Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:26]1([F:35])[CH2:29][N:28]([C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH2:27]1.[CH3:36][N:37](C=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:32]1([C:30]([N:28]2[CH2:29][C:26]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH2:12][C:11]([C:17]5[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=5)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=4)=[CH:7][C:2]=3[C:36]#[N:37])([F:35])[CH2:27]2)=[O:31])[CH2:33][CH2:34]1
Reactant: O=C(C1CC1)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: N#Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C1(F)CN(C(=O)C2CC2)C1
Temperature: 150 °C
Yield: 56 %

Procedure:
To a solution of (3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)(cyclopropyl)methanone (Example 83, 35 mg, 0.06 mmol) in DMF was added ZnCN (15 mg, 0.12 mmol) and the reaction was degassed with N2 purge. Pd(PPh3)4 (4 mg, 0.003 mmol) was added and the reaction mixture was heated under microwave irradiation at 150° C. for 15 minutes. Next, the reaction mixture was diluted with water and extracted with EtOAc (75 mL). The organic phase was dried (Na2SO4) and concentrated under vacuum. Crude product was chromatographed (12 g Redi-Sep column) eluting from 100% heptane to 60:40 EtOAc:heptane to afford the final product (18 mg, 56%) as a solid. 1H NMR (CDCl3) δ ppm: 8.08 (1H), 8.00 (1H), 7.70 (1H), 7.66 (2H), 4.98-4.52 (4H), 4.12 (1H), 3.73 (1H), 1.49 (1H), 1.10-0.81 (4H); m/z (Cl) 560 ([M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[O:28][CH3:29])C.[OH-].[Na+]>C(O)C.O>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([O:28][CH3:29])[CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 85 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
In a solution of 1.07 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methoxy benzoic acid ethyl ester in 30 ml of ethanol, a solution of 1.0 g of sodium hydroxide in 30 ml of water was added, stirred at 85° C. for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was adjusted to pH 2 to 3 with concentrated hydrochloric acid, and extracted with ethyl acetate (30 ml×2). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.0 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:23])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38]Cl>C(Cl)Cl>[C:1]([C:4]1[C:5]([F:23])=[C:6]([N:11]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[CH3:2]
Reactant: COCCOCCl
Reactant: CC(=O)c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCN(c1ccc(F)c(C(C)=O)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-benzenesulfonamide (2.88 g, 8.293 mmol) was dissolved in dry DCM (75 mL) under nitrogen atmosphere. DIPEA (1.55 mL, 9.12 mmol, 1.1 eq) was then added, followed by 2-methoxyethoxymethyl chloride (0.98 mL, 9.12 mmol, 1.1 eq) and the mixture was stirred at room temperature for 1 h. It was then diluted with DCM and washed with water and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by chromatography on silica gel (n-hexane/ethyl acetate 7:3) to give 2.25 g (62%) of N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzene-sulfonamide as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]([CH2:7][CH:8]=[O:9])[CH2:4][CH2:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)C>C1C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1([C:2]2[CH:3]([CH2:7][CH:8]=[O:9])[CH2:4][CH2:5][CH:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CCC1CCC=C1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CCC1CCC=C1c1ccccc1
Temperature: 80 °C
Yield: 61.6 %

Procedure:
(2-Bromo-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE1) (1.85 g, 9.32 mmol) in benzene (70 mL) was treated with Na2CO3 (14.0 mL, 2M in H2O.) and phenylboronic acid (2.27 g, 18.6 mmol) in EtOH (40 mL). Tetrakis(triphenylphosphine) palladium(0), Pd(PPh3)4 catalyst (1.61 g, 1.40 mmol) was added and the mixture was heated to 80° C. for 3.5 h. until no starting material remained. The benzene was replaced with diethyl ether and the mixture was filtered through celite. The filtrate was washed with sat. K2CO3, brine and dried over MgSO4. Pure (2-phenyl-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE2) 1.07 g (62%) was isolated by chromatography on silica gel. Use of (2-phenyl-cyclopent-2-enyl)acetaldehyde (Intermediate ONE2) in Method A (without formation of the fumarate) produced 4-[(2-phenylcyclopent-2-en-1-yl)methyl]-1,3-dihydro-2H-imidazole-2-thione (Compound 112).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH2:20][CH2:21][CH3:22])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([CH3:29])([O:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:11]2[CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=1)[CH3:28])[CH3:24]
Reactant: CCCn1c(-c2ccc([N+](=O)[O-])cc2)cc2ccc(O)cc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(-c2ccc([N+](=O)[O-])cc2)cc2ccc(OC(C)(C)C(=O)OCC)cc21

Procedure:
The above compound was prepared from 2-(4-nitro-phenyl)-1-propyl-1H-indole-6-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][N:33]=1>>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:40])=[O:39])=[CH:34][N:33]=1
Reactant: O=S(=O)(Cl)c1cnc(Cl)nc1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cnc(Cl)nc2)c1

Procedure:
By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (342 mg), sodium hydride (60% in oil, 120 mg), 15-crown-5 (0.60 mL) and 2-chloro-5-pyrimidinesulfonyl chloride (554 mg), the title compound was obtained as a yellow solid (yield 390 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2oncc2CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of methyl 3-[5-(4-methylphenyl)-4-isoxazolyl]propionate (2.00 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride (0.95 M hexane solution, 21.5 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. Sodium sulfate 10 hydrate (6.57 g) was added to the reaction mixture and the mixture was stirred for 2 hr, after which an insoluble material was filtered off. The filtrate was concentrated and the residue was subjected to silica gel column chromatography, and 3-[5-(4-methylphenyl)-4-isoxazolyl]propan-1-ol (1.53 g, yield 86%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 1.25–1.35 (1H, m), 1.8–2.0 (2H, m), 2.41 (3H, s), 2.7–2.85 (2H, m), 3.65–3.8 (2H, m), 7.29 (2H, d, J=8 Hz), 7.62 (2H, d, J=8 Hz), 8.19 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:15])/[CH:12]=[CH:13]/[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1CCN2C(=NCCC2)CC1.[N+:27]([CH3:30])([O-:29])=[O:28]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:15])[CH2:12][CH:13]([CH3:14])[CH2:30][N+:27]([O-:29])=[O:28])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[N+](=O)[O-]
Reactant: C/C=C/C(=O)Nc1ccc(C#N)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(CC(=O)Nc1ccc(C#N)c(Cl)c1)C[N+](=O)[O-]
Yield: 76.3 %

Procedure:
The compound obtained in Step 1 (21.69 g, 98.31 mmol), DBU (16.30 mL, 108.14 mmol) and nitromethane (6.00 g, 98.31 mmol) were stirred at room temperature for 14 hr. To the reaction solution was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 30% ethyl acetate/hexane) to give N-(3-chloro-4-cyanophenyl)-3-methyl-4-nitrobutanamide (21.20 g, 75 mmol, 77%) as a pale-orange powder.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]([CH3:20])[C:18](=[O:21])[CH:17]=[C:16]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[N:15]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].O>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]([CH3:20])[C:18](=[O:21])[CH:17]=[C:16]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[N:15]=2)[CH2:10]1
Reactant: Cn1c(N2CC[C@@H](NCc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cn1c(N2CC[C@@H](N)C2)nc(-c2ccncc2)cc1=O
Temperature: 95 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
To a solution of 2-((R)-3-benzylaminopyrrolidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (1.6 g, 4.4 mmol) and ammonium formate (0.55 g, 8.9 mmol) in tatrahydrofuran (15 ml), methanol (30 ml) and water (5 ml) was added 10% palladium on charcoal (wet, 160 mg). After stirring for 4 hours at 95° C., palladium on charcoal was removed by filtration. The solvent was evaporated off under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to afford 2-((R)-3-aminopyrrolidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (1.0 g, 84%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]#[C:10][Si](C)(C)C)[CH:5]=[CH:4][C:3]=1[N:15]=[C:16]1[S:20][CH2:19][C:18]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[N:17]1[CH2:25][CH:26]([CH3:28])[CH3:27].[OH-].[Na+]>CO.C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]#[CH:10])[CH:5]=[CH:4][C:3]=1[N:15]=[C:16]1[S:20][CH2:19][C:18]2([CH2:21][CH2:22][CH2:23][CH2:24]2)[N:17]1[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: Cc1c(C#C[Si](C)(C)C)ccc(N=C2SCC3(CCCC3)N2CC(C)C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(N=C2SCC3(CCCC3)N2CC(C)C)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 2-(2,3-dimethyl-4-(2-trimethylsilyl-1-ethynyl)phenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane (0.005 g, 0.0125 mmol) and NaOH (0.006 g, 0.15 mmol) in MeOH (2 mL) was stirred overnight at room temp. The reaction mixture was diluted with CH2Cl2 (20 mL), filtered, and the filtrate was concentrated under reduced pressure. Thre residue was purified by preparative TLC (2% EtOAc/Hex) to give 2-(2,3-dimethyl-4-ethynylphenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane (0.003.2 g, 78%): TLC (20% EtOAc/hex) Rf0.70.
Reaction SMILES: CS(C)=O.[C:5]([C:11]([O:13][CH3:14])=[O:12])#[C:6][C:7]([O:9][CH3:10])=[O:8].[NH2:15][C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=[C:18]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:17]=1[C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:33][C:32]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:15]=[C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:17]=12
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#Cc1c(-c2cccs2)nn(-c2ccccc2)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1nc2c(c(-c3cccs3)nn2-c2ccccc2)c(N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 60 h
Yield: 85.7 %

Procedure:
A dimethylsulfoxide (20 ml) solution of 10.0 g (70 mmol) of dimethyl acetylenedicarboxylate was dropwise added to a mixture comprised of 2.66 g (10 mmol) of 5-amino-1-phenyl-3-(thiophen-2-yl)pyrazole-4-carbonitrile, 27.6 g (200 mmol) of anhydrous potassium carbonate and 300 ml of dimethylsulfoxide, while cooling with ice, over a period of 30 minutes, and then stirred for further 60 hours at room temperature. During the stirring, the reaction liquid was changed from brown to greenish brown. After the reaction, the liquid reaction mixture was poured into 500 ml of water with ice and stirred for 30 minutes at room temperature. The blackish brown solid thus precipitated was taken out by filtration, dried in air and added to 20 ml of methanol. The white crystals thus formed were taken out by filtration and recrystallized from methanol to obtain 3.50 g of the entitled product as colorless crystals having a melting point of 178° to 180° C.
Reaction SMILES: C([NH:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:8][OH:9])[CH2:6][OH:7])(=O)C.[OH-].[Na+].Cl>CO>[NH2:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH2:8][OH:9])[CH2:6][OH:7]
Reactant: CC(=O)NC(CO)(CO)CCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(CO)(CO)CCCc1ccccc1
Temperature: 0 °C
Yield: 50 %

Procedure:
2-Acetamido-2-(3-phenylpropyl)-1,3-propanediol (600 mg) was dissolved in 25 ml of methanol and 11.9 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was poured into 30 ml of ice water and neutralized with dilute hydrochloric acid. The solvent was distilled away. Chloroform was added to the residue for extraction and the chloroform layer was washed and dried. The solvent was distilled away and the residue was purified by column chromatography (chloroform:methanol=9:1-4:1) to give 250 mg of 2-amino-2-(3-phenylpropyl)-1,3-propanediol as a pale yellow, oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CCc1cc(Br)ccc1NC(C)=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1NC(C)=O
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To a degassed solution of N-(4-bromo-2-ethylphenyl)acetamide (20 g, 0.082 mol) in toluene (1200 ml) and ethanol (400 ml), 4-chlorobenzene boronic acid (15.5 g, 0.099 mol) is added under an atmosphere of nitrogen, and the reaction mixture is heated to 80° C. Tetrakis(triphenylphosphine)palladium(0) (2.0 g, 0.0017 mol) is added followed by 2M aqueous potassium carbonate solution (160 ml). The reaction mixture is heated at reflux for 4 hours then cooled to room temperature. The reaction mixture is filtered through diatomaceous earth, and the filtrate is evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (3×500 ml) and the organic solutions are combined and concentrated under reduced pressure to give N-(4′-chloro-3-ethylbiphen-4-yl)acetamide (20.5 g).
Reaction SMILES: Cl.[O:2]=[C:3]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]2)[CH2:4][N:5]1[CH2:10][CH2:9]O[CH2:7][CH2:6]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>Cl>[O:2]=[C:3]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]2)[CH2:4][N:5]1[CH2:10][CH2:9][N:26]([C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([Cl:22])[CH:24]=2)[CH2:7][CH2:6]1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C1CCc2cc(C(=O)CN3CCOCC3)ccc2N1
Agent: Cl
Product: O=C1CCc2cc(C(=O)CN3CCN(c4cccc(Cl)c4)CC3)ccc2N1

Procedure:
5.0 Grams of 6-(1-oxo-2-morpholinoethyl)-3,4-dihydrocarbostyril monohydrochloride and 5.0 g of m-chloroaniline were mixed in 30 ml of concentrated hydrochloric acid and the mixture was heated at 200°-220° C. by removing water for 6 hours. After cooled the reaction mixture 100 ml of 5N-hydrochloric acid was added thereto and dissolved by heating and refluxed for 2 hours. Then the reaction mixture was cooled and poured into 100 ml of 8N-sodium hydroxide aqueous solution and the organic layer was extracted with chloroform. Chloroform was removed by distillation and the residue thus obtained was separated and purified by a preparative silica-gel thin layer chromatography, then recrystallized from dioxane-water to obtain 0.16 g of 6-{1-oxo-2-[4-(3-chlorophenyl)-1-piperazinyl]-ethyl}-3,4-dihydrocarbostyril in light yellow needle-like crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc2c(c1)NCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.9 %

Procedure:
To a stirred solution of 6-fluoro-1H-indole (21.0 g, 0.155 mol) in dioxane (210 mL) was added BH3—NEt3 (92 mL, 0.620 mol) and a 12 M solution of HCl (27 mL, 0.326 mol) dropwise. The reaction mixture was stirred at room temperature for 10 min then at reflux for 2.5 h. The mixture was cooled to room temperature, and 6 M HCl (210 mL) was added. The mixture stirred at room temperature for 10 min and then at reflux for 1.5 h. The dioxane was removed under reduced pressure, and the residue diluted with water (500 mL) and washed with diethyl ether (1×250 mL). The aqueous fraction was basified with 10% NaOH and extracted with diethyl ether (3×250 mL). The combined organic layers were washed with water (2×100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure, giving 22.3 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 5-bromo-2-chloro-3-nitropyridine (Combi-Blocks, San Diego, USA, 41.3 mmol) in concentrated HCl (45 ml) was cooled with an ice-bath. Was added portionwise over 1.5 h SnCl2 dihydrate (124 mmol). The RM was stirred for 24 h at rt then poured on ice and basified with 6 M aqueous NaOH (125 ml). The resulting slurry was filtered and the solid was taken in aqueous NaHCO3, sonicated and filtered. The solid was dissolved in EtOAc and water and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and evaporated to give the title compound as an off-white solid. (HPLC: tR 2.52 min (Method A); M+H=207 (BrCl pattern) MS-ES)
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[C:13](B(O)O)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[CH:10]=2)[N:5]=1.[NH4+].[Cl-]>CCOCC.O>[Br:3][C:4]1[C:13]([OH:1])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[CH:10]=2)[N:5]=1
Reactant: OO
Reactant: COc1ccc2nc(Br)c(B(O)O)cc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2nc(Br)c(O)cc2c1
Reaction time: 13 h
Yield: 100 %

Procedure:
Aqueous H2O2 (30%, 32.8 mL, 321 mmol) was added dropwise to a stirred solution of (2-bromo-6-methoxyquinolin-3-yl)boronic acid (4.64 g, 16.45 mmol) and NH4Cl (3.29 g, 61.5 mmol) in Et2O (82 mL) and water (82 mL). After 13 h, NH4Cl (3.29 g, 61.5 mmol) and aqueous H2O2 (30%, 32.8 mL, 321 mmol) were added, and the mixture was stirred for 48 h. The precipitate was collected and washed with water, then dried at 50° C. to afford the title compound (4.18 g, 100%) as a solid that was used directly in the subsequent step. LCMS (ES+) m/z 254, 256 (M+H)+,
Reaction SMILES: [N+](C1C=CC([O:10][P:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=CC=1)([O-])=O.CC=C(C)C.[CH2:43](O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.N12CCCN=C1CCCCC2>ClCCl>[CH2:43]([O:10][P:11]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc3[nH]nc(-c4cc5ccccc5[nH]4)c3c2)c2ccccc2)cc1
Agent: CC=C(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=P(OCc1ccccc1)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1

Procedure:
Phenylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester benzyl ester is prepared according to procedure F using 150 mg of phenyl-phosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester 4-nitrophenyl ester (prepared according to procedure F) in solution in 2 ml of dichloromethane stabilized with amylene, 310 μl of benzyl alcohol and 44 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction crude is purified by preparative LC/MS to obtain 16.9 mg of phenylphosphonic acid 3-(1H-indol-2-yl)-1-indazol-5-yl ester benzyl ester.