Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:6]=[CH:5]2.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:6]=[CH:5]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1cccc2cc(O)ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
A mixture of N-(6-hydroxy-naphthalen-1-yl)-acetamide (5.72 grams, 28 mmol), benzyl bromide (4.78 grams, 28 mmol) and potassium carbonate (4.14 grams, 30 mmol) in DMF (50 mL) was stirred at room temperature for 20 hours. The reaction was diluted with ether (250 mL) and was washed with saturated aqueous NaHCO3 (2×30 mL) and saturated aqueous NaCl (2×30 mL), dried MgSO4) and concentrated in vacuo. The crude residue was azeotroped with heptane (2×100 mL) to give a colored solid. The solid was filtered and washed with hexanes to give 5.0 grams of a colorless product. 1NMR (250 MHz, CDCl3): d 7.25 (m, 11 H), 4.4 (s, 2 H), 2.16 (s, 3 H).
Reaction SMILES: C(O[C:4](=[O:8])[O:5][CH2:6][CH3:7])C.[H-].[Na+].[Si:11]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH2:33][C:34]2=[O:39])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Si:11]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH:33]([C:4]([O:5][CH2:6][CH3:7])=[O:8])[C:34]2=[O:39])([C:24]([CH3:26])([CH3:27])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1=O
Reaction time: 4 h

Procedure:
To a solution of diethylcarbonate (10.3 ml) and sodium hydride (4.2 g, 60% in oil) in toluene (300 ml) was added 5-t-butyldiphenylsilyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene (17 g) at 100° C. The mixture was stirred for 4 hours at the same temperature and then the cooled solution was washed with sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 5-t-butyldiphenylsilyloxy-2-ethoxycarbonyl-1-oxo-1,2,3,4-tetrahydronaphthalene (20 g).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][Cl:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1>>[NH2:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][Cl:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: ClCc1ccc2c(Cl)ncnc2c1
Reactant: N
Product: Nc1ncnc2cc(CCl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To 15 ml of a saturated ethanolic ammonia solution is added 1.0 g (4.7 mmole) of 4-chloro-7-chloromethylquinazoline. The mixture is stirred at room temperature overnight. The precipitate which forms is collected to give 0.7 g of the title intermediate product, mp>300° C.; 77% yield. 1H NMR (d6-DMSO, 300 MHz) δ 8.38 (s, 1H), 8.20 (d, 1H), 7.78 (bs, 2H), 7.70 (s, 1H), 7.51 (d, 1H), 4.92 (s, 2H). EI MS, [M]+=193, 195 (Cl pattern).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4](C(=O)C)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].N1CCOCC1.[S].Cl.[C:22]([OH:25])(=[O:24])[CH3:23]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[C:3]([OH:13])=[C:4]([CH2:23][C:22]([OH:25])=[O:24])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: CC(=O)c1cc(F)c(F)c(F)c1O
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [S]
Solvent: O
Solvent: C1COCCN1
Product: O=C(O)Cc1cc(F)c(F)c(F)c1O
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(3,4,5-trifluoro-2-hydroxyphenyl)ethanone (7.5 g), p-toluenesulfonic acid monohydrate (0.375 g), morpholine (10 mL) and sulfur (2.0 g) was stirred at 120° C. for 5 hr, and allowed to cool to room temperature, and hydrochloric acid (20 mL) and acetic acid (20 mL) were added to the reaction mixture. The reaction mixture was stirred at 100° C. for 3 hr, allowed to cool to room temperature, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.0 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(C)=O>[CH2:31]([C:11]1[C:10]([CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:3]=1[C:1]#[N:2])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2c(C#N)cc(C)cc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)Nc2c(C(=O)O)cc(C)c(Cc3ccccc3)c2C#N)cc1
Yield: 79 %

Procedure:
To a solution of 1.5 g (4.3 mmol) of the product of Example 176 in 200 mL of acetone was added 4 g of K2CO3 and 5 ml of benzylbromide and the mixture was refluxed for 8 hours. The reaction mixture was then filtered and the acetone was removed in vacuo. The residue was dissolved in chloroform and washed well with water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The resulting residue chromatographed on silica gel luting with 30% Ethyl acetateexane to give 1.8 g (79%) of the desired product as a brown oil. Electrospray Mass Spec 527 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:51][CH2:52][CH:53]1[CH2:57][O:56][C:55]([CH3:59])([CH3:58])[O:54]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:51][CH2:52][CH:53]4[CH2:57][O:56][C:55]([CH3:59])([CH3:58])[O:54]4)[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: CC1(C)OCC(CCOS(C)(=O)=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCC4COC(C)(C)O4)c4cc(F)ccc34)nc12
Temperature: 65 °C
Yield: 92.2 %

Procedure:
To a solution of N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (80 mg, 0.135 mmol) in DMF (5 mL) was added 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate (36 mg, 0.162 mmol) followed by K2CO3 (56 mg, 0.405 mmol). The mixture was heated at 65° C. for 4 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (90 mg, 92%) The crude was used to the next step without purification. LCMS: (M+H)+=723.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH:12]1[CH2:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:15][CH2:14][CH2:13]1
Reactant: N#Cc1cc(F)cnc1Cl
Reactant: C1CNC1
Agent: Cl
Product: N#Cc1cc(F)cnc1N1CCC1
Yield: 78 %

Procedure:
Prepared in 78% yield from the product of Example 169A and azetidine hydrochloride according to the procedure described for Example 178A. MS (ESI+) m/z 177.8 (M+H)+; 1H NMR (DMSO-d6) δ 2.28-2.38 (m, 2H), 4.17-4.22 (m, 4H), 8.07 (dd, J=8.3, 2.9 Hz, 1H), 8.66 (dd, J=8.1, 3.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:24][CH2:23][CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Product: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (5.0 g, 25.3 mmol), 2-(4-methoxyphenyl)ethanamine (4.2 g, 28 mmol) and 4-N,N-Dimethylaminopyridin (3.3 g; 28 mmol) in methylenehloride (200 ml) was cooled to −10° C. N-ethyl-N′-(3-Dimethylaminopropyl)-carbodiimid hydrochloride (EDC, 5.3 g, 28 mmol) was added in several portions and the resulting mixture stirred overnight. The reaction mixture was poured into water and consecutively extracted with water, 2N NaOH and 1N HCl. Evaporation of the dried (NaSO4) extract yielded an oily residue that crystallized upon addition of n-heptan, which was used without further purification. Yield 7.0 g (21.2 mmol, 83%).
Reaction SMILES: Cl[CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[N:21][C:20]=1[NH2:26].O>CN(C)C=O>[CH3:6][O:5][C:3]([C:2]1[N:21]2[N:22]=[C:23]([CH3:25])[CH:24]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[C:20]2=[N:26][C:7]=1[CH2:8][CH3:9])=[O:4]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: Cc1ccc(-c2cc(C)nnc2N)c(C)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(-c3ccc(C)cc3C)cc(C)nn2c1C(=O)OC
Temperature: 140 °C

Procedure:
Methyl 2-chloro-3-oxopentanoate (7 mL) was added to a solution of the resulting 4-(2,4-dimethylphenyl)-6-methyl-3-pyridazinamine in N,N-dimethylformamide (60 mL), and the mixture was heated at 140° C. for 6 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid methyl ester as a crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12](Cl)(=[O:14])=[O:13])[N:11]=[C:4]2[N:3]=1.[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH2:19].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12]([NH:19][C:18]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:17]=3[CH3:16])(=[O:14])=[O:13])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Reactant: Cc1cccc(C)c1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(C)cccc3C)nc2n1
Yield: 97.7 %

Procedure:
A solution of 2.2 g (8.9 mmol) of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride, 1.01 ml (8.4 mmol) of 2,6-dimethylaniline, 0.7 ml (8.4 mmol) of dry pyridine and 4 mg of DMAP in 20 ml of CH2Cl2 was stirred at room temperature for 17 hours. The solvent was removed by evaporation and the residue was taken up in 0.5M NaOH. The solution was extracted with diethyl ether and the aqueous phase was acidified with 3N HCl to precipitate a solid. The solid was collected by filtration and dried in vacuo to yield 2.72 g (97 percent) of the desired product as a white solid, m.p. 263°-266° C. (decomp.): 1H NMR (DMSO-d6)δ10.4 (1H, broad S), 7.55 (1H, s), 7.2 (3H, s), 2.7 and 2.8 (3H each, s) and 2.1 (6H, s); IR (KBr) 3100, 2980-2780, 1628, 1540 and 1355 cm-1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:14]O)[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=NO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1N
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a 25° C. solution of 1-Benzyl-3-methyl-piperidin-4-one oxime in anhydrous THF (20 mL) was added LAH (1.0 M solution THF), (15 mL, 15 mmol). After being stirred at 50° C. overnight, the resultant mixture was quenched with 20% KOH solution. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude mixture ((±)-cis:(±)-trans=1:1) 1-benzyl-3-methyl-piperidin-4-ylamine (1). LCMS m/z: 205 (M+H)+. This material was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([C:28]([F:31])([F:30])[F:29])=[N:24][N:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:32](OCC)=[O:33].[O-]CC.[Na+].Cl>C(O)C>[OH:33][CH:32]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([C:28]([F:31])([F:30])[F:29])=[N:24][N:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c(C(F)(F)F)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c(C(F)(F)F)n1
Temperature: 78 °C
Yield: 81 %

Procedure:
1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.205 g, 0.548 mmol) and ethyl formate (0.132 mL, 1.64 mmol) were dissolved in anhydrous ethanol (1.1 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.00 mL, 2.74 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.178 g, 0.444 mmol, 81%).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[O:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([NH2:33])[CH2:25][CH2:24]1>>[O:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([NH:33][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:25][CH2:24]1
Reactant: NC1CCOc2ccccc21
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCOc3ccccc32)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 3,4-dihydro-2H-chromen-4-ylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.89 (s, 3H), 2.10 (bs, 1H), 2.42 (s, 3H), 4.11 (bs, 1H), 4.27 (bs, 1H), 4.93 (bs, 1H), 5.04 (bs, 1H), 5.31 (bs, 1H), 5.48 (bs, 1H), 6.75-6.88 (m, 3H), 7.20 (bs, 1H), 7.27 (bs, 1H), 7.42 (bs, 1H), 7.74 (bs, 1H), 8.02 (bs, 1H), 8.59 (bs, 1H), 10.63 (bs, 1H); MS (ESI) m/z 362.9 (M+1)+.
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][CH2:5][N:6]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])[CH3:7].[CH2:23]([NH2:26])[CH2:24][NH2:25]>>[NH2:19][C:18]1[C:13]([C:11]([NH:10][CH2:9][CH2:8][N:6]([CH2:5][CH2:4][C:3]([NH:25][CH2:24][CH2:23][NH2:26])=[O:22])[CH3:7])=[O:12])=[N:14][C:15]([Cl:21])=[C:16]([NH2:20])[N:17]=1
Reactant: NCCN
Reactant: COC(=O)CCN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Product: CN(CCNC(=O)c1nc(Cl)c(N)nc1N)CCC(=O)NCCN
Yield: 72 %

Procedure:
A solution of 20.4 g (61.7 mmol) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]-N-methyl-beta-alanine methyl ester and 36.0 g (0.6 mol) of ethylenediamine was heated at 40° C. fdr 2 days under an inert atmosphere. The excess ethylene diamine was evaporated. The residue was triturated with 2-propanol. There was obtained 15.2 g (44.4 mmol 72%) of 3,5-diamino-N-[2-[[3-[(2-aminoethyl)amino]-3-oxopropyl]methylamino]ethyl]-6-chloropyrazinecarboxamide as a white solid; mp 140°-142° C.; Rf =0.27, Solvent System A.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]2[C:36](=[C:37]([O:46][CH3:47])[CH:38]=[CH:39][CH:40]=2)[CH:35]=1>>[CH3:45][O:44][C:42]1[C:41]2[C:36](=[C:37]([O:46][CH3:47])[CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH2:33][O:1][CH:2]2[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]2)[CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3cccs3)cc2)C(O)C1
Reactant: COc1cc(CCl)cc2c(OC)cccc12
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3cccs3)cc2)cc2c(OC)cccc12

Procedure:
In an analogous manner to that described in Example 1 g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate [Example 123 b)] with 2-chloromethyl-4,8-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(4,8-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a beige solid; MS: 648 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Cl.[Br:12]Br>C(O)(=O)C>[Br:12][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1ccccc1C
Reactant: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)CBr
Reaction time: 3 h
Yield: 96 %

Procedure:
2′-Methylacetophenone (25.0 g, 186 mMole) was dissolved in glacial acetic acid (250 ml) and concentrated HCl (250 uL) was added followed by a dropwise addition of bromine (9.6 ml, 186 mMole) over 15 minutes. The mixture was stirred 3 hours and then concentrated under reduced pressure. The residue was taken up in ethyl ether and washed with saturated NaHCO3 solution. The ether layer was dried over Na2SO4, filtered, and concentrated to yield 38.0 g, (96%) of crude 2-bromo-2′-methylacetophenone which was used without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([CH3:38])[C:29]1=[O:39]>C(Cl)(Cl)(Cl)Cl>[CH3:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([CH2:38][Br:1])[C:29]1=[O:39]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccccc2n(C)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(=O)c(CBr)nc2ccccc21

Procedure:
N-bromosuccinimide (3.36 g., 0.0189 mol.) and benzoyl peroxide (0.06 g.) were added to a solution of 1,3-dimethyl-2(1H)-quinoxalinone (3.0 g., 0.017 mol.) in carbon tetrachloride (250 ml.). The mixture was heated at reflux for four hours. Removal of the solvent left a tan solid. Chromatography on silica gel with methylene-chloride as the eluent gave a tan solid. Recrystallization from methylene-chloride gave light tan needles. (2.33 g., m.p. 192.5°-193.5°. 53%).
Reaction SMILES: C(=O)([O-])O.[Na+].[O:6]=[C:7]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][CH2:33][CH3:34])=[CH:16][C:11]=2[O:10][C:9]([C:35]([O:37]CC)=[O:36])=[CH:8]1.C(O)C>O>[O:6]=[C:7]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][CH2:33][CH3:34])=[CH:16][C:11]=2[O:10][C:9]([C:35]([OH:37])=[O:36])=[CH:8]1
Reactant: CCCc1ccccc1OCCCCCCCOc1ccc2c(=O)cc(C(=O)OCC)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1ccccc1OCCCCCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1

Procedure:
A solution of 2.15 parts of sodium hydrogen carbonate in 40 parts of water was added to a refluxing solution of 3.0 parts of ethyl 4-oxo-7-[7-(2-n-propyl phenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylate in 50 parts of ethanol. More water was added to produce a clear solution which was refluxed for 2 hours. Acidification of the filtrate precipitated the acid as a semi-solid mass which was converted to a fine solid by persistent mechanical disruption of the gum cakes. The solid was filtered off, dried and crystallised from benzene/petrol (bp. 80°-100°) to furnish 2.8 parts of 4-oxo-7-[7-(2-n-propylphenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylic acid as white microcrystals, mp. 149°-150°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:18][C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[O:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC1(C)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
Palladium on carbon (5% w/w, 0.1 g.) was added to a solution of 2-[4-(4-chlorophenyl)-phenyl]-5,5-dimethyl-1,3-dioxolan-4-one (0.3 g.) in ethanol (50 ml.). The suspension was treated with hydrogen gas at 25° C. and atmospheric pressure for 1.5 hours. The catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in toluene (10 ml.) and the solution obtained was extracted with 1 M sodium hydroxide solution (10 ml.). The aqueous extracts were acidified with 2 M hydrochloric acid and extracted with toluene (2×10 ml.). By evaporation of the toluene extracts, there may thus be obtained 2-[4-(4-chlorophenyl)benzyloxy]-2-methylpropionic acid, as a waxy solid equivalent to that obtained in Example 12.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][S:27]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:40]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:22](=[CH:23][CH:24]=2)[NH:25][N:40]=[C:26]3[S:27]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(COc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1

Procedure:
A mixture of 4-[4-amino-3-(1-naphthylsulfonylmethyl)phenoxymethyl]-piperidine-1-carboxylic acid benzyl ester (0.74 g, 1.36 mmoles) in THF and 4M HCl (10 mL), under nitrogen, at 3° C. was treated dropwise with a solution of sodium nitrite (0.09 g, 1.42 mmoles) in H2O, poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound as an off white solid (0.71 g, 1.29 mmoles).