,3- or 1,4-cyclohexanebis(methylamine) and a dicarboxylic acid are described. These polyamides possess good stability and strength properties and are described as having relatively high melting points; for example, the polyamide of trans-1, 4cyclohexane-bis(methylamine) and adipic acid has a crystalline melting point of 345° C., whereas nylon 66 formed from hexamethylene diamine and adipic acid has a melting point of only 264° C. However, the high melting point advantage of these polyamides also gives rise to certain inherent disadvantages. For example, polyamides having crystalline melting points much above about 300° C. tend to decompose into degradation products prior to melting. As a result filaments formed from these high melting polyamides generally have poor processability and inferior properties. Although lower melting polyamides can be obtained with trans-1,4cyclohexanebis(methylamine) by condensation with longer chain carboxylic acids, the use of the longer chain acids results in a decrease in the dimensional stability of the resulting polyamide. An object of the present invention is to provide polyamides derived from components comprising a cyclohexanebis(alkylamine) which have good dimensional stability and which have substantially lower melting points than the corresponding polyamides derived from cyclohexanebis(methylamine).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38]([O:40]C)=[O:39])[CH:34]=[CH:35][CH:36]=1)[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38]([OH:40])=[O:39])[CH:34]=[CH:35][CH:36]=1)[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCCN3CCCC3=O)Cc3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCCN3CCCC3=O)Cc3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-33 (50 mg) and lithium hydroxide (20 mg) were added to tetrahydrofuran (5 ml) and water (1 ml), and the same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 39 mg (80%); MS APCI+ve 568 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[F:33])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH:6]1[C:18]([OH:20])=[O:19].S(Cl)([Cl:36])=O.[CH3:38]O>>[ClH:36].[ClH:36].[OH:1][CH:2]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[F:33])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH:6]1[C:18]([O:20][CH3:38])=[O:19]
Reactant: COc1ccc2ncc(F)c(C(O)CCC3CCN(C(=O)OC(C)(C)C)CC3C(=O)O)c2c1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)C1CNCCC1CCC(O)c1c(F)cnc2ccc(OC)cc12
Product: Cl
Reaction time: 48 h

Procedure:
A solution of 1.26 g of (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylic acid in 50-cm3 of methanol was cooled to a temperature in the region of −25° C. with stirring and under an inert atmosphere. 1.6-cm3 of thionyl chloride were added to this solution over 25 minutes. The mixture was brought to a temperature in the region of 20° C., while the stirring was continued for a further 48 hours. The reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C., taken up in 100-cm3 of toluene and the mixture was again concentrated-under reduced pressure (5 kPa). The residue was taken up in 50-cm3 of diisopropyl ether, triturated and concentrated to dryness under reduced pressure (5 kPa). 1.17 g of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate dihydrochloride were obtained in the form of a yellow powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[N:51]=[CH:52][C:53]([C:56]2[S:60][C:59]([C:61]#[N:62])=[CH:58][CH:57]=2)=[N:54][CH:55]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[N:54][C:53]([C:56]3[S:60][C:59]([C:61]#[N:62])=[CH:58][CH:57]=3)=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: N#Cc1ccc(-c2cnc(N)cn2)s1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3ccc(C#N)s3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A solution of triphenylphosphine (50.0 mg, 0.191 mmol) in methylene chloride (2 mL) cooled to 0° C. was treated with N-bromosuccinimide (35.0 mg, 0.197 mmol). The reaction mixture was stirred at 0° C. for 5 min and then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 51.0 mg, 0.154 mmol). The reaction mixture was allowed to warm to 25° C. over 15 min. The reaction mixture was then treated with 5-(5-amino-pyrazin-2-yl)-thiophene-2-carbonitrile (47.0 mg, 0.232 mmol) followed by pyridine (30.0 uL, 0.371 mmol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then diluted with methylene chloride and washed with a dilute aqueous hydrochloric acid solution. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH, 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(5-cyano-thiophen-2-yl)-pyrazin-2-yl]-3-cyclopentyl-propionamide (44.4 mg, 55.9%) as a yellow foam: mp 101–107° C. (foam to gel); (ES)+-HRMS m/e calcd for C24H23ClN4O3S2 (M+H)+515.0973, found 515.0974.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[C:10]2[C:17]([CH3:18])=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[Br:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[N:35][C:36]#[N:37])OC2C=CC=CC=2)[CH:23]=[CH:24][CH:25]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:26]/[C:27](/[N:6]2[CH2:7][CH:2]([CH3:1])[N:3]([C:9]3[C:10]4[C:17]([CH3:18])=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:4][CH:5]2[CH3:8])=[N:35]\[C:36]#[N:37])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c[nH]c2ncnc(N3C[C@@H](C)NC[C@@H]3C)c12
Reactant: N#CN=C(Nc1cccc(Br)c1)Oc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CC(C)N(/C(=N/C#N)Nc4cccc(Br)c4)CC3C)c12
Temperature: 150 °C
Yield: 19 %

Procedure:
The dimethyl piperazine from step A (80 mg, 0.32 mmol), phenyl N-3-bromophenyl-N′-cyanocarbamimidate, from Example 5, step A, (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.20 ml) were added to isopropanol (10 ml). The mixture was heated at 150° C. for 20 min in a microwave, then concentrated under vacuum. The material was purified prep HPLC (Sunfire C18 30×250 mm column, 10-100% MeCN:H2O (10 mM NH4OAc), 18 min., 45 ml/min) to give (E)-N-(3-bromophenyl)-N′-cyano-2,5-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (29 mg, 0.062 mmol, 19%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[CH2:7]O.[BrH:11].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>ClCCl>[Br-:11].[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[CH2:7][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1oc(C)c(CO)c1C
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1oc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Product: [Br-]
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
2,4,5-Trimethyl-3-carbethoxyfuran (40 g.) prepared in accordance with Helv. Chim. Acta., v. 15, 1112 (1932), was dissolved in ether (200 ml.) and added to a cooled slurry of lithium aluminum hydride (10 g.) in ether (200 ml.) After stirring a further 16 hours at room temperature a saturated, aqueous solution of sodium sulfate was added followed by the addition of magnesium sulfate (50 g.). The solids were filtered off and the solvents were concentrated to give crude alcohol, 2,4,5-trimethyl-3-hydroxymethyl furan (31 g.). A solution of this alcohol (4.2 g.) in dichloromethan (10 ml.) was added to a cooled slurry of triphenylphosphine hydrobromide (10 g.) in dichloromethane (40 ml.) and then left at room temperature for 15 minutes. Ether was then added and the solids formed were crystallized from a 1:5 parts by volume mixture of methanol and ethylacetate to give pure (2,4,5-trimethyl-3-furyl) methyl triphenylphosphonium bromide (10.2 g.) m.p. 223°-224°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]>[C:13]1([N:11]2[CH:10]=[CH:9][N:8]=[C:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Ic1ccccc1
Reactant: c1ccc(-c2ncc[nH]2)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ccnc2-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
2-(2-pyridyl)imidazole (6.91 g), iodobenzene (11.47 g), Cs2CO3 (25 g), and copper powder (15 g) were mixed in 60 mL anhydrous DMF in a 250 mL round bottom flask equipped with a magnetic stirrer and a reflux condenser. The mixture is degassed with N2 for 15 minutes at room temperature and then refluxed under N2 in an oil bath for 24 hours. The resulting mixture was cooled to room temperature and suction-filtered to remove the solid byproduct. The filtrate was extracted with EtOAc (3×100 mL). The combined organic layer was washed with H2O (2×100 mL) and then with saturated NaCl (2×150 mL), and subsequently dried with anhydrous Na2SO4. Evaporation of the solvent gave crude 1-phenyl-2(2-pyridyl)imidazole. The crude product is generally pure enough to use in making redox mediators, although the crude product may be further purified using a silica gel column and eluting with MeOH/CHCl3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cl[Mg]Cc1ccc(Cl)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1

Procedure:
To a solution of p-chlorobenzylmagnesium chloride in ethyl ether (prepared from 16 parts of p-chlorobenzyl chloride and 3 parts of magnesium turnings in 100 parts of ethyl ether) is added dropwise a solution of 19 parts of N-benzyl-4-piperidone in 50 parts of ethyl ether, the reaction vessel being cooled in an ice bath during the addition. When the addition is complete, mixture is refluxed for 2 hours, cooled, and the Grignard decomposed with saturated ammonium chloride solution. Evaporation of the ethyl ether gives N-benzyl-4-p-chlorobenzyl-4-hydroxypiperidine. ##STR13##
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[C:21]([C:26]#[N:27])=[N:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH:4]1[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8]([O:12][C:20]3[C:21]([C:26]#[N:27])=[N:22][CH:23]=[CH:24][N:25]=3)[CH:9]=[C:10]([CH3:11])[C:5]1=2)[CH3:18]
Reactant: N#Cc1nccnc1Cl
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nccnc3C#N)cc(C)c21
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.0 g, 4.0 mmol) and 3-chloro-pyrazine-2-carbonitrile (0.84 g, 6.0 mmol) in DMF (24 mL) was added cesium carbonate (2.68 g, 8.8 mmol). The mixture was heated to 80° C. for 2 hrs. The reaction was cooled down, diluted with H2O, acidified to pH 3 with aqueous HCl (1N). The mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (silica, Hexanes/Ethyl acetate=1:4) affording the title compound (1.30 g, 92%) as a white solid. 1H NMR (CDCl3) δ 8.40 (d, 1H), 8.29 (d, 1H), 7.36 (d, 1H), 7.11 (d, 1H), 5.69 (dd, 1H), 4.81 (s, 1H), 4.20 (q, 2H), 3.11 (dd, 1H), 2.44 (dd, 1H), 2.39 (s, 3H), 1.26 (t, 3H). MS found: (M+H)+=354.
Reaction SMILES: [CH3:1][N:2]([C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.O1CCCC1.[BH4-].[Na+].O>CO>[CH3:1][N:2]([C:14]1[N:15]=[CH:16][CH:17]=[CH:18][N:19]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCOc1ccc(CO)cc1)c1ncccn1
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzaldehyde (16.6 g) in methanol (40 ml)-tetrahydrofuran (40 ml) was added sodium borohydride (1.22 g) in portions at 0° C. After stirring for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residual crystals were recrystallized from ethyl acetate-bexane to obtain 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzylalcohol (15.3 g, yield 91%) as colorless crystals. m.p. 73-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][CH2:28][CH2:29]Cl)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C(=O)([O-])O.[Na+].[CH3:36][NH:37][CH3:38].O1CCCC1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][CH2:28][CH2:29][N:37]([CH3:38])[CH3:36])[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccn(CCCCl)c34)cc2Cl)c1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Product: Cl
Temperature: 25 °C
Reaction time: 26 h

Procedure:
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (560 mg) was dissolved in 2.0 M dimethylamine-tetrahydrofuran solution (5 mL), and the mixture was stirred at room temperature for 26 hrs. A 2.0 M dimethylamine-tetrahydrofuran solution (5 mL) was further added and the mixture was stirred at room temperature for 20 hrs. A 2.0 M dimethylamine-tetrahydrofuran solution (10 mL) was further added, and the mixture was stirred at room temperature for 24 hrs. After concentration of the reaction mixture under reduced pressure, saturated aqueous sodium hydrogen carbonate (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (35 mL×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→20:80), and 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the obtained amorphous solid. After concentration under reduced pressure, the residue was recrystallized from ethanol-ethyl acetate to give the title compound (428 mg).
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.C[Si](C)(C)[NH:16][C:17]1[C:18]([CH3:25])=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1.[F:28][C:29]([F:36])([F:35])[C:30](OCC)=O>C1CCCCC1>[CH3:24][O:23][C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][CH:21]=1)[NH:16][C:30]([C:29]([F:36])([F:35])[F:28])=[CH:25]2
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(N[Si](C)(C)C)c(C)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: COc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
Tetramethylethylenediamine (TMEDA) (49 g, 0.42 mole), under nitrogen, is treated with n-butyl lithium (168 mL of 2.57 N in hexanes, 0.42 mole) at 0° C., stirred for 0.5 hour at room temperature, treated dropwise with N-(trimethylsilyl)-4-methoxy-o-toluidine (40.0 g, 0.19 mole), heated at reflux temperature for 4 hours, cooled to -78° C., diluted with dry cyclohexane, treated dropwise with ethyl trifluoroacetate (45 g, 0.23 mole), stirred at -78° C. for 0.5 hour, warmed to room temperature and quenched with saturated NH4Cl solution. The mixture is extracted with diethyl ether. The combined extracts are washed sequentially with saturated NH4Cl and brine, dried over Na2SO4 and concentrated in vacuo to give a brown oil residue. The oil is chromatographed (silica gel/10% ethyl acetate in hexanes) to give the title product as white needles, 5.0 g (12% yield), mp 60° C. (after recrystallization from pentane), identified by IR, 1HNMR, 13CNMR, 19FNMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:25][C:26]1[CH:36]=[CH:35][C:29](/[CH:30]=[CH:31]/[N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH:30]([C:29]2[CH:35]=[CH:36][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:31][N+:32]([O-:34])=[O:33])[CH2:7][CH2:8][N:9]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(F)cc1
Reactant: CCOC(=O)C1CCN([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)CC1
Product: CCOC(=O)C1(C(C[N+](=O)[O-])c2ccc(F)cc2)CCN([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)CC1
Yield: 77 %

Procedure:
As described for example 1b, cis-rac-1-[2-(4-fluoro-phenyl)-cyclohexyl]-piperidine-4-carboxylic acid ethyl ester (1.0 g, 3 mmol) (using 4-fluoro-trans-beta-nitrostyrene instead of trans-beta-nitrostyrene) was converted to the title compound (1.2 g, 77%) which was obtained as a white solid. MS: m/e=501.4 (M+H).