Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Bi](Br)(Br)Br.O[CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10]>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: CCO
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(C)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To the solution of ethanol (77 mg, 1.67 mmol) in perchloromethane (80 mL) was added bismuth(III) bromide (743 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, the methyl 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) was added, the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl 4-(1-ethoxy ethyl)benzoate (191 mg, 55%) as oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3([CH3:26])[C:18]4[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:53][C:54]1[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C.O>[OH:60][C:57]1[CH:58]=[CH:59][C:54]([NH:53][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[O:16][CH2:15][C:14]([C:6]4[CH:5]=[CH:4][C:3]5[C:2]([CH3:27])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=5[CH:7]=4)([CH3:26])[C:18]=3[CH:19]=2)=[O:24])=[CH:55][CH:56]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)O)cc43)ccc21
Reactant: Nc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)Nc5ccc(O)cc5)cc43)ccc21

Procedure:
A solution of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-3-methyl-2H-1-benzofuran-5-carboxylic acid (100 mg, 0.275 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1,3-dicyclohexylcarbodiimide (112 mg, 0.55 mmol) and 4-aminophenol (30 mg, 0.255 mmol) in 5 ml of THF and 2 ml of DMF is stirred at room temperature for 6 hours. 30 ml of water and 30 ml of ethyl acetate are added. After stirring and separation of the phases by settling, the aqueous phase is extracted with 2×30 ml of ethyl acetate. The organic phases are then combined and washed twice with 30 ml of water and then dried over magnesium sulphate, and concentrated on a rotary evaporator under vacuum at 40° C. The product is then purified by flash chromatography on a column of silica (50% heptane/50% ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=N[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3.[CH:29](=O)C1C=CC=CC=1>>[CH2:21]([C:19]1[C:18](=[O:28])[C:7]2[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=[C:11]3[C:6]=2[N:5]([CH:20]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=1[S:12]3)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:29][CH:23]=1
Reactant: COc1cc2c3c(c1)c(=O)c(Cc1cccnc1)cn3-c1cc(Br)ccc1S2
Reactant: O=Cc1ccccc1
Product: COc1cc2c3c(c1)c(=O)c(Cc1ccccc1)cn3-c1cc(Br)ccc1S2
Yield: 46 %

Procedure:
According to Example 1 <step 4>, the compound (3 g) produced in Example 36 <step 2> was reacted with benzaldehyde (1.25 mL) to obtain the title compound (1.73 g; 46%).
Reaction SMILES: [CH3:1][C:2](=[CH2:30])[C:3]([N:5]1[C@@:9]2([CH2:13][CH2:12][N:11]([C@@H:14]([C:19]([O:21]CC3C=CC=CC=3)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2=[O:29])[CH2:8][CH2:7][CH2:6]1)=[O:4].O>CO>[CH3:30][C:2](=[CH2:1])[C:3]([N:5]1[C@@:9]2([CH2:13][CH2:12][N:11]([C@@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2=[O:29])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)OCc1ccccc1)C2=O
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 15 (65 mg, 0.16 mmol) in methanol (2.5 ml) were added aq. NAOH (1.6 ml, 1N) and H2O (1.6 ml) and the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated at reduced pressure, and the residue was partitioned between H2O (20 ml) and DCM (20 ml). The aqueous phase was acidified to pH=2 with aq HCl (10 ml, 0.1 N) and extracted with DCM (3×20 ml). The combined organic phases were washed with brine (25 ml), dried (Na2SO4) and concentrated at reduced pressure to afford 18 (44 mg, 85%) as a white solid. HPLC [Column Novapack C18 (Waters), 3.9×150 mm, Φ=1 ml/min, λ=214 nm, eluent: ACN/0.05% TFA, (25/75)] Rt=6.38 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[C:4]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH:7]=1
Reactant: NCCOCCO
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1c(NCCOCCO)cc(Cl)cc1NCCOCCO
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The mixture consisting of 0.1 mole (22.6 g) of 2,4,6-trichloronitrobenzene, 0.6 mole (63 g) of 2-(β-aminoethoxy)ethanol and 20 ml of dioxan is heated to reflux of the dioxon. After 4 hours, the reaction mixture is poured onto to 200 g of ice. The product expected crystallizes on acidifying with concentrated hydrochloric acid. After draining, washing with water and drying by heating under vacuum, the product is recrystallized from acetonitrile and then from toluene. It melts at 83° C.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[C:17]=1C(O)=O>C1(C)C=CC=CC=1>[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[C:17]=1[C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)c1c(F)cccc1I
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1c(F)cccc1I
Reaction time: 4 h
Yield: 125.5 %

Procedure:
N,N-Dimethylformamide di-t-butyl acetal (3.8 ml, 3.2 g) was added to a stirred mixture of 2-fluoro-6-iodobenzoic acid (1.25 g) in toluene (25 ml). The mixture was then stirred at 90° for 4 h, allowed to stand at room temperature for 60 h before further dimethylformamide di-t-butyl acetal (1 ml, 0.85 g) was added and heating continued at 90° for 90 min. After cooling, the orange solution was washed with water (50 ml), brine (50 ml), 10% aqueous lithium chloride solution and 8% aqueous sodium bicarbonate solution (50 ml), dried and concentrated in vacuo-to afford an orange liquid (1.9 g). Purification by chromatography eluting with System A (1:1) gave the title compound (1.37 g) as an orange liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13]=[CH2:14]>>[CH:13]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:14]
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: C=C
Product: C=Cc1cccc(CC(=O)OC)c1

Procedure:
Methyl 3-bromophenylacetate (8.0 g, 34.9 mmol) was reacted with ethylene using the procedure described in Example 6, step 1. The crude reaction product was purified by column chromatography (SiO2, 5% EtOAc in petroleum ether) to give 3,3′-bis-[(carbo-methoxy)methyl]stilbene and methyl 3-(ethenyl)phenyl-acetate as a white solid mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[C:18]#[N:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:23])(=O)=O>ClC(Cl)(Cl)Cl>[Cl:23][C:15]1[CH:14]=[C:13]([C:18]#[N:19])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[C:16]=1[CH3:17]
Reactant: CCOC(=O)c1ccc(-n2c(C)ccc2C#N)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-n2c(C#N)cc(Cl)c2C)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-(4-ethoxycarbonylphenyl)-5-methylpyrrole-2-carbonitrile (1.76 g) and silica gel (8.0 g, Mallinckrodt) in tetrachloromethane (26 ml) was added dropwise sulfuryl chloride (760 μl) at 5° C. under nitrogen atmosphere. The suspension was stirred at 5° C. for one hour and then at ambient temperature for half an hour. The mixture was filtered off and washed with a little amount of tetrachloromethane. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (elution by ethyl acetate/n-hexane=1/7) to yield 4-chloro-1-(4-ethoxycarbonylphenyl)-5-methylpyrrole-2-carbonitrile (1.36 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[N:28][C:21]=12>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:22]2[C:21]3[N:28]=[CH:27][NH:26][C:20]=3[CH:25]=[CH:24][N:23]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Clc1ccnc2[nH]cnc12
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccc3[nH]cnc23)CC1

Procedure:
EXAMPLE 88 was prepared from 4-aminomethyl-piperidine-1-carboxylic acid benzyl ester and 7-chloro-3H-imidazo[4,5-b]pyridine (7-chloro-3H-imidazo[4,5-b]pyridine was prepared according to Y. Mizuno, T. Itoh, K. Saito, Chem. Pharm. Bull., 12:866–872(1964): MS (m+1)=366.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][C@@H:21]([NH:23][CH3:24])[CH3:22])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:25].[C:26]([OH:29])(=O)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][C@@H:21]([N:23]([CH3:24])[C:26](=[O:29])[CH3:27])[CH3:22])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:25]
Reactant: CC(=O)O
Reactant: CN[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: CC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 27 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 2-chloro-4-[(5-{[(2S)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol (obtained as described in Example 56, preparation of starting materials) to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide in 27% yield; Mass spectrum MH+ 401.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: O=C1COc2ccc(F)cc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(F)cc2N1CCCCl
Yield: 77.5 %

Procedure:
6-Fluoro-4H-benzo[1,4]oxazin-3-one (8173MF55b) (0.090 g, 0.54 mmol), Cs2CO3 (0.263 g, 0.81 mmol) and 3-chloro-1-iodopropane (0.121 g, 0.59 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (8173MF55b) (0.102 g, 78%). 1HNMR(CDCl3) δ 6.95-6.91 (m, 1H), 6.82-6.78 (m, 11H), 6.72-6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.19-2.11 (m, 2H); 13CNMR(CDCl3) δ 164.6, 158.6 (d, J=240.7 Hz), 141.5 (d, J=2.3 Hz), 129.6 (d, J=10.5 Hz), 118.0 (d, J=9.3 Hz), 110.0 (d, J=23.1 Hz), 102.7 (d, J=28.8 Hz), 67.8, 42.3, 39.3, 30.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:14])=[C:6]([NH2:15])[CH:5]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([S:24](Cl)(=[O:26])=[O:25])[CH:23]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:14])=[C:6]([NH:15][S:24]([C:22]2[CH:23]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=2[O:28][CH3:29])(=[O:25])=[O:26])[CH:5]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)c(O)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2cc(Cl)ccc2OC)c(O)c(C(F)(F)F)c1

Procedure:
A suspension of 3-amino-4-hydroxy-5-trifluoromethyl-benzoic acid methyl ester (4.66 g, 19.8 mmol) and 5-chloro-2-methoxybenzenesulfonyl chloride (4.78 g, 19.8 mmol) in toluene (38 mL) was heated at reflux for 48 h. After cooling, the precipitate was collected by filtration and washed with toluene to afford 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-trifluoromethyl-benzoic acid methyl ester. Off-white solid, MS (ISP)=438.0 (M−H)−.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[N+:25]([O-:27])=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH:22][C:28](=[O:30])[CH3:29])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[N+:25]([O-:27])=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Product: CC(=O)Nc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(=O)(=O)NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: The mixture of 20 g of 4-(4-acetamidophenylamino)-3-nitro-5-sulfamoylbenzoic acid and 200 ml of acetic anhydride is refluxed for ten minutes while stirring under nitrogen. It is evaporated under reduced pressure, the residue triturated with water and dissolved in 200 ml of 2N aqueous sodium hydroxide. The solution is washed with diethyl ether, filtered and acidified with concentrated hydrochloric acid to pH of 1- and the precipitate filtered off, to yield the 4-(4-acetamidophenylamino)-3-nitro-5-acetylsulfamoylbenzoic acid melting at 175°-185°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:18](=[O:33])[C:19](=O)[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([OH:30])[CH3:29])[C:23]=1[OH:31])C>CO>[OH:31][C:23]1[C:24]([CH:28]([OH:30])[CH3:29])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]1[C:17](=[O:16])[C:18](=[O:33])[C:19]=1[NH:13][CH:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]1([CH3:12])[CH2:9][O:10][CH2:11]1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc(C(C)O)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(C)O)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 25.4 %

Procedure:
A mixture of 314 mg (1.73 mmol, 1.2 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine and 400 g (1.44 mmol, 1 eq) of 3-ethoxy-4-[2-hydroxy-3-(1-hydroxyethyl)phenylamino]cyclobut-3-ene-1,2-dione in 15 ml of methanol was heated at 50° C. for 2 days. The reaction medium was evaporated and the residue was chromatographed on silica gel HP (column RediSep Rf Gold 40 g, Spot II) eluted with dichloromethane/methanol (gradient). The amorphous solid was taken up with a little diethyl ether, filtered and dried under vacuum at 50° C. 151 mg of 3-[2-hydroxy-3-(1-hydroxyethyl)phenylamino]-4-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}cyclobut-3-ene-1,2-dione were obtained in the form of an orange solid. (Mp=129-131° C.). Yield=25%. LC/MS: 96.1% [412]: 2 diastereoisomers.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-])=O>CO.O1CCCC1.[Ni]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1c(N2CCCCC2)c[n+]([O-])c2ccccc12
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c(N2CCCCC2)cnc2ccccc12

Procedure:
The 4-nitro-3-piperidinoquinoline-N-oxide (4 g, 0.015 mol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (50 ml) and subjected to catalytic reduction in the presence of purified Raney nickel (2 ml). Upon isolation and purification by chromatography on an alumina column (developing solvent: CHCl3), 4-amino-3-piperidinoquinoline was obtained in an amount of 2.1 g (yield, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.CC([O-])(C)C.[K+].[C:19]([O:23][C:24]([N:26]1[C@@H:30]([CH3:31])[CH2:29]OS1(=O)=O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24](=[O:25])[NH:26][C@@H:30]([CH3:29])[CH2:31][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[CH3:12])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(C)n2C[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
5-Methoxy-2 methylindole (806 mg) was dissolved in DMF (25 mL) and cooled to 0° C. with an ice bath. Potassium tert-butylate (1M in THF, 6 mL) was added over 15 minutes and the resulting mixture was allowed to stir for further 30 minutes. (S)-4-Methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester IV (1.42 g) was added in one portion and stirring was continued at RT until TLC analysis showed complete consumption of the starting material. The reaction mixture was partitioned between ether and saturated NH4Cl solution and the organic layer was separated, washed with sat. NH4Cl and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography (CH2Cl2). The appropriate fractions were combined and evaporated to give the product as an off-white solid (1.42 g).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1.CO.[OH-].[Li+]>O1CCCC1>[C:20]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17](/[CH:16]=[N:15]/[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([NH:29][C:30](=[O:42])[C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:40])([F:41])[F:39])=[CH:33][CH:32]=3)[CH:6]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)ccc1C(=O)O)c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 28, starting with 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[4-(trifluoromethoxy)benzoyl]amino}benzoic acid methyl ester (0.31 g, 0.52 mmol), 1:1 methanol:tetrahydrofuran (10 mL) and 4N aqueous lithium hydroxide solution (0.39 mL). The crude material was crystallized from hot chloroform (10 mL) by the addition of room temperature hexanes (100 mL), and allowing the mixture to sit for 2 hours. The product was isolated and then triturated with hexanes to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[4-(trifluoromethoxy)benzoyl]amino}benzoic acid (0.29 g, 95%) as a white solid. mp=194.5-195.5° C. 1H NMR (500 MHz, DMSO-d6); δ 13.49 (bs, 1H), 12.46 (s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 8.05 (d, 2H), 8.00 (d, 1H), 7.70-7.66 (m, 6H), 7.58 (d, 2H), 7.46 (t, 2H), 7.37(t, 1H), 6.81 (d, 1H), 4.31 (t, 2H), 4.22 (t, 2H), 2.18 (m, 2H). Mass spec (MW 578.54); (ES+) m/z 577.43 Elemental analysis; Calculated for C31H25F3N2O6: C, 64.36; H, 4.36; N, 4.84. Found: C, 63.78; H, 4.18; N, 4.77.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[H][H]>C(O)(=O)C.O=[Pt]=O>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:7])[CH3:6]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccncc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(=O)NC1CCNCC1

Procedure:
A solution of the product of Example 2 (75 g) in 750 mL acetic acid was reduced over PtO2 catalyst at 60 psi hydrogen atmosphere at 60° C. for 7 hours. The solution was filtered, concentrated and triturated with ether to afford the title compound quantitatively as a white solid which was used directly in subsequent reactions.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Si]([O:19][CH2:20][CH2:21][O:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CO>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[O:22][CH2:21][CH2:20][OH:19]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1nccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: OCCOc1nccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
para-Toluenesulfonic acid (11.2 g, 58.0 mmol) was added to a sol. of 2-[2-(tert-butyldimethylsilanyloxy)ethoxy]thiazole (15.0 g, 58.0 mmol) in MeOH (300 mL) at 0° C. The mixture was stirred for 2 h at 0° C. Aq. sat. NaHCO3 was added until a pH of 6-7 was reached. The solvents were partially removed under reduced pressure, and the residue was diluted with EtOAc. The mixture was washed with aq. sat. NaHCO3 (1×), and the aq. phase was extracted back with EtOAc (1×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:1) yielded the title compound (5.43 g, 65%). LC-MS: tR=0.48 min, ES+: 146.09.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCCBr

Procedure:
In analogy to the procedure described in example 5) (a) 2-nitrophenol was treated with sodium carbonate followed by 1,3-dibromo-propane in N,N-dimethylformamide to yield the 1-(3-bromo-propoxy)-2-nitro-benzene as slightly green solid; MS: 259, 261 (M)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:3]=1.CC1(C)C(C)(C)OB([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]([F:50])([F:49])[F:48])=[CH:42][CH:41]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:27]([O:26][C:4]1[CH:3]=[C:2]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]([F:48])([F:49])[F:50])=[CH:42][CH:41]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)[OH:13])[CH:10]=2)[N:5]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC1(C)OB(Cc2ccc(OC(F)(F)F)cc2)OC1(C)C
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Oc1cc(Cc2ccc(OC(F)(F)F)cc2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2n1

Procedure:
A mixture of (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol (79 mg, 0.157 mmol) and 4,4,5,5-tetramethyl-2-(4-(trifluoromethoxy)benzyl)-1,3,2-dioxaborolane (80.5 mg, 0.267 mmol) in the presence of Pd(dppf)Cl2.CH2Cl2 (512 mg, 0.0157 mmol), Na2CO3 (33 mg, 0.314 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) was heated at 80° C. overnight. The reaction was diluted with EtOAc and water. The organics were concentrated and purified by silica column (80% EtOAc/hexanes) chromatography to yield (2-(tert-butoxy)-4-(4-(trifluoromethoxy)benzyl)quinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol.