Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]([NH:18][S@@](C(C)(C)C)=O)([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[OH-].[Na+]>ClCCl.Cl>[NH2:18][C@@:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH2:9][F:10])[CH2:11][C@H:12]([OH:17])[C:13]([F:15])([F:16])[F:14]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(R)-N-((2S,4S)-2-(3-bromophenyl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (1.83 g, 4.21 mmol) was dissolved in dichloromethane 37 mL and hydrogen chloride, 4.0M solution in 1,4-dioxane (5.27 ml, 21.07 mmol) was added dropwise. The reaction was stirred at room temperature for 10 min. The reaction was worked up by addition of 1N NaOH and extraction with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford (2S,4S)-4-amino-4-(3-bromophenyl)-1,1,1,5-tetrafluoropentan-2-ol that was used without further purification.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[OH:23])([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.N1C=CC=CC=1.[C:50](Cl)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>ClCCl>[C:50]([O:23][CH:22]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
In 200 ml of dried dichloromethane was dissolved 32.0 g (53.4 mmole) of 1-trityl-3-octadecylglycerol, and 22.4 ml of dried pyridine and then a solution of 6.7 ml (57.9 mmole) of benzoyl chloride in 100 ml of dried dichloromethane were added dropwise to the solution under stirring at 0° to 3° C. over the period of time of 30 minutes. The reaction mixture was stirred at room temperature for another 2 hours, and then concentrated under reduced pressure. 200 ml of ether was added to the residue, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 28.8 g (7%) of 2-benzoyl-3-octadecyl-1-tritylglycerol as an oily material.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3.[C:18]([NH:28][NH2:29])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>CN(C)C=O>[CH2:21]([O:20][C:18]([NH:28][NH:29][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CBr)C2
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNNC(=O)OCc1ccccc1)C2
Temperature: 150 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
The compound obtained in Example 338 (1.5 g, 5.1 mmol) was dissolved in dimethylformamide (40 ml), to which carbobenzoxy hydrazine (4.2 g, 25.3 mmol) was added, and stirred at 150° C. for 5 hours. The reaction mixture was poured into water, and then extracted with chloroform. The organic phase was washed with water, dried, and condensed under reduced pressure. As a result, 0.744 g of the title compound was obtained as a colorless solid (40.0%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[Cl:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][C:12]2[N:13]=[C:14]([O:30][CH2:31][CH2:32][CH3:33])[C:15]3[N:20]=[C:19]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[C:23]([CH3:29])[CH:22]=4)[O:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)(C)C.O>[Cl:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][C:12]2[N:13]=[C:14]([O:30][CH2:31][CH2:32][CH3:33])[C:15]3[N:20]=[C:19]([C:21]4[CH:22]=[C:23]([CH3:29])[C:24]([O:28][CH2:1][CH:3]5[CH2:4][O:5]5)=[C:25]([CH3:27])[CH:26]=4)[O:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1
Reactant: ClCC1CO1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC4CO4)c(C)c3)nc12
Temperature: 50 °C

Procedure:
A mixture of 218.5 μl of epichlorohydrine and 370 mg of 4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol in 4.4 ml of isopropanol and 1.2 ml of an aqueous 3 N sodium hydroxide solution was heated to 50° C. for 8 h. Then ethyl acetate and water were added and the layers were separated. The organic layer was extracted with water, dried over sodium sulfate, filtered and evaporated in vacuo to give 410 mg of the crude title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][C:14](F)=[CH:15][C:8]=2[Si:7]([CH3:18])([CH3:17])[CH2:6]1.C[Si]1(C)C2C=CC=C([F:30])C=2C(=O)NC1.C([Li])CCC.ClCCCBr>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[C:12]([F:30])=[CH:13][CH:14]=[CH:15][C:8]=2[Si:7]([CH3:18])([CH3:17])[CH2:6]1
Reactant: C[Si]1(C)CN(CCCCl)C(=O)c2ccc(F)cc21
Reactant: C[Si]1(C)CNC(=O)c2c(F)cccc21
Agent: ClCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si]1(C)CN(CCCCl)C(=O)c2c(F)cccc21

Procedure:
3-(3-Chloropropyl)-1,1-dimethyl-5-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline is obtained in a manner similar to that described in Example 11 for the preparation of 3-(3-chloropropyl)-1,1-dimethyl-7-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, but using 3.15 g of 1,1-dimethyl-5-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, 11.3 cm3 of n-butyllithium, 5.7 g of 1-chloro-3-bromopropane and 65 cm3 of tetrahydrofuran. After purification by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (99.5-0.5 by volume) as eluent, 1.15 g of 3-(3-chloropropyl)-1,1-dimethyl-5-fluoro-4-oxo 1,2,3,4-tetrahydro-3,1-benzazasiline are obtained.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8](=[NH:10])[NH2:9].CSC(=N)[NH2:14].[OH-].[K+].CS>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:9][C:8]([NH2:10])=[NH:14]
Reactant: CSC(=N)N
Agent: CS
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: N=C(N)N
Temperature: 50 °C

Procedure:
To a solution of 7-(1-aminopentyl)camptothecin (2.16 g, 5 mmol) in 10 ml of water was added S-methylisothiourea hemisulfate (0.7 g, 2.5 mmol) at room temperature. The mixture was heated at 50° C. for 5 hr under nitrogen. The gases developed during the reaction were passed through two flasks, each containing an ethanolic solution of KOH for trapping the CH3SH by-product. The mixture was then concentrated and 50 ml of acetone was added. The precipitate was filtered and recrystallized from water to give 2.72 g (95%) of guanidine sulfate. Colorless solid, MP 289-291° C.(dec.). IR (KBr): 2400-2620, 1775, 1650 cm−1. 1H NMR (DMSO-d6) δ 8.24 (1H, d, J 7.0 Hz), 7.80 (1H, m), 7.73 (1H, m), 5.42 (2H, s), 5.26 (2H, s), 3,11 (2H, m), 2.96 (2H, m), 1.82 (2H, m), 1.66-1.51 (6H, m), 8.87 (3H, t, J 6.8 Hz). C26H31N5O8S (573.63). Ms m/z: 573 (M+). Anal. Calcd for C26H31 N5O8S (573.63): C, 54.44: H, 5.45: N, 12.21. Found: C, 54.68; H, 5.31; N, 12.38.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([CH3:41])([CH3:40])[CH3:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1C(C)(C)C
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2C(C)(C)C)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29.3 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (960 mg, 0.005 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (3.00 g, 0.023 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-t-butyl-phenoxy)-but-2-enoic acid ethyl ester (1.60 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(2-t-butyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (585 mg, 28%) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OO)(=[O:15])C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N+:5]([O-:15])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC(=O)OO
Product: [O-][n+]1ccc(Cl)c2ccc(Cl)cc21
Reaction time: 18 h

Procedure:
4,7-Dichloroquinoline (20.4 g) and peracetic acid (32 wt. % [from Aldrich], 24 mL) are heated at reflux for 8 h and kept at room temp. for 18 h. The precipitate is collected and washed with hexane to give 23 g of 4,7-dichloroquinoline-N-oxide. 1.0 g (4.7 mmol) thereof is heated in phosphoryl chloride (3.7 mL) for 1½ h at reflux. The reaction mixture is concentrated and the residue is treated with 10% aq. NaOH (pH 9). The precipitate is collected, washed with water, and dried yielding 1.0 g of 2,4,7-trichloroquinoline. 250 mg thereof is heated with 15% H2SO4 (20 mL) and 1,4-dioxane (10 mL) in a sealed tube at 140° C. for 8 h. The mixture is kept at room temp. for 18 h. The precipitate is collected, washed with water, and dried affording 195 mg of 4,7-dichloro-2-quinolone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[ClH:27]>O>[ClH:27].[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CCCOCCCCCBr)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(CCCOCCCCCNCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
1-[3-[(5-Bromopentyl)oxy]propyl]-4-methoxybenzene (2.0 g) was added to benzylamine (6 ml) at 120° under nitrogen. The solution was stirred for 2 h at 120° then added (hot) to 2N hydrochloric acid (50 ml) and water (25 ml). The resulting precipitate was collected by filtration, washed with 2N hydrochloric acid, water and ER then dried at 50° under vacuum to give the title compound as a white solid (1.79 g) m.p. 118°-121°.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:15](Cl)(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[C:9]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(Cl)ccc2o1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCCCc1oc2ccc(Cl)cc2c1C(=O)c1ccc(OC)cc1

Procedure:
2-n-Butyl-5-chlorobenzofuran (9.5 g., 0.046 mol.) was acylated with 8 g. (0.047 mol.) of p-anisoyl chloride as described in the procedure of Example 1 to give 2-n-butyl-5-chloro-3-(4-methoxybenzoyl)benzofuran. Demethylation gives 2-n-butyl-5-chloro-3-(4-hydroxybenzoyl)benzofuran.
Reaction SMILES: [CH2:1]([Si:3]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:4][C:5]1([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:16]([Si:3]([CH2:1][CH3:2])([CH2:18][CH3:19])[O:4][C:5]1([C:12]([F:14])([F:13])[F:15])[CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH2:10]1)[CH3:17]
Reactant: [H][H]
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)C=C1
Agent: [Pd]
Solvent: CCO
Product: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC(=O)CC1

Procedure:
A solution of 291 mg of 4-triethylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one in 2 mL of absolute ethanol was treated with a few mg of 5% palladium on carbon, hydrogenated in a Parr shaker for one hour under 50 psig of hydrogen, and filtered. Concentration of the filtrate gave 4-triethylsiloxy-4-trifluoromethylcyclohexanone: 1H NMR (CDCl3) δ 0.45-1.16 (m, 15H), 1.92-2.89 (m, 8H); mass spectrum (70 eV) m/z (relative intensity) 267 (19, M-C2H5), 115 (45), 105 (33), 87 (100), 81 (22), 77 (67), 73 (20), 67 (29), 59 (57), 55 (84), 47 (20).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:12])[N:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:12])[N:3]=[C:2]([Cl:1])[CH:11]=[C:6]12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1nc(Cl)cc2n1CCCN2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1nc(Cl)cc2n1CCCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
To a suspension of 8-chloro-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (1 g, 2.32 mmol) and sodium hydride (0.28 g, 6.95 mmol) in N,N-dimethylformamide (10 mL) was added (bromomethyl)benzene (0.40 mL, 2.78 mmol) at room temperature, and stirred for 30 min at r.t. Purification via reverse phase column (0.3% TFA in water/acetonitrile) afforded the title compound (300 mg).
Reaction SMILES: [C:1]1([CH2:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:15]1[CH2:16][O:17][C:12]([CH3:13])([CH2:11][C:1]2[CH:2]=[CH:3][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:5][CH:6]=2)[O:14]1
Reactant: OCCO
Reactant: CC(=O)Cc1ccc(CC(C)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(=O)Cc1ccc(CC2(C)OCCO2)cc1

Procedure:
A mixture of 1,4-phenylene bis(propan-2-one), (17.12 g), ethane-1,2-diol (1.72 g) and a trace of 4-toluene sulphonic acid was heated under reflux in benzene for 2 hr. using a Dean and Stark apparatus. The solvent was evaporated and the residue chromatographed on silica. Elution with 1:3 diethyl ether:petrolroleum ether (40-60) gave 4-(2,2-(ethylenedioxy)propyl)phenyl propan-2-one, as a white solid (3.5 g). Further elution gave starting material (12.9 g).
Reaction SMILES: C([O:3][P:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:5][CH2:6][CH3:7])C.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>>[CH2:6]([O:5][P:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]1=[O:29])=[O:3])[CH3:7]
Reactant: CCOC(=O)CP(OCC)OCC
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Product: CCOC(=O)CP(=O)(CCCCN1C(=O)c2ccccc2C1=O)OCC

Procedure:
Heat 12.5 gm of ethyl (diethoxyphosphino)acetate with 16.9 gm of N-(4-bromobutyl)phthalimide in a melt at 180° for 5 hours under a nitrogen atmosphere. After cooling, chromatograph the mixture on a silica gel column, eluting with a gradient of 1% to 2% CH3OH in EtOAc. Isolate the major product by vacuum evaporation of the solvent from the combined fractions to obtain the title compound. Rf (silica gel; EtOAc:CH3OH, 99:1)=0.40.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH:16]=O>CO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:16]([C:15]3[C:14]([Cl:13])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:22])[O:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(N)c(O)c1
Solvent: CO
Product: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of 4-amino-3-hydroxy-benzoic acid methyl ester (2.0 g) in MeOH (100 mL) was added 2,6-dichlorobenzaldehyde (2.1 g). The reaction mixture was heated at 45° C. overnight, and then concentrated in vacuo. The residue was dissolved in THF (10 mL) and dichloromethane (90 mL). To the mixture solution was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.72 g). The reaction mixture was stirred for 1 h, diluted with NaHCO3 aqueous solution, extracted with EtOAc, and washed with brine. The extracts were dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 2:3 EtOAc/Hexane) gave 2-(2,6-dichlorophenyl)-benzooxazole-6-carboxylic acid methyl ester: MS (m/z) 321.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)=[O:5]>CO.[Pd]>[NH2:1][C:2]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CN1CCN(CCc2ccc(NC(=O)c3cccc([N+](=O)[O-])c3N)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(CCc2ccc(NC(=O)c3cccc(N)c3N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of 2-amino-N-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-3-nitro-benzamide (300 mg, 0.78 mmol) in MeOH (100 mL) were added Pd/C (10%, 30 mg) and the mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 1 h. The reaction mixture was filter over Celite to afford the title compound (261 mg, 94%). 1H NMR (MeOH-d4) δ 2.39 (s, 3H), 2.55-2.83 (12H), 6.62 (dd, J=9 Hz and 9 Hz, 1H), 6.86 (d, J=9 Hz, 1H), 7.08 (d, J=9 Hz, 1H), 7.22 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H). ESI-MS m/z 354.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:30]1([CH2:36][CH:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:37]([OH:38])[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 20 g (70.6 mmol) dibenzylamino-acetic acid ethyl ester in 240 ml tetrahydrofuran was stirred at −78° C. with 38.8 ml (77.6 mmol) lithium diisopropylamide (2M in heptane) for 30 minutes. 17.4 ml (77.6 mmol) phenylacetaldehyde were added and stirring was continued overnight. The mixture was allowed to warm to room temperature, water was added and most of the organic solvent was removed by distillation. About 20 g citric acid were dissolved in the aqueous residue. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1/5 yielded as first eluting fraction 5.4 g (19%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester, MS m/e (%): 404.3 (M+H+, 100) and as second eluting fraction 4.1 g (15%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester, MS m/e (%): 404.3 (M+H+, 100).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][CH2:34][NH2:35]>>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:35][CH2:34][CH2:33][C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: NCCc1cccs1
Product: c1cc(NC2CCNCC2)cc(-c2ccnc(NCCc3cccs3)n2)c1

Procedure:
Intermediate 7 was coupled with 2-thiophen-2-yl-ethylamine by procedure F and the resulting product deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 380. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.28 (d, 1H) 6.8-7.5 (m, 8H) 4.85 (m, 1H) 3.9 (m, 2H) 3.7 (m, 2H) 3.1-3.5 (m, 4H) 2.2-2.3 (m, 2H) 2.28 (m, 2H) 1.6-1.8 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Oc1cccc(F)c1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3cccc(F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-fluoro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-fluoro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[N:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N+:12]=[N-:13]>CO>[N:11]([C:14](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[Cl:2])[C:15]([O:17][CH3:18])=[O:16])=[N+:12]=[N-:13]
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=Cc1ccccc1Cl)N=[N+]=[N-]
Temperature: -18 °C
Reaction time: 3 h

Procedure:
Sodium pieces(3.678 g, 160 mmol) were added in portions to methanol (200 ml) over a 30 minute period. The resulting solution was cooled in a dry ice/acetone bath to −18° C. and then over one hour a mixture of 2-chlorobenzaldehyde (4.832 g, 40 mmol) and methyl azidoacetate (160 mmol) was added at a rate that maintained the temperature below −15° C. After three hours, the solution was stored at 5° C. for two days to give crystalline material which was collected by filtration and washed with cold hexane to give pure product as a yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)C=CC=CC=1.[Li+].[OH-].Cl>C1COCC1.O>[S:8]1[CH:9]=[CH:10][N:11]=[C:1]1[C:7]1[S:8][C:9]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccccc3)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2nc(-c3nccs3)sc2c1
Yield: 186.4 %

Procedure:
Ethyl 2-phenyl-benzothiazole-6-carboxylate 9q (130 mg, 0.45 mmol) was stirred with LiOH (43 mg, 1.8 mmol) in THF (4 mL) and H2O (2 mL) for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 9r (110 mg).