Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[C:7]([NH2:11])[N:8]([CH3:10])[N:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]1([O:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[C:12]1([O:18][C:19](=[O:20])[NH:11][C:7]2[N:8]([CH3:10])[N:9]=[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1nc(C2CCC2)cc1N
Solvent: CN(C)C=O
Product: Cn1nc(C2CCC2)cc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5-Cyclobutyl-2-methyl-2H-pyrazol-3-ylamine (0.156 g, 1.03 mmol) in dimethylformamide (3 ml) cooled to 0° C., is treated with phenylchloroformate (0.13 ml, 1.03 mmol) dropwise and left to stir at 0° C. for 1 hour. The reaction mixture is partitioned between ethylacetate and 1.0 M hydrochloric acid solution, and the organic phase washed with water, dried over magnesium sulphate and evaporated to yield (5-Cyclobutyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester. [M+H] 272.22
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:30])[CH2:15][C:16]3[C:24]4[C:19](=[C:20]([C:25]([O:27]CC)=[O:26])[CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:30])[CH2:15][C:16]3[C:24]4[C:19](=[C:20]([C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)c[nH]c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Yield: 85.5 %

Procedure:
A solution of ethyl 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxo-1,3-oxazolidin-3-yl]propyl}-1H-indole-7-carboxylate (55 mg, 0.129 mmol) and potassium hydroxide (70 mg, 1.3 mmol) in water (1 mL) and ethanol (2 mL) is stirred at room temperature for 3 days. The reaction mixture is neutralized with 1N hydrochloric acid, and the precipitated crystals are collected by filtration to give the title compound (44 mg, yield: 86%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[O:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[O:12]([C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][C:23]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:24][CH2:25]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COC(=O)c1ccc(F)cc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1Oc1ccccc1
Temperature: 130 °C

Procedure:
Methyl 4-fluoro-2-phenoxybenzoate (2 g) and 1,4-dioxa-8-azaspiro[4.5]decane (1.279 g) were combined in dimethylsulfoxideO (12 mL) in a 250 mL round-bottom flask. Sodium carbonate (1.291 g) was added. The reaction flask was sealed and heated to 130° C. overnight. The reaction mixture was diluted with ethyl acetate, washed thoroughly with water and with brine, and dried over MgSO4, filtered and concentrated to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:17]=3)[C:12]=2[NH:28][C:29]([C@H:31]2[CH2:36][CH2:35][C@H:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[O:30])=[O:10])=[N:6][CH:7]=1.Cl.O1CCOCC1.CO>O1CCOCC1>[NH2:20][C:15]1[N:14]=[C:13]2[C:12]([NH:28][C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:33][CH2:32]3)=[O:30])=[C:11]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[O:19][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4)CC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl (2-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-{[(trans-4-pyrrolidin-1-ylcyclohexyl)carbonyl]amino}furo[3,2-b]pyridin-5-yl)carbamate (280 mg) obtained in Example 96 is suspended in dioxane (3 ml). To the suspension is added 4 N hydrogen chloride-dioxane solution (3 ml). The reaction solution is warmed to room temperature, and thereto is added methanol (2 ml), followed by stirring for 8 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is suspended in diethyl ether. The precipitates are collected by filtration to give the title compound (266 mg) as hydrochloride. The resulting hydrochloride is suspended in chloroform and thereto is added saturated aqueous sodium hydrogen carbonate solution. The precipitated solid is collected by filtration to give the title compound (88 mg).
Reaction SMILES: C(OC([N:11]([C:19]([CH3:24])([CH3:23])[CH:20]([OH:22])[CH3:21])[C:12](=[O:18])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)=O)C1C=CC=CC=1.[CH2:25]([O:32][C:33]([NH:35][C@H:36]([C:41]([NH:43][C@@H:44]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@H:45]([OH:49])[C:46]([OH:48])=O)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]([NH:35][C@H:36]([C:41]([NH:43][C@@H:44]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C@H:45]([OH:49])[C:46]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:12]([NH:11][C:19]([CH3:23])([CH3:24])[CH:20]([OH:22])[CH3:21])=[O:18])=[O:48])=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(O)C(C)(C)N(C(=O)OCc1ccccc1)C(=O)[C@@H]1CCCN1
Product: CC(O)C(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Yield: 65.3 %

Procedure:
79 mg (0.24 mmol) of N-benzyloxycarbonyl-N-(1,1-dimethyl-2-hydroxypropyl)-L-prolinamide were subjected to debenzyloxycarbonylation in a similar manner to that described in Example 17, and then the resulting product was condensed with 106 mg (0.24 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid in a similar manner to that described in Example 1, to give 98 mg of the title compound as a colorless powder, melting at 102°-104° C.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([NH:33][S:35]([CH3:34])(=[O:37])=[O:36])[CH:30]=[CH:31][CH:32]=2)[N:22]=[CH:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(1-trityl-1H-imidazol-4-ylmethoxy)phenylamine (0.7 g, from above) and methanesulfonyl chloride (0.3 mL) in pyridine (12 mL) was stirred at room temperature overnight. Pyridine was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water and brine. After drying over sodium sulfate and evaporation of the solvent, N-[3-(1-trityl-1H-imidazol-4-ylmethoxy)-phenyl]methanesulfonamide (0.7 g) was obtained.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](O)=[O:4].[CH3:10][N:11]1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.C(OC(Cl)=O)C(C)C>C1COCC1>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([NH:11][CH3:10])=[O:4]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: CC(C)CC(Br)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)C(Br)CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To the solution of DL-alpha-bromoisocaproic acid in THF (4 ml) was added N-methylmorphine (0.18 ml, 1.63 mmol), followed by dropwise addition of isobutylchloroformate (0.15 ml, 1.16 mmol). A white solid precipitate was formed. After stirring at RT for 1.5 h, the white solid was filtered. Methylamine (1 ml, 2N in THF) was added to the filtrate. The reaction mixture was concentrated after 0.5 hour. The resultant crude material was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated to give the title compound, 2-bromo-N,4-dimethylpentanamide, (0.18 g, 78%) as an oil.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[C:9]([CH3:16])[CH:8]=1>C(=O)(O)[O-].[Na+]>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH2:15])=[O:2])=[C:9]([CH3:16])[CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(N)ccc1CC#N
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(N)ccc1CC(N)=O
Temperature: 25 °C
Yield: 50 %

Procedure:
Sulfuric acid (26 mL) was added to 2-(4-amino-2-methylphenyl)acetonitrile (0.500 g, 3.42 mmol) at 0° C. The mixture was warmed to rt for 4 h, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford the title compound (0.252 g, 50%) as a tan solid. MW=164.20. 1H NMR (DMSO-d6, 500 MHz) δ 7.09 (s, 1H), 6.81 (d, J=7.9 Hz, 1H), 6.74 (s, 1H), 6.39-6.35 (m, 1H), 6.33-6.29 (m, 1H), 4.78 (s, 2H), 3.19 (s, 2H), 2.10 (s, 3H); APCI MS m/z 165 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:9][NH:8][CH2:7]1)=[O:5].Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1>CO>[CH3:2][O:3][C:4]([CH:6]1[CH2:9][N:8]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7]1)=[O:5]
Reactant: COC(=O)C1CNC1
Reactant: Clc1ncccn1
Agent: Cl
Solvent: CO
Product: COC(=O)C1CN(c2ncccn2)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
To a stirred solution of 3-azetidine carboxylic acid methyl ester hydrochloride (150 mg, 0.99 mmol) and 2-chloropyrimidine (113.4 mg, 0.99 mmol) in methanol, was added TEA (200 mg, 1.98 mmol) at room temperature. The mixture was stirred at 50° C. for 5 hours and concentrated under reduced pressure. The residue was suspended in EtOAc (50 ml) and washed with water (15 ml), brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 1-pyrimidin-2-yl-azetidine-3-carboxylic acid methyl ester as a light yellow solid (137.3 mg, 72%): 1H NMR (CDCl3, 400 MHz) δ 8.37 (d, J=6.4 Hz, 2H), 6.58 (t, J=6.4 Hz, 1H), 4.30 (m, 4H), 3.77 (s, 3H), 3.56 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]3[CH2:12][CH2:11]3)=[N:6][N:5]2[C:13]=1[S:14]([N:17]=CN(CC(C)C)CC(C)C)(=[O:16])=[O:15].Cl>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]3[CH2:12][CH2:11]3)=[N:6][N:5]2[C:13]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: CC(C)CN(C=NS(=O)(=O)c1c(Cl)nc2ccc(C3CC3)nn12)CC(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1c(Cl)nc2ccc(C3CC3)nn12
Temperature: 100 °C

Procedure:
N′-(2-Chloro-6-cyclopropylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine (0.93 g, 2.26 mmol) was dissolved in dioxane (9.00 mL), and 36% conc. hydrochloric acid (9.0 mL, 107 mmol) was added dropwise to the solution under stirring at 100° C. The mixture was stirred for 15 hours at 100 to 105° C., then left and cooled to room temperature and concentrated under reduced pressure until crystals occurred. Water (30.0 mL) was poured into the residues, and the crystals were completely precipitated, then filtered, washed with water and washed with methanol, to give the title compound as white crystals. The yield was 0.31 g (50.4%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12](Cl)=[O:13].[OH:16][C@H:17]1[CH2:21][C:20](=[O:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:16][CH:17]1[CH2:21][C:20](=[O:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26])=[O:13]
Reactant: C=CCC1=C(C)[C@@H](O)CC1=O
Reactant: COC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: c1ccccc1
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@H](/C=C(\Cl)C(=O)OC)C2(C)C)CC1=O

Procedure:
(1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylic acid chloride and (4S)-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one were reacted to obtain (S) 2-methyl-4-oxo-3-(2-propenyl)-2-cyclopenten-1-yl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-15°±4° (c=0.25% in benzene)
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=1.C(N(C(C)C)CC)(C)C>>[CH2:25]([O:24][C:22]([C:18]1[S:17][C:16]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:20][C:19]=1[CH3:21])=[O:23])[CH3:26]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2NC[C@H]21
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2C[C@@H]3[C@H]2CCN3C(=O)OC(C)(C)C)nc1C
Yield: 99.5 %

Procedure:
The same operation as in Example (217a) was performed using tert-butyl (1R,5R)-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate obtained in Example (236a) (150 mg, 0.76 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (189 mg, 0.76 mmol) and diisopropylethylamine (0.26 mL, 1.51 mmol), to obtain 278 mg of the title compound as a yellow oily substance (100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[CH:21](C1OC(C)=CC(=O)C=1OCC1C=CC=CC=1)C>>[CH3:1][O:2][CH:3]([C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(C)O)o1
Product: COC(C)c1oc(C)cc(=O)c1OCc1ccccc1
Yield: 97 %

Procedure:
In an analogous procedure in the preparation of 2methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using 2-(1-hydroxyethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one (2.6 g, 10 mmol, 1 eq.) yielded the title compound as an orange oil (2.65 g, 97%). Further purification by column chromatography on silica gel (eluant: EtOAc) furnished the pure product as a bright yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: OB(O)c1cccc(Br)c1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example A.45) (1.50 g, 5.42 mmol) and commercially available 3-bromo-benzene-boronic acid (1.31 g, 6.52 mmol) according to the general procedure IVb. Obtained as a white solid (1.17 g, 54%). MS (EI) 395.9, 397.9 [(M)+]; mp 111° C.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].Br[CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.O>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH3:19]
Reactant: CCCCC(CC)CBr
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)CN1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.3 g) and 1-bromo-2-ethylhexane (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 140-160° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: [N:1](=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5])[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.CCOCC>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5])=[O:14]
Reactant: CN=C=O
Reactant: N#CC(=NO)c1cccs1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNC(=O)ON=C(C#N)c1cccs1

Procedure:
To a solution of 3.04 g. (0.02 mole) of alphaoximino-2-thienylacetonitrile and 2 drops of triethylamine in 50 ml. of ether was added 1.14 g. (0.02 mole) of methylisocyanate in 10 ml. of ether. After 1 hour the solid was filtered and crystallized from benzene to give 3.8 g. of product melting at 154°-155° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][CH2:11]CCCC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:16]1OC1CCC.[OH-].[Na+].Cl>O>[C:3]([CH:2]1[CH2:16][CH:8]([CH2:9][CH2:10][CH3:11])[O:7][C:1]1=[O:6])(=[O:4])[CH3:5]
Reactant: CCCC1CO1
Reactant: CCCCCCCCOC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC1CC(C(C)=O)C(=O)O1
Temperature: 24 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
n-Octyl acetoacetate (313.3 g, 1.42 moles), 1,2-pentylene oxide 101.8 g, 1.18 moles) and 157.5 g distilled water were combined in a reactor. A solution of 59.6 g sodium hydroxide (1.49 moles) in 59.6 g distilled water was added over a one-hour period while maintaining the temperature in the range of 22 to 26° C. The reaction mixture was then allowed to stir for an additional 111/2 hours while maintaining the temperature between 28° C. and 36° C. The reaction mixture was then acidified to pH 5.8 by the addition of concentrated hydrochloric acid. After separation of the organic and aqueous phases, the organic layer was stripped under reduced pressure to remove the n-octanol and any unreacted n-octyl acetoactetate. 3-Acetyl-5-propyldihydro-2(3H)-furanone ##STR12## was recovered upon distillation in 62.4% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH3:12].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[CH2:11]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[Cl:1])[CH3:12]
Reactant: O=C(O)c1ccncc1Cl
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A suspension of 3-chloro-isonicotinic acid (1.0 g, 6.35 mmol) in thionyl chloride (10 ml) was heated under reflux for 2.5 hours. After cooling to ambient temperature, the solution was concentrated to dryness and then azeotroped with toluene (10 ml) to afford an oil. The resultant oil was added dropwise over 10 minutes to a cooled (0° C.) solution of ethanol (15 ml) and DIPEA (5 ml). The reaction was stirred at room temperature for 18 hours then concentrated in vacuo before water (20 ml) was added. The solution was extracted with ethyl acetate (30 ml) and the organic phase was dried over sodium sulfate then concentrated to give the title compound as an orange oil (1.1 g, 94%). 1H NMR (CDCl3, 400 MHz) 8.72 (s, 1H), 8.59 (d, J=4.9 Hz, 1H), 7.63 (dd, J=4.9 Hz, 0.5 Hz, 1H), 4.44 (q, J=7.3 Hz, 2H), 1.42 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16]Br.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH2:15][O:14][CH3:13])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: OCCNCc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCCN(CCO)Cc1ccc(Cl)nc1
Temperature: 95 °C
Yield: 58.6 %

Procedure:
A stirred mixture of 6.0 grams (0.03 mole) of 2-{[(6-chloro(3-pyridyl))methyl]amino}ethan-1-ol (known compound), 4.6 grams (0.033 mole) of 2-bromoethyl methyl ether and 5.8 grams (0.045 mole) if diisopropylethylamine in 120 mL of 1,4-dioxane was heated at 95° C. for 36 hours. After this time the reaction mixture was cooled to ambient temperature and was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, eluting with a mixture of methanol and methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.3 grams of 2-{[(6-chloro(3-pyridyl))methyl](2-methoxyethyl)amino}ethan-1-ol as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12][C:13](Br)([CH2:16]Br)[CH:14]=O>C(O)(=O)C>[Br:12][C:13]1[CH:14]=[N:4][C:3]2[C:5]([CH:16]=1)=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=2[I:1]
Reactant: O=CC(Br)(Br)CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)c2ncc(Br)cc2c1
Temperature: 110 °C

Procedure:
2-Iodo-4-nitroaniline (5.3 g) in acetic acid (40 ml) was treated with 2,2,3 tribromopropanal (5.9 g) and the mixture was heated at 110° C. for 2 h after which it was cooled to room temperature and filtered. The filtered solid was washed with diethyl ether, suspended in water and treated with saturated sodium hydrogen carbonate. Extraction with ethyl acetate, drying over sodium sulphate, filtration and evaporation under reduced pressure gave the desired product, 3-bromo-8-iodo-6-nitro-quinoline, as a yellow solid after chromatography (silica; hexane/ethyl acetate) (M+379).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:5]([NH2:13])=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Temperature: 25 °C
Yield: 90 %

Procedure:
1-[5-bromo-2-nitro-4-(trifluoromethyl)phenyl]-1H-imidazole (15.50 g, 0.0461 mol) is stirred with SnCl2.2H2O (51.77 g, 0.2274 mol) in ethanol (78 mL) at 80° C. for 2 hours. After cooling down to room temperature, the mixture is concentrated and partitioned between water (200 mL) and ethyl acetate (250 mL). Sodium hydrogencarbonate powder is added to adjust the pH to 8. The milky suspension is filtrated, the cake is washed with ethyl acetate and the combined organic phases are washed with water and dried over sodium sulfate. Concentration affords the title compound as a pale yellow solid (12.70 g, 90.0%)
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[N:3]1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>O1CCOCC1>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[O:20][C:2]([CH3:1])([CH3:12])[N:3]=[C:4]2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[CH:17][CH:16]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1ccccc1C1=NC1(C)C
Solvent: C1COCCO1
Product: Cc1ccccc1C1=NC(C)(C)OC1c1ccc(N(C)C)cc1

Procedure:
3.3 g of 2,2-dimethyl-3-(o-tolyl)-2H-azirine and 2.5 g of p-(dimethylamino)benzaldehyde were exposed to light for 2 hours in 290 ml of 1,4-dioxane (with the light source described in Example 2). After removing the solvent in a water-jet vacuum, the residue was chromatographed on aluminum oxide (neutral, activity 1), the elution was carried out with n-heptane/ether (9:1). Crystallization from ethanol/water gave 5-[p-(dimethylamino)phenyl]-2,2-dimethyl-4-(o-tolyl)-3-oxazoline which melted at 89°-90° C. after drying for 16 hours at 30° C. and 13 Torr.