Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4](=[O:7])[CH:5]=[CH2:6])O.[C:8]1(C)C=C[C:11](S(O)(=O)=O)=[CH:10][CH:9]=1.[CH2:19]([OH:23])CCC>>[CH2:8]([O:23][CH2:19][C:5](=[CH2:6])[C:4]([NH2:3])=[O:7])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCO
Reactant: C=CC(=O)NCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: C=C(COCCCC)C(N)=O

Procedure:
A reaction vessel equipped with a condenser, a stirrer, a thermometer, a nitrogen gas introducing tube and a dropping funnel was charged with 50.6 parts of N-methylolacrylamide and 148 parts of butanol and adjusted to pH 3.0 by adding p-toluenesulfonic acid. The reaction was started with refluxing and terminated for about four hours. The reaction product was neutralized with dimethylaminopropylmethacrylamide and butanol was removed under a reduced pressure to obtain 75 parts of n-butoxymethylacrylamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH2:37]([S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40])[CH3:38].C(SCC[CH2:56][OH:57])C.Cl.Cl.CS(CCCN1CCNCC1)(=O)=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:56]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][CH2:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])[CH2:46][CH2:47]3)=[O:57])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCSCCCO
Reactant: CCS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Agent: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(=O)(=O)CC)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (example 4) was reacted with 1-(3-ethanesulfonyl-propyl)-piperazine dihydrochloride (prepared from 3-ethylsulfanyl-propan-1-ol in an analogous manner as the method described for 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride) to give the title compound. HR-MS (ES, m/z) calculated for C39H51N4O4SCl2 [(M+H)+] 741.3003, observed 741.2998.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 20.9 g (0.1 mole) of 2-(4-methylphenyl)benzoxazole, 17.8 g (0.1 mole) of N-bromosuccinimide, and 0.4 g (0.2 mole %) of benzoyl peroxide in carbon tetrachloride is heated at reflux for 20 hours. After cooling to room temperature, the reaction is diluted by the addition of carbon tetrachloride, and the solid byproducts are removed by filtration. The filtrate is concentrated in vacuo, and the product is purified by recrystallization from benzene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].[CH3:29][C:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[O:32][N:31]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27][C:35]([C:33]4[O:32][N:31]=[C:30]([CH3:29])[CH:34]=4)=[O:36])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Reactant: Cc1cc(C(=O)O)on1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)c3cc(C)no3)COC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 1 using intermediate 4 instead of intermediate 1 and 3-methylisoxazole-5-carboxylic acid instead of 3-fluoro-5-(trifluoromethyl)benzoic acid and was obtained as white solid. MS: 516.1 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.N[C:24]1[CH:29]=CC=C[CH:25]=1>>[C:1]1([NH:4][C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([B:14]3[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:12][CH:13]=2)=[O:6])[CH:3]=[CH:2][CH:29]=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: Nc1ccccc1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3ccccc3)cc2)OC1(C)C

Procedure:
A procedure analogous to that used for the preparation of 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was used, using aniline as the amine component.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.Br[CH2:9][C:10]1([CH3:36])[CH:14]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])[N:13]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:12]2[S:11]1>P([O-])([O-])([O-])=O.CC(C)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:9][C:10]2([CH3:36])[CH:14]([C:15]([O:17][CH2:18][C:19]([Cl:20])([Cl:21])[Cl:22])=[O:16])[N:13]3[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:12]3[S:11]2)=[N:4][N:3]=1
Reactant: Cc1nnc(S)s1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: Cc1nnc(SCC2(C)S[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
5-Methyl-1,3,4-thiadiazole-2-thiol (0.16 g) was dissolved in a mixture of pH 6.5 phosphate buffer (5 ml) and acetone (10 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and acetone was distilled off and thereafter the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.09 g) from the second and third fractions each of which was separated into about 30 ml.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]=[N+]=[N-])[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-(-)-4-[4-[5-(azidomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 7, 12.05 g) in dry tetrahydrofuran (96 mL) under N2 is treated with triphenylphosphine (8.29 g) over five minutes, and the resulting mixture is stirred at ambient temperature for two hours. The mixture is then treated with water (3.1 mL), heated up to 40° C., stirred at 40° C. for five hours and at ambient temperature for 12 hours, and then concentrated under reduced pressure to give a viscous oil which is chromatographed on silica gel (70-230 mesh, 500 g), eluting with a gradient of methanol/methylene chloride (2.5/97.5-15/85). Pooling and concentration of those fractions with an Rf =0.26 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 136-137° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]([CH3:17])[CH:11]2[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Cl:23][C:24]1[C:33](Cl)=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.O>COCCOCCOC>[Cl:23][C:24]1[C:33]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([O:7][CH3:6])=[CH:16][CH:15]=3)[CH:11]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]2[CH3:17])=[N:32][C:31]2[C:26]([N:25]=1)=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: COC(=O)CC1c2cc(OC)ccc2NC1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: COC(=O)CC1c2cc(OC)ccc2N(c2nc3ccccc3nc2Cl)C1C

Procedure:
Anhydrous sodium acetate (3.6 g.) was added to a mixture of methyl 5-methoxy-2-methylindolin-3-ylacetate (8.0 g.) and 2,3-dichloroquinoxaline (6.8 g.) in diethyleneglycol dimethyl ether (150 ml.), and the mixture was heated under reflux for 12 hrs. The mixture was then cooled and poured into water (800 ml.), and the aqueous suspension was extracted with ethyl acetate (3 × 50 ml.). The combined extracts were washed successively with water (4 × 30 ml.) and a saturated aqueous solution of sodium chloride (50 ml.), and then dried (MgSO4) and evaporated. The resultant syrup was chromatographed on chromatographic silica gel (M.F.C., 300 g.) using an increasing gradient of diethyl ether in petroleum ether (b.p. 40°-60° C.) (polarity increased by incremental addition of 10% v/v ether.) The combined eluate was evaporated to give methyl 1-(3-chloroquinoxalin-2-yl)-5-methoxy-2-methylindolin-3-ylacetate, m.p. 155°-157° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH:44][C:45]([C:47]1[S:48][C:49]2[CH2:50][NH:51][CH2:52][CH2:53][C:54]=2[N:55]=1)=[O:46]>ClCCl.CN(C=O)C>[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH:44][C:45]([C:47]1[S:48][C:49]2[CH2:50][N:51]([C:1]([O:19][C:16]3[CH:15]=[CH:14][C:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:18][CH:17]=3)=[O:2])[CH2:52][CH2:53][C:54]=2[N:55]=1)=[O:46]
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)Oc1ccc(-c3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1,1′-Carbonyldiimidazole (1.0 mmol) was added to biphenyl-4-ol (1.0 mmol) dissolved in of dichloromethane (5.0 mL). Catalytic amount of p-toluenesulphonic acid was added and mixture was stirred at room temperature for 2 to 3 h This solution was then added to N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained from step VIII of example 1 (1.0 mmol) in 10 mL of dry DMF. Reaction mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to yield the title compound.
Reaction SMILES: Br(O)(=O)=O.[Br:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.N1C=CC=CC=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].CO>C(Cl)Cl>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:11][C:9]1[S:10][C:6]([Br:5])=[CH:7][N:8]=1)=[O:24]
Reactant: Nc1ncc(Br)s1
Reactant: O=C(Cl)CCCCBr
Agent: [O-][Br+2]([O-])O
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: O=C(CCCCBr)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromothiazol-2-amine bromate (1 g) in methylene chloride (12 mL) was added a solution of pyridine (0.68 mL) and 5-bromopentanoyl chloride (0.54 mL) in methylene chloride (0.7 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added with methanol (0.7 mL) and concentrated under reduced pressure. The obtained residue was added with 1 N hydrochloric acid (13 mL). The obtained solid was washed with tert-butyl methyl ether and dried to give the titled compound (1.06 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)C=Cc1ccnc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C=Cc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
3-(2-Bromo-pyridin-4-yl)-acrylic acid (5.0 g, 21.9 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (2.4 g, 24.1 mmol), HOBT (5.9 g, 43.9 mmol), EDAC (8.4 g, 43.9 mmol) and triethylamine (9.1 mL, 65.8 mmol) were added to N,N-dimethylformamide (100.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with ethyl acetate. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.6 g of the titled compound as a white solid.
Reaction SMILES: [CH2:1]([C:6]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][NH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:16]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([NH:25][C@H:26]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:27](O)=[O:28])=[O:24])[N:18]=[CH:17]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>CN(C=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C@@H:26]([NH:25][C:23](=[O:24])[CH2:22][CH2:21][C:19]2[N:18]=[CH:17][NH:16][CH:20]=2)[C:27](=[O:28])[N:8]2[CH2:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:9]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(C[C@@H](NC(=O)CCc2c[nH]cn2)C(=O)O)cc1
Reactant: CCCCCC1(c2ccccc2)CNC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCC1(c2ccccc2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Reaction time: 4 h
Yield: 53.7 %

Procedure:
70 mg (0.345 mmol) of 3-pentyl-3-phenylazetidine and 100 mg (0.315 mmol) of (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoic acid are solubilized in 1 ml of DMF. 67 mg (0.345 mmol) of EDC and 47 mg (0.345 mmol) of HOBT are added to this solution. The whole is left to stir for 4 hours and is then treated with 1N sodium hydroxide and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol). 85 mg of N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 49%.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[NH2:11][C:12]1[NH:13][C:14](=O)[C:15]2[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=2[N:17]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH2:11])[N:13]=[C:14]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:15]=2[N:21]=1
Reactant: c1nc[nH]n1
Reactant: Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
A solution of 1,2,4-triazole (1.4 g, 20 mmol) and phosphorus oxychloride (1.4 mL, 15 mmol) in dry acetonitrile (40 mL) was adder to a stirred suspension of 2-amino-6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (1 g, 5 mmol) and DIEA (4.4 mL, 25 mmol) in dry acetonitrile (30 mL). The mixture was stirred at room temperature for 24 hours. 2 molar equivalents of 1,2,4-triazole (0.7 g, 10 mmol), 1.5 equivalent of phosphorus oxychloride (0.7 mL, 7.5 mmol) and 2.5 equivalents of DIEA (2.2 mL, 12.5 mmol) were added to the mixture. After stirring at room temperature for 48 hours, the same amount of the above reagents was added again. The reaction mixture was stirred for 7 full days and the yellow precipitate was filtered off, washed successively with acetonitrile, DCM and ether. The solid was dried under vacuum, providing the pure title compound as a yellow solid (667 mg, yield 53%) which was characterised as follows: MS (m/z) 248.8 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[CH2:13][CH2:12]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40].C(N(CC)C(C)C)(C)C.[CH2:56]([O:58][C:59](=[O:64])[CH2:60][CH2:61][CH2:62]Br)[CH3:57]>C(#N)C.ClCCl>[CH2:56]([O:58][C:59](=[O:64])[CH2:60][CH2:61][CH2:62][NH:1][C@H:2]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[CH2:15][CH2:16]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40])[CH3:57]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(N2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 32.4 %

Procedure:
To a solution of 3-((R)-2-amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(3-nitro-benzyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (3-58) (55 mg, 0.086 mmol) in acetonitrile (2 mL) were added N,N-diisopropylethylamine (37 μl, 0.271 mmol) and 4-bromo-butyric acid ethyl ester (15 μl, 0.086 mmol) in the order, followed by stirring at 95° C. for 12 hrs. The solution was cooled to room temperature, diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic layer thus formed was separated and concentrated. The residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 21 mg of the compound as a colorless oil (yield 33%). 1H NMR (300 MHz, CDCl3) δ 1.19 (3H, t), 1.65 (2H, m), 2.24 (4H, m), 2.33 (3H, s), 2.37-2.50 (4H, m), 2.74 (2H, m), 3.60 (4H, m), 4.02-4.09 (4H, m), 4.16 (1H, m), 5.40 (2H, dd), 7.20-7.40 (7H, m), 7.49 (1H, t), 7.53 (1H, d), 7.76 (1H, d), 8.10 (1H, dd), 8.18 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc(CN2CCN(c3cccc(Cl)c3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A solution of 13.5 g (0.050 mol) of 1-(3-chloro-phenyl)-piperazine in 500 ml of tetrahydrofuran was treated with 35 ml (0.25 mol) of triethylamine and 18.2 g (0.050 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 10 g (63%) of 5-[4-(3-chloro-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as beige crystals; m.p. 222°-226°.
Reaction SMILES: [Cl-].[CH2:2]([O:6][C:7]1[C:12]2[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH2+:21][CH2:20][CH2:19]3)=[N:14][O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH:3]([CH3:5])[CH3:4].[O:24]1[C:26]2([CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:25]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH2:2]([O:6][C:7]1[C:12]2[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:25][C:26]4([OH:24])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)=[N:14][O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)COc1cccc2onc(OCC3CC[NH2+]CC3)c12
Reactant: C1CC2(CCO1)CO2
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)COc1cccc2onc(OCC3CCN(CC4(O)CCOCC4)CC3)c12
Yield: 67.7 %

Procedure:
A solution of 4-{[(isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidinium chloride (40.9 mg, 0.120 mmol, EXAMPLE 8, step 4), 1,6-dioxaspiro[2.5]octane (30.4 mg, 0.266 mmol, Phosphorus and Sulfur and Related Elements 1984, 19, 113) and N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) in ethanol (1 mL) was stirred overnight at room temperature. Solvent was evaporated, and the residual oil was purified by NH gel column chromatography (hexane/ethyl acetate 4:1) to give 34.0 mg (68%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[N:11]=[C:10]([CH3:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.CO.[BH4-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH:10]([CH3:19])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2cccc(Cl)c2)n2ncc(C#N)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC1CC(c2cccc(Cl)c2)n2ncc(C#N)c2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an unweighed amount of 7-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in Ex. 14) in a stirred mixture of one liter of tetrahydrofuran and one liter of methyl alcohol, under nitrogen was added 20.0 g of sodium borohydride, portionwise. The mixture was stirred for 8 hours at room temperature, then allowed to stand for 3 days providing two layers. The top layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give a yellow oil. The oil was dissolved in 250 ml of chloroform and filtered through hydrous magnesium silicate and evaporated to a yellow oil. The oil was triturated with ether, forming crystals on scratching. The crystals were collected to give the desired product as white crystals, mp 192°-195° C.
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CN=C(C(N)=O)C=1.Cl.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Product: COC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Methyl 4-(4-aminophenoxy)pyridine-2-carboxylate was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from the product of step 1 and 4-aminophenol.