Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([NH:16][OH:17])=[O:15]>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[N:16]([OH:17])[C:14](=[O:15])[C:13]2[C:12](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:11]=1
Reactant: Nc1ccccc1C(=O)NO
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: C1COCCO1
Product: O=c1c2ccccc2nc(-c2ccccc2Cl)n1O
Yield: 51.7 %

Procedure:
35 g (0.2 mol) of o-chlorobenzoyl chloride are added to a solution of 30.4 g (0.2 mol) of o-aminobenzhydroxamic acid in 250 ml of dioxane at 20°-30° C. The mixture is boiled under reflux for 3 hours, the solvent is then distilled in vacuo, 100 ml of ether are added to the residue, and the crystalline product is filtered off under suction. It is dissolved in 300 ml of 5% strength sodium hydroxide solution, the solution is filtered and the filtrate is acidified with concentrated hydrochloric acid. The precipitated product is then filtered off under suction and rinsed with water. In this manner, 28.2 g (52% of theory) of 2-(2-chlorophenyl)-3-hydroxy-3,4-dihydro-4-oxo-quinazoline are obtained in the form of crystals of melting point 211° C.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]>CCOCC>[OH:11][CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:3]#[CH:2]
Reactant: CCCCC=O
Reactant: C#CCBr
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)CCCC
Temperature: 30 °C

Procedure:
A suspension of 24.3 g. (1.0 mole) of magnesium in 90 ml of dry ether is stirred at room temperature under nitrogen with 100 mg. of mercuric chloride. The reaction is initiated by the addition of 2 ml. of propargyl bromide and maintained by the dropwise addition of a solution of 119.5 g. (1.0 mole) of propargyl bromide and 107.7 g. (1.25 mole) of valeraldehyde in 300 ml. of dry ether. While the initial reaction is quite vigorous and is maintained at 30° C. only by cooling in an ice bath it may become necessary to heat the mixture to reflux temperature after about a third of the ether solution is added in order to maintain the reaction. After the addition is complete the reaction mixture is refluxed until most of the magnesium is dissolved (several hours) and the reaction mixture is decanted from excess magnesium into 1500 ml. of stirred ice-cold ammonium chloride solution. The ether layer is separated and the aqueous layer is extracted three times with 300 ml. portions of ether. The combined ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. Evaporation of the ether under vacuum leaves about 115 mg. of yellow oil, which is distilled through a 15 cm. Vigreaux column at 18 mm. The fraction boiling at 81°-82° C. is collected (36 g.) and the higher-boiling and lower-boiling distillates may be redistilled to yield additional product. The infrared absorption spectrum shows at most a trace of allene (5.1 μ) and gas-liquid partition chromatography shows a purity of about 98% for the main fraction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:20][CH2:19][C:15]1[CH:16]=[N:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: NCc1cncc(F)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1cncc(F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (1.20 g, 5.45 mmol), (5-fluoropyridin-3-yl)methanamine (757 mg, 6.0 mmol) and potassium carbonate (3.015 g, 21.82 mmol) in N,N-dimethylformamide (8 mL) was heated at 80° C. for 1 hour. After cooling, the mixture was diluted with ethyl acetate and the mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound which was used without further purification. MS (ESI) m/z 327 (M+H)+.
Reaction SMILES: B.[CH2:2]=[C:3]1[CH2:9][O:8][CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1.[OH-:17].[Na+].OO>C1COCC1.CCCCCC>[OH:17][CH2:2][CH:3]1[CH2:9][O:8][CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1
Reactant: [OH-]
Reactant: C=C1COCCN(C(=O)OC(C)(C)C)C1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(CO)C1
Temperature: 25 °C

Procedure:
1M borane in THF (450 mL, 0.45 mol, 0.9 eq) was added under stirring and cooling on an ice bath to a stirred in a stream of argon solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (Preparation 79, 107 g, 0.5 mol, 1 eq) in THF (300 mL). The reaction mixture was heated to 25° C. and stirred at this temperature for 3 h. Then the reaction mixture was cooled to 0-10° C. and treated at this temperature sequentially with 3N sodium hydroxide (170 mL) and 30% hydrogen peroxide (66 mL). The obtained homogenous mixture was stirred overnight, then treated with hexane (45 mL), and dried over potassium carbonate. The organic layer was decanted from the precipitate, which was washed with DCM. The organic layers were evaporated in vacuo, and the residue was purified rapidly (due to instability of the product on silica gel) by chromatography (carbon tetrachloride/chloroform/isopropanol 100:0:0→0:100:0→0:90:10) on silica gel (1.2 kg; 63-100 μm) to give title compound as a colorless oil in (85 g, 0.368 mol, 72%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:13])([CH3:12])[NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.Br[C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[N:19][CH:20]=1.[C@H]1(N)CCCC[C@@H]1N.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I.O>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:13])([CH3:12])[N:9]([C:15]3[CH:20]=[N:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: CC1(C)NC(=O)c2ccc(Cl)nc21
Reactant: OCc1cncc(Br)c1
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)c2nc(Cl)ccc2C(=O)N1c1cncc(CO)c1
Yield: 92 %

Procedure:
2-Chloro-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (intermediate A-16 [G], 39.2 mg, 0.2 mmol), (5-bromo-pyridin-3-yl)-methanol (example 3 [A], 74.8 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), (1S,2S)-cyclohexane-1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in dioxane (5 mL). The reaction mixture was subjected to microwave reaction at 140° C. for 1 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (55.7 mg, 92%) as solid. MS: 304.1 (M+H+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[C:8]([C:11]1[C:12]([CH2:35]Br)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[CH:18][C:17]([O:31][CH3:32])=[C:16]([O:33][CH3:34])[CH:15]=2)(=[O:10])[CH3:9].O>CN(C)C=O>[C:8]([C:11]1[C:12]([CH2:35][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[CH:18][C:17]([O:31][CH3:32])=[C:16]([O:33][CH3:34])[CH:15]=2)(=[O:10])[CH3:9]
Reactant: c1nc[nH]n1
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C(C)=O)c(Cn3cncn3)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
Oily sodium hydride (60%, 0.372 g) was added to a solution of 1H-1,2,4-triazole (0.594 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 15 minutes. Then, 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (3.3 g) was added, and the mixture was stirred at 80° C. for 40 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave 3-acetyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline (1.4 g, 42%). This compound was recrystallized from ethanol to give colorless prisms, mp. 180°-181° C.
Reaction SMILES: [CH3:1][C:2]([C@H:18]1[C@@H:21]([CH2:22][CH:23]=[O:24])[NH:20][C:19]1=[O:25])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:3][C:2]([C@@H:18]1[C:19](=[O:25])[NH:20][C@@H:21]1[CH2:22][C:23]([OH:28])=[O:24])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:6])[CH3:1]
Reactant: CC(C)=O
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one (9 mg) in acetone (1 ml) was added 2N Jones reagent (60 μl) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. After addition of isopropyl alcohol (100 μl), the mixture was evaporated in vacuo. The residue was taken up in chloroform (20 ml) and washed with brine. The aqueous layer was extracted with chloroform (5 ml). The combined organic layers were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, and evaporated to give {(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxo-azetidin-2-yl}acetic acid (7 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:11]1C=CC=C2[C:12]=1[CH2:13][CH2:14]C2=O)(O)=[O:9].Cl.CNC>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:8](=[O:9])[CH2:11][CH2:12][C:13]#[CH:14])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: CNC
Agent: Cl
Product: C#CCCC(=O)Nc1ccncc1

Procedure:
The desired product was prepared by substituting 4-pentynoic acid and 4-aminopyridine for 4-carboxy-1-indanone and dimethylamine hydrochloride, respectively, in Example 40. MS (APCI(+)) m/e 175.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[CH3:23][C:22]([NH:26][C:27]([NH:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:7]([F:14])=[CH:8][C:9]([F:13])=[CH:10][C:11]=1[F:12])=[O:4])=[O:28])([CH3:25])[CH3:24]
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F

Procedure:
Following the procedure of Example 58 only using the product of Example 50 and t-butylisocyanate, the title compound was obtained, mp 205°-206° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([Cl:7])[C:4]([NH:8][C:9]2[NH:13][CH2:12][CH2:11][N:10]=2)=[C:3]([Cl:14])[CH:2]=1.Br[CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:14][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=1[N:8]([C:9]1[NH:10][CH2:11][CH2:12][N:13]=1)[CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19]
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: C=C(C)CCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)CCN(C1=NCCN1)c1c(Cl)cccc1Cl
Temperature: 120 °C

Procedure:
A mixture of 6.9 gm (0.03 mol) of clonidine, 5.6 gm of 4-bromo-2-methyl-1-butene, and 5 ml of triethylamine in 25 ml of toluene was heated for 24 hours at 120° C. After cooling, the solvent was decanted, and the residue remaining was dissolved in 1 N hydrochloric acid. After extraction with ether several times (the ethereal extracts were abandoned), the solution was extracted with ether in fractions at stepwisely rising pH values (alkalizing with 2 N sodium hydroxide solution). The thin-layer chromatographically uniform ether extracts were united and dried over MgSO4, and the ether was evaporated in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].C([Li])CCCCC.[C:17]([N:24]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl-].[NH4+]>C(OCC)C>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]1([OH:29])[CH2:27][CH2:28][N:24]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:25]1
Reactant: Fc1cccc(Br)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)C1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of 1-bromo-2,3-difluorobenzene (8 g, 41.4 mmol) in dry diethyl ether (100 mL), under nitrogen, was added dropwise at −78° C., n-hexyllithium (2.3 M in hexane, 18 ml, 41.4 mmol). The mixture was stirred for 1 min after which a solution of 1-N-boc-3-pyrrolidone (7.66 g, 41.4 mmol) in dry diethyl ether (50 mL) was added dropwise. The resulting mixture was brought to ambient temperature and stirred for 2 h, aqueous saturated ammonium chloride solution (50 ml) was added and the mixture was extracted with ethylacetate (2×50 ml). The combined organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (8.12 g, 66%). MS m/z (rel. intensity, 70 eV) 243 (26), 198 (48), 141 (33), 127 (38), 57 (bp).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21].[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O.CN(C=O)C>[F:33][C:2]([F:1])([F:32])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:34]2[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35]2)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-n4cc5c(n4)CCCC5)cc3C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)butyl)amino)benzoic acid obtained in step B, ethyl (3R)-piperidine-3-carboxylate (0.157 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (158 mg), 1-hydroxybenzotriazole monohydrate (156 mg), N,N-diisopropylethylamine (0.267 mL), 4-dimethylaminopyridine (6.21 mg) and DMF (1.2 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (155.4 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:32]=[CH:31][C:10]2[N:11]3[C:15]([CH2:16][NH:17][CH2:18][C:9]=2[CH:8]=1)=[N:14][N:13]=[C:12]3[CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1>ClCCl>[Cl:6][C:7]1[CH:32]=[CH:31][C:10]2[N:11]3[C:15]([CH2:16][N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C:9]=2[CH:8]=1)=[N:14][N:13]=[C:12]3[CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:23][CH2:24]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.2 %

Procedure:
Methanesulfonyl chloride (0.1 ml, 1.29 mmol) was added to an ice cooled solution of the amine of example 4 (200 mg, 0.53 mmol) in dichloromethane (5 ml) and stirred at room temperature for 20 hours. The dichloromethane was evaporated off under reduced pressure and the residue purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant, to afford the title compound as a brown foam (71 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:12]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: OCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of ethyl 5-bromonicotinate (10.0 g, 43.46 mmol) in anhydrous THF (20 mL) was added dropwise to a slurry of LiAlH4 (1.91 g, 47.81 mmol) in anhydrous THF (200 mL) under argon at −78° C. and the mixture was stirred for 1.5 h at the same temperature, then warmed to r.t. The reaction mixture was added 15 ml of aqueous HCl (1 M) slowly at −78° C., the mixture was then warmed to rt and added anhydrous Na2SO4, stirred for overnight. The resulting mixture was filtered through celite and the solvent was removed under reduced pressure to give crude (5-bromopyridin-3-yl)methanol, which was used in the next step without purification. To a solution of (5-bromopyridin-3-yl)methanol (10.6 g, 56.40 mmol) in DMF (30 mL) was added, under argon, imidazole (9.98 g, 146.5 mmol) followed by triisopropylsilyl chloride (TIPS—Cl) (15.53 mL, 73.29 mmol). After stirring for 24 h at room temperature the reaction mixture was evaporated to dryness. Purification by flash chromatography (silica gel, hexanes/EtOAc, 9:1) gave 3-bromo-5-((triisopropylsilyloxy)methyl)pyridine as a colourless oil (11.8 g, 81% overall). 1H NMR (CDCl3): d: 1.00-1.237 (m, 21H), 4.837 (s, 2H), 7.849 (s, 1H), 8.480 (s, 1H), 8.556 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:3]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)C(OCC)=O>CS(C)=O.[Cl-].[Na+].O.O>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:2](=[O:1])[CH2:3][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:15]=1
Reactant: CCOC(=O)C(C(=O)c1cccnc1)c1ccsc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Cc1ccsc1)c1cccnc1
Temperature: 160 °C
Yield: 67.8 %

Procedure:
To a solution of ethyl 3-oxo-3-(pyridin-3-yl)-2-(thiophen-3-yl)propanoate (2 g, 7.26 mmol) in DMSO (20 mL) was added catalytic amount of brine (0.2 mL). The reaction mixture was heated at 160° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was concentrated in vacuo and purified by column chromatography to afford Intermediate 56 (1 g, yield 68%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[F:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1F
Reaction time: 1 h

Procedure:
At 0° C., 0.258 ml (2.7 mmol, 1.0 eq.) of tert-butanol was added to a solution of 500 mg (2.7 mmol) of 2-fluoro-4-nitrobenzoic acid and 1.03 g (5.4 mmol, 2.0 eq.) of para-toluenesulphonyl chloride in 5.4 ml of pyridine, the mixture was stirred for 60 min and a further 0.258 ml (2.7 mmol, 1.0 eq.) of tert-butanol was added. The reaction mixture was stirred for another 18 h and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the residue. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 14%-20% mixtures). Yield: 524 mg (75% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[NH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ccc2ccccc2n1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc3ccccc3n2)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and 2-(aminomethyl)quinoline in DME. ES-MS m/e (%): 342 (M+H+, 100).
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[N:20]=[CH:21][CH:22]=[CH:23][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:35]=[CH:34][C:29]([O:30][CH2:31][CH2:32][NH2:33])=[CH:28][CH:27]=1>>[OH:1][CH:3]([CH2:4][NH:33][CH2:32][CH2:31][O:30][C:29]1[CH:34]=[CH:35][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[CH2:2][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[N:20]=[CH:21][CH:22]=[CH:23][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: COc1ccc(OCCN)cc1
Reactant: CC1OC1Oc1ccc(-c2nc3cccnc3c(=O)n2C)cc1
Product: COc1ccc(OCCNCC(O)COc2ccc(-c3nc4cccnc4c(=O)n3C)cc2)cc1

Procedure:
This compound was prepared analogous to Example 24 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-methyl-3,4-dihydro-pyrido[2,3-e]pyrimidin-4-one and 2-(4-methoxy-phenoxy)ethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:42](=[O:43])[C:41]2[CH:45]=[C:37]([CH2:36][C:30]3[C:31](=[O:35])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[C:28](=[O:51])[C:29]=3[CH3:50])[CH:38]=[CH:39][C:40]=2[O:46][C:47](=[O:49])[CH3:48])=[CH:3][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(Cl)nc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(Cl)nc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 54.8 %

Procedure:
5-Amino-2-chloropyridine (0.206 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.142 g, 0.293 mmol, 55%).