Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([OH:14])=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:17])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([Cl:17])=[O:14])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1nc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COc1nc(Cl)c(Cl)cc1Cl

Procedure:
To a stirred slurry of 30 g (0.1237 mole) 3,5,6-trichloro-2-pyridyloxyacetic acid in 500 ml methylene chloride, 1 ml N,N-dimethylformamide was added. Then 16.2 g [10 m' (0.136 mole)] thionyl chloride was added dropwise. The mixture was refluxed 31/2 hours. The solvent was stripped in vacuo to give the 3,5,6-trichloro-2-pyridyloxyacetyl chloride as an oil, which was used in step (b) without further isolation.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:18]([NH:20][NH2:21])=O>C(O)CCC>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:18]=[N:20][N:21]=3)[N:4]=2)[CH:9]=1
Reactant: NNC=O
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: FC(F)(F)c1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 6.0 g. of 3-chloro-6-(α ,α ,α-trifluoro-m-tolyl)pyridazine (prepared as in Example 11), 2.78 g. of formylhydrazine and 75 ml. of butyl alcohol is allowed to stir at reflux tremperature for 48 hours. The reaction mixture is concentrated free of solvent and the residue is dissolved in ethyl alcohol, treated with activated charcoal and filtered. The filtrate is cooled in an ice bath and the cream colored solid is collected. The solid is heated with diethyl ether and the mixture is filtered. The solid is recrystallized from ethyl acetate to afford the product of the example as cream colored crystals, m.p. 140°-143° C.
Reaction SMILES: [S:1]1([CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:3])=[O:2].[CH2:8]([Li])[CH2:9][CH2:10]C.C(Br)C#C>C1COCC1>[CH2:10]([CH:4]1[CH2:5][CH2:6][CH2:7][S:1]1(=[O:3])=[O:2])[C:9]#[CH:8]
Reactant: O=S1(=O)CCCC1
Reactant: [Li]CCCC
Agent: C#CCBr
Solvent: C1CCOC1
Product: C#CCC1CCCS1(=O)=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of sulfolane (1.0 g, 8.32 mmol) in THF (5 mL) at −78° C. is added n-butyllithium (5.7 mL of 1.6 M in hexane, 9.1 mmol) dropwise and the solution is stirred at −78° C. for 20 min. To this is added a solution of propargyl bromide (992 mg, 8.34 mmol) in THF (5 mL) dropwise and the mixture is allowed to warm to RT overnight. The mixture is quenched with 1N HCl and extracted with EtOAc. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The residue is purified by flash chromatography using hexane/EtOAc (6:4) as eluent to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH:18]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=3)[C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCC(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 27% yield: mp 174-175° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.0 Hz, 2H), 7.39-7.20 (m, 7H), 6.01 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.14-4.02 (m, 1H), 3.93-3.79 (m, 1H), 3.35-3.24 (m, 1H), 3.09-2.96 (m 1H), 2.90-2.80 (m, 1H), 2.61 (s, 3H), 2.34-2.19 (m, 1H), 1.95-1.81 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.4, 162.3, 155.3, 152.6, 142.4, 137.8, 129.3, 128.8, 127.9, 127.7, 125.7, 125.6, 125.5, 118.8, 45.9, 44.2, 44.1, 36.2, 24.4, 17.2; MS (ES+) m/z 474.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=2)=[C:16]([Cl:29])[CH:15]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C>[Cl:29][C:16]1[CH:15]=[C:14]([CH2:12][N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)[CH:28]=[CH:27][C:17]=1[O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#Cc1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2Cl)nc1
Yield: 53.6 %

Procedure:
Using a method similar to Example 365, step 2, using 3-phenyl-pyrrolidine (0.160 g, 1.09 mmol), 6-(4-formyl-2-chloro-phenoxy)-nicotinonitrile (0.250 g, 0.966 mmol), sodium triacetoxyborohydride (0.308 g, 1.45 mmol), and acetic acid (0.090 mL, 1.57 mmol) in 1,2-dichloroethane (10.7 mL), after silica gel chromatography (7:3 hexanes:ethyl acetate), provides 0.202 g (54%) of the title compound as a clear syrup: mass spectrum (electrospray): m/z=390.1 (M+1); 1H NMR (CDCl3): 8.41 (d, 1H, J=2.4 Hz), 7.92 (dd, 1H, J=2.4, 8.8 Hz), 7.50 (d, 1H, J=2.0 Hz), 7.32 (dd, 1H, J=2.0, 8.3 Hz), 7.30-7.26 (m, 4H), 7.21-7.16 (m, 1H), 7.13 (d, 1H, J=8.3 Hz), 7.07 (d, 1H, J=8.3 Hz), 3.70-3.62 (m, 2H), 3.42-3.32 (m, 1H), 3.03 (t, 1H, J=8.8 Hz), 2.87-2.79 (m, 1H), 2.75-2.68 (m, 1H), 2.54 (t, 1H, J=7.8 Hz), 2.40-2.29 (m, 1H), 1.96-1.85 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:22][C:19]=1[CH:20]=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH2:20][C:19]2[CH:22]=[C:23]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)[CH:24]=[CH:25][C:18]=2[O:17][CH3:16])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1ccc(-c2ccncc2)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(-c2ccncc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
A stirred suspension of amine (295) (131 mg, 0.61 mmol) and aldehyde (296) (130 mg, 0.61 mmol) in THF (1 mL) and toluene (1 mL) was treated with AcOH (42 μL, 0.73 mmol) at RT. After stirring 1.5 h, the resultant suspension was treated with sodium triacetoxyborohydride (181 mg, 0.86 mmol) and stirred for 18 h. The reaction was diluted with aqueous NaHCO3 and extracted into EtOAc. The organic phase was dried (Na2SO4), filtered, the solvent removed in vacuo and the residue chromatographed with 10% MeOH in EtOAc to afford the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[C:14]([CH2:13][CH2:12][NH:11][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9])([OH:16])=[O:15]
Reactant: NCCC(=O)O
Reactant: CC(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(Cc1ccccc1)NCCC(=O)O
Reaction time: 18 h
Yield: 60.2 %

Procedure:
Phenylacetone (100 mg, 0.745 mmol) was dissolved in anhydrous methanol (2.0 ml). Beta-alanine (398 mg, 4.47 mmol) was added, followed by sodium cyanoborohydride (94 mg, 1.49 mmol). After 18 hours of stirring under nitrogen, the reaction mixture was filtered, and the filtrate solvent was removed in vacuo. The resulting crude material was purified on four 1.0 millimeter C18 reverse-phase preparative thin layer chromatography plates eluted with H2O/methanol/acetic acid (40/60/0.4). The material obtained was dissolved in ethyl acetate (20 ml) and was extracted with 1.0M sodium bicarbonate (3×20 ml). The aqueous extracts were combined, the pH was adjusted to 4 with 1.0M hydrochloric acid, and the solvent was removed in vacuo. The resulting crystalline solid was then triturated twice with 50-milliliter portions of ethyl acetate and filtered. The filtrates were combined, and the solvent was removed in vacuo to yield 93 milligrams of N-carboxyethyl-amphetamine.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C@@H:30]([CH3:46])[C:31](N2[C@H](C)[C@H](C3C=CC=CC=3)OC2=O)=[O:32])[CH:21]=1)[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-:47].[Li+].OO.Cl>O>[CH:6]1([C:4]([N:3]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C@@H:30]([CH3:46])[C:31]([OH:32])=[O:47])[CH:21]=2)[CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]1
Reactant: [OH-]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)N2C(=O)O[C@@H](c3ccccc3)[C@H]2C)cc(C(F)(F)F)c1)C(=O)C1CC1
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)O)cc(C(F)(F)F)c1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cyclopropanecarboxylic acid ethyl-{3′-[(R)-1-methyl-2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-2-oxo-ethyl]-4,5′-bis-trifluoromethyl-biphenyl-2-ylmethyl}-amide (0.036 g, 0.06 mmol) in THE (1 mL) and H2O (1 mL) was added lithium hydroxide (0.005 g, 0.11 mmol) and hydrogen peroxide (29%; 0.01 mL, 0.11 mmol), and the reaction was stirred at room temperature overnight. The mixture was acidified to pH 5 with 10% aqueous HCl are extracted with EtOAc. The crude material was purified by preparative HPLC to give the title compound. M+H is 488.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12]Br)[C:5]([O:7][CH3:8])=[O:6].[C:14]([CH:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][NH:24][CH:21]1[CH2:22][CH2:23][CH:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:19][CH2:20]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: COC(=O)c1ccc(CBr)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC2CCC(C(C)(C)C)CC2)c(Br)c1

Procedure:
To a solution of the product from Example 224 Step B (assume 4.76 mmol) in 5 mL of N,N-dimethylformamide was added 1.02 mL (5.71 mmol) of 4-tert-butylcyclohexylamine and 1.7 mL (9.76 mmol) of N,N-diisopropylethylamine. The resultant mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate and the organic layer washed sequentially with three portions of water and one portion of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (biotage) using 5% ethyl acetate/hexanes as eluent to provide both the cis isomer and the desired trans isomer. 1H NMR (500 MHz, CD3OD) δ 8.18 (s, 1H), 7.97 (d, 1H, J=8 Hz), 7.58 (d, 1H, J=8 Hz), 3.93 (s, 2H), 3.91 (s, 3H), 2.43-2.37 (m, 1H), 2.08-2.01 (m, 2H), 1.85-1.79 (s, 2H), 1.19-4.99 (m, 5H), 0.86 (s, 9H). HPLC/MS (ESI) m/z (M+H)=384.2 (2.47 min.).
Reaction SMILES: [OH-].[OH:2][CH2:3][CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([OH:14])=[O:13])[CH3:10].OCC[N+](C)(C)C.C(OC(=O)CCCCC)C>>[CH3:18][CH2:17][CH2:16][CH2:15][CH:11]([C:12]([O-:14])=[O:13])[CH2:9][CH3:10].[CH3:6][N+:5]([CH2:4][CH2:3][OH:2])([CH3:8])[CH3:7]
Reactant: CCCCC(CC)C(=O)O
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CCCCCC(=O)OCC
Product: CCCCC(CC)C(=O)[O-]

Procedure:
272.13 g of a 40% solution of choline hydroxide and 145.73 g of 2-ethylhexanoic acid were stirred vigorously for 30 min at RT in a glass flask with reflux condenser, heatable oil bath, mechanical stirrer and internal thermometer. Water and methanol were distilled off in a rotary evaporator at 30-45° C. under a vacuum increased gradually to 20 mbar. The product was then taken up in n-hexane and re-evaporated in the rotary evaporator and dried at 0.1 mbar and 40° C. for 2 h, giving a slightly colored, viscous liquid whose 1H-NMR spectrum showed equimolar ratios of choline and ethylhexanoate, but only a weak signal in the region of aliphatic carboxylic acids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH:5]=[CH:6][C:7]=1[F:8].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37](O)=[O:38])[C:34]([CH3:40])=[N:33]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:37]([C:35]2[C:34]([CH3:40])=[N:33][N:32]([CH3:31])[CH:36]=2)=[O:38])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1ccccc1-c1ccc(F)c(Cl)c1
Reactant: Cc1nn(C)cc1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(C)cc1C(=O)Nc1ccccc1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At room temperature, 0.47 g of 3′-chloro-4′-fluoro-2-aminobiphenyl and 0.82 g of bis(2-oxo-3-oxazolidinyl)phosphoryl chloride were added to a solution of 0.30 g of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid and 0.43 g of triethylamine in 30 ml of dichloromethane. The mixture was stirred at room temperature for 12 hours. The mixture was then washed successively twice with dilute hydrochloric acid, twice with aqueous sodium bicarbonate solution and once with water. The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography using cyclohexane/methyl tert-butyl ether 1:2. This gave 0.56 g of the desired product as white crystals of m.p. 177-180° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=S)=[CH:7][N:6]=[C:5](C)[N:4]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:14]=1[NH2:15].C1(C)C=C[C:24]([S:27](O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:14]=1[NH:15][CH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][C:5]([S:27][CH3:24])=[N:6][CH:7]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CNc1nc(C)ncc1C=S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1nc(SC)ncc1CNc1c(Cl)cccc1Cl
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 298 %

Procedure:
A mixture of 6 g (32.8 mmol) of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde, 5.5 g (33.9 mmol) of 2,6-dichloroaniline and 1 g (5.3 mmol) of 4-toluenesulfonic acid in 70 ml of toluene was heated under reflux with azeotropic removal of water for 17 hours. The mixture was concentrated to a volume of about 10 ml under reduced pressure and then treated with 120 ml of ethanol. The suspension obtained was heated to 75° C. and treated over a period of 15 minutes with 6.2 g (160 mmol) of sodium borohydride pellets. The mixture was stirred for a further 15 minutes and cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was stirred in a mixture of 200 ml of 2M sodium hydroxide solution and 200 ml of ethyl acetate for 1 hour. The phases were separated and the organic phase was dried over magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure and flash chromatography of the residue using diethyl ether/hexane (3:7) for the elution gave 5.2 g (48%) of 5-(2,6-dichlorophenyl)aminomethyl-4-methylamino-2-methylthio-pyrimidine as a white solid.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[OH-:10].[Na+:11].C.OO>O>[Na+:11].[CH2:1]([P:3]([OH:4])([CH2:6][CH2:7][C:8]([O-:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCP(=O)(O)CCCO
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCC(=O)[O-]
Temperature: 70 °C
Yield: 93 %

Procedure:
15.2 g (0.1 mol) of ethyl-3-hydroxypropylphosphinic acid (produced as in Example 5) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.45 g of charcoal with 5% Ft and 1% Bi is added, the suspension is heated to 70° C. and 30% strength hydrogenperoxide solution is passed into the suspension at a flow rate of 1 mol equivalent per hour while the pH of the suspension is maintained at pH=9 by adding 2N NaOH solution. After the reaction is ended, the reaction solution is filtered to remove the catalyst, the filter residue is washed and the water is distilled off in vacuo to obtain 19.3 g (93% of theory) of 3-(ethylhydroxyphosphinyl)propionic acid sodium salt (colorless solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH:44]([OH:48])[CH2:45][CH2:46][CH3:47])[CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:48][CH:44]([CH2:43][CH2:42][N:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)[CH2:45][CH2:46][CH3:47])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCC(O)CCN1CCN(C)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC(CCN1CCN(C)CC1)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 13.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-(4-methylpiperazino)-3-hexanol (52 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (12 mg, yield 11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:25][C:26](Br)=[O:27].[NH2:29][CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:25][C:26]([NH:29][CH:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:27])=[CH:22][CH:23]=1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1
Reactant: NC1CCc2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1

Procedure:
prepared by reaction of 1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 1-Aminoindan
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[CH2:28][C@H:27]([N:29]3[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]3)[C@@H:26]([OH:36])[C@H:25]2[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:16]=1)=[O:14].FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:105]([NH:107][CH:108]3[CH2:113][CH2:112][N:111]([C:114]4[CH:119]=[CH:118][CH:117]=[CH:116][N:115]=4)[CH2:110][CH2:109]3)=[O:106])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:111]1([C:114]2[CH:119]=[CH:118][CH:117]=[CH:116][N:115]=2)[CH2:112][CH2:113][CH:108]([NH:107][C:105](=[O:106])[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[C@@H:24]3[CH2:28][C@H:27]([N:29]4[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]4)[C@@H:26]([OH:36])[C@H:25]3[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:16]=2)=[O:14])[CH2:109][CH2:110]1
Reactant: NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)NC1CCN(c2ccccn2)CC1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (3-amino-propyl)-amide trifluoroacetate (Example 63) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42). MS (ES+) m/e 815 (MH+)
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>N1C=CC=CC=1>[C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([CH2:16][CH2:17][O:18][S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccc2nc(-c3ccccc3)[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3nc(-c4ccccc4)[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzimidazole 190 (50 mg) was dissolved in pyridine (5 mL) and tosyl chloride (40 mg) was added as a solid. The reaction was allowed to stir for 16 h under nitrogen at room temperature before being quenched by addition of a saturated, aqueous solution of NH4Cl. This mixture was extracted with EtOAc which was in turn washed with dilute acid to ensure complete removal of pyridine. The organic layer was separated, dried over Na2SO4, and solvent removed under reduced pressure to give 191 which was used directly without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1C=CC=C(C(OO)=O)C=1.[S:31]([O-:35])([O-])(=[O:33])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([S:31]([CH3:21])(=[O:35])=[O:33])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CSc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)ncc2C1
Reaction time: 4 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-2-methylthio-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.20 g) in methylene chloride (80 ml) was added metachloroperbenzoic acid (3.37 g). After stirring for 4 hours, a 10% aqueous solution (100 ml) of sodium thiosulfate and a saturated aqueous solution (100 ml) of sodium bicarbonate were added to the reaction mixture and the mixture was separated into layers. The water layer was extracted with methylene chloride (2×50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:acetone=20:1→10:1), whereby the title compound (2.34 g) was obtained as a colorless solid.