Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]=[CH2:24]>C(#N)C>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Yield: 88.5 %

Procedure:
Methyl 3-hydroxy-4-nitro-benzoate 1b (7 g, 35.50 mmol) was dissolved in 100 mL of anhydrous acetonitrile followed by the addition of potassium carbonate (14.70 g, 106.50 mmol) and 3-bromopropene (6.2 mL, 71 mmol) successively, the reaction mixture was heated to reflux for 3 hours with stirring. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was added with 150 mL of ethyl acetate, washed with water (100 mL×3) and saturated sodium chloride solution (100 mL×3) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 3-allyloxy-4-nitro-benzoate 1c (7.45 g, yield: 89.0%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6].[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27]>>[OH:27][C@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[CH2:25][NH:24][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:3]([CH2:2][OH:1])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:23])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-4-(4-oxo-1-piperidinyl)benzamide (which was obtained in Example 173) (0.13 g, 0.4 mmol) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (0.12 g, 0.48 mmol) (which was obtained in Example 10) according to the procedure shown for Example 180 to give 0.16 g of an off-white solid; m.p. 120–122 °C.; MS (ES) m/z: 549.3 (MH+); HRMS (ES) Calcd. for C27H41N4O6S (MH+); 549.2741. Found: 549.2735.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:10]=2[N:11]=[C:12]([NH:15][NH2:16])[CH2:13][N:14]=1.[CH:22]1([C:28](Cl)=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:10]=2[N:11]2[C:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:16][N:15]=[C:12]2[CH2:13][N:14]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc2c(s1)-n1c(nnc1C1CCCCC1)CN=C2c1ccccc1Cl
Reaction time: 3 h
Yield: 58.2 %

Procedure:
5-(2-Chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno[2,3-e] [1,4]diazepine (20 g) was suspended in chloroform (200 ml) at room temperature. Cyclohexanecarboxylic acid chloride (10.1 g) was added, and the mixture was stirred for 3 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated to give an oil. The oil was dissolved in a mixed solvent of toluene (200 ml) and acetic acid (5.4 ml), and the mixture was refluxed for 3 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate), and isopropyl ether was added to give 15 g of 4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine.
Reaction SMILES: O[CH2:2][CH:3]1[C:9]2=[N:10][C:11]([CH3:19])=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:13]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Br:40][CH2:2][CH:3]1[C:9]2=[N:10][C:11]([CH3:19])=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:13]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)c1cc2c(nc1C)C(CO)CCCC2
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc2c(nc1C)C(CBr)CCCC2
Yield: 107 %

Procedure:
In an atmosphere of argon, ethyl 9-hydroxymethyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (263.0 mg, 1.00 mmol) was dissolved in methylene chloride (5.0 ml), the solution was mixed with triphenylphosphine (393.0 mg, 1.50 mmol) at 0° C. and then with carbon tetrabromide (663.3 mg, 2.00 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction solution was mixed with saturated sodium bicarbonate aqueous solution and water and extracted with ethyl acetate, and the resulting organic layer was washed with water and saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:5) to obtain the title compound (349.1 mg, quantitative) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.O1CCCC1.CC(C)([O-])C.[K+].Cl[CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[N:3]=1
Reactant: CS(=O)(=O)CCCl
Reactant: Brc1cc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCn1ccc(Br)n1
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
To a solution of 3-bromo-1H-pyrazole obtained in Step C of Example 6 (600 mg) in N,N-dimethylformamide (40 mL) was added potassium tert-butoxide tetrahydrofuran solution (1 M, 6.12 mL) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added 1-chloro-2-(methylsulfonyl)ethane obtained in Step A (873 mg) at room temperature, and the mixture was stirred for 2 hr. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (730 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+]([O-])=O)[CH:3]=1.[N+](C1C=CC(N)=CC=1O)([O-])=[O:15]>[Cu]Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[OH:15])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Nc1ccc([N+](=O)[O-])c(O)c1
Agent: Cl[Cu]
Product: O=[N+]([O-])c1ccc(Cl)cc1O

Procedure:
It is known that the fluorine compound mentioned may be prepared over long reaction times (32 hours) in ethers such as dioxane, using phase transfer catalysis at low temperatures (30° C.) (JP 63310851 A2). Working in water produces an isomeric ratio of about 7:1. Nothing is known from this source about the separation of the isomers. Furthermore, it is known that the chlorine compound may also be prepared in solvent/water mixtures in yields of about 90% (DE 29 39 056). In an earlier known process (DE 29 35 629) aqueous alkali metal hydroxide solutions are used in polar aprotic solvents and emulsifiers (20 hours, 60° C., 81%) for this reaction. Finally it is known that in general 2-nitrohalophenols may be prepared by the reaction of the corresponding nitrohalobenzenes at high temperatures (155° C., 2 hours) in anhydrous media. 4,5-dichloro-2-nitrophenol may be obtained in 77% yield in this way (DE 26 14 264). 2-nitro-5-chlorophenol may be obtained by reacting 4-chloronitrobenzene with KOH at 50° C. in the presence of glass bodies (FR 1 581 400). The same oxidation may be performed in 85-87% yield in solvents, for example 1,2-dimethoxyethane, using phase transfer catalysis (18-crown-6) (Izv. Akad. Nauk. SSSR, Ser. Khim., (11) 2635-2636). Yields of about 90% may be obtained in tertiary alcohols when using aqueous potassium hydroxide solution (6 hours, 60° C.) (JP 52142031). Nitration of 3-chlorophenol has long been known (Uhlemann, Chem. Ber. (1878), 1161; De Kiewiet, Stephen, J. Chem. Soc. (1931), 84). This nitration may also be performed in acetic acid at 0° C. (Roberts, Rhys, J. Chem. Soc. (1937), 39, 41) or using sodium nitrate and dilute sulfuric acid (Hodgson, Moore, J. Chem. Soc. 127 (1925), 1600). A variant is the reaction of 3-chloroaniline with dilute nitric acid (Uhlemann, loc. cit.) or gases containing nitrogen oxides (NOx); however, isomers are produced besides the desired product (v. Auwers, Deines, Fortschr. Ch. Phys. 18, 59; Chem. Zentralblatt, 1924 (II) 2268). In addition, reactions of 4-chloro-1,2-dinitrobenzene with aqueous alkali metal hydroxide solution (Laubenheimer, Chem. Ber. 9 (1876), 768) and of 2-nitro-5-aminophenol with copper(I) chloride in the sense of a Sandmeyer reaction (Phillips, J. Chem. Soc. (1930), 1910, 1913) are known, 2-nitro-5-chlorophenol being obtained.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([F:25])[F:24])[CH:17]=2)=[CH:10][C:9]=1[CH3:26])([O-])=O>O.C(O)C.[Fe]>[F:25][CH:23]([F:24])[O:22][C:18]1[CH:17]=[C:16]([S:15][C:11]2[CH:10]=[C:9]([CH3:26])[C:8](=[CH:13][C:12]=2[CH3:14])[NH2:5])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Sc1cccc(OC(F)F)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Sc2cccc(OC(F)F)c2)c(C)cc1N
Temperature: 60 °C

Procedure:
7.7 ml of glacial acetic acid (0.135 moles) are added to a solution of 30 g of 2-nitro-5-(3-difluoromethoxyphenylthio)-p-xylene (0.092 moles) in H2O (40 ml) and ethanol (400 ml); 34.7 g of Fe in powder form (0.621 moles) are carefully added to the reaction mixture kept under stirring at 60° C. The temperature is brought to 90° C. and the mixture is kept under stirring for 1.5 hours. When the reaction is completed (GC and TLC analyses), the mixture is cooled to room temperature; the solid is filtered on a celite bed. The ethanol is concentrated at reduced pressure. The crude product obtained is washed with a saturated solution of sodium bicarbonate and extracted with ethyl acetate.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH:13]1[C:25]2[CH:24]([CH2:26][O:27][C:28](ON3C(=O)CCC3=O)=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1>CC(C)=O.C(OCC)(=O)C>[CH:13]1[C:25]2[CH:24]([CH2:26][O:27][C:28]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
To 2-amino-acetamide hydrochloride (Compound 31, 10.0 g, 90.5 mmol), a 10% aqueous solution of sodium carbonate (600 ml) and acetone (250 ml) were added; next, under ice cooling, a solution of N-(9-fluorenylmethoxycarbonyloxy)succinimide (30.5 mg, 90.5 mmol) in acetone (250 ml) was added drop by drop. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure; the residue obtained was dissolved in ethyl acetate, the organic phase was sequentially washed with a 2N aqueous solution of citric acid, aqueous sodium hydrogen carbonate and saturated brine, after which it was dried with magnesium sulfate. The solid was filtered and concentrated under reduced pressure, after which crystallization from methanol was conducted to yield the desired 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-acetamide (Compound 32; 27.7 g, quant).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH:7]([C:9]#[N:10])[CH3:8])(=[O:5])[OH:4])[CH3:2].[CH2:11](O)[CH2:12][CH2:13][CH2:14][OH:15]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH:7]([C:9]#[N:10])[CH3:8])(=[O:4])[O:5][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH3:2]
Reactant: CCP(=O)(O)CC(C)C#N
Reactant: OCCCCO
Solvent: Cc1ccccc1
Product: CCP(=O)(CC(C)C#N)OCCCCO
Reaction time: 4 h
Yield: 91.9 %

Procedure:
540 g (3.0 mol) of ethyl(2-cyano-2-methylethyl)phosphinic acid (produced as in Example 6) are at 80° C. dissolved in 400 ml of toluene and admixed with 315 g (3.5 mol) of 1,4-butanediol and esterified at about 100° C. during 4 h in a distillation apparatus equipped with a water trap. After the esterification has ended, the toluene is separated off in vacuo to leave 643 g (92% of theory) of 4-hydroxybutyl ethyl(2-cyano-2-methylethyl)phosphinate as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.[OH-].[Na+]>O.C(O)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(Cl)cc1C(=O)O

Procedure:
A mixture of 17.2 g (0.1 mole) of 5-chlorosalicylic acid, 28 g. of potassium carbonate, 25 ml. of methyl iodide, and 100 ml. of N,N-dimethylformamide was heated at 60° C. for 16 hours. The mixture was diluted with water and extracted with diethyl ether. The ether extracts were evaporated and the residue dissolved in benzene. The resulting solution was washed with 5 percent sodium hydroxide solution and dried over magnesium sulfate. Evaporation provided a residue which was mixed with 100 ml. of ethanol and 100 ml. of 10 percent sodium hydroxide solution and heated at reflux for two hours. The mixture was evaporated to provide a residue which was washed with 5 percent hydrochloric acid solution, and recrystallized from carbon tetrachloride to provide white solid 5-chloro-2-methoxybenzoic acid, m.p. 95°98° C.
Reaction SMILES: [CH:1]([N:3]([O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[C@@H:4]([CH3:33])[C@@H:5]([CH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[C:6](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:7])=[O:2].[S:41]1[CH:45]=[CH:44][N:43]=[C:42]1[NH:46][C:47](=[O:54])[C@@H:48]([NH2:53])[C:49]([CH3:52])([CH3:51])[CH3:50].C1C=CC2N(O)N=NC=2C=1.CCOC(C)=O>CN(C=O)C>[CH3:52][C:49]([CH3:51])([CH3:50])[C@H:48]([NH:53][C:6](=[O:7])[C@H:5]([CH2:20][CH:21]1[CH2:22][CH2:23][CH:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][CH2:26]1)[C@@H:4]([N:3]([CH:1]=[O:2])[O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[CH3:33])[C:47](=[O:54])[NH:46][C:42]1[S:41][CH:45]=[CH:44][N:43]=1
Reactant: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)N(C=O)OC1CCCCO1
Reactant: CC(C)(C)[C@H](N)C(=O)Nc1nccs1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)N[C@H](C(=O)Nc1nccs1)C(C)(C)C)N(C=O)OC1CCCCO1
Temperature: 41 °C
Yield: 45.5 %

Procedure:
A mixture of pentafluorophenyl (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(4-phenylcyclohexylmethyl)butanoate (0.25 g, 0.44 mmol), (2S)-2-amino-3,3-dimethylbutanoic acid 1,3-thiazol-2-ylamide (0.10 g, 0.49 mmol), HOBt (6.1 mg, 0.040 mmol) and TEA (0.07 g, 0.67 mmol) in DMF (3 mL) is heated at 41° C. for 18 h. The reaction mixture is poured into a mixture of hexanes (100 mL) and EtOAc (100 mL) and the resulting mixture is washed with water, 1 M aqueous sodium carbonate and water. The organic phase is dried (sodium sulfate) and concentrated in vacuo and the residue is purified by column chromatography on silica gel with EtOAc-hexanes (1:1) as eluent to give 0.12 g (46%) of (2R,3S)-3-(formyltetrahydropyranyloxyamino)-2-(4-phenylcyclohexylmethyl)butanoic acid [(1S)-2,2-dimethyl-1-(1,3-thiazol-2-ylcarbamoyl)-1-propyl]amide as a white solid.
Reaction SMILES: C(O[CH:5]([C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C.CN(C)P(N(C)C)(N(C)C)=O.CO.O1CCCC1.[I-].[Sm+2].[I-]>C(OCC)(=O)C>[F:20][C:13]1[CH:12]=[C:11]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=1
Reactant: CCOC(=O)C(OC(C)=O)c1cc(F)cc2ccoc12
Agent: [I-]
Agent: [Sm+2]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(F)cc2ccoc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
A mixture of 1.43 gm (5.10 mMol) ethyl 2-acetoxy-2-(5-fluorobenzofur-7-yl)acetate, 7.31 gm (40.8 mMol) hexamethylphosphoramide, 0.20 gm (6.12 mMol) methanol, and 153 mL (15.3 mMol) samarium(II) iodide tetrahydrofuran complex (0.1 M in tetrahydrofuran) was stirred at room temperature under a nitrogen atmosphere for 15 minutes. The reaction mixture was then diluted 10 fold with ethyl acetate, washed with water, and concentrated under reduced pressure to provide 1.09 gm (96%) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example J34) (227 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow oil (290 mg, 60%).
Reaction SMILES: [OH:1][CH:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH:6]1[CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17]C)=[O:16].C([O-])(=O)C.CO.[OH-].[Na+]>O>[OH:1][CH:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH:6]1[CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([OH:17])=[O:16]
Reactant: CCCCCC(O)C=CC1CCC2(OCCO2)C1C(CCCCC)C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C=CC1CCC2(OCCO2)C1C(CCCCC)C(=O)O

Procedure:
A solution of 3.85 g. of 7-(3-hydroxy-1-octenyl)-1,4-dioxaspiro[4.4]non-6-ylheptanoic acid, methyl ester, acetate in 75 ml. of methanol was treated with 75 ml. of 1N sodium hydroxide and kept at 25° for 0.5 hours. The reaction mixture was diluted with water, washed with ether, acidified with acetic acid and extracted with ether. After washing and drying, the ether extract was evaporated and the residue chromatographed on silica. Elution with 50% ethyl acetate-hexane afforded 0.94 g. of the title product, λmaxfilm 3.0 (shoulder), 3.4, 5.75, 6.85, 8.75, 9.25, 10.4 μ. NMR: 6.35 (S, 2, OH), 5.52 (M, 2, 13 and 14-H), 4.05 (M, 1, 15-H), 3.92 (S, 4, ketal) ppm.
Reaction SMILES: ClC1C=CN=NC=1C1C=CC=CN=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[N:30]=[C:29]([Sn](CCCC)(CCCC)CCCC)[CH:28]=[CH:27][CH:26]=2)[N:20]=1)CCC.N1C=CC=CC=1C1N=NC(C2N=C(C3C=CC=C(C4N=NC(C5C=CC=CN=5)=CC=4)N=3)C=CC=2)=CC=1>>[CH:27]1[CH:28]=[CH:29][N:30]=[C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:19][N:20]=2)[CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc([Sn](CCCC)(CCCC)CCCC)n2)n1
Agent: Clc1ccnnc1-c1ccccn1
Agent: c1ccc(-c2ccc(-c3cccc(-c4cccc(-c5ccc(-c6ccccn6)nn5)n4)n3)nn2)nc1
Product: c1ccc(-c2ccccn2)nc1
Yield: 68 %

Procedure:
Stille coupling of two mol of 3-chloro-6-(pyridin-2-yl)pyridazine 8a with the precursor 2,2′-bis(tributylstannyl)-6,6′-bipyridine 60 gives the disubstituted product 61 with a yield of 68% (Scheme 28). In practice, a slight excess of chloropyridazine 8a is added in order for all the monosubstituted product formed to be consumed.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[C:19](=[O:33])[N:20]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:21][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>N1C=CC=CC=1.C(OCC)(=O)C>[C:42]([O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[CH2:21][N:20]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:33])=[CH:40][CH:39]=1)(=[O:44])[CH3:43]
Reactant: O=C1[C@H](Cc2ccc(O)cc2)N2C(=O)CCN(C(=O)NCc3ccccc3)C2CN1Cc1cccc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)CC3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (6S)—N-benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in pyridine (1 ml), acetic anhydride 1 ml (10.579 mmol) was added and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with 10% citric acid (10 ml) 3 times and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[N+:17]([O-:19])=O)([C:3](OCC)=[O:4])=[O:2]>CN(C)C=O.[Pt]>[OH:19][N:17]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([O:15][CH3:16])[CH:11]=2)[NH:8][C:1](=[O:2])[C:3]1=[O:4]
Reactant: CCOC(=O)C(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(=O)c(=O)n(O)c2c1
Temperature: 0 °C
Yield: 36 %

Procedure:
0.10 g (0.4 mmol) N-ethoxalyl-4-methoxy-2-nitroaniline in 10 ml dimethylformamide was hydrogenated at atm. pressure by using 5% Pt-C (0.01 g) as a catalyst. The reaction mixture was filtered and 10 ml 1N hydrochloric acid was added. The reaction mixture was cooled to 0° C. and the precipitate was filtered off, washed with water, ethanol and ether to give 0.03 g (39%) of 1-hydroxy-7-methoxyquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 12.0 (broad s), 7.0 (3H, m), 3.8 (3H, s). MS (m/e): 208 (M+, 70%), 163 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH:14]([CH3:16])[CH3:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:17]I>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:17])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(O)c(OC(C)C)c1
Reactant: CI
Product: COC(=O)c1cc(Cl)c(OC)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Methyl 3-chloro-5-isopropoxy-4-methoxybenzoate (4) (1.06 g, 95%) was prepared from methyl 3-chloro-4-hydroxy-5-isopropoxybenzoate (3) (1.00 g, 4.09 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that methyl iodide was used instead of cyclopentyl bromide and the mixture was stirred at RT for 18 h.