Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C@@H:6]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH3:7].CC(C[AlH]CC(C)C)C>>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][C@@H:6]([CH3:7])[CH:5]=[CH:4][CH2:3][OH:2]
Reactant: COC(=O)C=C[C@H](C)OC1CCCCO1
Agent: CC(C)C[AlH]CC(C)C
Product: C[C@@H](C=CCO)OC1CCCCO1
Yield: 88 %

Procedure:
4(S)-(Tetrahydro-pyran-2-yloxy)-pent-2-enoic acid methyl ester (10 g, 46.7 mmol) was reduced with DIBAL-H according to the procedure described in J. Chem. Soc., Perkin. Trans. 1 1994, 2791 to yield 4(S)-(Tetrahydro-pyran-2-yloxy)-pent-2-en-1-ol in 88% yield.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][C:6](O)([CH3:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(=O)CC.N#N>C1(C)C=CC=CC=1>[CH3:29][C:6]1[C@@H:7]2[C@@H:23]([C@:24]3([CH3:27])[C:4]([CH:5]=1)=[CH:3][C:2](=[O:1])[CH2:26][CH2:25]3)[CH2:22][CH2:21][C@@:20]1([CH3:28])[C@H:8]2[CH2:9][CH2:10][C@@H:11]1[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CC[C@H](O)CC1=CC3(C)O
Agent: CC(C)[O-]
Agent: N#N
Agent: [Al+3]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(C)=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 89.2 %

Procedure:
A mixture of methyl 7-hydroxy-7-methylchol-5-en-24-oate (8) (2.0 g, 4.78 mmoles), aluminum isopropoxide (1.17 g, 5.72 mmoles), 2-butanone (8.6 ml, 96 mmoles) in toluene (40 ml) was heated at 80° in a N2 atmosphere for 6 hrs. About 15 ml of solvent was distilled from the reaction mixture at atmospheric pressure. Toluene (30 ml) was added, and the mixture was extracted with 3N HCl (2 times), H2O (3 times) and dried with MgSO4. Evaporation in vacuo gave 1.7 g of an orange oil that was purified by flash chromatography on silica gel with hexane-EtOAc (7:2 and 2:1) to give 0.62 g of pure 9 as a colorless syrup. NMR (CDCl3): δ 0.76 (s, 3H, 18-Me); 0.94 (d, 3H, 20-Me); 1.08 (s, 3H, 19-Me); 3.67 (s, 3H, CO2Me); 5.59 (s, 1H, 4-H); 5.95 (s, 1H, 6-H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:13][C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:13][C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])s1)c1cccc([N+](=O)[O-])c1

Procedure:
By following the procedure of the first part of Example 1, but using m-nitrobenzoyl chloride (27.8 g), 2-amino-5-nitrothiazole (21.8 g) and pyridine (100 ml), there was obtained 3-nitro-N-(5-nitro-2-thiazolyl)benzamide, m.pt 200°-201°, after recrystallisation from acetic acid.
Reaction SMILES: C([O:8][CH:9]1[CH2:12][CH:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH:25][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][NH:30]3)[CH3:24])[CH2:10]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[N:15]=[C:14]([C@@H:23]([NH:25][C:26]3[N:34]=[CH:33][N:32]=[C:31]4[C:27]=3[N:28]=[CH:29][NH:30]4)[CH3:24])[N:13]([CH:11]3[CH2:12][CH:9]([OH:8])[CH2:10]3)[C:17]=2[CH:18]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC(OCc2ccccc2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC(O)C1
Temperature: 0 °C
Yield: 46.9 %

Procedure:
A mixture of [(S)-1-[1-(3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl]-(9H-purin-6-yl)amine (0.13 g, 0.29 mmol) in DCM (5 mL) was cooled to 0° C. To this mixture was added boron tribromide (2.1 mL, 1.43 mmol) dropwise and the resultant mixture stirred at RT for 2 h. The reaction mixture was quenched with MeOH (2 mL) and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 390 as an off-white glassy solid (50 mg, 50%). 1H NMR (DMSO-d6): δ 8.98 (1H, s), 8.55-8.37 (2H, m), 7.93 (1H, d, J=9.74 Hz), 7.69 (1H, dd, J=8.92, 4.99 Hz), 7.21 (1H, t, J=9.90 Hz), 5.89 (1H, s), 4.86-4.75 (1H, m), 4.05-3.95 (1H, m), 2.97-2.62 (4H, m), 1.70 (3H, d, J=6.75 Hz)
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]([CH3:26])([CH3:25])[CH2:13][O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=O)=O)=CC=1.[C-:28]#[N:29].[K+].O>CS(C)=O>[C:28]([CH2:11][C:12]([CH3:25])([CH3:26])[CH2:13][O:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)(=[O:16])=[O:17])#[N:29]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)CC#N)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of toluene-4-sulfonic acid 3-toluene-4-sulfonyloxy-2,2-dimethylpropyl ester (5.0 g, 12.1 mmol) in DMSO (15 mL) is added KCN (789 mg, 12.1 mmol). The mixture is stirred at 80° C. for 18 h then cooled to RT. The mixture is poured into water and extracted with ether. The organic layer is dried over sodium sulfate the filtrate concentrated. The crude material is purified by column chromatography to give the title compound.
Reaction SMILES: [N:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]([C:24]1[C:25](=[O:48])[C:26]2[CH:31]=[N:30][C:29](S(CC)(=O)=O)=[N:28][C:27]=2[N:37]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[CH2:44][CH2:43][CH2:42]3)[CH:38]=1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[C:25](=[O:48])[C:26]2[CH:31]=[N:30][C:29]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][S:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)(=[O:9])=[O:8])=[CH:13][CH:14]=3)=[N:28][C:27]=2[N:37]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[CH2:44][CH2:43][CH2:42]3)[CH:38]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(=O)(=O)CC)ncc2c1=O
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCS(=O)(=O)N4CCOCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (65 mg, 0.24 mmol) and 8-indan-5-yl-2-ethanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (42 mg, 29%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.35 (s, 1H), 8.53 (s, 1H), 8.01 (br, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.30 (m, 3H), 7.19 (d, J=7.8 Hz, 1H), 6.94 (br, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.72 (t, J=4.5 Hz, 4H), 3.25 (t, J=4.7 Hz, 4H), 3.08 (m, 6H), 3.01 (t, J=7.4 Hz, 2H), 2.24 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:48]=[CH:47][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][N:19]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([O:45]C)=[O:44])=[CH:39][CH:38]=2)[CH:20]2[CH2:29][CH2:28][CH2:27][C:26]3[N:25]=[C:24]([C:30]([O:32]CC)=[O:31])[CH:23]=[CH:22][C:21]2=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:48]=[CH:47][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][N:19]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]([OH:45])=[O:44])=[CH:41][CH:42]=2)[CH:20]2[CH2:29][CH2:28][CH2:27][C:26]3[N:25]=[C:24]([C:30]([OH:32])=[O:31])[CH:23]=[CH:22][C:21]2=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(COc2ccccc2CCN(CCc2ccc(C(=O)O)cc2)C2CCCc3nc(C(=O)O)ccc32)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
35 mg (0.05 mmol) of ethyl 5-[(2-{2-[(4-tert-butylbenzyl)oxy]phenyl}ethyl){2-[4-(methoxycarbo-nyl)phenyl]ethyl}amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 43A) were taken up in 1 ml of THF and 1 ml of water, and 7 mg (0.16 mmol) of lithium hydroxide monohydrate were added. The reaction was stirred at 50° C. overnight. After the reaction had gone to completion, the THF was removed on a rotary evaporator and the mixture that remained was diluted with water. The mixture was then acidified with 1 M hydrochloric acid and extracted repeatedly using a 1:1 mixture of ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulphate, filtered and concentrated to dryness. This gave 29 mg (0.04 mmol, content 91%, 81% of theory) of the title compound as a yellowish solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=O)[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[CH3:19][C:20]1([CH3:37])[CH2:25][CH:24]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH2:23][C:22]([CH3:36])([CH3:35])[NH:21]1>CO>[CH3:18][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([NH:33][NH:32][C:30](=[O:31])[CH2:29][CH2:28][C:27]([NH:26][CH:24]2[CH2:23][C:22]([CH3:35])([CH3:36])[NH:21][C:20]([CH3:37])([CH3:19])[CH2:25]2)=[O:34])=[O:12])[CH2:5][C:4]([CH3:16])([CH3:17])[NH:3]1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)CC(NC(=O)CCC(=O)NN)CC(C)(C)N1
Solvent: CO
Product: CC1(C)CC(NC(=O)CCC(=O)NNC(=O)C(=O)NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
Into a 3-necked 50 ml flask was introduced a 60.9% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate in methanol (4.27 g, 0.01 mole), N-(2,2,6,6-tetramethyl-4-piperidinyl)-N'-aminosuccinamide (2.7 g, 0.01 mole) and 25 ml of anhydrous methanol. The flask was equipped with a thermometer, a magnetic stirrer and a Dean Stark trap with a reflux condenser. The reaction mixture was heated to reflux for 1/2 hour. Liquid chromatography of the reaction mixture indicated that the starting materials had essentially disappeared and there was one new peak corresponding to the product. The reaction mixture was filtered hot to remove some insoluble material. The filtrate was stripped to dryness on a rotatary evaporator under reduced pressure. The residue was scraped out of the flask and pulverized into a white powder with a mortar and pestle. The white powder was air dried on a watch glass overnight. The product weighed 1.0 grams and had a melting range of 130°-135° C. An infrared scan (nujol mull) of the product contained a strong carbonyl band at 1655 cm-1 and two moderate carbonyl bands at 1575 and 1495 cm-1.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCN2CCC[C@@H](Cl)C2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3COc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
Sixty-percent sodium hydride (0.34 g, 8.6 mmols) was washed with petroleum ether, and then suspended in 30 ml of dimethyl sulfoxide. To the suspension were added 1.38 g (7.0 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 1.8 g (6.3 mmols) of (R)-(-)-3-chloro-1-(3,4-dimethoxyphenethyl)piperidine [[α]D25 =-20.3° (c=0.9, ethanol)] in 5 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 12 hours and at 40° C. for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:5. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and extracted with a mixed solvent of chloroform and methanol at a ratio of 200:1. This mixed solvent was then distilled off under reduced pressure to give 0.85 g of (S)-(-)-5,11-dihydro-5-[1-(3,4-dimethoxyphenethyl)-2-pyrrolidinyl-methyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 30%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[C:6]3[C:12]([C:13]#[C:14][Si](C)(C)C)=[N:11][N:10]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH:1]1([C:4]2[C:5]([N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[C:6]3[C:12]([C:13]#[CH:14])=[N:11][N:10]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(C#C[Si](C)(C)C)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1nn(Cc2ccc(OC)cc2)c2ncc(C3CC3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (280 mg, 0.50 mmol) was placed in THF (8 mL) at 0° C. TBAF (0.54 mL, 0.54 mmol) was then added, and the reaction stirred for 30 minutes at room temperature. The reaction was then poured into saturated Na2CO3, and extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give the crude product, which was purified by column chromatography to give tert-butyl 4-(5-cyclopropyl-3-ethynyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (250 mg, 96% yield).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+].O>[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(COC)OC>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:36]5[CH:35]=[N:34][N:33]([C:26]([CH3:25])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (500 mg, 0.001 mol) and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (594 mg, 0.0015 mol) were reacted under microwave (uW), palladium catalyzed Suzuki coupling conditions with Pd(dppf)Cl2 and Cs2CO3 water and dimethoxyethane to give ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate together with the corresponding acid. LC/MS (ESI+): m/z 490 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([NH:12][C:13]([O:15]C3C=CC=CC=3)=O)=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23]1>O1CCCC1.C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9]([CH:8]=[CH:7][C:6]([NH:12][C:13]([N:22]3[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23]3)=[O:15])=[N:5]2)=[CH:10][CH:11]=1
Reactant: C1=CCNCC1
Reactant: O=C(Nc1ccc2ccc(Cl)nc2n1)Oc1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)N1CC=CCC1
Temperature: 4 °C
Yield: 72.7 %

Procedure:
To a solution of 2-chloro-7-phenoxycarbonylamino-1,8-naphthyridine (15 g) in anhydrous tetrahydrofuran (500 cc), anhydrous acetonitrile (500 cc) and 1,2,5,6-tetrahydropyridine (4.2 g) are added. The mixture is heated under reflux for 45 minutes. The solution is concentrated under reduced pressure (4 kPa) to a volume of 100 cc. After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-1,2,5,6-tetrahydropyridine-1-carboxamide (10.5 g) is produced, m.p. 173° C.
Reaction SMILES: [Na].Cl.[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][Cl:8])[CH3:4].[CH2:11]([O:13][C:14]([C:16]1[NH:17][C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:19]2[C:24]=1[CH:23]=[CH:22][C:21]([Cl:25])=[CH:20]2)=[O:15])[CH3:12].[Cl-].[Na+]>CN(C)C=O.C(O)C>[ClH:8].[CH2:11]([O:13][C:14]([C:16]1[N:17]([CH2:4][CH2:3][N:5]([CH2:9][CH3:10])[CH2:6][CH3:7])[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:19]2[C:24]=1[CH:23]=[CH:22][C:21]([Cl:25])=[CH:20]2)=[O:15])[CH3:12]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Meanwhile, in a second flask, 4.6 g. of sodium are dissolved in 100 ml. of ethanol and treated at 0° C. with 34.5 g. of 2-diethylaminoethyl chloride hydrochloride. After dilution with 50 ml. of dimethylformamide and stirring for 30-40 minutes in an ice-bath, the obtained fine suspension is added dropwise at 0°-2° C. over a period of 15-20 minutes to the sodium derivative of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester prepared as in the foregoing paragraph. The mixture is subsequently stirred for 30 minutes at room temperature and then heated at 60° C. for 3 hours. After cooling, the mixture is poured into 4 liters of ice-water, 200 g. of sodium chloride are added and the separated oily product is immediately extracted with methylene chloride. The organic phase, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is then taken up in 200 ml. of ether, treated with 280 ml. of 0.5-N hydrochloric acid and thoroughly shaken. After cooling in an ice-bath, the crystallized hydrochloride is removed by filtration under suction, washed with water and ether and then dissolved in 700 ml. of methylene chloride. The aqueous layer is separated; the organic phase is dried over sodium sulfate, filtered and treated portionwise with 450 ml. of ether, whereby there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride in the form of colorless crystals having a melting point of 248°-250° C. (decomposition). Crystallization from methylene chloride/ether does not increase the melting point.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C.O>[C:1]1([C:7]2[N:12]=[C:11]([OH:13])[C:10]([N+:15]([O-:17])=[O:16])=[C:9]([OH:14])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cc(O)nc(-c2ccccc2)n1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)nc(-c2ccccc2)nc1O
Temperature: 50 °C

Procedure:
To a suspension of 2-Phenyl-4,6-dihydroxypyrimidine (12 g) in 35 mL of acetic acid is added 12 mL of 90% nitric acid and the mixture is heated at 50° C. for 45 min. The reaction mixture is diluted with 150 mL of water and the product is collected, washed with water and ethanol and oven dried to afford 2-Phenyl-5-nitro-4,6-dihydroxypyrimidine as a pink solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:21][CH3:22])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[N-:23]=[C:24]=[O:25].[K+].Cl>>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[NH:23][C:24](=[O:25])[NH:2][C:3]=2[CH2:21][CH3:22])[CH:7]=[C:8]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]=1[OH:16])([CH3:14])([CH3:13])[CH3:15]
Reactant: CCC(N)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Product: CCc1[nH]c(=O)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 50.2 %

Procedure:
By following the same procedure as in Example 6 using 3.3 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-butanone hydrochloride, 1.62 g of potassium isocyanate, and 1.6 ml of concentrated hydrochloric acid and recrystallizing the reaction product from aqueous isopropanol, 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazoline was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)=[CH2:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1cccc(CC(=O)OCC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cccc(CC)c1
Temperature: 30 °C
Reaction time: 7 h
Yield: 77 %

Procedure:
To a solution of ethyl 2-(3-vinylphenyl)acetate (640 mg, 3.6 mmol) in ethanol (10 mL) was added 10% of Pd/C (100 mg) and stirred at 30° C. under hydrogen atmosphere (15 psi) for 7 hours. Then the solution was filtered and the solvent was removed in vacuo (500 mg, yield 77%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO[C:18](C)([CH3:20])[CH3:19].COC(OC)(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O.C1COCC1>[C:4]([O:3][C:1]([N:8]1[C@H:9]([C:13]([OH:15])=[O:14])[C@@H:10]([CH3:12])[O:11][C:18]1([CH3:20])[CH3:19])=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: COC(C)(C)C
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O

Procedure:
Boc-L-threonine (600 g, 2.74 mol) was added to methyl-tert-butyl ether (3.6 L) and THF (1.2 L) followed by 2,2-dimethoxypropane (1710 g, 16.42 mol) and pyridinium p-toluenesulfonate (171.9 g, 684 mmol) and the suspension heated to reflux for 20 hours. The reaction was cooled and diluted with water (3 L) and stirred to achieve a solution. The organic layer was collected, washed with water (1.8 L), and diluted with methyl-tert-butyl ether (4.2 L). A solution of NaOH in water (109 g in 120 mL) was added and the mixture stirred for 20 minutes. The mixture was concentrated to low volume to effect precipitation. The resulting solid was filtered and collected as the sodium salt of the title compound.