Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]=[CH:7][CH:8]([CH3:15])[CH2:9][C:10](OCC)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH:1]1([CH:6]=[CH:7][CH:8]([CH3:15])[CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(C)C=CC1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C=CC1CCCC1)CCO
Yield: 59 %

Procedure:
A solution of ethyl 5-cyclopentyl-3-methylpent-4-enoate (16.8 g; 80 mmol; obtained according to Streinz, L., Romanuk, M., Sorm, F., Sehnal, F. DE 2 444 837, priority 20.09.1973) in diethyl ether (30 ml) was added dropwise to a suspension of lithium aluminum hydride (3.0 g; 80 mmol) in the same solvent (110 ml), and the reaction mixture was stirred at reflux for 1 hour. Water (3.5 ml), then 15% NaOH solution, and again water (3.5 ml) were added, the precipitate filtered off and washed with MTBE (30 ml). The combined organic phases were washed with 1 N HCl (200 ml) and brine (3×100 ml), dried (MgSO4), concentrated in vacuo, and distilled (79-82° C./0.07 torr) to give 7.8 g (59% yield) of 5-cyclopentyl-3-methylpent-4-en-1-ol.
Reaction SMILES: ClC1C=CC(/C=C(/N2C=NC=N2)\C(=O)C(C)(C)C)=CC=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[C:30](/[N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)\[C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].Cl.N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.Cl.N[C@@H](C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.Cl.N[C@@H](C(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.Cl.N[C@@H](C)C(CC1C=CC=CC=1)(CC1C=CC=CC=1)O.Cl.N[C@@H](CC1C=CC=CC=1)CO>>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[C:30](/[N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)\[CH:31]([OH:36])[C:32]([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: CC(C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1

Procedure:
Reaction was carried out in the same manner as in Example 1 except that (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one was replaced by (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one, and that (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol hydrochloride was replaced by (S)-2-amino-1,1-diphenylpropan-1-ol hydrochloride, (S)-2-amino-1,1-diphenyl-3-methylbutan-1-ol hydrochloride, (S)-2-amino-1,1-dibenzylpropan-1-ol hydrochloride and (S)-2-amino-3-phenylpropan-1-ol hydrochloride, to obtain (+)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. The results were summarized in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5]([CH:7]([N:11]2C(=O)C3=CC=CC=C3C2=O)[C:8]([OH:10])=[O:9])[O:4][N:3]=1.O.NN.C(O)(=O)C>O>[NH2:11][C@@H:7]([C@H:5]1[O:4][N:3]=[C:2]([Cl:1])[CH2:6]1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C(C1CC(Cl)=NO1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CC(=O)O
Product: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Reaction time: 7 h
Yield: 58.4 %

Procedure:
To 710 mg (2.3 mmole) of 3-chloro-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid in 15 ml of water is added 260 μl of hydrazine hydrate and the solution stirred at 50° for 7 hours. After cooling, the solution is adjusted to pH 5.5 with acetic acid (80 μl), filtered, and the precipitate washed with 13 ml water. The filtrate is diluted with 200 ml of 2-butanol and allowed to crystallized in the refrigerator for 18 hours. Filtration yielded 240 mg of (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazole acetic acid; concentrating the mother liquors approximately 15% afforded 50 mg of a second crop of (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazole acetic acid (71%). Tlc: Rf 0.40 (60/20/15/5; MEK/Acet/H2O/AcOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:27]1([N:33]=[C:34]=[S:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[S:35])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)=[CH:24][CH:23]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc(C2=NN(c3ccccc3)C(c3ccc(N)cc3)C2)cc1
Solvent: CC#N
Product: COc1ccc(C2=NN(c3ccccc3)C(c3ccc(NC(=S)Nc4ccccc4)cc3)C2)cc1

Procedure:
3.4 g of 5-(4-aminophenyl)-3-(4-methoxyphenyl)-1-phenyl-2-pyrazoline and 1.5 g of phenyl isothiocyanate were reacted in acetonitrile for 5 hours at room temperature, and the product was reprecipitated from 30 ml of dimethylformamide-methanol to obtain 2.7 g of the desired end compound. m.p. 153°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:25].[Na+].O.OP([O-])(O)=O.[Na+]>CC#N.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:25])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccccc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.5 %

Procedure:
To a solution of 6-chloro-5-phenyl-1H-indole-3-carbaldehyde (90 mg, 0.35 mmol) in MeCN (4 mL), tert-butanol (4 mL) and 2-methyl-2-butene (4 mL, 27.5 mmol) at 0° C. was added a solution of sodium chlorite (327 mg, 4.88 mmol) and sodium phosphate monobasic hydrate (761 mg, 4.88 mmol) in water (4 mL) dropwise. The ice bath was removed and the solution was stirred at room temperature. After 6 hours, additional sodium chlorite (327 mg, 4.88 mmol) and sodium phosphate monobasic hydrate (761 mg, 4.88 mmol) were added as solids and the resulting solution was stirred at room temperature for an additional 14 hours. The reaction mixture was concentrated in vacuo and the aqueous residue was extracted with EtOAc (30 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC to afford the title compound (30.0 mg, 31%) as a white solid. MS (ES+) 271.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (br. s., 1H), 11.96 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.48-7.38 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])[C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:29]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:11](=[O:13])[C@H:9]([CH3:10])[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccccc1C#N
Reactant: CCCCCCNCCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)C(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1ccccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 0.81 g of the crude N-t-butoxycarbonyl-(2-cyanophenyl)alanine and 0.67 g of dihexylamine in 8 ml of N,N-dimethylformamide were added 0.55 g of 1-hydroxybenzotriazole monohydrate and 0.69 g of N-ethyl-N′-dimethylaminopropylcarbodiimide hydrochloride, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% aqueous potassium bisulfate solution, a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane-ethyl acetate=4:1) to give 1.01 g of N-t-butoxycarbonyl-(2-cyanophenyl)alanine dihexylamide.
Reaction SMILES: C([BH3-])#N.[Na+].Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:21][C:22]([CH:24]2[CH2:29][CH2:28][C:27](=[N+:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:26][CH:25]2[C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[NH:21][C:22]([CH:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[CH2:26][CH:25]2[C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[O:23])=[CH:11][CH:12]=1
Reactant: O=C(NC(c1ccc(F)cc1)c1ccc(F)cc1)C1CCC(=[N+]2CCOCC2)CC1c1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NC(c1ccc(F)cc1)c1ccc(F)cc1)C1CCC(N2CCOCC2)CC1c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A second reaction vessel was charged with MeOH (2 mL), cooled to −78° C. using a dry-ice/acetone cooling bath, and treated with sodium cyanoborohydride (0.105 g, 1.673 mmol), followed by the dropwise addition of HCl (1.339 mL, 1.673 mmol, 1.25 M in MeOH). After stirring at −78° C. for approximately 5 min, the material from Step A was added portion wise over approximately 15 min. The reaction was gradually warmed to rt and aged for 12 h. A solution of aq. 5 M NaOH was added until the pH of the reaction mixture was basic. The biphasic mixture was filtered through a plug of Celite™ while rinsing with EtOAc. The organic layer of the filtrate was separated and washed with saturated aq. NaCl, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel via gradient elution with 0-50% EtOH/EtOAc. The purified fractions were combined and concentrated to afford the faster eluting isomer (at * carbon) as Example 3 [HPLC/MS: 509.3 (M+1); Rt=2.85 min] and the slower eluting isomer (at * carbon) as Example 4 [HPLC/MS: 509.3 (M+1); Rt=2.83 min].
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[CH3:10][S:11]([O:9][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:13])=[O:12]
Reactant: OCc1cccnc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccnc1F

Procedure:
A solution of (2-fluoropyridin-3-yl)methanol (400 mg, 3.1 mmol), methanesulfonyl chloride (0.37 mL, 4.7 mmol) and triethylamine (0.88 mL, 6.30 mmol) in dichloromethane (10 mL) was stirred at rt for 16 h. The mixture was then diluted with dichloromethane and washed with H2O, then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give (2-fluoropyridin-3-yl)methyl methanesulfonate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>C(Cl)Cl.CO.CCOCC>[ClH:38].[N:11]1([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:29])([F:30])[F:31])=[O:22])=[CH:18][N:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cnc(N2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester from above was suspended in methylene chloride and methanol. To this mixture was added hydrogen chloride in ether (4N, 3 mL). The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was dried in vacuum. The resulting solid was triturated with dry ether and then filtered to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-piperazin-1-yl-pyrimidin-5-yl)-amide hydrochloride salt. LC-MS calcd for C19H17F3N6O2 (m/e) 418.39, obsd 419.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-:24].[K+].[K+].OO.O>CS(C)=O>[NH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:24])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(N)CCc1ccc(Oc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(N)CCc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
4-(4-(3-Amino-3-methylbutyl)phenoxy)benzonitrile hydrochloride (1.04 g, 32.8 mmol) was dissolved in DMSO (30 ml) and treated with potassium carbonate (0.68 g, 49.2 mmol, 1.5 eq.) with stirring. After 10 minutes, hydrogen peroxide (7 ml, 30% aqueous solution) was added dropwise slowly. The mixture was allowed to stir for 16 hours and then added to 300 ml of water, causing a white precipitate. The material was filtered and dried to give a white solid (908 mg, 93%). NMR, MS
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].N([O-])=O.[Na+].[Br-:17].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Br:17])=[C:3]([OH:12])[CH:4]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: [Br-]
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: COC(=O)c1ccc(Br)c(O)c1
Temperature: 100 °C

Procedure:
To a suspension of methyl 4-amino-3-hydroxybenzoate 69 (21.7 g, 127 mmol) in water (115 mL) at 0° C. was added a solution of sodium nitrite (9.1 g, 127 mmol) in water (50 mL). The resultant mixture was stirred at 0° C. for 1 h. Meanwhile, copper sulfate pentahydrate (42.4 g, 169 mmol) was dissolved in water (135 mL) with heating and sodium bromide (26.4 g, 257 mmol) was added slowly with stirring. The resultant dark green solution was stirred for 5 min, and then was treated with a solution of sodium sulfite (11.3 g, 90 mmol) in water (40 mL). The resultant lime green slurry was stirred for 5 min, and then cooled by the addition of ice. The ice water was decanted off, carefully avoiding dryness. The residue was rinsed with water (3×) and the resultant white solid was dissolved in 115 mL concentrated HBr (115 mL). This acidic copper bromide solution was added to the diazonium salt suspension (see above) at 0° C. The resultant mixture was gradually heated up to 100° C., then stirred at this temperature for 1 h. Significant foaming was observed. After this time, the reaction mixture was cooled and brought to pH 4-5 by the addition of sodium carbonate. EtOAc was added and the mixture was filtered. The filtrate was extracted with EtOAc (3×). The organic layers were dried over Na2SO4 and filtered to give 70. 1H NMR (400 MHz CDCl3) δ: 3.91 (s, 3H), 5.81 (br s, 1H), 7.48 (dd, J=8.5 Hz, 1.4 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.68 (s, 1H). MS (EI) m/z (M−H−) 229.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:9]=[CH:8][C:7]=1[CH2:25][C:26]([NH2:28])=[O:27].N1C=CC=CC=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)[N:9]=[CH:8][C:7]=1[CH2:25][C:26]([NH2:28])=[O:27]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a suspension of 60 mg of 4-[(2,3-difluorobenzyl)amino]-6-([4-(piperazin-1-yl)phenyl]amino)pyridine-3-carboxyamide (the compound of Example 220) in 2 mL of methylene chloride, under ice cooling, 20 mg of pyridine and 28 mg of methanesulfonyl chloride were added, and stirred at room temperature for 30 minutes. To the reaction mixture, saturated sodium bicarbonate in water was added, extracted with chloroform:methanol (5:1), washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 47 mg (65%) of the title compound as a brown powder.
Reaction SMILES: COC([N:5]1[CH:10]=[C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH2:8][C:7]([CH:17]=[O:18])=[CH:6]1)=O.C(N(CC)CC)C>CO>[CH3:16][N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]1[CH2:8][C:7]([CH:17]=[O:18])=[CH:6][NH:5][CH:10]=1
Reactant: COC(=O)N1C=C(C=O)CC([C@@H]2CCCN2C)=C1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1C1=CNC=C(C=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104 %

Procedure:
To a solution of (S)-3-formyl-5-(1-methyl-pyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester III (0.0124 g, 0.05 mmol) in 2 mL of anhydrous MeOH was slowly added triethylamine (0.02 mL, 0.15 mmol), and the reaction mixture was stirred at RT for 1 day. Evaporation of the solvent afforded a quantitative yield (0.010 g) of (S)-5-(1-methyl-pyrrolidin-2-yl)-1,4-dihydro-pyridine-3-carbaldehyde IV as a yellow oil. The product was used without further purification. IR (thin film, neat, NaCl): 3416–3244, 2957, 1595, 1509, 1377, 1228 cm−1. 1H NMR (CDCl3, 300 MHz) δ 9.14 (s, 1 H), 6.85 (d, 1 H, J=6 Hz), 6.48 (s, 1 H), 6.00–5.99 (m, 1 H), 3.05–3.00 (m, 3 H), 2.45 (m, 1 H), 2.19–2.11 (m, 4 H), 1.83–1.67 (m, 4 H); 13C NMR (CDCl3, 75 MHz) δ 189.59, 146.95, 119.91, 119.01, 112.67, 70.03, 57.03, 40.69, 28.96, 22.80, 20.37. HRMS Calcd for C11H16N2O: 193.1341 [M+H]+. Found: 193.1334 [M+H]+. [α]28D−80.7 (c=0.55, CH2Cl2).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15][CH2:16][CH2:17]C.IC(C)C.OC1O[C@@H](CO)[C@H](O)[C@H](O)[C@H]1O>>[CH:16]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH3:17])[CH3:15]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: CC(C)I
Product: CC(C)C1c2ccccc2-c2ccccc21

Procedure:
Fluorene (15.0 g, 90.4 mmol), n-BuLi (48.1 ml, 120 mmol, 2.5 M in hexane), RX=2-iodopropane (14.0 ml, 139.6 mmol). 42 was isolated as a yellowish solid (18.7 g, quant.). The analytical data were identical with these to be found in the literature (M. A. Schmidt, H. G. Alt, W. Milius, J. Organomet. Chem. 1996, 525, 15).
Reaction SMILES: [CH3:1][C:2]1[C:22](=[O:23])[C:20](=[O:21])[C:5]2[C@@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C@@:7]3([O:13][CH3:14])[C@H:11]4[NH:12][C@H:10]4[CH2:9][N:8]3[C:4]=2[C:3]=1[OH:24].[CH3:25]NN=NC1C=CC(C)=CC=1.C(Cl)Cl.CO>C(Cl)Cl.C(OCC)C>[CH3:1][C:2]1[C:3](=[O:24])[C:4]2[N:8]3[C@@:7]([O:13][CH3:14])([C@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C:5]=2[C:20](=[O:21])[C:22]=1[O:23][CH3:25])[C@H:11]1[NH:12][C@H:10]1[CH2:9]3
Reactant: CNN=Nc1ccc(C)cc1
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(O)=C(C)C(=O)C3=O)N1C[C@@H]1N[C@@H]12
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A 100 mg (0.30 mmole) quantity of 7-hydroxy9a-methoxymitosane and 100 mg (0.67 mmole) quantity of 3-methyl-1-p-tolyltriazene was dissolved in 2 ml methylene chloride and 10 ml diethyl ether. The solution, after gently refluxing for 6 hours was stirred at room temperature for 18 hours. TLC [methylene chloride:methanol (90:10)] revealed the appearance of a deep purple spot at Rf =0.36 with a trace amount of impurity at Rf =0.41. The reaction mixture was concentrated to dryness and chromatographed on Woelm neutral alumina employing methylene chloride and methylene chloride:methanol (30:1) as eluting solvents. Fractions containing the component at Rf =0.36 were pooled and concentrated to dryness. Precipitation of the dry residue from methylene chloride and hexane afforded the title compound as a fine amorphous purple powder (25 mg, 24%), mp 161°.
Reaction SMILES: [C:1]1([CH:11]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:12][O:13][CH2:14][CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:15][CH2:14][O:13][CH2:12][CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:37][CH2:36]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2cccc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCN(CCOCC(OC2CCCCO2)c2cccc3ccccc23)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 7.5 g of 1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane, 2.65 ml of N-methylpiperazine, 3.96 g of potassium carbonate and 38 ml of N,N-dimethylformamide was stirred for 2 hours at 90°-100° C. The reaction mixture was cooled and added to a mixture of 100 ml of diethyl ether and 100 ml of ice water. The organic layer was separated. The aqueous layer was extracted twice each with 25 ml of diethyl ether. The extracts were combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=10/1) to obtain 3.36 g of colorless, oily 2-[2-(4-methylpiperazin-1-yl)ethoxy]-1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)ethane (compound No. 258).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].C(Cl)(Cl)Cl.[NH:40]1[CH2:45][CH2:44][CH:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:40]3[CH2:45][CH2:44][CH:43]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:42][CH2:41]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCOCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 94 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (36 mg, 0.072 mmol) in THF (2 mL)/CHCl3 (2 mL) were added 4-(4-piperidinyl)morpholine (37 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (41 mg, 94%). LC-MS m/z 607 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.33 (m, 2H), 1.83 (d, 2H), 2.30 (s, 3H), 2.38 (m, 1H), 2.55 (m, 4H), 2.75 (t, 2H), 3.33 (m, 1H), 3.68 (m, 3H), 4.11 (s, 2H), 4.23 (m, 1H), 4.45 (m, 2H), 7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H), 7.68 (s, 1H), 7.85 (d, 1H).