Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH:15]([NH2:19])([CH2:17][CH3:18])[CH3:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:15]([NH:19][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)N
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Yield: 96 %

Procedure:
5-Chlorosulfonyl-2-fluoro-benzoic acid (A, 0.506 g, 0.0021 mol), sec-butylamine (E, 0.155 g, 0.00212 mol) and DIEA (1.1 mL, 0.00636 mol) in CH2Cl2 were stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (MeOH containing 10% AcOH)/CH2Cl2) to give 5-sec-Butylsulfamoyl-2-fluoro-benzoic acid (F, 0.56 g, 96%). After drying overnight under vacuum, F (0.56 g, 0.0020 mol) in SOCl2 (5 mL) was heated at 80° C. for 3 hours, after which the SOCl2 was evaporated and the residue was dried overnight. The residue was then dissolved in tetrahydrofuran (5 mL), 3,4-difluoro-phenylamine (D, 0.26 g, 0.0020 mol) was added followed by DIEA (0.8 mL). The mixture was heated to 70° C. overnight. The solvent was evaporated, followed by ethyl acetate extraction. After purification by silica gel chromatography (ethyl acetate/hexane), 0.45 g (57%) of 5-sec-butylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide (DVR-23) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]>[Pd].C(O)C>[CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCCOc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCN1CCCOc2cc(N)ccc21
Reaction time: 2 h

Procedure:
9-Ethyl-3-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (0.865 g, 3.89 mmol) and 10% Palladium on Carbon (50% Wet) (0.400 g) in Ethanol (25 mL) were shaken under an atmosphere of Hydrogen (40 psi). After 2 h, the mixture was filtered through Celite, washing with ethanol. Conc. in vacuo afforded 9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine in quantitative yield. 1H-NMR (CDCl3): 6.75 (d, 1H, J=8.0 Hz), 6.32 (m, 2H), 4.04 (t, 2H, J=5.4 Hz), 3.43 (s, 2H), 3.09 (m, 4H), 1.96 (m, 2H), 1.14 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7](Cl)[CH:6]=1)=[O:4].Cl.[CH2:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20][CH2:19][NH:18]1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20][CH2:19][N:18]1[C:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: c1ccc2c(c1)CCCNC2
Reactant: COC(=O)c1cc(Cl)nc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 110 °C
Reaction time: 120 h
Yield: 43.9 %

Procedure:
The mixture of 2-chloroquinoline-4-carboxylic acid methyl ester (3 g, 13.5 mmol), 2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride (3 g, 16.3 mmol), potassium carbonate (4.5 g, 32.6 mmol), tetrabutylammonium iodide (300 mg) and toluene (60 mL) was heated with stirring at 110° C. for 5 days. The solvent was removed under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:4) to give 1.97 g of product as a yellow solid. MS obsd. (ESI+) [(M+H)+] 333.
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[Cl:21])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[CH3:22][OH:23]>C1(C)C=CC=CC=1>[CH3:22][O:23][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[Cl:21])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(C(Br)c2cnoc2C2CC2)c(Cl)c1
Solvent: Cc1ccccc1
Product: COC(c1ccc(S(C)(=O)=O)cc1Cl)c1cnoc1C1CC1

Procedure:
A mixture of 4-[bromo-(2-chloro-4-methanesulphonylphenyl)-methyl]-5-cyclopropylisoxazole (2.5 g) and methanol (2.0 ml) in toluene was stirred at reflux for 16 hours. The resultant solution was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with water, dried (MgSO4), and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluted with ethyl acetate and petroleum ether to give 4-[methoxy-(2-chloro-4-methanesulphonyl-phenyl)methyl]-5-cyclopropylisoxazole (compound 307, 1.40 g) as a colourless oil, NMR: (CDCl3) 1.0(4H, m), 2.1 (1H, m), 3.0(3H,s), 3.3(3H, s), 5.6(1H,s), 7.9(4H,m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O-])(O)=O.[Na+]>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[NH:9][CH:11]=[N:8][C:6]=2[CH:7]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(Br)cc(N)c1N
Agent: [Na+]
Solvent: O=CO
Product: Cc1cc(Br)cc2nc[nH]c12
Yield: 82 %

Procedure:
A mixture of 72 (1.27 g, 6.32 mmol) in formic acid (10 mL) was heated at reflux overnight. The reaction mixture was concentrated in vacuo to afford brown oil, which was treated with a satd. aq. NaHCO3. The aqueous solution was extracted with EtOAc (3×300 mL). The extracts were dried MgSO4), filtered and concentrated to afford 1.09 g (82%) of 5-bromo-7-methyl-1H-benzo[d]imidazole (74) as yellow solid; MS (ESI) m/z 211.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:18][OH:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([F:17])[CH:8]=1.C(N(CC)CC)C.O.O.P([O-])(O)(O)=[O:30].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>ClCCl.CS(C)=O.C(OC(=O)C)C.O1CCCC1>[Cl:1][C:2]1[C:3]([C:18]([OH:30])=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([F:17])[CH:8]=1
Reactant: O=P([O-])(O)O
Reactant: OCc1noc(-c2ccc(C(F)(F)F)c(F)c2)c1Cl
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1noc(-c2ccc(C(F)(F)F)c(F)c2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a stirred solution of (4-chloro-5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazol-3-yl)methanol (580 mg, 1.96 mmol) and triethylamine (1.930 mL, 13.73 mmol) in dichloromethane (9.6 mL) and DMSO (1.60 mL), sulphur trioxide pyridine complex (1.25 g, 7.85 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature before removal of the volatiles in vacuo. The resultant crude residue was diluted with ethylacetate (20 mL), washed with 2N HCl (30 mL), water (30 mL) and brine (30 mL). The organic phase was dried with Na2SO4, filtered and evaporated to dryness in vacuo. This crude mixture was dissolved in tBuOH/H2O (4:1) (20 mL), and to this sodium dihydrogen phosphate dihydrate (1.07 g, 6.87 mmol) and a solution of 2-methyl-2-butene (860 mg, 12.26 mmol) in tetrahydrofuran (5 mL), was added. Finally sodium chlorite (222 mg, 2.45 mmol) was added and the reaction mixture stirred overnight. The reaction mixture was evaporated to dryness, partitioned between ethyl acetate (20 mL) and water (15 mL) and the aqueous phase acidified to pH 4 with acetic acid. The organic layer was removed and then the aqueous layer extracted with ethyl acetate (3×20 mL). The organics were combined, dried with Na2SO4, filtered and evaporated to dryness in vacuo. The resulting residue was purified by silica gel chromatography, eluting with dichloromethane to 20% methanol/(acetic acid) in dichloromethane, to afford 4-chloro-5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (0.4 g, 1.29 mmol).
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH2:13][CH2:12][C:11](=[N:14]O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[C:1]1([S:7][CH:8]2[CH2:13][CH2:12][CH2:11][NH:14][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C1CCC(Sc2ccccc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: c1ccc(SC2CCCNCC2)cc1

Procedure:
Following an analogous procedure to that of Sasatani, S. et al. described in Tetrahedron Letters, Vol. 24 (No. 43), pp 4711-4712 (1982), 4-phenylthiocyclohexanone oxime is reacted with diisobutyl aluminum hydride in methylene chloride to give the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][NH2:13])=O)=[CH:5][CH:4]=1.[N:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[C:17]=[S:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[S:30]1[CH:31]=[CH:32][N:33]=[C:29]1[NH:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:16][C:17]2[S:18][C:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=3)=[N:12][N:13]=2)=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(N=C=S)cc1
Reactant: NNC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2nnc(Cc3ccc(C(F)(F)F)cc3)s2)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 15.1 %

Procedure:
A mixture of (4-trifluoromethyl-phenyl)-acetic acid hydrazide (55 mg, 0.25 mmol, 1.5 equiv), 4-isothiocyanato-N-thiazol-2-yl-benzenesulfonamide (50 mg, 0.2 mmol, 1.0 equiv) and sodium carbonate (20 mg, 0.18 mmol, 1.1 equiv) in 1.0 mL of ethanol was heated at 85° C. After 16 h, the heterogeneous reaction mixture was concentrated in vacuo, diluted with 500 μL of acetonitrile, filtered, and purified via reverse phase HPLC. The fraction containing product was lyophilized to afford the product as an off-white solid (15 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Reaction time: 15 h

Procedure:
A 50 g. portion of p-methoxybiphenyl and 30 g. of succinic anhydride are mixed in 600 ml. of nitrobenzene and cooled to about 5° C. A 73 g. portion of aluminum chloride is added in portions keeping the temperature at about 5° C. The mixture is then stirred for 15 hours and allowed to stand at room temperature. The mixture is poured into ice and then steam distilled until no more nitrobenzene comes over. The residue solidifies and is dissolved in 1,250 ml. of water containing 63 g. sodium carbonate. The solution is boiled with charcoal, filtered and the filtrate is chilled. The precipitate is filtered at room temperature and the gummy mixture is acidified with HCl and cooled. The precipitate is triturated with 50% acetic acid and the insoluble portion is recovered by filtration giving 4'-methoxy-γ-oxo-4-biphenyl-butyric acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[N:4]=[CH:3]1.[C:12]1([NH:22]C(=O)C)C2CCCCC=2C=CC=1.Cl.NC1C2CCCCC=2C(C#N)=CC=1>>[NH2:11][C:10]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]([C:12]#[N:22])=[CH:8][CH:9]=1
Reactant: Cn1cnc2c(N)cccc21
Reactant: CC(=O)Nc1cccc2c1CCCC2
Agent: Cl
Agent: N#Cc1ccc(N)c2c1CCCC2
Product: Cn1cnc2c(N)ccc(C#N)c21

Procedure:
The title compound was prepared from compound 9A by procedures analogous to those described in Experiment 2 (2A to 2D).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)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.COCCOC>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: Cc1ccccc1B(O)O
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
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: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1cccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Temperature: 100 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.089 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (89 μL, 0.178 mmol), (Ph3P)4Pd (3 mg, 0.003 mmol) (Aldrich), and 2-methylphenylboronic acid (15 mg, 0.110 mmol) (Aldrich) in 3 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes elution) to provide a crude yellow oil containing product. Recrystallization from chloroform-pentane yielded pure (Z)-1,3-dihydro-4-(2-methylphenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield 20 mg, 75%) as yellow needle-like crystals (mp 195-197° C.).
Reaction SMILES: B.CSC.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[O:10][CH:11]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH2:12][CH:13]=[CH2:14].O.B1([O-])O[O:30]1.O.O.O.O.[Na+]>C1COCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[O:10][CH:11]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH2:14][OH:30]
Reactant: C=CCC(Oc1ccc(OC)c(OC)c1)c1ccc(C#N)cc1
Reactant: [O-]B1OO1
Agent: B
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC(CCCO)c2ccc(C#N)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
Borane-methyl sulfide complex (2 M in ether, 11 mL, 22 mmol) was added dropwise to a cooled (−5° C.) solution of 4-[1-(3,4-dimethoxyphenoxy)-3-butenyl]benzonitrile (from step (i) above; 17.6 g, 56.8 mmol) in dry THF (15 mL) over a period of 15 minutes (during which time the reaction temperature rose to 0° C.). The resulting mixture was stirred at between 0 and 10° C. for 1.5 h, before being allowed to warm to rt. Stirring was continued for a further 3.5 h at this temperature before water (22 mL) and sodium perborate tetrahydrate (11 g, 66 mmol) were added. The biphasic mixture was stirred for 2 h at rt before the water layer was separated and extracted with ether. The combined organic layers were washed with brine, dried and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel, eluting with IPA:ethyl acetate:heptane (5:25:70) to yield 14.5 g (77%) of the sub-title compound.
Reaction SMILES: [CH2:1]([PH:7](=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]=[O:15]>>[CH2:1]([P:7]([CH2:14][OH:15])(=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[PH](=O)OCCCC
Reactant: C=O
Product: CCCCCCP(=O)(CO)OCCCC

Procedure:
The title compound was prepared from n-hexylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography, eluting with dichloromethane containing 5% methanol, gave an oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:12]2[C:16](=N)[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH2:23]>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:12]2[C:16](=[O:23])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: O
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=N
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 20 °C

Procedure:
A suspension of 10 g of 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-imino-imidazoline-2-one, 35 ml of 22° Be aqueous hydrochloric acid and 35 ml of water was refluxed for an hour, cooled to 20° C and poured into water. The mixture was vacuum filtered and the recovered precipitate was washed and dried to obtain 9.5 g of 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione melting at 149° C. A microanalytical sample after crystallization from ethanol melted at 149° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-nitro-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A28) (6.46 g, 17.7 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a white solid (0.93 g, 16%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([OH:11])[C@@H:9]([CH2:12][OH:13])[O:8][C@H:7]1[N:14]1[CH:21]=[CH:20][C:18](=O)[NH:17][C:15]1=[O:16].C[N:23]1CCCC1.Cl[Si](C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+](C1C=CC(O)=CC=1)([O-])=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([OH:11])[C@@H:9]([CH2:12][OH:13])[O:8][C@H:7]1[N:14]1[CH:21]=[CH:20][C:18]([NH2:23])=[N:17][C:15]1=[O:16]
Reactant: CN1CCCC1
Reactant: COCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
2′-O-(2-Methoxyethyl)uridine (6.05 g, 20.0 mmol), 1-methylpyrrolidine (20 ml, 0.192 mol), chlorotrimethylsilane (7.6 ml, 59.9 mmol) and dry acetonitrile (100 ml) were stirred together at room temperature. After 1 hour, the reactants were cooled to 0° C. (ice-water bath) and trifluoroacetic anhydride (7.1 ml, 50.3 mmol) was added dropwise over 5 minutes. After a further period of 30 minutes at 0° C., 4-nitrophenol (8.35 g, 60 mmol) was added to the stirred reactants which were maintained at 0° C. After 3 hours, the products were poured into saturated aqueous sodium hydrogencarbonate (200 ml), and the resulting mixture was extracted with dichloromethane (3×100 ml). The combined organic layers were dried (MgSO4), and evaporated under reduced pressure. Concentrated aqueous ammonia (d 0.88, 20 ml) was added to a stirred solution of the residue in dioxane (100 ml), contained in a sealed flask that was then heated at 55° C. for 24 hours. The resulting yellow solution was concentrated under reduced pressure, and the residue was evaporated with absolute ethanol (3×50 ml). The products were fractionated by short column chromatography on silica gel: the appropriate fractions, which were eluted with dichloromethane-methanol-triethylamine (93:7:0.5 to 90:10:0.5 v/v) were evaporated under the reduced pressure to give the title compound as an off-white solid (5.07 g 84%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)[C:3]=1[CH3:21].[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[NH:25][CH2:24]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:3]=2[CH3:21])[CH2:24]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1cc(C)cc(-c2nc3cc(F)ccc3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2nc3cc(F)ccc3c(N3CC(C)(C)c4ncc(N5CCOCC5)cc43)c2C)c1
Temperature: 100 °C

Procedure:
To a stirred solution of 4-chloro-2-(3,5-dimethylphenyl)-7-fluoro-3-methylquinoline (39 mg, 0.13 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (30 mg, 0.13 mmol) in toluene (1.5 mL) was added Pd2dba3 (12 mg, 0.013 mmol), XPhos (12 mg, 0.026 mmol) and sodium tert-butoxide (25 mg, 0.26 mmol) and the reaction was heated in the microwave for 1 h at 100° C. After this time the reaction was cooled to rt and treated with EtOAc (100 mL) and water (40 mL). The separated organic layer was washed with NaCl (saturated aqueous solution, 40 mL), dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(3,5-dimethylphenyl)-7-fluoro-3-methylquinoline as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.84 (1H, dd, J=10.0, 2.5 Hz), 7.77 (1H, dd, J=9.3, 6.0 Hz), 7.60 (1H, d, J=2.3 Hz), 7.23-7.29 (1H, m), 7.17-7.21 (2H, m), 7.11 (1H, d, J=1.8 Hz), 5.79 (1H, d, J=2.3 Hz), 3.82 (2H, s), 3.73-3.78 (4H, m), 2.93-3.04 (4H, m), 2.39-2.44 (6H, m), 2.27 (3H, s), 1.58 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=497 (M+1).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[OH:9][C:10]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].[Cl-].[NH4+]>>[O:9]1[C:10]2[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]([OH:13])[CH2:2]1
Reactant: O=Cc1cccc(O)c1O
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Product: Oc1cccc2c1OCC2O
Yield: 38.1 %

Procedure:
To a solution of trimethylsulfoxonium iodide (16.7 g) in dimethylsufoxide (75 ml), sodium hydride (3.19 g) was added, and the resultant mixture was stirred for 1 hour. A solution of 2,3-dihydroxybenzaldehyde (10 g) in dimethylsufoxide (75 ml) was added thereto and the resultant mixture was stirred for 2 days. To the resultant reaction solution, saturated ammonium chloride aqueous solution was added, and extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline, dried over anhydrous sodium sulfate, and filtered. From the reaction mixture, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 80:20), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (4.2 g) as yellow solid.
Reaction SMILES: C1(C)C=CC(S(O[C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:23][NH2:24]>C(O)C>[CH3:23][NH:24][C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:12]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C/C=C/c2cccnc2)cc1
Solvent: CCO
Product: CN[C@@H](C)C/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A mixture of (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (9.00 g, 28.35 mmol), methylamine (200 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 1.20 g (24.0%) of a colorless oil, bp 90–100° C. at 0.5 mm Hg.