Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([O-:20])=[O:19]>C(OCC)(=O)C>[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:25])([O-:20])=[O:19]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a stirred solution of 13.81 g. (0.1 mole) of m-nitroaniline in 100 ml. of dry ethyl acetate is added 11.13 g. (0.11 mole) of triethylamine. To the solution is added a solution of 18.56 g. (0.1 mole) of m-nitrobenzoylchloride in 100 ml of ethyl acetate. The mixture is refluxed for 6.5 hours. The reaction mixture is allowed to stand at room temperature overnight. The precipitate is removed by filtration. The filtrate is evaporated to dryness in vacuo. The residue is recrystallized from absolute ethanol. There is obtained 5.79 g. of yellow needles that melt at 188°-189°.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.C(Cl)Cl.[C:29](OC(=N)N(C(C)C)C(C)C)([CH3:32])([CH3:31])[CH3:30]>C1C=CC=CC=1>[C:29]([O:22][C:21]([C:5]1[N:4]2[C:24](=[O:25])[CH:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[CH:9]([S:15][C:16]1[NH:17][N:18]=[N:19][N:20]=1)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:23])([CH3:32])([CH3:31])[CH3:30]
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12

Procedure:
To a suspension of 19.3 g. (0.05 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 500 ml. of dry methylene chloride is added in one portion 30.0 g. (0.15 mol.) of O-t-butyldiisopropylpseudourea in 50 ml. of methylene chloride and the mixture is stirred at ambient temperature for 24 hours. The precipitate is removed by filtration and the filtrate is evaporated to give a residue which is taken up in 200 ml. of benzene and filtured again. The filtrate is extracted with three 100 ml. portions of cold 1 N hydrochloric acid. The aqueous extracts are layered with ethyl acetate and the pH is adjusted to 7.5 by addition of solid sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with two 150 ml. portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to dryness to give 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4 -carboxylic acid t-butyl ester.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:14]=23)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)O)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c2) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH2:2][CH3:3].[H-].[Na+].[Br:12][C:13]1[C:14]([CH2:31]Cl)=[C:15]2[N:21]=[CH:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]2=[N:17][CH:18]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:12][C:13]1[C:14]([CH2:31][N:7]2[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]2=[O:9])=[C:15]2[N:21]=[CH:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]2=[N:17][CH:18]=1
Reactant: CCCC1CNC(=O)C1
Reactant: COc1ccc(Cn2cnc3c(CCl)c(Br)cnc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCCC1CC(=O)N(Cc2c(Br)cnc3c2ncn3Cc2ccc(OC)cc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
4-propylpyrrolidin-2-one x1 (0.23 g, 1.1 eq, 1.8 mmol) is dissolved in absolute DMF (10 ml). Then 60% NaH (0.072 g, 1.1 eq, 1.8 mmol) is added at 0° C. in a flow of argon. The reaction mixture is stirred for 10 min at 0° C., and then for 10 min at room temperature to complete the reaction. The mixture is cooled again to 0° C. and a solution of 6-bromo-7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine x212 (0.59 g, 1 eq) in absolute DMF (5 ml) additionally containing 0.1 g (0.2 eq, 0.32 mmol) of tetrabutylammonium bromide is added dropwise to the obtained suspension. The reaction mixture is stirred for 4 h at 5° C., then overnight at room temperature. The DMF is evaporated at 45° C. under 1 mmHg. The residue is partitioned in 10% aqueous NaH2PO4/ethyl acetate mixture. The aqueous layer is subjected to additional extraction with ethyl acetate. The combined extracts are dried with anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silicagel to afford 0.52 g of 1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x213.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11](C(O)=O)[N:12]=[C:13]([O:14][CH:15]([CH3:17])[CH3:16])[C:8]2=[CH:7][N:6]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([O:14][CH:15]([CH3:17])[CH3:16])[C:8]2=[CH:7][N:6]=1
Reactant: CC(C)Oc1nn(C(=O)O)c2nc(Oc3ccc(F)cc3F)ncc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Yield: 36.1 %

Procedure:
6-(2,4-Difluoro-phenoxy)-3-isopropoxy-pyrazolo[3,4-d]pyrimidine-1-carboxylic acid (190 mg) was treated with a solution of CF3CO2H (0.3 mL) in CH2Cl2 (5 mL) at room temperature for four hours. The reaction mixture was then concentrated under reduced pressure and the residue was purified by flash column chromatography flushing with 30% ethyl acetate in hexanes to give 60 mg of 6-(2,4-difluoro-phenoxy)-3-isopropoxy-1H-pyrazolo[3,4-d]pyrimidine, m.p. 143.7-145.0° C., MS (M+1)+: 307.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42])[C:34](Cl)=O.O>CN(C)C=O>[Cl:30][C:31]1[CH:32]=[C:33]([C:34]2[O:1][N:2]=[C:3]([C:4]3[C:14]4[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:9][C:8]=4[CH:7]=[CH:6][CH:5]=3)[N:22]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:42])[CH3:43]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=N)NO)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A mixture of 1,1-dimethylethyl 9-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 65) (32.9 g, 107 mmol) and triethylamine (17.9 ml, 128 mmol) in dry N,N-dimethylformamide (DMF) (200 ml) was cooled in ice/water under nitrogen. A solution of 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (Preparation 102) (28.7 g, 123 mmol) in DMF (100 ml) was added over ca 20 minutes. When the addition was complete the mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature, then at 120° C. for 3 hours. The mixture was allowed to cool and was poured into water (1 liter). The resulting solid was extracted into ethyl acetate (3×300 ml) and the extracts combined, washed with 1M hydrochloric acid (2×250 ml), then 1M sodium carbonate solution (3×250 ml), brine (250 ml), dried (sodium sulphate) and evaporated. The residue was purified by chromatography on silica. Eluting with a 10-40% gradient of ethyl acetate in isohexane to give the title compound as a crystalline solid (42.7 g) MS (ES): C25H2835ClN3O5 requires 485; found 486 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=[O:8].[C:10](Cl)(=O)[C:11](Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ncsc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1scnc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-methylthiazole-5-carboxylic acid was dissolved in DCM, cooled to 0° C., added oxalyl chloride (7.6 ml, 88 mmol) and DMF (2 drops). Reaction mixture was stirred for 30 mins and DCM was removed on rotavapour. Residue was dissolved in MeOH at 0° C. and stirred for 30 mins at rt. MeOH was removed on rotavapour and crude was worked up (AcOEt/H2O) to obtain the title compound (4.1 g) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.83 (s, 1H), 4.35 (q, J 7.2, 2H), 2.78 (s, 3H), 1.37 (t, J 7.2, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6](=[O:7])[C:5](I)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:3]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O>>[CH3:1][C:2]1([CH3:19])[C:6](=[O:7])[C:5]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:3]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(I)C1=O
Reactant: OB(O)c1ccco1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccco2)C1=O
Yield: 22.2 %

Procedure:
250 mg of 2,2-dimethyl-4-iodo-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone was 86 mg of furan-2-boronic acid by a procedure similar to the procedure in Example 2 to afford 47 mg of 2,2-dimethyl-4-(2-furanyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. NMR: δ1.56 (s, 6H), 3.11 (s, 3H), 6.51 (m, 1H), 6.89 (d, J=3.6 Hz, 1H), 7.37 (d, J=3.6 Hz, 1H), 7.97 (m, 4H). IR (cm−1): 2989, 1703, 1409, 1317, 2989, 1703, 1409, 1317, 1148, 959, 771.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:7])[C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[O:9])=[CH:18][CH:17]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)CCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Adipoyl chloride (45.8 g, 0.25 mol) was added over a 30-45 minute period to a mechanically stirred suspension of aluminum chloride (83.3 g, 0.625 mol) in fluorobenzene (235 ml, 2.5 mol) maintained at 5°-10° C. The yellow slurry was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured onto approximately 1000 g of ice containing 100 ml of concentrated hydrochloric acid. The resulting suspension was separated by decantation and washed several times with water. The organic layer was distilled to remove excess fluorobenzene and the solid residue collected by filtration, washed with water, and dried at 110° C. The crude solid was recrystallized from approximately 1000 ml of toluene to afford 57.0 g (76% yield) of 1,4-bis(4-fluorobenzoyl) butane; mp 165°-167° C.; 'H NMR (CDCl3) δ1.2-2.1 (m, 4H, CH2), 3.00 (t, 4H, O=CCH2 , J=7.0 Hz), 7.0-8.2 (m, 8H, aromatic). Anal. Calcd. for C18H16F2O2 : C, 71.51%; H, 5.33%; F, 12.57%. Found: C, 71.68%; H, 5.38%; F, 12.78%.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Cl:7][C:8]1[CH:22]=[C:21]([F:23])[C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[C:10]([F:24])[CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:7][C:8]1[CH:22]=[C:21]([F:23])[C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[CH2:1])=[CH:15][CH:14]=2)=[C:10]([F:24])[CH:9]=1
Reactant: O=Cc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (8.7 g, 24.35 mmol) and KOt-Bu (3.4 g, 30.3 mmol) in dry THF (20 mL), which was stirred at room temperature for 1 h under nitrogen, was added a solution of 4-(4-chloro-2,6-difluorophenoxy)benzaldehyde (5.4 g, 20.10 mmol) in THF (8 mL). The mixture was stirred at room temperature overnight, and quenched with water. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (2.6 g, 9.75 mmol, 48.5% yield). LCMS: rt=4.06 min, [M+H+]=267
Reaction SMILES: C[O-].[Na+].[C:4]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].Br[CH2:14][CH2:15][CH2:16][CH2:17]Br>CN(C=O)C>[CH2:11]([O:10][C:4]([C:5]1([C:6](=[O:7])[CH3:8])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])[CH3:12]
Reactant: BrCCCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(C)=O)CCCC1
Temperature: 90 °C
Yield: 78.7 %

Procedure:
27.2 g (0.4 mol) of sodium methoxide are initially introduced into 300 ml of DMF at approx. 40° C. and stirred. A mixture of 26 g (0.2 mol) of ethyl acetoacetate and 43 g (0.2 mol) of 1,4-dibromobutane is slowly added dropwise to this suspension and the reaction mixture is stirred for approx. 24 hours at this temperature. Towards the end of the reaction, the temperature may optionally be raised to 90° C. for a further hour. The precipitated sodium bromide is filtered out, the DMF removed and the residue fractionated. 29 g (78%) of 1-acetyl-1-cyclopentanecarboxylic acid ethyl ester are obtained. Bp.: 136° C. (1500 Pa); IR: 1745 cm−1 (C═O, ester), 1713 cm−1 (C═O, ketone); MS: m/e=142 (M−42), 114, 101, 96, 86, 67, 43.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[OH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>C1COCC1.CCN(CC)CC>[OH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:2][C:3]#[N:4])[CH2:8][CH2:7]1
Reactant: OC1CCNCC1
Reactant: N#CCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCN1CCC(O)CC1
Temperature: 47.5 °C
Yield: 56858.5 %

Procedure:
BrCH2CN (28.55 g, 0.238 mmol) was added dropwise to a solution of 4-hydroxypiperidine (24.98 g, 0.216 mol) and Et3N (33.18 mL, 0.238 mmol) in dry THF (100 mL) under N2, maintaining the temperature between 45-50° C. After addition of BrCH2CN, the solution was refluxed for 30 min., before allowing the solution to cool down to room temperature. The title-compound was afforded as a straw-coloured oil (18.97 g, 63%) after purification by flash chromatography using ether/CH3OH (19:1) as eluent. dH (250 MHz; CDCl3); 1.65 (m, 2H, 1×CH2CH2CH and 1×CHCH2CH2), 1.75 (s, 1H, OH), 1.95 (m, 2H, 1×CH2CH2CH, 1×CHCH2CH2), 2.45 (m, 2H, 1×NCH2CH2 and 1×NCH2CH2), 2.78 (m, 2H, 1×NCH2CH2 and 1×NCH2CH2), 3.55 (s, 2H, NCH2CN) and 3.75 (m, 1H, CH2CHOH); δC (62.9 MHz; CDCl3); 33.96, 46.09, 49.73, 66.58 and 114.71 (CN); IR υmax/cm−1; 3375(broad), 2230, 1420, 1330, 1150 and 1060; FAB MS, m/z(M+H)+ 141.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:19][N:20]([CH2:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][S:29][CH2:30][CH2:31]N)[N:27]=1)[CH3:21]>>[CH3:21][N:20]([CH2:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][S:29][CH2:30][CH2:31][NH:4][C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[N:27]=1)[CH3:19]
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccncc1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Product: CN(C)Cc1nc(CSCCNc2ncc(Cc3ccncc3)c(=O)[nH]2)cs1

Procedure:
Following the procedure of Example 1, 2-nitroamino-5-(4-pyridyl)methyl-4-pyrimidone was reacted with 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine to yield 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(4-pyridyl)methyl-4-pyrimidone as a trihydrochloride salt melting at 200°-202° C. after recrystallization from a methanol/ethanol solvent mixture.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:35](CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23](=[O:24])[NH2:35])=[CH:19][CH:20]=2)=[CH:26][CH:27]=1)[C:28](=[O:32])[N:29]([CH3:30])[CH3:31])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
Acid compound 33 (0.7 g, 1.58 mmol) was dissolved in DCM (25 mL). Triethylamine (0.26 mL, 1.89 mmol) and BOP reagent (0.77 g, 1.74 mmol) were added and the reaction mixture stirred at room temp for 15 min under an atmosphere of argon. Ammonia gas was then bubbled gently through the solution for 15-20 min to complete the reaction. Excess ammonia was degassed, the solvent was removed under reduced pressure and the residue was suspended in EtOAc (75 mL). The organic layer was washed with 0.5 N NaOH (2×10 mL), water (2×25 mL), and brine (1×30 mL), dried and concentrated under reduced pressure to yield the amide compound 38 (0.7 g, quantitative yield). 1H NMR (400 MHz, DMSO-d6): 7.33 (d, J=8.4 Hz, 2H), 7.30 (br, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.93 (overlapped d, J=8.8 Hz, 2H0, 6.92 (overlapped d, J=8.8 Hz, 2H), 6.78 (br, 1H), 5.50 (d, J=8.0 Hz, 1H), 2.90 (s, 3H), 2.84 (s, 3H), 2.79 (t, J=8.0 Hz, 2H), 2.35 (t, J=8.0 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.[CH3:12][Li]>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH:9]([OH:10])[CH3:12])=[CH:4][CH:3]=1
Reactant: [Li]C
Reactant: C=C(C=O)c1ccc(C)cc1
Solvent: CCOCC
Product: C=C(c1ccc(C)cc1)C(C)O
Temperature: -78 °C

Procedure:
2.34 g of aldehyde 38 is dissolved in 150 ml of diethyl ether and cooled to −78° C. under nitrogen. 20 ml of methyllithium solution (1.6 M in diethyl ether) is now added in drops. After 1.5 hours at this temperature, it is quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel with ethyl acetate/hexane, whereby in addition to 237 mg of starting material, 1.06 g of title compound 39 accumulates as a colorless oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][OH:23]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][OH:23])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NCCO
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Product: OCCNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and 2-aminoethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)[NH2:5].Cl[C:11]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1.C(O)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: Nc1cc(Br)cc(Br)c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1ccnc(Nc2cc(Br)cc(Br)c2)n1
Temperature: 120 °C
Yield: 85.4 %

Procedure:
A solution of 3,5-dibromoaniline (2.93 g, 11.67 mmol), 2-chloro-4-methylpyrimidine (1.5 g, 11.67 mmol), and acetic acid (0.701 mL, 12.25 mmol) in 1,4-dioxane (23.5 mL) was sealed in a pressure vessel under an argon atmosphere and heated at 120° C. for 17 hours. After being cooled to room temperature, the reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (40 mL). The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Silica gel flash chromatography (10% to 30% ethyl acetate/hexanes) afforded N-(3,5-dibromophenyl)-4-methylpyrimidin-2-amine (3.6 g, 9.97 mmol, 85% yield, 95% purity) as a light yellow solid. MS ESI: [M+H]+ m/z 343.8.