Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C1COCC1.N1CCOCC1>ClCCl>[C:2]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:14])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccnc(C(=O)O)c1
Reactant: CN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(C(=O)N2CCOCC2)c1
Yield: 79.6 %

Procedure:
Suspend 4-tert-butyl-pyridine-2-carboxylic acid hydrochloride (11.14 g, 51.8 mmol) in 50 mL dichloromethane, add 4-methylmorpholine (10.48 g, 11.4 mL, 104 mmol), stir, add 100 mL THF and stir the suspension a few minutes. Add N,N′-carbonyldiimidazole (8.4 g, 51.8 mmol) to the stirring suspension, note moderate gas evolution and stir the light suspension at room temperature for 30 to 90 minutes. Add morpholine (13.54 g, 13.61 mL, 155 mmol) via pipet, stir overnight at room temperature. Dilute the suspension with 400 mL dichloromethane, wash with 400 mL saturated aqueous sodium bicarbonate solution and back-extract the aqueous phase with 100 mL dichloromethane. Combine organic layers and wash with 300 mL portions of saturated sodium bicarbonate (once) and dilute aqueous saturated sodium chloride (three times). Dry the organic layers over MgSO4 concentrate to an oil and purify on a 400 g silica cartridge with a gradient of 0→10% acetone in EtOAc over 20 minutes. Pool, concentrate, and dry fractions to provide 10.24 grams of a viscous colorless oil. LCMS (ES) m/z 249 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].I[C:33]1[C:34]2[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=2[N:36]=[CH:37][N:38]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:33]3[C:34]4[CH:41]=[CH:40][NH:39][C:35]=4[N:36]=[CH:37][N:38]=3)=[O:5])=[N:7][CH:8]=[C:9]([Cl:30])[CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:27])([F:29])[F:28]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]ccc12

Procedure:
Prepared from 259 mg (0.52 mmol) of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxy-methyl-amide, 213 mg (0.52 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.26 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 2 mL methanol and 2 mL 6N hydrochloric acid mixture to give after purification 40 mg of the final product as a yellow solid.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O:16][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:15])(=[O:19])=[O:18]
Reactant: ClCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)OCc2ccccc2)c(NCc2ccco2)cc1Cl

Procedure:
In a similar manner to Example 3, furosemide can be reacted with benzyl chloride in DMF to yield benzyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)amino]benzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[N:30](S(C4C=CC(C)=CC=4)(=O)=O)[CH:31]=[CH:32][C:25]=23)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[NH:30][CH:31]=[CH:32][C:25]=23)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCN[C@H](C)C6)nn45)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc5[nH]ccc45)n3n2)CCN1
Temperature: 60 °C
Yield: 91.2 %

Procedure:
Added to a solution of 0.230 g (0.40 mmol) of 2-(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine obtained in step 3.3, in 5 ml of methanol, is 0.13 ml (0.76 mmol) of a 6N aqueous solution of sodium hydroxide. The mixture is heated at 60° C. for 30 minutes then poured into 100 ml of water. The product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The residue obtained is recrystallized in acetonitrile in order to give 0.156 g of 2-(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine after drying.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O.CCOC(C)=O>[CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1CCC(OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a stirred solution of 8-(benzyloxy)-1,4-dioxaspiro[4.5]decane (12 g, 48.3 mmol) in acetone was added HCl (2 M, 50 mL, 100 mmol). The reaction mixture was heated to 50° C. overnight, cooled to room temperature, diluted with EtOAc, and washed with water and sodium bicarbonate solution. The organic layer was dried, and concentrated to give the title compound. 1H NMR (600 MHz, CDCl3) δ 7.25-7.36 (m, 5H); 4.58 (s, 2H); 3.81 (m, 1H); 2.60 (m, 2H); 2.25 (m, 2H); 2.13 (m, 2H); 1.94 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[CH:26]=[CH:25][C:15]3[CH2:16][CH2:17][N:18]([CH:21]4[CH2:24][CH2:23][CH2:22]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:7][N:6]=1)=[O:4]>C(O)C.[OH-].[Na+]>[CH:21]1([N:18]2[CH2:19][CH2:20][C:14]3[CH:13]=[C:12]([O:11][C:8]4[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=4)[CH:26]=[CH:25][C:15]=3[CH2:16][CH2:17]2)[CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylic acid methyl ester (E122) (880 mg, 2.5 mmol) was dissolved in a mixture of ethanol (15 ml) and 2N sodium hydroxide (4 ml). The resulting mixture was stirred at room temperature for 0.5 hours and then concentrated in vacuo to remove the organic solvents. The reaction mixture was then acidified to pH 5 (2N hydrochloric acid) and the resulting precipitates were filtered, washed with water and dried under vacuum to afford the title compound (E123a); MS (ES+) m/e 340 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:26]=O)=[CH:23][C:24]=1[CH3:25])=[O:19])[CH3:12].C(OC(C1C(C=O)(C)C=CN1)=O)C>>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:26]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:23][C:24]=1[CH3:25])=[O:19])[CH3:29]
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Reactant: O=C1Cc2ccccc2N1
Agent: CCOC(=O)C1NC=CC1(C)C=O
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)cc1C
Yield: 21 %

Procedure:
Oxindole (66.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide (prepared from 3-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester by method B then C) to give 39 mg (21%) of the title compound.
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[S:7][C:8](Cl)=[C:9]2[CH2:13][N:12]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:11][C:10]=12>CO.[Pd]>[S:14]([N:12]1[CH2:13][C:9]2=[CH:8][S:7][CH:6]=[C:10]2[CH2:11]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)N2Cc3c(Cl)sc(Cl)c3C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2Cc3cscc3C2)cc1
Yield: 7.4 %

Procedure:
28 g of 10% palladium-on-charcoal containing 50% water and then 96 g (1.52 mol) of ammonium formate are added, under a nitrogen atmosphere, to a solution of 28.34 g (0.81 mol) of 1,3-dichloro-5-tosyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole in 800 ml of methanol. The mixture is heated at reflux for 3 hours, 28 g of wet palladium-on-charcoal are then added and reflux is maintained for 24 hours. After filtration through diatomaceous earth, the filtrate is evaporated to dryness and the residue is recrystallized from methanol. 16.64 g of a white solid are obtained. Yield 73%. Melting point: 125°-127° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]2[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C=O)C>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]2[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:2][CH3:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1NCCCCCCl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCCCCNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
Under a nitrogen atmosphere, solid sodium thiomethoxide (1.38 g, 18.7 mmol, 95% pure) was added to a solution of 6-benzyloxy-N-(5-chloropentyl)-3-nitroquinolin-4-amine (6.24 g, 15.6 mmol) in DMF. The reaction was stirred at ambient temperature for 30 minutes and then heated at 80° C. for one hour, at which time a yellow precipitate formed. The reaction mixture was partitioned between water (390 mL) and dichloromethane (150 mL). The aqueous layer was washed with dichloromethane (100 mL), and the combined organic fractions were washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a red oil. An analysis by nuclear magnetic resonance spectroscopy indicated the presence of a large amount of starting material. The reaction product was dissolved in DMF (78 mL), treated with sodium thiomethoxide, and heated at reflux for two hours. The work-up described above was repeated, and the crude product was purified by column chromatography on silica gel (eluting with 70:30 ethyl acetate:hexane) to provide 5.1 g of 6-benzyloxy-N-[5-(methylthio)pentyl]-3-nitroquinolin-4-amine as a yellow oil.
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][C:7](Cl)=[O:8])[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]12.[C:16]([O:19][CH2:20][C:21]1[CH2:22][S:23][C@@H:24]2[CH:31]([NH:32][C:33](=[O:62])[C:34]([C:37]3[N:38]=[C:39]([NH:42]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:40][CH:41]=3)=[N:35][OH:36])[C:30](=[O:63])[N:25]2[C:26]=1[C:27]([OH:29])=[O:28])(=[O:18])[CH3:17].C(NCC)C.C(OC(C)C)(C)C.C(O)=O.O>C(Cl)Cl.O>[C:16]([O:19][CH2:20][C:21]1[CH2:22][S:23][C@@H:24]2[CH:31]([NH:32][C:33](=[O:62])[C:34](=[N:35][O:36][C:7](=[O:8])[CH2:6][N:5]3[C:4](=[O:10])[C:3]4=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]4[C:1]3=[O:15])[C:37]3[N:38]=[C:39]([NH2:42])[S:40][CH:41]=3)[C:30](=[O:63])[N:25]2[C:26]=1[C:27]([OH:29])=[O:28])(=[O:18])[CH3:17]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: CCNCC
Solvent: CC(C)OC(C)C
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(=O)CN3C(=O)c4ccccc4C3=O)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.08 h

Procedure:
0.335 g of phthalimidoacetyl chloride were added to a suspension of 0.756 g of the syn isomer of diethylamine 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate in 4 ml of methylene chloride and after standing at room temperature for 5 minutes, 10 ml of isopropyl ether was added to the mixture. The mixture was vacuum filtered and the recovered product was empasted with water and was dried to obtain a raw product. The product in 2 ml of a 2-1 formic acid-water mixture was stirred for 20 minutes at 35°-40° C. and 10 ml of water was added thereto. The mixture was vacuum filtered and the product was taken up in ether and vacuum filtered again. The product was dried and dissolved in 4 ml of acetone. The mixture was vaccum dried and was crystallization from 10 ml of ether to obtain 0.280 g of the syn isomer of 3-acetoxymethyl-7-[2 -(2-amino-4-thiazolyl)-2-phthalimidoacetoxyiminoacetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1.[Cl-].[CH:17]1([Zn+])[CH2:19][CH2:18]1.C1COCC1.C1([Mg]Br)CC1.C1COCC1.[NH4+].[Cl-]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Zn+2].[Cl-].C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH:17]2[CH2:19][CH2:18]2)[N:7]=1
Reactant: [Zn+]C1CC1
Reactant: Clc1ccc(-c2cc(Cl)nc(Cl)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br[Mg]C1CC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Clc1ccc(-c2cc(C3CC3)nc(Cl)n2)cc1
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 2,4-dichloro-6-(4-chloro-phenyl)-pyrimidine (2.6 g, 10.0 mmol) and tetrakis(triphenylphosphine)palladium (0.69 g, 0.6 mmol) in THF (10 mL) was added at 20° C. a 0.25 M cyclopropylzinc chloride/THF solution (120 mL, 30 mmol; freshly prepared by stirring a mixture of 60 mL of 0.5 M cyclopropylmagnesium bromide/THF and 60 mL of 0.5 M zinc chloride/THF for 1 h at 0° C., followed by 1 h at 20° C.) and the mixture was refluxed in an atmosphere of argon for 3 h. After the slow addition of sat. aqueous NH4Cl solution (20 mL) at 0° C. the mixture was partitioned between AcOEt and 10% sodium chloride solution. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel using AcOEt/cyclohexane (1:19 v/v) as eluent to give 2-chloro-4-(4-chloro-phenyl)-6-cyclopropyl-pyrimidine (1.12 g, 42%) as a light yellow solid. MS (ISP) 265.1 [(M+H)+]; mp 70-72° C.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2cncnc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cncnc3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-pyrimidin-5-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].CS(O)(=O)=O.[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>C(COC)OC.C(O)C>[CH2:11]([O:18][C:19]([NH:4][CH2:3][CH2:2][CH2:1][NH2:5])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCN
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: NCCCNC(=O)OCc1ccccc1
Temperature: 20 °C

Procedure:
In the process for the preparation of the novel compound of the general formula (I) according to the aforesaid second aspect of this invention, there is employed as the starting compound such a mono-amino-protected derivative of the α,ω-alkanediamine as represented by the general formula (II) shown hereinbefore. This mono-amino-protected derivative of the formula (II) may be prepared by anyone of known various methods but preferably may be prepared in accordance with the method of Atwell & Denny [see the "Synthesis", page 1032 (1984)]. More specifically, for example, an aqueous solution of propane-1,3-diamine is adjusted to pH 3.8 with methane-sulfonic acid, followed by addition of ethanol. The resulting solution is added dropwise with a solution of benzyloxycarbonyl chloride in dimethoxyethane under stirring at 20° C. At the same time, to the resulting mixture is added an aqueous solution of potassium acetate so that the pH of the reaction mixture is maintained at 3.5-4.5 during the reaction, whereby one of the amino groups of the propane-1,3-diamine can be selectively benzyloxycarbonylated to afford N-(benzyloxycarbonyl)-propane-1,3-diamine in a high yield (see Referential Example 2 given hereinafter).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])=[O:37]
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)c1cccc(CCl)c1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of (R)-2-Amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (30.5 mg, 0.092 mmol) in DCM (1 mL) cooled to 0° C. was added DIEA (17.4 μL, 0.1 mmol) followed by 3-chloromethyl benzoylchloride (14.2 μL, 0.1 mmol). Upon completion of addition, the reaction mixture was allowed to warm slowly to rt. where it stirred overnight. After this time, the solution was diluted with dichloromethane and quenched by the addition of aqueous NaHCO3. The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified via SiO2 chromatography to give the (R)-3-(chloromethyl)-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)benzamide as a clear glassy solid (23.7 mg, 58% yield). MS found: 447.3 (M+), 449.3 (M+2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2Cl.Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:17][NH:18][C:19]([NH2:21])=[O:20]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(NNC(N)=O)c2cc1OC
Yield: 30 %

Procedure:
2.2 g of 6,7-dimethoxy-4-chloro-quinazoline were dissolved in 50 ml of absolute dimethylformamide, 2.2 g of semicarbazide hydrochloride and 5 g of anhydrous potash were added thereto while stirring. The mixture was stirred for 5 hours at 50° C., and the precipitate formed thereby was suction-filtered off, stirred with water, and then recrystallized from dimethylformamide. The crude product was obtained with a 30% yield; m.p. 247°-249° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:29])[NH:17][CH2:18][CH:19]([OH:28])[CH:20]([OH:27])[CH:21]([OH:26])[CH:22]([OH:25])[CH2:23][OH:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:29])[NH:17][CH2:18][CH:19]([OH:28])[CH:20]([OH:27])[CH:21]([OH:26])[CH:22]([OH:25])[CH2:23][O:24][C:36]([C:35]3[CH:52]=[CH:53][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCC(O)C(O)C(O)C(O)CO)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1ccc(C(OCC(O)C(O)C(O)C(O)CNC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
Compound 35 (5.0 g, 12.4 mmol) was dissolved in 100 ml of pyridine and azeotropically boiled. After this operation was conducted two times, the product was dissolved in 100 ml of dry pyridine and cooled with ice in a nitrogen stream. 4,4′-Dimethoxytrityl chloride (5.0 g, 14.9 mmol) and dimethylaminopyridine (1.5 g, 12.4 mmol) were added, the temperature was gradually increased from under ice cooling to room temperature, and this was followed by stirring at room temperature for 17 hours. After the pyridine was evaporated under reduced pressure, the residue was diluted with 500 ml of ethyl acetate. After water was added, the organic phase was separated, after which the water phase was again extracted with ethyl acetate. The ethyl acetate phase was washed with saturated brine, after which it was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the concentrate was purified by silica gel column chromatography (CHCl3:MeOH=10:1) to yield the desired compound (Compound 36: 5.06 g) at a percent yield of 57.9%.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)([CH3:16])[C:11]([O:13]CC)=[O:12])=[O:8]>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)([CH3:16])[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CCOC(=O)C(C)(NC(=O)c1cccc(Cl)c1)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(C)(NC(=O)c2cccc(Cl)c2)C(=O)O)cc1
Yield: 90.2 %

Procedure:
1.2 g (0.02M) of potassium hydroxide was dissolved in a mixed solution of 30 ml of ethanol and 5 ml of H2O. To this solution, 3.5 g (0.01M) of ethyl 2-(m-chlorobenzamido)-2-(p-tolyl)propionate obtained in Example I was added. The resulting solution was heated for 1 hr with reflux, cooled and distilled in vacuo to remove ethanol. The remainder was adjusted into pH 2 with 2 N HCl solution and extracted with methylene dichloride. Thereafter, the extract was distilled in vacuo, to give 2.9 g of the titled compound: 92 % Yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C(O)C>[CH2:10]([NH:13][C:7]1[C:2]([NH2:1])=[C:3]([Cl:9])[N:4]=[CH:5][N:6]=1)[CH:11]=[CH2:12]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: C=CCN
Solvent: CCO
Product: C=CCNc1ncnc(Cl)c1N
Temperature: 80 °C

Procedure:
A mixture of 5-amino-4,6-dichloro pyrimidine (3.0 g, 0.018 mol) and allyl amine (1.5 ml, 0.020 mol) was taken in ethanol (30 ml) and heated at 80° C. for 16 hrs. Solvent was removed to get crude product which was further purified by column chromatography to get pure N*4*-Allyl-6-chloro-pyrimidine-4,5-diamine as off white solid (2.30 g, 68%).