Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:14]2[C:13](=[O:15])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:20])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Temperature: 160 °C
Reaction time: 12 h

Procedure:
2-Chloro-5-chloromethylpyridine (8.1 g, 0.05 mol) and potassium phthalimide (10.2 g, 0.055 mol) were mixed together at ambient temperature (20° C.) and the resulting mixture was then heated with stirring at 160° C. for 12 hours. The reaction mixture was then cooled to ambient temperature (20° C.) and dichloromethane was added until most of the solid residue had dissolved. The dichloromethane extract was then washed with water (2×150 ml) and brine (1×200 ml), dried using magnesium sulphate, and evaporated under reduced pressure to give a light-brown solid. The title product, N-(6-chloro-3-pyridylmethyl) phthalimide, was isolated from this solid by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with 10% v/v ether/ dichloromethane as eluent, as a buff solid (10.70 g, 78.5%), mp 140° to 142° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]=[CH:6][C:7]2[CH2:13][CH2:12][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:10][C:8]=2[N:9]=1)[CH3:2].[ClH:33]>CO.O1CCOCC1>[ClH:33].[CH2:1]([S:3][C:4]1[N:5]=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1ncc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCSc1ncc2c(n1)CNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A suspension of 81 mg (0.185 mmol) of trityl compound from Step D in 0.5 mL of methanol was treated with 4 N hydrogen chloride solution in dioxane. The reaction mixture was stirred at ambient temperature for 2 h, then concentrated under nitrogen and then in vacuo. Trituration with ether gave 47 mg (˜100%) of the title compound as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH3:10])=[N:8][C:7]([Br:11])=[CH:6][N:5]=1.[CH3:12][N:13]([CH3:28])[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:19]2[S:24](Cl)(=[O:26])=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC>[CH3:12][N:13]([CH3:28])[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:19]2[S:24]([NH:3][C:4]1[C:9]([CH3:10])=[N:8][C:7]([Br:11])=[CH:6][N:5]=1)(=[O:26])=[O:25]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Cc1nc(Br)cnc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 18 h
Yield: 32.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.1 g) was added portionwise to a stirred solution of 2-amino-5-bromo-3-methyl-pyrazine (0.188 g) in 1,2-dimethoxyethane (DME; 4 ml). After 5 minutes 5-dimethylamino-1-naphthalenesulphonyl chloride (0.3 g) was added, in a single portion, and the reaction was allowed to a stir for 18 hours. 2M Aqueous citric acid solution (10 ml) was added and the reaction was extracted with dichloromethane (3×25 ml). The combined extracts were dried (MgSO4) and evaporated to give a brown oil. The oil was purified by chromatography on silica gel, eluting with dichloromethane/diethyl ether (1:1) to give 5-dimethylanino-N-(5-bromo-3-methyl-2-pyrazinyl)-1-naphthalenesulphonamide as a cream solid (0.138 g, 33%), m.p. 171-172° C.; mass spectrum (+ve FAB, DMSO/methanol/NBA): 421 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3c(F)cccc3Cl)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(Cc5c(F)cccc5Cl)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-4-(4-(2-chloro-6-fluorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.045 g, 0.11 mmol), ethanol (3.2 ml), and 4-dimethylaminobenzaldehyde (0.022 g, 0.15 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 6 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column, which was eluted with diethyl ether/dichloromethane (v/v; 1:1). The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.09 g, 16%); 1H-NMR (500 Mz, DMSO-d6) 2.68 (br s, 4H, piperazine N(CH2)2), 2.99 (s, 6H, N(CH3)2), 3.63 (br s, 4H, piperazine N(CH2)2), 3.70 (s, 2H, NCH2), 6.80 (d, J=8.56 Hz, 2H) and 8.00 (d, J=8.55 Hz, 2H) (3,5-C6H4—NMe2 and 2,6-C6H4—NMe2) 7.26 (t, J=9.78 Hz, 1H) and 7.40 (m, 2H) (ArH), 8.03 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.12 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:26][C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]([CH2:26][C:27]#[N:28])[C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)n1CC#N

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 7) was treated with bromo-acetonitrile and potassium carbonate in N,N-dimethylformamide at room temperature to yield the {4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-6-oxo-6H-pyrimidin-1-yl}-acetonitrile as a yellow solid; m.p. 213-215° C. (decomposition); MS: [M+H]+=372.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([C:2]1[S:1][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:17]
Reactant: O=C1NCCCc2ccsc21
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCCl)c1cc2c(s1)C(=O)NCCC2
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of 2 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 2.5 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride under cooling. The mixture was stirred for 30 minutes, refluxed under heating and poured into water, and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was crystallized from ethyl acetate-isopropyl ether to give 1.2 g of 2-(4-chlorobutyryl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as white crystals, m.p. 163°-165° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([Br:9])=[C:7]([C:10]([OH:12])=[O:11])[S:6][N:5]=1)[CH3:2].[OH-].[K+:14]>CO>[K+:14].[Br:9][C:8]1[C:4]([O:3][CH2:1][CH3:2])=[N:5][S:6][C:7]=1[C:10]([O-:12])=[O:11]
Reactant: CCOc1nsc(C(=O)O)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1nsc(C(=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
To a solution of 3-ethoxy-4-bromoisothiazole-5-carboxylic acid (2.02 g, 0.0080 mol) in methanol (8 ml) there was added a solution of potassium hydroxide (0.45 g, 0.0080 mol) in methanol (8 ml). The resulting solution was stirred at ambient temperature for 10 minutes and concentrated to dryness in vacuo. The residue was dried (60°, 0.1 mm) to give 4-bromo-3-ethoxyisothiazole-5-carboxylic acid potassium salt (2.24 g, 97%, mp 265°-268° (d)).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]1[CH:16]=[N:15][CH:14]=[C:13]([C@H:17]2[NH:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:22]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:13]2[CH:14]=[N:15][CH:16]=[CH:11][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: c1cncc([C@@H]2CCCCN2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1cccc(Br)n1)N1CCCCC1c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
After 6-bromopicolinic acid (565 mg, 2.80 mmol) was suspended in acetonitrile (25 ml), anabasine (499 mg, 3.07 mmol), N,N-diisopropylethylamine (0.73 ml, 4.20 mmol), and HBTU (1.27 g, 3.36 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (40% EtOAc/Hexanes), to obtain 255 mg of white solid (26%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=[CH2:13]>>[CH3:14][C:12](=[CH:13][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:11]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=C(C)C(=O)OCC
Product: CCOC(=O)C(C)=Cc1ccc([N+](=O)[O-])cc1
Yield: 46 %

Procedure:
The procedure described in Example 26 is repeated, but using 5.05 g (25 mmols) of 4-bromonitrobenzene and 3.43 ml (27.5 mmols) of ethyl methacrylate. After a reaction time of 8 hours at 130° C. and working up as described in Example 1, recrystallising the crude product from methanol gives 2.70 g (11.5 mmols) of ethyl α-methyl-4-nitrocinnamate in the form of yellow crystals of melting point 75° C.; yield 46% of theory (conversion figure 4600; Pd content 0.01 mol %). Analysis for C12H13NO4 (molecular weight 235.24): calculated C 61.27; H 5.57; N 5.96, found C 61.18; H 5.57; N 6.24.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]([C:10]1[C:11]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:14][CH:15]=1)=[O:9].Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>O>[CH2:37]([NH:36][C:11]1[C:10]([C:8]([NH2:7])=[O:9])=[CH:15][N:14]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[N:12]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCc4ccccc4)n3)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cnc(Nc2ccc(N3CCNCC3)cc2)nc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A 10 ml 1,4-dioxane solution of 738 mg of tert-butyl 4-(4-{[5-(aminocarbonyl)-4- (benzylamino)pyrimidin-2-yl]amino }phenyl)piperazin- 1 -carboxylate was mixed with 2.77 ml of 4 M hydrogen chloride/1,4-dioxane solution and 3 ml of water, followed by stirring at 90° C. for 2 hours. The reaction mixture was cooled down to room temperature, diluted with water, mixed with saturated sodium bicarbonate aqueous solution and then extracted with an ethyl acetate-THF mixed solution. After washing of the organic layer with saturated brine and subsequent evaporation of the solvent, the resulting solid was recrystallized (THF-ethanol) to obtain 413 mg of 4-benzylamino-2- {[4-(piperazin- 1 -yl)phenyl]amino}pyrimidine-5- carboxamide as ivory-colored crystals.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([O:22]CC)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC(OC/C=C/C(=O)OCC)c1ccc(CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCC(OC/C=C/C(=O)O)c1ccc(CC(C)C)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-ethyl 4-[1-(4-isobutylphenyl)pentyloxy]-2-butenoate in ethanol and 1,4-dioxane was added a 4N aqueous solution of sodium hydroxide. After being stirred at 80° C. for 5 hours, the mixture was cooled, concentrated and acidified with diluted hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent and silica gel column chromatography of the residue afforded the object compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:20][CH2:19]1>C(O)(=O)C>[CH2:1]([N:8]([CH2:18][CH2:19][OH:20])[C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CO1
Reactant: NC(=O)c1ccccc1NCc1ccccc1
Solvent: CC(=O)O
Product: NC(=O)c1ccccc1N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
o-Benzylaminobenzamide (62 g) was added to a cold solution of 85 ml ethylene oxide in 500 ml acetic acid, the mixture stirred 22 hours at room temperature and concentrated on the rotovap to remove 250 ml acetic acid. The remainder was made alkaline with 10% NaOH and the solid filtered washed with water and recrystallized from 300 ml ethyl acetate to give 48.5 g. product, m.133-7°.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[NH2:10][C:11](N)=[O:12].O>CN1CCCC1=O>[OH:3][C:2]1[N:4]=[C:5]([OH:6])[C:7]([C:11]([NH2:10])=[O:12])=[C:8]([OH:9])[N:1]=1
Reactant: NC(N)=O
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1c(O)nc(O)nc1O
Yield: 96.5 %

Procedure:
A mixture of 128 grams of barbituric acid and 120 grams of urea in 200 ml of 1-methyl-2-pyrrolidone was heated at 145° for 15 minutes. Hot water was then added to the reaction mixture; a white solid precipitated and was collected by filtration. The precipitate was washed with hot dimethylformamide and dried to give 165 grams of 2,4,6-trihydroxy-5-pyrimidinecarboxamide; mp, >270°. The mass spectrum of the product was consistent with the assigned structure.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[CH3:21][N:22]([CH3:27])[CH2:23][C:24](O)=[O:25].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:20]=[C:17]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[O:13][C:14]4[CH:15]=[CH:16][C:3]([CH2:2][O:1][C:24](=[O:25])[CH2:23][N:22]([CH3:27])[CH3:21])=[CH:4][C:5]=4[C:6]([C:7]=23)=[N:19][NH:18]1
Reactant: O=c1[nH]nc2c3c(cccc13)Oc1ccc(CO)cc1-2
Reactant: CN(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)CC(=O)OCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of compound 57 (0.5 mmol) in anhydrous DMF was added dimethyl glycine (0.75 mmol) and EDC (0.75 mmol) and DMAP (catalytic amount). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo. To the residue, 100 mL of ethyl acetate was added. The organic layer was washed with water, and brine, then dried with MgSO4. The Solvents were removed to afford a colorless oil, which was re-crystallized in EtOAc/Hexanes to afford an off-white solid 59 in 30% yield. MS (ES+): 352; MP: 227-230° C.; 1H-NMR (CDCl3, 400 MHz): 10.15 (s, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.06 (dd, J=8.0 and 1.0 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.53 (dd, J=8.0 and 1.0 Hz, 1H), 7.47 (dd, J=8.5 and 2.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 5.21 (s, 2H), 3.26 (s, 2H), 2.37 (s, 6H); Anal. Calcd. for C19H17N3O4: C, 64.95; H, 4.86; N, 11.96. Found: C, 64.95; H, 4.78; N, 12.14.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]=[O:11].O>CO>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][OH:11]
Reactant: O=Cc1ccncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccncc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium borohydride (601 mg, 15.9 mmol) in anhydrous methanol (25 mL) was added a solution of 3-chloropyridine-4-carbaldehyde (1.5 g, 10.6 mmol) in anhydrous methanol (5 mL) at 0° C. The mixture was stirred for 1 hour at room temperature. Water was added and extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (3-chloropyridin-4-yl)methanol was obtained as a white solid (1.4 g, 90% yield) and used for next step without further purification; 1H NMR (400 MHz, CDCl3): δ 2.41 (t, J=5.9 Hz, 1H), 4.83 (dd, J=0.8 Hz, J=5.9 Hz, 2H), 7.52-7.55 (m, 1H), 8.51 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]4[O:16][C:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:18][N:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Na].[NH:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]=[C:3]1[NH2:11].[C:12](OCC)(=[O:17])[CH2:13][C:14]([O-])=[O:15]>CO.CCOCC>[OH:17][C:12]1[N:11]=[C:3]2[NH:2][C:6]3([CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:5][N:4]2[C:14](=[O:15])[CH:13]=1
Reactant: NC1=NCC2(CCCC2)N1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: O=c1cc(O)nc2n1CC1(CCCC1)N2
Temperature: 100 °C
Yield: 74 %

Procedure:
2.37 g of sodium are added in a fractionated way to 10 mL of MeOH. After total dissolution, 5.68 g of 1,3-diazaspiro[4.4]non-2-en-2-amine solubilized beforehand in 5 mL of MeOH, and then 25.38 mL of ethyl malonate are added. The mixture is heated to 100° C., after 4 h of heating, the medium is dry concentrated. The oil obtained is taken up in ether. The precipitate is filtered and the residue is then taken up in 10 mL of H2O and acidified with conc. HCl until pH 3-4. The formed precipitate is filtered, washed with ether and dried in the oven in vacuo. 3.97 g (yield=74%) of 7′-hydroxyspiro[cyclopentane-1,2′-imidazo[1,2-a]pyrimidin]-5′-one are obtained as a beige solid.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=[CH:23][C:15]1=2)C(=O)OC1C=CC=CC=1>C(O)C.O.[OH-].[Na+]>[CH3:1][NH:2][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=[CH:23][C:15]1=2
Reactant: CN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNCCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 78 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of phenyl methyl(2-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (65 mg, 0.144 mmol) in ethanol (4 mL) was added sodium hydroxide (57.4 mg, 1.436 mmol) as a solution in water (2 mL). The resulting mixture was heated to 78° C. and stirred overnight. The mixture was then cooled to room temperature, diluted with water and sodium hydroxide, and extracted with dichloromethane (5×). The combined organics were dried, filtered, concentrated, and then chromatographed in 10% (2M NH3 in MeOH) in dichloromethane, giving the desired product (22 mg, 46%). 1H NMR (DMSO-d6) δ 7.69 (d, J=3.3 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H), 7.07 (t, J=4.4 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.53-6.44 (m, 2H), 6.29 (brs, 2H), 3.54-3.51 (m, 2H), 3.3 (m, 2H), 3.04-3.00 (m, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.32 (s, 3H); MS-EI: (m/z, %) 332 (M+, 75), 288 (97), 260 (100); EI-HRMS calculated for C16H20N4S2 (M+), calculated: 332.1129, observed: 332.1145. HPLC: 95% by area.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17].Cl>CC(C)=O>[Cl:13][CH2:14][CH2:15][C:16]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)=[O:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: CC(C)=O
Product: O=C(CCCl)N1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
8.2 g (50 mmol) of 6-nitroindoline (prepared as described in Preparation 4) were dissolved in 100 ml of acetone, and 6.35 g (50 mmol) of 3-chloropropionyl chloride were added to the solution while ice-cooling, which resulted in the reaction mixture becoming a suspension. This suspension was stirred at room temperature for 1 hour, after which it was heated under reflux for 2 hours, and formed a solution. The resulting solution was cooled to room temperature, and then 10% w/v aqueous hydrochloric acid was added, and the precipitated crystals were collected by filtration. The crystals thus obtained were dried over phosphorous pentoxide in a desiccator under reduced pressure by means of a vacuum pump overnight to obtain 12.7 g (50 mmol) of the title compound as crystals, melting at 127°-128° C. (yield: 100%).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Product: COc1cc(C=Cc2ccc(F)cc2)cc(OC)c1C(C)C

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate and 4-fluorobenzaldehyde in the same procedure as described in example 21.