Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29].CCN(CC)CC>C1(C)C=CC=CC=1>[N+:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][C:28]([N:4]2[C:5]3[C:10](=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]4[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=4)=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=3)[C:2]([CH3:26])([CH3:1])[C:3]2=[O:25])=[O:29])=[CH:36][CH:35]=1)([O-:39])=[O:38]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)C3(C)C)cc1

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)4-methoxy-benzamide (200 mg), 4-nitrophenyl chloroformate (166 mg; 0.83 mmol) and NEt3 (0.2 ml) in dry toluene (3 ml) is stirred in a microwave apparatus at 150° C. for 800 s. The resulting precipitate is collected by filtration and washed with cold toluene. After drying under reduced pressure the compound (240 mg) is obtained.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:48])[CH2:45][CH2:46][CH3:47]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:48])[CH2:45][CH2:46][CH3:47]
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: CCCC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise butyryl chloride (0.1 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.389 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.149 g colorless crystals. Mp 122° C. Mass spectrum, m+ =399. Anal (C24H35N5O6) theory C, 58.88; H, 7.21; N, 14.32; found C, 58.60; H, 7.15; N, 14.30.
Reaction SMILES: [NH2:1]C1C=CC(S(N(CC)CC)(=O)=O)=CC=1.C([O:18][C:19](=O)[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)C.C[Al](C)C>ClC(Cl)C>[C:27]1([CH:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:19]([NH2:1])=[O:18])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Reactant: CCOC(=O)C(c1ccccc1)c1ccncc1
Agent: C[Al](C)C
Solvent: CC(Cl)Cl
Product: NC(=O)C(c1ccccc1)c1ccncc1
Yield: 299.6 %

Procedure:
As described in Example 1, 4-Amino-N,N-diethyl-benzenesulfonamide (242 mg, 1.06 mmol, 2.0 equiv) was coupled with phenyl-pyridin-4-yl-acetic acid ethyl ester (128 mg, 0.53 mmol, 1.0 equiv) using trimethylaluminum (0.53 mL, 0.53 mmol, 2 equiv) in dichloroethane (20 mL). Standard work-up and purification of the residue by rotary chromatography (5% methanol/methylene chloride) provided N-(4-Diethylsulfamoyl-phenyl)-2-phenyl)-2-phenyl-2-pyridin-4-yl-acetamide (337 mg)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH:11]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)[CH2:20][CH2:21]2)[CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Reaction time: 1 h

Procedure:
1.8 g (16 mmol) of methanesulphonyl chloride are added slowly to a cooled solution of 4.4 g (14.6 mmol) of 4-amino-1-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, Example 16, in 30 ml of pyridine. The mixture is left for 1 hour at 0° C., left at room temperature for 4 hours and poured into ice-cold water, the resulting mixture is extracted with chloroform and 3.7 g of 4-methylsulphonamido-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are obtained, which product may be recrystallised in ethyl ether, with a melting point of 132° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>C(O)C.O>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc(OCc2ccccc2)cc1
Yield: 61.6 %

Procedure:
Prepared according to the method described in Example 24b) from 4-(benzyloxy)phenol (1.00 g), (±)-α-(chloromethyl)-3-pyridinepropanol (0.50 g) and sodium hydroxide (0.23 g) in ethanol (20 ml) and water (5 ml) with heating at reflux for 45 minutes. After work up the residue was purified by column chromatography over silica eluting with dichloromethane:ethanol (19:1) and then using a fresh column of silica eluting with ethyl acetate to give the title compound as a solid (0.58 g). Recrystallisation from ethyl acetate:hexane gave colourless crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:24].[CH:25]1([NH:28][CH2:29][C@@H:30]2[C@H:34]([F:35])[CH2:33][NH:32][CH2:31]2)[CH2:27][CH2:26]1>>[CH:25]1([NH:28][CH2:29][C@@H:30]2[C@H:34]([F:35])[CH2:33][N:32]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]4[C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[F:19])=[CH:4][C:3]=3[F:24])[CH2:31]2)[CH2:27][CH2:26]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 48 %

Procedure:
Using 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (355 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid as a pale yellow powder (229 mg).
Reaction SMILES: [C:1]([N:8]([CH3:16])[C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([CH2:13][OH:14])[CH:10]([CH3:11])[CH3:12])[CH3:16])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](CO)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
20.0 g Boc-MeVal-OH (86.5 mmol; Fluka) were dissolved in 80 ml THF and cooled to 0° C. 130 ml 1M BH3-THF (0.13 mol; Fluka) were added at 0° C. over 1 h and the clear, colo reaction mixture was warmed up and stirred at RT for 1 h. The reaction mixture was again cooled to 0° C., 75 ml deionized water were carefully added at 0-5° C. over 0.5 h and after warming up to RT stirring was continued for 1 h. To the colorless solution were added 150 ml 10% Na2CO3 all at once and after stirring for 1 h the reaction mixture was extracted with 600 ml and 300 ml ethyl acetate. The organic layers were washed with brine and dried (Na2SO4). Removal of the solvent by rotary evaporation gave 17.4 g (94%) product as colorless oil. 1H-NMR:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:10]=1[O:11][C:12]1[N:17]=[C:16]([S:18][CH3:19])[N:15]=[C:14](Cl)[C:13]=1[N+:21]([O-:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:10]=1[O:11][C:12]1[N:17]=[C:16]([S:18][CH3:19])[N:15]=[C:14]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:13]=1[N+:21]([O-:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1nc(NCc2ccccc2)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Temperature: 50 °C
Yield: 65 %

Procedure:
To 6-(2-benzyloxy-5-cyanophenoxy)-4-chloro-5-nitro-2-methylthiopyrimidine (2.5 g, 5.83 mmol) in 50 mL acetonitrile at 0° C. was added cesium carbonate (2.47 g, 7.58 mmol) followed by benzylamine (0.64 mL) and the reaction mixture was heated at 50° C. for 4 hours. The reaction was filtered, the filtrate evaporated and the residue chromatographed on silica gel (ethyl acetate:hexane) to afford 1.82 g (65%) of 6-(2-benzyloxy-5-cyanophenoxy)-4-(benzyl)amino-5-nitro-2-methylthiopyrimidine, a compound of formula (E).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>C(Cl)Cl.C(O)(=O)C>[CH2:1]([NH:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH:14]=[O:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCNC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-butyl-2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetamide (2 grams) in methylene chloride (10 ml) was added a mixture of oxalyl chloride (1.46 grams), dimethyl sulfoxide (1.36 ml) and methylene chloride (12 ml) at −65 to −60° C. under nitrogen atmosphere and stirred for 45 minutes. Triethylamine (5 ml) was added to the reaction mixture at −65 to −60° C., stirred for 60 minutes and then added to ice-water. The reaction mixture was acidified with acetic acid solution and stirred. Both organic and aqueous layers were separated and organic layer washed with water followed by sodium chloride solution. The solvent from organic layer was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(=O)(SC)OCCO[C:25](=O)[C:26]1C=CC=C[CH:27]=1>>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[C:2]1[CH:4]=[CH:27][CH:26]=[CH:25][CH:3]=1
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: CSC(=O)OCCOC(=O)c1ccccc1
Product: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)c1ccccc1

Procedure:
Following the procedures for synthesizing [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (17) and replacing compound (2) with compound (215) affords [(1-benzoyloxyethoxy)carbonyloxy]succinimide (216).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C([O-])(=O)/C=C/C([O-])=[O:13]>>[C:1]([OH:8])(=[O:7])[C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:13]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: O=C(O)/C=C/C(=O)O
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
An NH4 fumarate suspension with 400 g/l (calculated as fumaric acid) is introduced in a vessel and set at pH 8.0. The fumarate is first introduced partly in undissolved form. 35 g/l of cell mass (calculated as dry mass)--grown according to example A--is suspended in this liquid. After 36 hours incubation at 32° C., 378 g of L-malic acid per liter of fermentation liquid is produced.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:9]1[CH2:14][CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10]1.[NH2:24][C:25]1[CH2:46][O:45][CH2:44][C@:27]2([C:40]3[CH:39]=[C:38](Br)[CH:37]=[C:36]([F:42])[C:35]=3[O:34][C:33]3[C:28]2=[CH:29][C:30]([OH:43])=[CH:31][CH:32]=3)[N:26]=1.O>O1CCOCC1.[NH4+].[Cl-].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:24][C:25]1[CH2:46][O:45][CH2:44][C@:27]2([C:40]3[CH:39]=[C:38]([C:11]4[CH2:10][O:9][CH2:14][CH2:13][CH:12]=4)[CH:37]=[C:36]([F:42])[C:35]=3[O:34][C:33]3[C:28]2=[CH:29][C:30]([OH:43])=[CH:31][CH:32]=3)[N:26]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(O)ccc1Oc1c(F)cc(Br)cc12
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@@]2(COC1)c1cc(O)ccc1Oc1c(F)cc(C3=CCCOC3)cc12
Temperature: 120 °C

Procedure:
In a microwave vial, the potassium phosphate (0.771 g, 3.63 mmol), PdCl2(AmPhos)2 (0.064 g, 0.091 mmol) and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.356 g, 1.695 mmol) were loaded. The (S)-5-amino-2′-bromo-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol (0.459 g, 1.211 mmol) was added as a solution in dioxane (6 mL). Water (2.4 mL) was added and argon gas was blown through the vessel, which was sealed and heated by microwave at 120° C. for 30 min. The residue was taken up in half-saturated aqueous NH4Cl (30 mL) and the aqueous phase was extracted with 5% MeOH/DCM (3×25 mL). The organics were combined, washed with brine (7 mL), dried over sodium sulfate and concentrated to afford crude (S)-5-amino-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=[C:6](N)[N:7]=1.[Sb](Cl)(Cl)[Cl:13].C(ON=O)(C)(C)C>ClCCCl.C(Cl)(Cl)Cl>[Cl:13][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=1
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Reactant: Cl[Sb](Cl)Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Clc1nc(Cl)c2cc[nH]c2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.8 %

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (500 mg, 2.97 mmol) in 1,2-dichloroethane (40 mL) at −10° C. under argon was added antimony chloride (750 mg, 3.29 mmol). After stirring for 5 min, tert-butylnitrite (2.50 mL, 20.8 mmol) was added to the solution. The reaction was stirred at −10° C. for 3 h. The reaction was diluted with CHCl3 (100 mL) and poured into ice water (50 mL). The CHCl3 layer was separated, washed with brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=50:50) yielded 239 mg (43%) of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a tan solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][N:21]=1>>[CH3:27][N:26]([C:24]1[CH:23]=[CH:22][N:21]=[C:20]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=3)[CH2:2][CH2:3]2)[N:25]=1)[CH3:28]
Reactant: CN(C)c1ccnc(Cl)n1
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Product: CC(=O)NCc1ccc(CN2CCN(c3nccc(N(C)C)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide obtained in Example 78(2) instead of N-(4-chloromethylphenylmethyl)acetamide and 2-chloro-4-(N,N-dimethylamino)pyrimidine instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=152-155° C.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24]2.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:36][C:20]([F:35])([F:19])[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:43][C:40]1[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=1)[C:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24]2
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2[nH]1
Reactant: OCc1ccncc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A solution of 1.47 g (5.83 mmol) of 1,1′-(azodicarbonyl)dipiperidine in 50 ml of toluene is added dropwise to a solution of 1 g (3.89 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate, 0.63 g (5.83 mmol) of 4-pyridylcarbinol and 1.46 ml (5.83 mmol) of tributylphosphine in 50 ml of toluene. The reaction mixture is stirred overnight at room temperature and then concentrated under reduced pressure and chromatographed on a column of silica (eluent: dichloromethane/methanol). 1.05 g of expected product are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:15])[CH:8]=[C:9]2[C:13]=1[N:12]([CH3:14])[CH:11]=[CH:10]2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(O)=O.[Na+]>CCOCC>[Br:15][C:7]1[CH:8]=[C:9]2[C:13](=[C:5]([CH2:3][OH:2])[CH:6]=1)[N:12]([CH3:14])[CH:11]=[CH:10]2
Reactant: COC(=O)c1cc(Br)cc2ccn(C)c12
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cn1ccc2cc(Br)cc(CO)c21
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a solution of 5-Bromo-1-methyl-1H-indole-7-carboxylic acid methyl ester (260 mg, 0.97 mmol) in Et2O (50 mL) was added LAH (40.5 mg, 1.1 mmol) at 0 C under nitrogen atmosphere. The solution was warmed to room temperature. Sat. NaHCO3 was added and the solution was extracted with EtOAc. The combined organic layer was dried with MgSO4 and was filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 50% EtOAc in Hexane as the eluent to afford the desirable product (5-Bromo-1-methyl-1H-indol-7-yl)-methanol (200 mg, 86%) as colorless oil.
Reaction SMILES: I/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)#[CH:19]>>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[CH:2][C:19]#[C:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:6]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: Cc1ccc(-c2cc(C)ccc2/C=C/I)cc1
Product: Cc1ccc(-c2cc(C)ccc2C=CC#Cc2ccc(C(=O)O)cc2)cc1
Yield: 28.4 %

Procedure:
In a similar manner to that of Example 1(e), by reaction of 3.69 g (11.0 mmol) of 2-((E)-2-iodovinyl)-5,4'-dimethylbiphenyl obtained in Example 13(f) with 1.60 g (10.0 mmol) of methyl 4-ethynylbenzoate, 1.00 g (27%) of the expected compound is obtained in the form of a white powder with a melting point of 123-125° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1SC(C)(C)C(N1CCN(C(C2C=C(C=CC=2F)C[C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[NH:27][N:26]=2)=O)CC1)=O.OOS([O-])=O.[K+].C(OCC)(=O)C>CO.O>[C:28]1(=[O:35])[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[N:26][NH:27]1
Reactant: CC(C)(Sc1ccc(Cl)cc1Cl)C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]ncc2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 4-(3-(4-(2-((2,4-dichlorophenyl)thio)-2-methylpropanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (2.5 g, 15 mmol) in MeOH (25 mL) was added dropwise a solution of Oxone (9.98 g, 30 mmol) in water (25 mL) at 0° C. after addition reaction mixture stirred at 0° C. for 4 h. The progress of reaction was checked by TLC using mobile phase 50% ethyl acetate in pet ether. The reaction mixture was evaporated on a rotatory evaporator under reduced pressure to afford the semisolid off-white compound. The suspension was diluted with water and then extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and solvents were evaporated on a rotatory evaporator under reduced pressure to afford 4-(3-(4-(2-(2,4-dichlorophenyl)sulfinyl)-2-methylpropanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (39) as off-white crystals compound (1.4 g, 32%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH:5]=1.[P:23]([O-:32])([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26].C([SiH](CC)CC)C.CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([O:14][C:15]2[CH:20]=[CH:19][C:18]([P:23]([O:28][CH:29]([CH3:31])[CH3:30])([O:24][CH:25]([CH3:27])[CH3:26])=[O:32])=[CH:17][CH:16]=2)[CH:5]=1
Reactant: COC(=O)c1cc(Oc2ccc(Br)cc2)cc(OC(C)C)c1
Reactant: CC(C)OP([O-])OC(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(OC(C)C)c1
Temperature: 90 °C
Yield: 65 %

Procedure:
To a stirred solution of 3-(4-bromo-phenoxy)-5-isopropoxy-benzoic acid methyl ester (5.00 g) in toluene (120 mL) was added diisopropyl phosphite (2.80 mL), dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) dichloromethane adduct (1.00 g, 1.37 mmol), triethylsilane (0.44 mL, 2.74 mmol), and Et3N (5.72 mL, 41.1 mmol) at rt. DCM (12 mL) was added to the reaction flask which was purged with nitrogen. The mixture was heated at 90° C. overnight. Cooled to rt and concentrated. EtOAc and water were added and the mixture was filtered through a pad of Celite to remove the insoluble. The organic layer was separated, washed with brine (1×), dried with anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column (6×25 cm, hexane/EtOAc, v/v=5:1, 1:1). Fractions containing the product were pooled and concentrated to give 3-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid methyl ester (4.0 g, 65%) as yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.77 (dd, J=9, 13 Hz, 2H), 7.36 (dd, J=1, 2 Hz, 1H), 7.26 (m, 1H), 7.02 (dd, J=4, 9 Hz, 2H), 6.76 (dd, J=2, 2 Hz, 1H). 4.63-4.74 (m, 2H), 4.54-4.62 (m, 1H), 1.37 (d, J=6 Hz, 6H), 1.33 (d, J=6 Hz, 6H) 1.24 (d, J=6 Hz, 6H).