Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]([CH3:34])([CH2:17][CH:18]([CH2:31][CH2:32][OH:33])[CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]([CH3:34])([CH2:17][CH:18]([CH2:31][CH:32]=[O:33])[CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)(C)CC(CCO)CCCCO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)CC(CC=O)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.4 mL (48 mmol) dimethyl sulfoxide in 140 mL dry methylene chloride at -78° C. is added dropwise 3.0 mL (35 mmol) oxalyl chloride. The solution is stirred for 15 minutes and a solution of 2.57 g (7.1 mmol) methyl 2,2-dimethyl-4-(2-hydroxyethyl)-8-(t-butyldimethylsiloxy)octanoate in 20 mL dry methylene chloride is added slowly. The solution is stirred at -60° C. for 15 minutes and 15 mL (0.11 mole) triethylamine is added. The reaction is allowed to warm to room temperature and diluted with methylene chloride. The organic layer is washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase is dried, filtered and concentrated to dryness. The oil is dissolved in ether and the solution is washed with water. The organic phase is dried, filtered and concentrated to give methyl 2,2-dimethyl-4-formylmethyl-8-(t-butyldimethylsiloxy)-octanoate; NMR (CDCl3) delta 9.8 (t,1H), 3.67 (s,3H), 1.2 (s,6H), 0.89 (s,9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10](O)=[O:11])#[N:2].C(=O)([O-])[O-].[K+].[K+].BrC[C:32]([O:34][C:35]([CH3:38])(C)C)=[O:33].[CH3:39][C:40]([CH3:42])=[O:41]>>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:21])([F:23])[F:22])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10]([O:41][C:40]([C:32]([O:34][CH2:35][CH3:38])=[O:33])([CH3:42])[CH3:39])=[O:11])#[N:2]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)OC(=O)C=Cc1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of 0.4 gram (0.001 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid in 25 mL of acetone were added in succession 0.2 gram (0.001 mole) of potassium carbonate and 0.2 gram (0.001 mole) of 1,1-dimethylethyl bromoacetate. Upon completion of the addition, the reaction mixture was stirred at 25° C. for 25 minutes, and then it was heated to reflux where it was stirred for one hour. After this time, the reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was shaken with methylene chloride and water. The organic layer was washed with water and then dried with calcium sulfate. The mixture was filtered through silica gel. The silica gel filter pad was washed with petroleum ether. The combined filtrates were concentrated under reduced pressure, yielding 0.5 gram of 1,1-dimethylethoxycarbonylmethyl 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylate; m.p. 110° -112° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[OH:13][C:14]1[N:21]=[C:20](C)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(Br)C=C>C1COCC1>[CH2:1]([C:20]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([OH:13])[N:21]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Cc1ccc(C#N)c(O)n1
Reactant: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCCc1ccc(C#N)c(O)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
n-Butyllithium (100 mL of a 1.6 M solution in hexanes, 160 mmol, 2.5 equiv) was added via cannula over 10 min to a solution of diisopropylamine (22.4 mL, 160 mmol, 2.5 equiv) in THF (600 mL) at −78° C. The resulting pale yellow solution was stirred at −78° C. for 5 min, then was warmed to 0° C. for an additional 5 min. 2-Hydroxy-6-methylnicotinonitrile (8) (8.58 g, 64.0 mmol, 1 equiv) was added as a solid in small portions over 15 min and the deep orange solution thus obtained was stirred for 1 h at 0° C. Allyl bromide (8.31 mL, 96.0 mmol, 1.5 equiv) was then added and the reaction mixture was warmed to 23° C., maintained at that temperature for 30 min, and was partitioned between 1.0 M HCl (300 mL) and EtOAc (2×250 mL). The combined organic layers were dried over Na2SO4 and were concentrated. The resulting orange solid was triturated with boiling Et2O (100 mL) and subsequently cooled to 23° C., then was filtered through a medium frit, washed with Et2O (2×50 mL) and air-dried to give a1 (6.42 g, 58%) as a tan solid: mp=122-125° C.; IR (KBr pellet, cm−1) 2223, 1654; 1H NMR (DMSO-d6) δ 2.32-2.37 (m, 2H), 2.62 (t, 2H, J=7.6), 4.96-5.06 (m, 2H), 5.69-5.83 (m, 1H), 6.23 (d, 1H, J=7.3), 8.03 (d, 1H, J=7.3), 12.55 (s, br, 1H); Anal. C10H10N2O·0.10H2O: C, H, N.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([N:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1)(OC(C)(C)C)=O>C(O)C>[NH:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1.[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: O[C@@H]1CCNC1
Yield: 98.2 %

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.255 g, 1.34 mmol), N-Boc-(R)-(−)-3-pyrrolidinol (0.251 g, 1.34 mmol) and ethanol (5 mL) to give the title compound as a pale yellow oil (0.34 g): MS (m/e): 88 (M+1).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:29](=[O:30])[N:6]2[C:7]([C:13]([O:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[C:8]([CH2:11][OH:12])[CH2:9][S:10][C@H:5]12)=[O:2].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[O:37]1CCC[CH2:38]1>>[CH:1]([NH:3][CH:4]1[C:29](=[O:30])[N:6]2[CH:7]([C:13]([O:15][CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:14])[C:8]([CH2:11][O:12][C:38]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])=[CH:9][S:10][C@H:5]12)=[O:2]
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: C1CCOC1
Reactant: C1CCNCC1
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(COC(=O)N3CCCCC3)=CS[C@H]12
Reaction time: 0.42 h

Procedure:
To a solution of benzhydryl 7-formamido-3-hydroxymethyl -3-cephem-4-carboxylate (4.24 g) in tetrahydrofuran (80 ml), N,N'-carbonyldiimidazole (1.62 g) was added under ice cooling, followed by stirring at the same temperature for 1 hour and 25 minutes. Then, the resulting solution was added with a solution of piperidine (0.85 g) in tetrahydrofuran (10 ml) and stirred at the same temperature for 1 hour and 20 minutes. Further stirring was conducted for one hour at room temperature. The reaction mixture was added with piperidine (0.17 g), followed by stirring at room temperature for 11 hours and 10 minutes and then, the
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=1)[OH:39]>>[OH:39][CH:38]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=1)[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: NCC(O)c1ccc2ccccc2c1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc3ccccc3c2)N(C(=O)c2ccc(-c3ccccc3OC)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and (1RS)-2-amino-1-(2-naphthyl)ethanol, the title compound was obtained in 67% purity by HPLC. MS(ESI+): m/z=538.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])(=O)=O.CN(P(N(C)C)(N(C)C)=O)C.[Br-:31].[K+].O>C1COCC1.C1OCCOCCOCCOCCOCCOC1>[CH3:11][C:10]([CH3:12])=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][Br:31]
Reactant: [Br-]
Reactant: CC(C)=CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)=CCCCCBr
Yield: 76.6 %

Procedure:
A solution of 11 g of 6-methyl-5-heptenyl tosylate in 100 ml of THF were added 10 ml of HMPA, 50 g of potassium bromide and 300 mg of 18-crown-6, and the resulting mixture was refluxed for 5 hours. After cooling, water was added, and the mixture was concentrated, the residue was extracted with pentane 3 times, the combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate water and saturated brine, dried and concentrated to give 8 g of an oily substance. This oily substance was distilled (bp 70° C./5 mm Hg) to yield 5.7 g of a pure bromide.
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.[C:26](=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:4]1[CH2:5][CH2:6][CH:7]([N:8]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:26]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: [K+]
Solvent: CC#N
Product: c1cc2ncn(C3CCNCC3)c2cn1

Procedure:
To a mixture of 3-fluoro-4-nitropyridine-N-oxide (3.46 g) and tert-butyl 4-aminopiperidine-1-carboxylate (2.745 g) in acetonitrile (150 ml) was added anhydrous potassium carbonate (2.74 g) and the resulting mixture was refluxed for 8 hours. The mixture was filtered and washed well with dichloromethane. The organics were concentrated to dryness and the residue was purified by column chromatography eluting with a mixture of ethyl acetate and dichloromethane (1:1) to give the titled compound as a yellow solid. Yield 3.25 g. NMR (d6 DMSO) 1.4 (s, 9H), 1.5 (M, 2H), 1.9 (m, 2H), 2.95 (m, 2H), 3.9 (m, 3H), 7.5 (dd, 1H), 7.85 (d, 1H), 8.05 (d, 1H) 8.4 (d, 1H).
Reaction SMILES: ClCC[CH2:4][C:5]1(O)[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH2:6]1.[OH-:14].[Na+].S(=O)(=O)(O)O.C([O:24][CH2:25][CH3:26])(=O)C>>[CH:9]1([C:10]([C:5]2[CH:4]=[CH:26][C:25]([OH:24])=[CH:7][CH:6]=2)=[O:14])[CH2:8][CH2:11]1
Reactant: CCOC(C)=O
Reactant: [OH-]
Reactant: O=CC1=CCC(O)(CCCCl)C=C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(c1ccc(O)cc1)C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
4-chloropropyl(4-hydroxyphenyl)methanone (25.1 g, 127 mmol) was added to a 2 N aqueous solution of sodium hydroxide (283 mL, 566 mmol) in several portions under ice cooling. The reaction mixture was allowed to warm up to room temperature, and was stirred for 6 hours, and then dilute sulfuric acid (1.8 N) was added to the reaction mixture under ice cooling until a pH value of 2 was obtained. The reaction mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with water and brine, and then was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1, v/v) to give the title compound (17.7 g, yield: 86%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: NCCc1cccc(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCc2cccc(F)c2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 160 °C
Yield: 44.5 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(3-fluorophenyl)ethanamine (300 mg, 2.16 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. for in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (160 mg) as a yellow solid. LC-MS (ES) m/z=364 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.86-2.90 (m, 2H), 3.51-3.56 (m, 2H), 5.39 (s, 2H), 6.04 (s, 2H), 6.29 (s, 1H), 6.97-7.43 (m, 6H), 7.70 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.C(N(CC)CC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CN(C=O)C>[F:10][C:4]1[CH:3]=[C:2]([CH2:20][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: C=CC(=O)OCC
Reactant: Oc1c(F)cc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Temperature: 110 °C
Reaction time: 21 h

Procedure:
In a 350-mL pressure-glass was added 4-bromo-2,6-difluorophenol (23.82 g, 0.11 mol), triethylamine (55 mL, 0.39 mol), ethyl acrylate (34.27 g, 0.34 mol), DMF (50 mL), palladium (II) acetate (1.29 g, 5.75 mmol), and followed by tri-o-tolyphosphine (2.34 g, 7.6 mmol) under N2. The mixture in the sealed glass was stirred at 110° C. overnight (21 hours), cooled to room temperature and added EtOAc (150 mL) and stirred for 30 minutes, filtered through celite and rinsed with EtOAc (3×100 mL). The filtrate was acidified with 2N HCl to pH ˜2. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined and washed with water (2×100 mL), brine (100 mL) and dried over sodium sulfate. After filtration, heptane (200 mL) was added and the solution was concentrated in vacuo. The resulting precipitate was filtered, washed with heptane (2×50 mL) and dried to afford the desired product as a light-yellow solid. The mother liquor was concentrated in vacuo to obtain additional desired product (10) as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.50 (d, J=15.9 Hz, 1H), 7.09 (d, J=8.3 Hz, 2H), 6.29 (d, J=15.9 Hz, 1H), 5.54 (br, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36](C)(C)C)=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40].C(=O)([O-])[O-].[NH4+:45].[NH4+]>CO>[ClH:40].[ClH:40].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:45])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 83.5 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.butyloxycarbonylpropyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 83.5% of theory, Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1) C29H31N5O3 (497.6) ##EQU15##
Reaction SMILES: [CH2:1]1[C:10](=[O:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.ClC(Cl)(Cl)C(O)=O.[N-:19]=[N+]=[N-].[Na+]>O>[CH2:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][CH2:1][C:10](=[O:11])[NH:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2ccccc2C1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: O=C1CCc2ccccc2CN1
Reaction time: 9 h
Yield: 72.6 %

Procedure:
At 65° C., β-tetralone (5 g, 34.2 mmol) was dissolved in trichloroacetic acid (56 g, 0.34 mol). Sodium azide (3.3 g, 50 mmol, 1.5 eq.) was then added in portions. The mixture was stirred for 9 h and then water (400 mL) was added. The mixture was extracted with dichloromethane (3×200 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The crude mixture was then recrystallized from dichloromethane/hexane to give 1,2,4,5-tetrahydro-benzo[c]azepin-3-one (4 g): 1H NMR (300 MHz, CDCl3) δ 7.2 (m, 4H), 4.37 (d, 1H), 3.1 (m, 2H), 2.8 (m, 2H) and 1,3,4,5-tetrahydro-benzo[d]azepin-2-one (1.5 g): 1H NMR (300 MHz, CDCl3) δ 7.2 (m, 4H), 3.84 (s, 2H), 3.6 (m, 2H), 3.12 (t, 2H).
Reaction SMILES: Cl[C@H]([B:8]([O-:10])[O-:9])CCC[CH2:6][Br:7].[CH3:11][Mg]Br.[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1>>[BH:8]([O-:10])[O-:9].[Br:7][CH2:6][CH2:16][CH2:15][CH2:14][C@H:18]([OH:17])[CH3:11]
Reactant: C1CCOC1
Reactant: [O-]B([O-])[C@@H](Cl)CCCCBr
Reactant: C[Mg]Br
Product: C[C@@H](O)CCCCBr
Product: [O-]B[O-]

Procedure:
The Grignard reaction was performed, as in example 2, with the following amounts: DICHED (R)-1-chloro-5-bromopentylboronate, 20.04 g; 3.0N methylmagnesium bromide, 16.7 ml; 150 ml of THF. The oxidation of the DICHED boronate to give (R)-6-bromohexan-2-ol was performed by dissolving the DICHED 5-bromo-1-methylpentylboronate in THF (10 ml) in a 50 ml flask. Water (10 ml) was added and the solution. The solution was cooled to 0° C. while stirring under argon. Sodium carbonate (16.5 ml of a 3M solution) was added, followed by 8 ml of 30% hydrogen peroxide. The solution was filtered, 20 ml of pentane added, and filtered again. The aqueous phase was separated and washed with pentane (2×10 ml). The organic phase was dried over sodium sulfate, filtered and the solvent evaporated to give (R)-6-bromo-hexan-2-ol in a crude yield of 8.9 g. Vacuum distillation provided a yield of 7.1 g (84%) of pure material with a rotation of -13.89 [α]549.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14](=[NH:19])[CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20](N(CC)CC)C.[C:27]([OH:30])(=O)[CH3:28]>C(O)(C)C>[CH2:15]([C:14]1[N:13]([C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][CH2:3][O:2][CH3:1])[C:28]([CH:27]=[O:30])=[CH:20][N:19]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCN(CC)CC
Reactant: CCCCC(=N)Nc1ccc(OC)cc1OCOC
Reactant: CC(=O)O
Solvent: CC(C)O
Product: CCCCc1ncc(C=O)n1-c1ccc(OC)cc1OCOC
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To a solution of N-(2-Methoxymethoxy-4-methoxyphenyl)pentanamidine (5.10 g, 0.019 mol) in iso-propanol (50 ml) was added triethylamine (3.20 ml, 0.0230 mol), acetic acid (1.4 ml, 0.025 mol) and 2-bromo-1,3-dicarboxaldehyde propane (3.20 g, 0.0211 mol), respectively. The mixture was stirred at reflux for 5 h and then cooled to room temperature. After filtration and concentration, The crude residue was dissolved in ethyl acetate and washed with 10% sodium bicarbonate solution, water, dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography of the residue (silica gel, 25% ethyl acetate/hexane) afforded the title compound as a dark yellow oil (3.85 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](O)([CH2:16][CH3:17])([CH3:15])[CH3:14].C([Li])CCC>S(Cl)(Cl)=O.CN(C)C=O.CCOCC>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[O:5]
Reactant: O=C(O)c1cc(Cl)c(Cl)nc1Cl
Reactant: CCC(C)(C)O
Agent: [Li]CCCC
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(C)(C)OC(=O)c1cc(Cl)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 3117.6 %

Procedure:
The product of Example 11 (2.5 g, 11 mmol) was slurried in thionyl chloride (30 mL) containing 2 drops of dry dimethylformamide (DMF). The slurry was heated to reflux at which time all components fully dissolved into solution. Reflux was continued for an additional three hours. After cooling to ambient temperature, the excess thionyl chloride was removed in vacuo and the resulting oily residue was taken up in diethyl ether (Et2O) (20 mL) and cooled to 0° C. in an ice bath. A solution of t-amyl alcohol (0.88 g, 10 mmol) in Et2O (15 mL) was cooled to -10° C. in a dry ice bath and n-butyllithium (1.6 M solution in hexanes, 6.5 mL, 1 eq) was added dropwise over 10 minutes, keeping the temperature below 0° C. The solution was warmed to ambient temperature, charged to an addition funnel under nitrogen and added dropwise to the nitrogen-purged ethereal solution of the acyl chloride prepared above. After complete addition, the solution was warmed to ambient temperature with stirring overnight. The solution was washed with saturated brine (3×200 mL) and the organics were dried over Na2SO4, filtered, and the solvent removed in vacuo to give t-amyl 2,5,6-trichloronicotinate (92.46 g) as an orange oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:14])=O.O=P(Cl)(Cl)[Cl:19]>>[Br:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccncc12
Reactant: O=P(Br)(Br)Br
Product: Brc1ccnc2ccncc12
Product: Clc1ccnc2ccncc12

Procedure:
Paudler et al., J. Heterocyclic Chem. 2 (4), 393-8 (1965), show the synthesis and NMR spectra of various 4-substituted-1,6-naphthyridines, for example, the reaction of 4-hydroxy-1,6-naphthyridine with POBr3 or POCl3 to obtain 4-bromo-1,6-naphthyridine or 4-chloro-1,6-naphthyridine, respectively. Also shown is the reaction of 4-bromo-1,6-naphthyridine with dimethylamine to produce 4-dimethylamino-1,6-naphthyridine and the reaction 4-chloro-1,6-naphthyridine with piperidine or hydrazine to produce 4-(1-piperidinyl)-1,6-naphthyridine or 4-hydrazino-1,6-naphthyridine, respectively.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Cl)=[CH:3][CH:2]=1.[C:9](=O)([O:13]CC)[O:10][CH2:11][CH3:12]>S1(CCCC1)(=O)=O.CC1C(CN2CCC(N3CCC(N4C(=O)NC5C4=CC=CC=5)CC3)CC2)=CC=CC=1>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([C:9]([O:10][CH2:11][CH3:12])=[O:13])=[CH:3][CH:2]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: CCOC(=O)OCC
Agent: Cc1ccccc1CN1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: O=S1(=O)CCCC1
Product: CCOC(=O)c1ccc(C)cc1
Temperature: 170 °C
Reaction time: 44 h
Yield: 77.9 %

Procedure:
A mixture of 7.73 g of p-toluyl chloride, 5.91 g of diethyl carbonate, and 0.85 g of TBPB in 25 ml of sulfolane was heated at 170° C. under reflux. After 44 hours, the reaction mixture was added to 200 g of crushed ice and this was extracted twice with 25-ml portions of hexane. The combined extracts were dried over anhydrous Na2SO4 and distilled to obtain 6.4 g (78 percent yield) of ethyl p-toluate, b.p. 120°-1° C./20 mm.