Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.[CH3:7][N:8]1[CH2:16][C:15]2[C:10](=[C:11]([N+:26]([O-:28])=[O:27])[CH:12]=[CH:13][C:14]=2B2OC(C)(C)C(C)(C)O2)[C:9]1=[O:29].[CH3:30][C:31]1([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:36][CH2:35][C:34](OS(C(F)(F)F)(=O)=O)=[CH:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:30][C:31]1([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:36][CH2:35][C:34]([C:14]2[CH:13]=[CH:12][C:11]([N+:26]([O-:28])=[O:27])=[C:10]3[C:15]=2[CH2:16][N:8]([CH3:7])[C:9]3=[O:29])=[CH:33][CH2:32]1
Reactant: CN1Cc2c(B3OC(C)(C)C(C)(C)O3)ccc([N+](=O)[O-])c2C1=O
Reactant: CCOC(=O)C1(C)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(C)CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 70 °C
Yield: 84.3 %

Procedure:
A mixture of dioxane and water (15 mL, 4:1) was degassed for 30 min. 2-Methyl-7-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (373 mg, 1.19 mmol), ethyl 1-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-ene-1-carboxylate (Compound 282E, 300 mg, 0.92 mmol), Pd (PPh3)4 (106 mg, 0.092 mmol), and cesium carbonate (747 mg, 2.3 mmol) were then added. The reaction mixture was heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered and concentrated to dryness, the residue was purified by column chromatography (SiO2, 5% ethyl acetate/dichloromethane) to give 278 mg (yield: 77%) of the desired compound. 1H NMR (CDCl3, 300 MHz): δ=1.26 (t, J=6.9 Hz, 3 H), 1.76-1.78 (m, 1 H), 2.07-2.22 (m, 3 H), 2.40 (m, 1 H), 2.80-2.42 (m, 1 H), 3.21 (s, 3 H), 4.15 (q, J=6.9 Hz, 2 H), 5.92 (s, 1 H), 7.44 (d, J=8.5 Hz, 1 H), 7.70 (d, J=8.5 Hz, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[OH:18].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][CH2:7][C@@H:6]([OH:18])[C@@H:5]([CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[S:11][C:10]=2[CH:12]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc2c(c1)SC(CCCCl)C(O)CO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)S[C@H](CCCN1CCN(c3ccccc3)CC1)[C@H](O)CO2
Temperature: 80 °C

Procedure:
A mixture of 4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol 500 mg, N-phenylpiperazine (500 mg), potassium iodide (50 mg), potassium carbonate (400 mg) and N,N-dimethylformamide (10 ml) is heated at 80° C. for 8 hours with stirring. The reaction mixture is poured into water, extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue is submited to column chromatography on silica gel eluting with hexane-ethyl acetate-methanol (10:10:1) to give cis-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol (colorless oil) which is isolated as the dihydrochloride (amorphous powder).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8]/[C:9](/[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:24]\[OH:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(CC(c1ccccc1)c1ccccc1)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O/N=C(\CC(c1ccccc1)c1ccccc1)c1ccncc1

Procedure:
In analogy to example 1, step 2, from 3,3-diphenyl-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white solid, MS (ESI+): m/z=303.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:31]=3)[CH2:26][CH2:25]2)=[O:19])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)CC(=O)N1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC1=C(C(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)C(c2ccc(F)c(F)c2)CC(=O)N1

Procedure:
Prepared by Procedure AC and Scheme AM using 4-(3,4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 553.0 (M+H)+.
Reaction SMILES: C(OC1C=C([SH:15])C=CC=1)C1C=CC=CC=1.[CH:16]([O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)N)([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:21]=[C:22]([SH:15])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)([CH3:18])[CH3:17]
Reactant: COc1cc(N)cc(OC(C)C)c1
Reactant: Sc1cccc(OCc2ccccc2)c1
Product: COc1cc(S)cc(OC(C)C)c1

Procedure:
Prepared as described for 3-benzyloxy-benzenethiol SM28 starting from 3-isopropoxy-5-methoxyaniline. MS m/z: 199 [M+H]+
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Br[C:10]1[CH:11]=[C:12]2[C:25]3[CH:15]([CH2:16][C@@H:17]4[C@@H:22]([C:23]=3[CH:24]=1)[CH2:21][C@H:20]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:19][N:18]4[CH3:34])[CH2:14][N:13]2[Si](C(C)(C)C)(C)C>>[Cl:1][C:10]1[CH:11]=[C:12]2[C:25]3[C:15]([CH2:16][C@@H:17]4[C@@H:22]([C:23]=3[CH:24]=1)[CH2:21][C@H:20]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:19][N:18]4[CH3:34])=[CH:14][NH:13]2
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3C(C[C@H]2N(C)C1)CN4[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Cl)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With N-chlorosuccinimide and 3-(13-bromo-1-tert-butyldimethylsilyl-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.C([O-])(=O)C.[Na+]>CCOCC.[Pd]>[F:9][C:7]1[CH:8]=[C:3]([CH3:2])[CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(F)cc(F)c1
Reaction time: 24 h

Procedure:
A mixture of 1-(bromomethyl)-3,5-difluorobenzene (50 g, 0.24 mol), 10% Pd/C (3 g) and sodium acetate (140 g, 1.7 mol) in anhydrous ether (250 mL) was stirred under hydrogen at atmospheric pressure for 24 hr. The mixture was filtered and the filtrate was dried over anhydrous Na2SO4, filtered and used directly in the next step. 1H-NMR (500 MHz, CDCl3): δ 6.56 (d, 2H, J=6.0 Hz), 6.47 (t, 1H, J=9.0 Hz), 2.22 (s, 3H).
Reaction SMILES: O[CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[OH:43].C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[O:43][C:3]([N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14])([CH3:2])[CH3:4]
Reactant: Oc1cc(F)ccc1F
Reactant: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(Oc1cc(F)ccc1F)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(2-Hydroxy-1-methylethyl)-1H-isoindole 1,3(2H)-dione (Becker, Y. J. J. Org. Chem. 1980, 45, 2145-51) was diluted with 40 mL THF then treated in order with 7.0 g triphenyl phosphine, 4.0 g of 2,5-difluorophenol and finally with 5.0 mL of diethylazocarboxylate. The reaction became warm to the point of reflux and was allowed to cool to room temperature and stirred at room temperature overnight. The solvent was removed in vacuo and the resulting brown oil was taken up in ethyl acetate (EtOAc). The solution was washed sequentially with aqueous sodium bicarbonate, aqueous ammonium chloride, and brine. Removal of the solvent gave an oil which was chromatographed on silica gel, eluting with 10% ethyl acetate-hexane, to afford 5.4 g of the title compound of Step A as a clear colorless oil: 1H NMR (CDCl3) δ1.57 (d, 3H), 4.22 (dd, 1H), 4.57 (t, 1H), 4.82 (m, 1H), 6.55 (m, 1H), 6.70 (m, 1H), 6.95 (m, 1H), 7.72 (m, 2H), 7.82 (m, 2H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>>[C:1]1([O:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCBr
Reactant: Oc1ccccc1
Product: OCCCCCCCOc1ccccc1

Procedure:
alkylating a phenol with 7-bromo-1-heptanol to provide 7-(phenyloxy)-1-heptanol;
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:15][CH:8]1[C:7]2[C:11](=[CH:12][C:4]([O:3][CH:2]([F:1])[F:14])=[CH:5][CH:6]=2)[C:10](=[O:13])[O:9]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccc(OC(F)F)cc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1OC(Br)c2ccc(OC(F)F)cc21
Temperature: 76 °C
Yield: 101.1 %

Procedure:
A suspension of 6-difluoromethoxy-3H-isobenzofuran-1-one (1 g, 5 mmoles), prepared as described in example 94, in CCl4 (10 ml), under N2, was added with N-bromosuccinimide (0.91 g, 5.1 mmoles) and the mixture was heated at 76° C. A solution of α,α′-azaisobutyronitrile (0.01 g) in CHCl3 (1 ml) was slowly added. The mixture was refluxed for 1.5 hours, then cooled, filtered over celite and washed with CCl4. By drying, 1.41 g of the title compound were obtained as an oil (quantitative yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[ClH:2].[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
55 mg (0.11 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl]-[1,2,4]triazolo[1,5-c]pyrimidine hydrochloride (Example 52A), 27.3 mg (0.14 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile hydrochloride (Example 2A) and 0.12 ml (0.69 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 28 mg (43% of theory) of the product as a solid.
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[O:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH2:6]([O:5][P:4]([C:3]([C:1]#[N:2])=[CH:27][CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)(=[O:11])[O:8][CH2:9][CH3:10])[CH3:7]
Reactant: O=CC1CCOCC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of diethyl cyanomethylphosphonate (50.0 g, 282 mmol), ammonium acetate (9.0 g, 117 mmol), acetic acid (9 ml) in toluene (200 mL), tetrahydropyran-4-carbaldehyde (32.2 g, 282 mmol) were added. The reaction mixture was stirred at room temperature for two hours and then heated at reflux for 1.5 hours. After cooling down, the reaction mixture washed with saturated sodium bicarbonate solution three times, brine one time and then dried over magnesium sulfate. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield [1-cyano-2-(tetrahydropyran-4-yl)-vinyl]-phosphonic acid diethyl ester as a colorless oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9](Cl)=[O:10])[CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:10])[CH2:14]2)=[CH:21][CH:22]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(Cl)C1CN2CCC1CC2
Product: O=C(NC1CCN(CCc2ccc(F)cc2)C1)[C@@H]1CN2CCC1CC2

Procedure:
1-Azabicyclo[2.2.2]octane-3-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-azabicyclo[2.2.2]octane-3-carboxamide.
Reaction SMILES: Cl.[NH2:2][OH:3].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]=O)[CH:6]=[CH:5]1>N1C=CC=CC=1>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]=[N:2][OH:3])[CH:6]=[CH:5]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1cccc2cc[nH]c12
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (0.574 g) was added portionwise to a solution of 1H-indole-7-carbaldehyde (1 g) in pyridine (5 ml) at RT. The resulting solution was heated to reflux and kept at that temperature for 1 hour. The solvent was evaporated. Ethyl acetate (50 mL) was added and the resulting solution was washed with aqueous hydrochloric acid (0.5 M, 40 mL). The organic fraction was separated and dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 1H-indole-7-carbaldehyde oxime (D1) as a colorless oil which, upon standing, solidified to give a waxy solid (1.1 g). MS (ES): C9H8N2O requires 160; found 161.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.B.[Na]>CO>[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: COc1cccc(C=O)c1OC
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Temperature: 25 °C
Yield: 72 %

Procedure:
1.0 g of α-(aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride was suspended in 5 ml of methanol, and after adding thereto 0.85 g of 2,3-dimethoxybenzaldehyde, 0.63 ml of triethylamine was added dropwise to the mixture while stirring at room temperature. The mixture was heated under reflux for 30 minutes, and 0.24 g of sodium boron hydride was added slowly to the mixture while stirring under ice cooling. After the foaming stopped, the mixture was concentrated. The residue was subjected to a separating procedure with chloroform and water, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 1.07 g of α-[[(2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 96°-97° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO.CCOCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[CH:17])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#Cc1ccc([C@H]2CC[C@H](CCC)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.8g of 1[-4-(trans-4-propylcyclohexyl)phenyl]-2-trimethylsilylacetylene, 0.4 g of potassium carbonate and 50 ml of methanol/ether (2:1) was stirred at room temperature for 1 hr. Then, the mixture was partitioned between water and ether and the organic phase was washed in succession with saturated sodium chloride solution and water, dried over magnesium sulfate, filtered over Celite and evaporated. After chromatography of the residue over 150 silica gel with cyclohexane 1.95 g of 4-(trans-4-propylcyclohexyl)phenylacetylene were obtained as a colourless solid.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.CN(C=O)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:22]([O:12][CH2:11][C:9]1[N:10]=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=[C:2]([OH:1])[N:7]2[N:8]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(O)n2nc(CO)nc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(O)n2nc(COC(C)=O)nc2n1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 25.7 g of 7-hydroxy-2-hydroxymethyl-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine, 200 of DMF, 47 ml of acetic anhydride and 1 g of p-toluenesulfonic acid was stirred at 60° C. for 24 hours. The reaction mixture was condensed and 100 ml of methanol was added to the crystals precipitated residue, and the mixture was stirred. Then, crystals were collected by filtration, washed with methanol and dried to obtain 8.9 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12].CN(C)C(N(C)C)=N>C1COCC1>[F:9][C:10]([F:17])([F:16])[C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])=[O:12]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCCN1C(=O)C(F)(F)F

Procedure:
(R)-proline (20 g, 0.174 mol) was placed in a 500 mL round-bottom flask. To this was added 100 mL THF and ethyl trifluoroacetate (50 g, 0.34 mol). The solution was purged with argon and 1,1,3,3-tetramethylguanidine (30 g, 0.261 mol) was added dropwise. The solution was allowed to stir until all the (R)-proline had dissolved (approximately 35 minutes). The solvent was removed in vacuo and the residue dissolved in CH2Cl2 (200 mL). The solution was washed with 6N HCl (aqueous, 2×100 mL). The organic layer was separated and dried with Na2SO4, filtered and the solvent removed in vacuo to give as an oil which crystallized upon standing; yield 29 g (79%), m.p. 48°-51° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:6][CH:7]([O:9][CH2:10][CH3:11])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=COCC
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C=C(C)C(=O)OC(C)OCC
Reaction time: 1 h
Yield: 80 %

Procedure:
To a mixture of 1.00 g of methacrylic acid and 0.836 g of ethyl vinyl ether was added 2 mg of p-toluenesulfonic acid monohydrate, and a reaction was allowed at room temperature for 1 hour. The conversion ratio of methacrylic acid was 82%, with the conversion ratio of ethyl vinyl ether of 94%. Accordingly, 1-ethoxyethyl methacrylate was obtained with the reaction yield of 80% and the selection ratio to ethyl vinyl ether of 85%, and a polymer of ethyl vinyl ether was produced.
Reaction SMILES: C(O[CH2:8][N:9]1[C:13](=[O:14])[C:12]2[C:15]([CH:21]([CH3:23])[CH3:22])=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[S:10]1(=[O:25])=[O:24])(=O)C(C)(C)C.[BrH:26]>C(O)(=O)C.O>[Br:26][CH2:8][N:9]1[C:13](=[O:14])[C:12]2[C:15]([CH:21]([CH3:23])[CH3:22])=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[S:10]1(=[O:25])=[O:24]
Reactant: Br
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)C(C)(C)C)C2=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 2-(pivaloyloxymethyl)-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1.33 kg, 3.62 mol), 48% HBr in acetic acid (1 L) and 3 L of acetic acid was stirred on a steam bath (90°-95° C.) for 1.5 hours. The solvent (acetic acid) was removed under vacuum to give a thick slurry of an off-white residue which was diluted with 10 L of cold water and stirred for 30 minutes. The crude product was collected by filtration, washed first with 6 L of water and then with 3 L of saturated sodium bicarbonate solution. The crude solid was dried at 60°-70° C. for 20 hours and then was recrystallized from a mixture of 5 L of ethyl acetate and 6 L of hexane. Two crops were collected to give 1.16 kg (92%) of 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, as an off-white solid, m.p. 157°-159° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([OH:22])[C:14]#[C:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CCOCC>[C:7]1([CH:13]([OH:22])[CH2:14]/[CH:15]=[CH:16]/[N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCN(CC)CC#CC(O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCN(/C=C/CC(O)c1ccccc1)CC
Reaction time: 5 h

Procedure:
To an ethereal solution (1000 ml) of lithium aluminum hydride (57.0 g) was added a solution of N-(4-phenyl-4-hydroxy-2-butynyl)-N,N-diethylamine (164.05 g) in ether (500 ml) with stirring under ice-cooling for 1.5 hours, and then stirring was continued for 5 hours at room temperature. Water was added to the cooled reaction mixture in order to decompose excess lithium aluminum hydride. The precipitates were filtered, and the filtrate was evaporated and distilled to afford N-(4-phenyl-4-hydroxy-2-trans-butenyl)-N,N-diethylamine, b.p., 116°-120° C./0.12 mmHg.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[Cl:7])\[CH3:22])[CH3:17]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1cc(Cl)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cc(Cl)ccc1Cl
Temperature: 23 °C
Yield: 38 %

Procedure:
Potassium t-butoxide (7.50 g, 0.067 mol) was added to a stirred solution of 2,5-dichloro-phenol (5.46 g, 0.033 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,5-dichloro-phenoxy)-but-2-enoic acid ethyl ester (3.45 g, 37%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: OB(O)c1ccccc1Cl
Product: Clc1ccccc1-c1ncc(Br)cn1
Yield: 69 %

Procedure:
Obtained (0.400 g, yield 69%) following the procedure described in Intermediate 21, starting with 5-bromo-2-iodopyrimidine (2.14 mmol, 0.61 g), 2-chlorophenylboronic acid (2.37 mmol, 0.37 g).