Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC.C1CCCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12]
Reactant: [Li]c1ccccc1
Reactant: COc1cccc2c1CCC2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CCOCC
Product: COc1cccc2c1CCC2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a solution of 9.38 g (0.057 mol) of 4-methoxy-1-indanone in 250 ml of ether cooled to 0° C. was added dropwise over 5 min 33.72 ml (0.0607 mol) of 1.8M phenyllithium in cyclohexane/ether and the mixture was stirred at room temperature for 1 h. An additional (10 ml) phenyllithium solution was added and stirred at room temperature for 1 h. To the reaction mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 ml), and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 14.3 g of crude 4-methoxy-1-phenyl-indan-1-ol which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12](O)=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[CH2:1]([N:8]1[C:12]([Cl:23])=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1nnn(Cc2ccccc2)c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)CCc1nnn(Cc2ccccc2)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 1.0 g. (4 mmol.) of 1-benzyl-4-(2-carbethoxyethyl)-5-hydroxy-1,2,3-triazole in 2 ml. of phosphorus oxychloride is added 0.5 g. (5 mmol.) of phosphorus pentachloride. The reaction mixture is stirred at 25° for 2 hours, then warmed on a steam bath for 10 minutes and evaporated to dryness. The residue is dissolved in 0.5 ml. of phosphorus oxychloride and the solution is neated to reflux for 30 minutes, cooled and evaporated to dryness to give 1-benzyl-4-(2-carbethoxyethyl)-5-chloro-1,2,3-triazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH2:14][OH:15])=[N:10]2)=[C:5]2[NH:16][CH:17]=[CH:18][C:4]=12.C([Mg]Br)C.N1C=CC=CC=1.Cl[C:30](=[O:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1>[OH:15][CH2:14][C:11]1[N:12]=[CH:13][N:9]([C:6]2[N:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]3[C:18]([C:30](=[O:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][NH:16][C:5]=23)[N:10]=1
Reactant: COc1cnc(-n2cnc(CO)n2)c2[nH]ccc12
Reactant: CCOC(=O)C(=O)Cl
Agent: CC[Mg]Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c[nH]c2c(-n3cnc(CO)n3)ncc(OC)c12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of (1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)methanol (70 mg, 0.285 mmol) in THF (5 mL) was added ethylmagnesium bromide (1.284 mL, 1.284 mmol) at −40° C. After stirring at −5° C. for 1H, pyridine (0.012 mL, 0.143 mmol) was added quickly. The mixture was cooled to −40° C. and ethyl 2-chloro-2-oxoacetate (0.130 mL, 1.142 mmol) was added. After stirring at −40° C. for 30 min, the reaction mixture was quenched by adding i-PrOH and water. The mixture was extracted with EtOAc (2×40 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4 and concentrated under vacuum to give crude product ethyl 2-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (70 mg, 0.203 mmol, 71.0% yield). LCMS: m/z 346.1 (M+H)+, 1.42 min (method 8).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3]([CH:17]1[CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:25])[CH2:16]1)=[O:5]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C1CC(C(=O)C(F)(F)F)Cc2ccccc21
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one necked round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50 mL of ether was then added over about 5 min. The reaction mixture was then stirred at room temperature for 14 h and then was diluted with 100 mL of 3N HCl. The phases were separated and the organic layer washed with 3N HCl, brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo. The residue was then taken up in 70 mL of boiling ethanol/water and allowed to cool to room temperature whereupon crystals of 2-trifluoroacetyl-1-tetralone formed which were isolated by filtration and air dried to give 32 g, 81% of pure product with mp 48°-49° C. 1H NMR CDCl3 δ2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR CDCl3 δ72.0. EI GC-MS M+=242.
Reaction SMILES: [OH-].[K+].FC(F)(F)C([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:20][O:21][CH3:22])=[C:13]([CH2:17][O:18][CH3:19])[CH:14]=2)[CH2:9]1)=O>O.CO>[NH2:7][CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH2:17][O:18][CH3:19])=[C:12]([CH2:20][O:21][CH3:22])[CH:11]=2)[CH2:16]1
Reactant: COCc1cc2c(cc1COC)CC(NC(=O)C(F)(F)F)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1cc2c(cc1COC)CC(N)C2

Procedure:
A solution of potassium hydroxide (150 mg, 2.60 mmol) in water (0.5 ml) is added to a solution of 2-(trifluoroacetylamino)-5,6-bis(methoxymethyl)indane (240 mg, 0.75 mmol) in methanol (3 mL) and the mixture is heated at reflux for 2.5 hours. The solvent was removed in vacuo and the residue is partitioned between aqueous sodium hydroxide (10 mL) and ethyl acetate (20 mL). The organic extract is dried (MgSO4) and the solvent is removed in vacuo to leave the product as a dark oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14].C(N(CC)CC)C.[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26]>CN(C=O)C>[Br:23][CH:24]([CH3:28])[C:25]([NH:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14])=[O:26]
Reactant: NC(=O)c1cnn(C2CCOCC2)c1N
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Br)C(=O)Nc1c(C(N)=O)cnn1C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of C2 (5.0 g, 23.8 mmol) and triethylamine (3.65 mL, 26.2 mmol) in anhydrous DMF (50 mL) was cooled in an ice bath and treated drop-wise with 2-bromopropanoyl bromide (5.4 g, 25 mmol). The mixture was stirred at 0° C. for 30 mins, warmed to room temperature and stirred at ambient temperature for an additional 2 h. The reaction was partitioned between EtOAc (200 mL) and aqueous 2N hydrochloric acid (500 mL); the organic phase was washed with saturated aqueous sodium bicarbonate solution (400 mL), saturated aqueous sodium chloride solution (200 mL) and dried over sodium sulfate. Filtration and concentration of the filtrate provided crude C24 as an orange residue, which was used in the next step without purification,
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CNCCNC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCNCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 1,4-diazepan, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.69 minutes; C22H23Cl2N5O2 (460.36); mass spectrum: (M−H)−=459/461/463 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[N:9]=1)([CH3:4])[CH3:3].[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1>ClCCl>[CH3:4][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([NH:13][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=3)(=[O:34])=[O:33])[CH:14]=[CH:15][CH:16]=2)[N:9]=1)([CH3:1])[CH3:3]
Reactant: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(N)c2F)n1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2F)n1
Reaction time: 2 h
Yield: 81.3 %

Procedure:
3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline (70 mg, 0.204 mmol), 3-fluorobenzenesulfonyl chloride (40 mg, 0.204 mmol), and pyridine (0.162 mg, 2.04 mmol) were dissolved in dichloromethane (2 mL). After 2 h stirring, the reaction mixture was placed on silica gel and chromatography (0 to 30% EtOAc/Hexanes over 25 min.) to obtain N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide (83 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (s, 1H), 8.42 (d, J=5.49 Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.42 (m, 2H), 7.39-7.31 (m, 2H), 7.24 (t, J=7.87 Hz, 1H), 6.57 (d, J=5.31 Hz, 1H), 2.52 (s, 3H), 1.37 (s, 9H); MS (ESI); 499 (M−H)−.
Reaction SMILES: C[N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[C:16]([O:20][C:21](=[O:30])[NH:22][CH:23]1[CH2:28]CC(=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].N>>[C:16]([O:20][C:21](=[O:30])[NH:22][CH:23]1[CH2:24][CH2:25][C:3]2[N:2]=[C:7]([CH3:8])[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[CH2:28]1)([CH3:18])([CH3:19])[CH3:17]
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])c(=O)n1C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: N
Product: Cc1nc2c(cc1[N+](=O)[O-])CC(NC(=O)OC(C)(C)C)CC2
Temperature: 60 °C
Reaction time: 5 h
Yield: 28.3 %

Procedure:
To a sealed tube was added 1,6-dimethyl-3,5-dinitropyridin-2(1H)-one (0.16 g, 0.76 mmol), tert-butyl(4-oxocyclohexyl)carbamate (0.19 g, 0.91 mmol), and ammonia (1M in methanol, 9 mL). The resulting mixture was allowed to stir for 5 h at 60° C. and then allowed to cool to rt and concentrated. The residue was purified by column chromatography to give tert-butyl(2-methyl-3-nitro-5,6,7,8-tetrahydroquinolin-6-yl)carbamate (0.066 g, 28%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(Cl)c2cccnc2c1O
Temperature: 170 °C
Yield: 23.8 %

Procedure:
5Chloro-8-hydroxyquinoline (5.00 g) and potassium carbonate (11.54 g) are mixed together in a stainless steel bomb and heated to 170° C. under 800 p.s.i. CO2 for 7 days. The reaction is cooled and the resulting solid is dissolved in 800 mL water. The insoluble material is filtered and partitioned between 800 mL water and 400 mL EtOAc in a separatory funnel. The aqueous layer is washed with EtOAc (3×400 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, washed with water and dried. The crude product is triturated with i-PrOH and dried to yield 1.481 g of the title product as a brown solid.
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:23])=[N-]>C(Cl)Cl.CCOCC>[CH3:23][O:18][C:17](=[O:19])[C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH3:20]
Reactant: C=[N+]=[N-]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A stirred solution of N-BOC-N-methyl-(D)-phenylalanine (3 g, 10.5 mmol) in methylenchoride (25 ml) is treated at 0° C. with slight excess of diazomethane in ether (25 ml). The reaction mixture is stirred at 0° C. and concentrated in vacuo to give N-BOC-N-methyl-(D)-phenylalanine methyl ester as a colorless oil. The above crude material is dissolved in a mixture of trifluoroacetic acid (8 ml) and ethanedithiol (2 ml) and stirred under nitrogen at r.t. for 1 hour. A 4M solution of hydrogen chloride in dioxane (3.6 ml) is added. The hydrochloride is precipitated by addition of ether (400 ml) and hexane (300 ml), filtered and washed with ether to give N-methyl-(D)-phenylalanine methyl ester hydrochloride (2.4 g) as a white powder. A solution of the above N-methyl-(D)-phenylalanine methyl ester hydrochloride (2.4 g, 10 mmol) and, 5-dimethylbenzoic acid (1.8 g, 11 mmol) in DMF (15 ml) at 0° C. is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.2 ml, 11 mmol). The reaction mixture is slowly warmed to r.t. and stirring continued overnight. The homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 1:2 to give N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine methyl ester as a colorless oil. [a]D =+111° (c=0.94, ethanol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]([CH3:26])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:7][CH2:6]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:26][N:12]([CH2:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([CH2:4][CH2:3][CH2:2][O:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:6][CH2:7]1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CN(C[C@H]1CC[C@H](CCCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-N-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 3-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyl)-propyl ester as colorless solid, MS: 472 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:11][CH2:10][CH2:9]1>C1COCC1.C(O)C.[Pd]>[N:8]1([CH2:7][CH2:6][O:5][C:4]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:3]=2[O:2][CH3:1])[CH2:11][CH2:10][CH2:9]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(N)ccc1OCCN1CCC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 100.7 %

Procedure:
1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine (53.5 mg, 0.21 mmol) was dissolved in a 1:1 mixture of THF and ethanol (7 ml) and 10% palladium on carbon paste (150 mg) introduced. The reaction mixture was stirred under an atmosphere of hydrogen for 50 hours at RT. The catalyst was filtered off over filter-aid and the filtrate evaporated to give 4-[2-azetidin-1-yl-ethoxy]-3-methoxy-phenylamine as a brown oil (47 mg, 100%). This material was treated with 3-phenoxyphthalic anhydride in the same manner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in Example A4 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4](=[O:19])[CH:3]=1.[N:20]([O-])=[O:21].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4](=[O:19])[C:3]=1[N:20]=[O:21]
Reactant: COc1ccc(Cn2c(=O)cc(N)n(C)c2=O)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cn2c(=O)c(N=O)c(N)n(C)c2=O)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a solution of 6-amino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (4.3 g, 16.45 mmol) in water (20 mL) and acetic acid (20 mL) was added sodium nitrite (3.4 g, 49.4 mmol) in small portions at 70° C. After addition, the mixture was stirred at 70° C. for 4 h. The reaction was cooled and concentrated. The solids were collected, washed with water and dried under vacuum to give 6-amino-3-(4-methoxybenzyl)-1-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione (4.1 g, 85.9% yield) as purple solid. LCMS retention time 0.885 min; LCMS MH+ 291.
Reaction SMILES: [H-].[Na+].[C:3]([N:5]=[C:6]1[NH:10][CH2:9][CH2:8][NH:7]1)#[N:4].Cl[C:12]1[C:17]2[CH:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:16]=2[O:15][C:14]([CH3:25])([CH3:24])[N:13]=1>CN(C)C=O>[C:22]([C:19]1[CH:20]=[CH:21][C:16]2[O:15][C:14]([CH3:24])([CH3:25])[N:13]=[C:12]([N:7]3[CH2:8][CH2:9][NH:10][C:6]3=[N:5][C:3]#[N:4])[C:17]=2[CH:18]=1)#[N:23]
Reactant: CC1(C)N=C(Cl)c2cc(C#N)ccc2O1
Reactant: N#CN=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)N=C(N2CCNC2=NC#N)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.8 %

Procedure:
To a suspension of sodium hydride (0.24 g) in dimethylformamide (10 ml) was added 2-cyanoiminoimidazolidine (1.00 g) with ice-cooling and the mixture was stirred at room temperature for 10 minutes. Then, 4-chloro-6-cyano-2,2-dimethyl-2H-1,3-benzoxazine (1.09 g) was added to the mixture and the mixture was stirred at room temperature for additional 5 hours. The reaction mixture was extracted with addition of ethyl acetate and an aqueous sodium bicarbonate solution. The ethyl acetate layer was successively washed with water and aqueous saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was crystallized from ether to obtain 6-cyano-4-(2-cyanoimino-imidazoline-1-yl)-2,2-dimethyl-2H-1,3-benzoxazine (0.23 g) (Compound 19).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:12](=[O:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:18][CH2:19][CH:15]([N:11]([CH3:10])[C:12](=[O:14])[CH3:13])[CH2:16]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)N(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N(C)C1CCN(c2ccc(C=O)cc2)C1
Temperature: 120 °C

Procedure:
A solution of 4-fluorobenzaldehyde (2.01 g, 16.2 mmol) and N-methyl-N-(pyrrolidin-3-yl)acetamide (1.92 g, 13.5 mmol) in DMF (20 mL) was treated with K2CO3 (2.24 g, 16.2 mmol). The mixture was heated at 120° C. under nitrogen for 18 hours, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% methanol/ethyl acetate, to afford N-(1-(4-formylphenyl)pyrrolidin-3-yl)-N-methylacetamide.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:7]([NH:14][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of chloromethyltrimethylsilane (325g, 370ml, 2.65 mole) and benzylamine (835g, 850ml, 7.78 mole) was heated at 120° C. (oil bath temperature) for 2h. A white solid began appearing after only 10 minutes and a viscous mixture eventually resulted. The reaction mixture was allowed to cool, then basified with potassium carbonate solution and extracted twice with ether. The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was purified by distillation. The excess benzylamine was removed in the first fractions (b.p. 47-62° C. at 2mmHg). The title compound (D16) was obtained as a colourless oil (380g, 74%) b.p. 75-80° C. at 2mmHg.
Reaction SMILES: [CH2:1]([CH:7]([C:12](=[O:33])[CH2:13][CH:14]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([CH:7]([CH:12]([OH:33])[CH2:13][CH:14]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC(CC(=O)C(CCCCCC)C(=O)OC)OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(CC(O)C(CCCCCC)C(=O)OC)OC1CCCCO1
Temperature: -5 °C
Yield: 96.3 %

Procedure:
7.76 g of methyl 2-hexyl-3-oxo -5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate (0.017 mol) were dissolved in 500 ml of THF while gassing with argon, treated with 20 ml of MeOH and cooled to -5° C. 5.3 g of sodium borohydride (0.14 mol) were added portionwise while stirring in such a manner that the temperature did not exceed 0° C. After stirring for 3 hours the excess sodium borohydride is filtered off, the reaction mixture was hydrolyzed (to pH 6) with 2N hydrochloric acid in the cold and the solvent was evaporated off. The residue was extracted with ether and the ethereal phase was dried and evaporated. There were obtained 7.71 g of methyl 2-hexyl-3-hydroxy-5-[(tetrahydro-2 H-pyran-2-yl)oxy]hexadecanoate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](=O)[C:31](O)=[O:32])[CH:24]=1>C(O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]2[C:31](=[O:32])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)[CH:10]=3)[C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:24]=1
Reactant: O=C(O)C(=O)Cc1cccnc1
Reactant: Nc1cccnc1Nc1cccc(/C=C/c2ccncc2)c1
Solvent: CCO
Product: O=c1c(Cc2cccnc2)nc2cccnc2n1-c1cccc(/C=C/c2ccncc2)c1
Yield: 47.4 %

Procedure:
A mixture of 3-amino-2-[3-[(E)-2-(4-pyridyl)vinyl]phenylamino]pyridine (575 mg) and 3-(3-pyridyl)pyruvic acid (0.37 g) in ethanol (10 ml) was stirred under reflux for 1.5 hours. After evaporation of the solvent, the residue was chromatographed on silica gel column (chloroform-methanol, 9:1) and crystallized from ethanol to give 2-(3-pyridylmethyl)-4-[3-[(E)-2-(4-pyridyl)vinyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (395 mg)