Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.CO>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:methanol (40:60 v/v, 12 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:methanol (40:60 v/v, 71 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.04. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was filtered, washed with methanol (2×25 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 5.1 g of ibandronate sodium crystal form R.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27]C(OCC)C)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:42]C2CCCCO2)[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:33][C@@H:23]([CH2:22][CH2:21][C@H:20]([C@@H:19]1[C@:35]2([CH3:41])[C@H:16]([C@H:15]3[C@H:38]([CH2:37][CH2:36]2)[C@:39]2([CH3:40])[C:12]([CH2:11][C@@H:10]([OH:42])[CH2:9][C@@H:8]2[OH:7])=[CH:13][CH2:14]3)[CH2:17][CH2:18]1)[CH3:34])[C:24]([OH:27])([CH3:25])[CH3:26]
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C[C@H](CC[C@H](F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
A mixture of 0.356 g. (0.00053 mole) of [1α,3β,24S]-1,3-bis-[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene, 15 ml. of methanol and 0.05 g. of p-toluenesulfonic acid monohydrate was stirred at 25° for 3 hr. The mixture was quenched with 0.25 g. of sodium bicarbonate and stirring for 0.5 hr. The mixture was evaporated to dryness. The residue was triturated with ethyl acetate, filtered, and evaporated to dryness to yield [1α,3β,24S]-24-fluorocholest-5-en-1,3,25-triol.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:54])[C:28]([CH3:53])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][CH2:46][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[CH:1]1([NH:7][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:54])[C:28]=3[CH3:53])[CH:37]=[CH:38][C:39]=2[O:45][CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: NC1CCCCC1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)NC3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 12.7 %

Procedure:
Cyclohexylamine (0.149 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.215 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.032 g, 0.0634 mmol, 13%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:12]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)cc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(F)cc(Br)cc1C=O
Temperature: 70 °C
Yield: 94 %

Procedure:
To a solution of 5-Bromo-3-fluoro-2-hydroxy-benzaldehyde (2.0 g, 9.13 mmol), in DMF (10 mL) was added Cs2CO3 (3.56 g, 10.95 mmol) and iodomethane (2.59 g, 18.26 mmol) and heated at 70° C. for 6 h. Reaction mixture was diluted with EtOAc (25 mL) and filtered, filtrate was washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silicagel column chromatography (EtOAc:Hex, 1:3) gave pure 5-Bromo-3-fluoro-2-methoxy-benzaldehyde (2.0 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1>CS(C)=O.CCOC(C)=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]([NH:26][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:25])=[CH:20][CH:19]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:25])=[CH:20][CH:19]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(Cl)cc2)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2ccc(Cl)cc2)n1

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (96 mg, 0.40 mmol) and 1-(4-chlorophenyl)ethanamine (204 mg, 1.31 mmol, 3.3 equiv) in DMSO (1 mL) was heated at 110° C. for 3 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)-3-(2-((R)-1-(4-chlorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((S)-1-(4-chlorophenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([CH2:15][N:16]([CH2:39][CH:40]2[CH2:42][CH2:41]2)[C:17]2[C:18]([S:36]([CH3:38])=[O:37])=[N:19][N:20]3[C:25]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])=[CH:24][CH:23]=[CH:22][C:21]=23)[CH2:14][CH2:13]1.O.C(OCC)(=O)C>ClCCl>[CH:12]1([CH2:15][N:16]([CH2:39][CH:40]2[CH2:42][CH2:41]2)[C:17]2[C:18]([S:36]([CH3:38])(=[O:9])=[O:37])=[N:19][N:20]3[C:25]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])=[CH:24][CH:23]=[CH:22][C:21]=23)[CH2:13][CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(S(C)=O)nn12
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(S(C)(=O)=O)nn12
Reaction time: 4 h
Yield: 5.4 %

Procedure:
m-Chloroperbenzoic acid (91 mg) was added to a solution of N,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfinyl)pyrazolo[1,5-a]pyridin-3-yl]amine (162 mg) in dichloromethane (10 mL) at 0° C., and the mixture was stirred for 4 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (10 g), and the title compound (9 mg) was obtained from the n-hexane:ethyl acetate (1:2) fraction as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOC(CBr)OCC
Reactant: COc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(COc1ccc(OC)cc1Br)OCC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step A (1.01 g, 5 mmol), 2-bromo-1,1-diethoxyethane (1.05 g, 5.25 mmol) and Cs2CO3 (2.04 g, 6 mmol) in DMF (10 mL) was stirred at 120° C. for 2 hrs. The reaction was cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (eluted with PE:EtOAc=6:1) to the title compound (2.7 g, 85%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.12 (d, J=3.0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.81 (dd, J=9.0, 3.0 Hz, 1H), 4.87 (t, J=5.2 Hz, 1H), 4.02 (d, J=5.2 Hz, 2H), 3.84-3.78 (m, 2H), 3.77 (s, 3H), 3.73-3.67 (m, 2H), 1.27 (t, J=7.1 Hz, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:34]1[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]1)=[O:20])=[N:5]2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(Cl)c(Cl)cc4nc3OC)CC2)c1
Yield: 68 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 68%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.74-3.78 (m, 4H), 3.79 (s, 6H), 4.15 (s, 3H), 6.07 (s, 1H), 6.11 (s, 2H), 7.33 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][O-:12].[Na+]>CN(C)C=O.CO.[Cu]Br>[CH3:11][O:12][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C[O-]
Agent: [Cu]Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cnc2[nH]ccc2c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a mixture of 5-bromo-7-azaindole (1 g, 0.005 mol) in N,N-Dimethylformamide (20 mL) and methanol (20 mL) were added sodium methoxide (13 g, 0.24 mol) and Copper (I) bromide (0.7 g, 0.0048 mol) at room temperature. The reaction mixture was stirred at 120° C. under nitrogen for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The organic layer was collected, washed with a solution of ammonium chloride and ammonium hydroxide (4:1), brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (81, 0.4 g, 50%). MS (ESI) [M+H+]+=149.09.
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:30]([N:34]([C:45]([O:47][CH2:48]Cl)=[O:46])[CH2:35][C:36]([O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])=[O:37])([CH3:33])([CH3:32])[CH3:31]>CO>[C:4]1(/[CH:3]=[CH:2]/[C:1]([O:11][CH2:48][O:47][C:45](=[O:46])[N:34]([C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:35][C:36](=[O:37])[O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])=[O:10])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CC(C)(C)N(CC(=O)OCC[Si](C)(C)C)C(=O)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)N(CC(=O)OCC[Si](C)(C)C)C(=O)OCOC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-cinnamic acid (23.1 mmol) and 1.0 M tetrabutylammonium hydroxide (22.2 mmol) in methanol are stirred for one hour, and the methanol is removed. THF is added. To this solution is added 2-(trimethylsilyl)ethyl 2-(tert-butyl((chloromethoxy)carbonyl)amino)-acetate (18.5 mmol) and the mixture is stirred at room temperature for 24 hr. The solvent is removed and the residue is diluted with ether. The resulting solution is washed with water and brine. The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 5.01 g (61%) MS (ESI) m/z 436.3.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C@@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:10]([S:17](Cl)(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCOCC1.[OH-].[Na+]>[CH2:10]([S:17]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[C@@H:3]([CH2:5][CH3:6])[CH3:4])(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC[C@@H](C)[C@@H](N)C(=O)O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a solution of D-isoleucine (3 g, 22.9 mmol) in dioxane (184 ml), 1N aqueous sodium hydroxide (23 ml) and then benzylsulfonyl chloride (6 g, 34.4 mmol) were added and stirred at room temperature. After 3 hours, the reaction mixture was adjusted to pH 2 with 2N aqueous hydrogen chloride and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated under reduced pressure and the residue was applied to flash column chromatography (Merck Silicagel 60; mobile phase: dichloromethane:methanol=10:1, 4:1) to give N-(benzyl-sulfonyl)-D-isoleucine (6.3 g, 22.2 mmol; yield 97%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=[NH:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:29]=2)[CH2:34][CH2:33]1
Reactant: N=C(NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: O=C(N1CCSCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 164 mg (1.640 mmol) of N-hydroxycyclopropanecarboximidamide were reacted Yield: 352 mg (47% of theory)
Reaction SMILES: [C:1]([NH:9][CH:10](P(OC)(OC)=O)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([O:30][C:31]1[CH:38]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:36]=[CH:35][C:32]=1[CH:33]=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:1]([NH:9]/[C:10](=[CH:33]/[C:32]1[CH:35]=[CH:36][C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:38][C:31]=1[O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:1]([NH:9]/[C:10](=[CH:33]\[C:32]1[CH:35]=[CH:36][C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:38][C:31]=1[O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NC(=O)c1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1)NC(=O)c1ccccc1
Product: COC(=O)/C(=C\c1ccc(OCc2ccccc2)cc1OCc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of methyl benzoylamino(dimethoxyphosphoryl)acetate (4.25 g) in dry tetrahydrofuran (30 mL) is treated with sodium hydride (0.66 g, 60% dispersion in mineral oil) under nitrogen. After stirring for 15 minutes a solution of 2,4-dibenzyloxybenzaldehyde (4.74 g) in dry tetrahydrofuran (15 mL) is added dropwise. The reaction mixture is stirred at room temperature for 18 hours, evaporated and the residue partitioned between ethyl acetate (100 mL) and water (75 mL). The organic phase is washed with brine (50 mL), dried over magnesium sulphate and evaporated. The residual yellow oil is purified by flash chromatography on silica eluting with initially with dichloro-methane then with a mixture of dichloromethane and ethyl acetate (9:1 v/v). Fractions homogeneous in the required products are evaporated to give methyl (E)-2-benzoylamino-3-(2,4-dibenzyloxyphenyl)acrylate (1 g) as a yellow foam, and methyl (Z)-2-benzoylamino-3-(2,4-dibenzyloxyphenyl)-acrylate (1.6 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH:18]=[O:19])[CH:3]=1.[CH2:20]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1)[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:20]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:2]2[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH:18]=[O:19])[CH:3]=2)=[CH:32][CH:33]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)CCCCOc1ccc(Br)cc1C=O
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc(OCCCCC(=O)OCC)c(C=O)c2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A suspension of ethyl 5-(4-bromo-2-formylphenoxy)pentanoate (9.0 g) and 4-(2-butoxyethoxy)phenylboric acid (7.8 g) and potassium carbonate (9.1 g) in toluene (100 ml), ethanol (10 ml) and water (10 ml) was stirred under an argon atmosphere for 30 minutes. After addition of tetrakis(triphenyl)phosphine palladium (1.6 g), the solution was heated at 100° C. for 12 hours under an argon atmosphere. The solution was allowed to cool. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain brown amorphous ethyl 5-[[4′-(2-butoxyethoxy)-3-formyl[1,1′-biphenyl]-4-yl]oxy]pentanoate (12.0 g).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[CH3:16][O:17][C:18](=[O:31])[C@@H:19]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH2:20].Cl.[O:33]1CCC[CH2:34]1>>[CH3:16][O:17][C:18](=[O:31])[C@@H:19]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH:20][C:34]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:33]
Reactant: CC(C)(C)O
Reactant: C1CCOC1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of tert-butanol, 10.1 g of BOC-anhydride and 12.27 g of diisopropylethylamine dissolved in 30 ml of tetrahydrofuran are added at 0° to a suspension of 12.12 g of D-tryptophan methyl ester hydrochloride in 80 ml of abs. tetrahydrofuran. After being stirred for two hours at room temperature, the reaction mixture is poured into ice/470 ml of 0.3N HCl and extracted three times with ethyl acetate. The combined organic phases are washed once with water and twice with sat. NaCl solution, dried (MgSO4) and concentrated by evaporation. The residue is made into a slurry in diethyl ether/petroleum ether and filtered with suction. The title compound is thus obtained in the form of colourless crystals having a melting point of 148-1490. Rf (methylene chloride)=0.24.
Reaction SMILES: N1C=CC=CC=1.O[CH2:8][C:9]1[C:21]2[C:20]3[CH:19]=[C:18]([CH3:22])[CH:17]=[CH:16][C:15]=3[N:14]([CH3:23])[C:13]=2[C:12](=[O:24])[N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:10]=1.CS([Cl:35])(=O)=O.ClCCl>O1CCCC1>[Cl:35][CH2:8][C:9]1[C:21]2[C:20]3[CH:19]=[C:18]([CH3:22])[CH:17]=[CH:16][C:15]=3[N:14]([CH3:23])[C:13]=2[C:12](=[O:24])[N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)c1c(CO)nn(-c3ccccc3)c(=O)c1n2C
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(CCl)nn(-c3ccccc3)c(=O)c1n2C
Temperature: 60 °C
Reaction time: 15 h
Yield: 49.8 %

Procedure:
50 ml of pyridine are added to a suspension of 9.5 g (29.7 mmol) of 1-(hydroxymethyl)-5,8-dimethyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one in 600 ml of tetrahydrofuran heated to 60° C. 4.5 ml (59.4 mmol) of methanesulphonyl chloride are added and the mixture is left standing for 15 h at room temperature. 500 ml of dichloromethane are added, the precipitate is removed by filtration, separation is carried out by settling and the organic phase is washed with water. It is dried over sodium sulphate and the solvent is evaporated under reduced pressure. 5 g (14.8 mmol) of product are obtained, which product is used as is in the following stage.
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17].Cl.C([O:47][C:48](=[O:52])[CH2:49][NH:50][CH3:51])C>>[F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31]([N:50]([CH3:51])[CH2:49][C:48]([OH:47])=[O:52])=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17]
Reactant: CCOC(=O)CNC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)N(C)CC(=O)O)c2)cc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 120D and sarcosine ethyl ester hydrochloride was processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.96 (s, 1 H), 6.85-7.34 (m, 11 H), 6.69 (m, 1 H), 6.49 (m, 2 H), 4.08 (s, 2 H), 4.05 (s, 2 H), 3.94 (m, 4 H), 2.98 (s, 3 H), 2.89 (s, 3 H), 2.80 (s, 1 H), 2.50 (m, 2 H), 2.33 (s, 3 H), 1.90 (m, 2 H); MS (ESI) m/z 682 (M+H+).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]([CH2:25][CH3:26])([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[CH2:9][CH2:10]OS(C)(=O)=O)(=O)=O.[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1(C)C=CC=CC=1>[NH3:22].[CH2:25]([C:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[CH2:7][CH2:6][N:33]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:10][CH2:9]1)[CH3:26]
Reactant: CCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCN1CCC(CC)(c2cccc([N+](=O)[O-])c2)CC1
Product: N
Yield: 100.2 %

Procedure:
To a solution of 3-ethyl-5-((methylsulfonyl)oxy)-3-(3-nitrophenyl)pentyl methanesulfonate (Preparation 62, 850 mg, 2.1 mmol) in toluene (6 ml) under an atmosphere of nitrogen was added hexylamine (1.66 ml, 12.6 mmol). The reaction mixture was heated under reflux for 16 h, then it was concentrated in vacuo to give the crude product. This was purified by silica (25 g) column chromatography eluting with ethyl acetate:hexane:0.880 ammonia (49:50:1) to give the title compound as a clear oil (335 mg, 50%).