Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)#[N:2].[N-:14]=[N+:15]=[N-:16].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:2]1[NH:14][N:15]=[N:16][C:1]=1[CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: N#CCSc1ccc(C(=O)O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(SCc2nn[nH]n2)cc1
Yield: 15.7 %

Procedure:
A mixture of 4-cyanomethylsulfanylbenzoic acid (27.2 g, 0.14 mol), sodium azide (11.8 g, 0.18 mol) and ammonium chloride (9.7 g, 0.18 mol) in DMF (1000 mL) was refluxed overnight under N2. The mixture was concentrated in vacuo. The residue was suspended in cold water and extracted with diethyl ether. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. Water was added and the precipitate was filtered off. The aqueous layer was concentrated in vacuo, water was added and the precipitate filtered off. The combined impure products were purified by column chromatography using DCM:MeOH=9:1 as eluent, affording the title compound (5.2 g, 16%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.C([O:14][C:15](=O)[CH:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH3:17])C.OS(O)(=O)=O>O>[CH2:19]([O:18][CH:16]([CH3:17])[CH2:15][OH:14])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCOC(C)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(C)CO
Reaction time: 3.5 h
Yield: 40.7 %

Procedure:
4.5 g of LiAlH4 was added to 150 ml of ether and the mixture was stirred for 3.5 hours. To the mixture was added dropwise 38.8 g of (-)-ethyl-2-octadecyloxypropionate in the same manner as in Example 6, and the mixture was stirred for 20 minutes. Then, 50 ml of water was added thereto and 10% H2SO4 aqueous solution was further added to give a pH of 7-8. The ether layer was separated, dried with MgSO4 and filtrated. Ether was distilled off and the residue was subjected to distillation under reduced pressure, whereby 14.0 g of (+)-2-octadecyloxypropanol was obtained by collecting a fraction of 175°-179° C./0.9 mmHg.
Reaction SMILES: C([CH2:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16](=[O:25])[C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])(O)=O>ClCCCl>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:5]2[CH3:4])=[O:25]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C

Procedure:
A suspension of 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (2-5 g) in 1,2-dichloroethane (60 ml) was refluxed for 14 hours. The solvent was removed under reduced pressure and the residual solid was treated with hot ethanol (45 ml) to afford 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonyl-4-methylquinoline (2.08 g) as a colorless prism.
Reaction SMILES: O[N:2]([CH2:14][CH2:15][CH3:16])[CH:3]1[CH2:12][C:11]2[N:10]=[CH:9][CH:8]=[C:7]([CH3:13])[C:6]=2[CH2:5][CH2:4]1.Cl>[Cl-].[Cl-].[Cl-].[Ti+3].CO>[CH3:13][C:7]1[C:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH2:14][CH2:15][CH3:16])[CH2:12][C:11]=2[N:10]=[CH:9][CH:8]=1
Reactant: CCCN(O)C1CCc2c(C)ccnc2C1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: CCCNC1CCc2c(C)ccnc2C1

Procedure:
This compound was prepared from the product of Step 7 (4.4 g, 20 mmol), titanium trichoride, 20 wt. % solution in 20-30 wt. % hydrochloric acid (23 ml, 30 mmol), and methanol (50 ml) using the procedure described in Example 11. The crude product (4.2 g, 81%) was converted into the product of Step 9 without purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]1([CH3:20])[C:12]([C:17](Cl)=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:20])=[O:18]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccccc2C)c(Cl)c1Cl

Procedure:
The Friedel-Crafts procedure of Example 24a is repeated with 35.4 g of 2,3-dichloroanisole, 32.4 g of o-toluoyl chloride and 28 g of AlCl3 being combined in 125 ml of 1,2-dichloroethane to yield a product of 2,3-dichloro-4-methoxy-2'-methylbenzophenone.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[N:44]=[C:43]([C:45]([OH:47])=[O:46])[CH:42]=[CH:41][CH:40]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH:14]=[C:13]3[C:39]2[N:44]=[C:43]([C:45]([OH:47])=[O:46])[CH:42]=[CH:41][CH:40]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(C(=O)O)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 90 °C

Procedure:
To a solution of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (500 mg, 0.957 mmol) and 6-bromopicolinic acid (280 mg, 1.436 mmol, Sigma-Aldrich) in DME (10 mL)/water (2.5 mL) was added Na2CO3 (304 mg, 2.871 mmol) and Pd(PPh3)4 (111 mg, 0.096 mmol) and Ar gas was bubbled for 5 min. The reaction mixture was heated at 90° C. for 4 h. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give crude product, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 518.2 (M+1).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
While cooling on ice, Boc-L-Pro-OH (1.08 g, 5.0 mmol) and benzyl bromide (0.893 ml, 75 mmol) were reacted in DMF (10 ml) in the presence of triethylamine (10.5 ml, 75 mmol) to obtain Boc-L-Pro-OBzl as an oily product. This product was reacted under ice-cooling with 2 N HCl/dioxane (5 eq.) for three hours to obtain H-L-Pro-OBzl-HCl.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]([CH2:16][CH2:17][NH:18][S:19](/[CH:22]=[CH:23]/[C:24]([F:27])([F:26])[F:25])(=[O:21])=[O:20])C(=O)OC(C)(C)C)[CH:3]=1.Cl>O1CCOCC1>[F:27][C:24]([F:25])([F:26])/[CH:23]=[CH:22]/[S:19]([NH:18][CH2:17][CH2:16][NH:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)(=[O:20])=[O:21]
Reactant: Cc1ccnc(N(CCNS(=O)(=O)/C=C/C(F)(F)F)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccnc(NCCNS(=O)(=O)/C=C/C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a cooled solution (0° C.) of tert-butyl N-(4-methyl-2-pyridyl)-N-[2-[[(E)-3,3,3-trifluoroprop-1-enyl]sulfonyl-amino]ethyl]carbamate (190 mg, 0.464 mmol) in dioxane (10 ml) was added HCl (4M solution in dioxane, 3.5 ml, 14 mmol). The mixture was stirred at 0° C. for 30 minutes and then for 48 hours at room temperature. The mixture was evaporated to dryness under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution and DCM. Layers were separated and the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over sodium sulfate, concentrated under reduces pressure and the residue was purified by column chromatography (silica, gradient of 10 to 100% heptane in ethyl acetate) to yield 103 mg of a white solid (0.33 mmol, 72%)
Reaction SMILES: [CH2:1]([O:4]C1CCCCO1)[C:2]#[CH:3].C([Mg]Br)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17]>CCOCC.O1CCCC1>[OH:4][CH2:1][C:2]#[C:3][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: C#CCOC1CCCCO1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(C#CCO)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
A solution of 3.3 ml (23.2 mmols) of tetrahydro-2-(2-propinyloxy)-2H-pyran [R. A. Earl et al., Organic Syntheses 60, 81 (1981)] in 23 ml of anhydrous tetrahdrofuran was added dropwise to 7.8 ml (23.2 mmols) of a 3 molar solution of ethyl-magnesium bromide in ether at room temperature in the course of 30 minutes. The mixture was then subsequently stirred at room temperature for 1.5 hours. This solution was added dropwise to a well-stirred solution, cooled to -20° C., of 5.0 g (23.2 mmol) of 4-nitrobenzyl chloroformate in 25 ml of tetrahydrofuran in the course of 1.5 hours. The mixture was then subsequently stirred at -15° C. for 30 minutes and at 0° C. for 1.5 hours, and was then left to stand at 0° C. for 12 hours, whereupon the magnesium salts crystallized out. The salts were filtered off, with exclusion of moisture, and washed two times with a little toluene. The filtrate solution was washed 5 times with saturated NaCl solution and dried over MgSO4. The solvent was evaporated off in vacuo, the residue was dissolved in 25 ml of anhydrous methanol and the solution was stirred with 1 ml of the ion exchanger Dowex-50-X4 (H+ form, prewashed with anhydrous methanol) at room temperature for 1 hour. The ion exchanger was separated off, the filtrate solution was concentrated in vacuo and, finally, the residue was dried under a high vacuum. The treatment with the ion exchanger was repeated as described above. The crude product was chromatographed on 300 g of silica gel (toluene:ethyl acetate 4:1) and 2.07 g (38%) of 4-nitrobenzyl 4-hydroxy-2-butinoate were obtained as colorless crystals, melting point: 93°-94° C., RF : 0.27 (toluene:ethyl acetate 4:1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][C:5]([C:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1Br.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[NH2:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:4][C:5]([C:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCCC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(c2cc(OCC3CC3)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Yield: 73.4 %

Procedure:
A mixture of ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd (PPh3)4 (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (4.6 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([Si:4]([CH3:23])([CH3:22])[O:5][CH2:6][CH2:7][CH2:8][S:9](=[O:21])[CH2:10][CH2:11][CH2:12][O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:3].FC(F)(F)C([NH2:29])=O.[O-2].[Mg+2].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[NH:29]=[S:9](=[O:21])([CH2:10][CH2:11][CH2:12][O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:8][CH2:7][CH2:6][O:5][Si:4]([CH3:23])([CH3:22])[C:2]([CH3:24])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCCS(=O)CCCO[Si](C)(C)C(C)(C)C
Reactant: NC(=O)C(F)(F)F
Agent: [Rh+2]
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCS(=N)(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a solution of 2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane 8-oxide in anhydrous dichloromethane (150 mL) was added trifluoroacetamide (7.60 g, 2 eq), magnesium oxide (5.256 g. 4 eq), rhodium acetate dimer (432 mg, 0.03 eq), and (diacetoxyiodo)benzene (15.75 g, 1.5 eq) under nitrogen atmosphere at room temperature. The greenish reaction mixture was stirred at room temperature for 18 hours. Then additional amount of trifluoroacetamide (3.0 g), rhodium acetate dimer (300 mg), (diacetoxyiodo)benzene (5.0 g), and anhydrous DCM (100 mL) was added. The mixture was stirred at room temperature for another 3 hours and then filtered through a pad of celite and silica gel. The pad was washed first with DCM followed by MeOH-DCM (1:5). The filtrate was concentrated and the brown oil was taken up into methanol (200 mL). Potassium carbonate (22.53 g, 5 eq) was added to the newly formed solution. After the mixture was stirred at room temp for 2 hours, it was filtered through a pad of celite and silica gel. The pad was washed first with DCM-EtOAC (1:1) followed by a later 10% (v/v) addition of MeOH with stirring of the sediment on top of the pad. The filtrate was concentrated and the residue mixture was treated with DCM-EtOAc (2:3) with stirring at room temp for 30 minutes. The mixture was filtered again through a pad of celite and silica gel. This filtration and concentration circle may be repeated a couple of times such that most of the solid by-product was removed and a reddish oil was obtained. Purification by a gradient column chromatography (EtOAc-HEX 1:20 to 1:1) provided the title compound as a redish oil (9.538 g) with a total yield of 72% for 4 steps.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:17]([OH:19])=O)[CH:6]=1.[O:20]=[C:21]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[NH:37][O:38][C:39](=[O:41])[N:40]=3)[CH:34]=2)[O:29][C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22]1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:17]([N:26]2[CH2:27][CH2:28][C:23]3([CH2:22][C:21](=[O:20])[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([C:36]5[NH:40][C:39](=[O:41])[O:38][N:37]=5)[CH:34]=4)[O:29]3)[CH2:24][CH2:25]2)=[O:19])[CH:6]=1
Reactant: COc1cccc2c(OCCO)cc(C(=O)O)cc12
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nc(=O)o[nH]3)cc21
Product: COc1cccc2c(OCCO)cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5noc(=O)[nH]5)ccc3O4)cc12

Procedure:
The compound was prepared according to the procedure described in the Example 1, using 4-(2-hydroxyethoxy)-8-methoxy-2-naphthoic acid instead of 4,8-dimethoxyquinoline-2-carboxylic acid, and 3-[4-oxospiro(chroman-2,4′-piperidin)-6-yl]-5-oxo-1,2,4-oxadiazole instead of 4-oxospiro(chroman-2,4′-piperidin)-6-yl acetamide. 1H-NMR (400 MHz, DMSO-d6) δ; 8.24 (1H, d, J=4.0 Hz), 8.04 (1H, dd, J=4.0, 8.0 Hz), 7.86 (1H, d, J=8.0 Hz), 7.75 (1H, s), 7.51 (1H, t, J=8.0 Hz), 7.34 (1H, d, J=8 Hz), 7.09 (1H, d, J=8 Hz), 7.00 (1H, s), 4.40-4.22 (1H, m), 4.20 (2H, t, J=4.0 Hz), 4.01 (3H, s), 3.92-3.89 (2H, m), 3.75-3.30 (3H; m), 3.03 (2H, s), 2.12-1.75 (4H, m). MS [M+H]+=546.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH:15]([CH2:22][O:23][CH2:24][CH3:25])[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])C.[OH-].[Na+]>C(O)C.Cl>[CH2:24]([O:23][CH2:22][CH:15]1[CH2:14][CH2:13][CH2:12][C:11]2[NH:10][C:9]3[CH:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[C:18]([CH2:19][O:20][CH3:21])[C:17]=3[C:16]1=2)[CH3:25]
Reactant: CCOCC1CCCc2[nH]c3cnc(C(=O)OCC)c(COC)c3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCC1CCCc2[nH]c3cnc(C(=O)O)c(COC)c3c21
Yield: 104.5 %

Procedure:
5,6,7,8-Tetrahydro-5-ethoxymethyl-4-methoxymethyl-betacarboline-3-carboxylic acid ethyl ester (0.51 g) is refluxed in ethanol (25 ml) with 1 normal sodium hydroxide solution (4.3 ml) for 3 hours. Then the solution is mixed with 5.3 ml of IN hydrochloric acid and evaporated. The residue is boiled out with ethanol, 0.49 g of 5,6,7,8-tetrahydro-5-ethoxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid is obtained from the ethanol extract after treatment with carbon by evaporation. Melting point, 250° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1.Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([O:16][CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Reactant: BrCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(OCCc4ccccc4)cc23)cn1
Yield: 50 %

Procedure:
According to the general procedure using: 27 (60 mg, 0.174 mmol), (2-bromo-ethyl)-benzene (143 μL, 1.05 mmol), K2CO3 (241 mg, 1.74 mmol) and n-Bu4NI (6.4 mg, 17 μmol) in acetone (4.0 mL) were heated at reflux overnight. Standard workup and purification by PTLC using AcOEt:hexane=6:4 (v/v) as eluent gave 28r as a clear oil (39 mg, 50%).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:14][CH2:15][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[OH:17])[CH2:11]2)=[CH:6][CH:5]=1.B(Br)(Br)Br.N>C(Cl)Cl>[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:14][CH2:15][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[OH:17])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1)CC(NCC(O)c1cccc(Cl)c1)CC2
Agent: BrB(Br)Br
Agent: Cl
Agent: N
Solvent: ClCCl
Product: Oc1ccc2c(c1)CC(NCC(O)c1cccc(Cl)c1)CC2
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3.7 g of 2-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl) ethanol hydrochloride, obtained as described in Example 7, in 60 ml of anhydrous methylene chloride, there is added dropwise, under a nitrogen stream and at the temperature of -20° C., 60 ml of a 1M solution of boron tribromide in methylene chloride. The reaction mixture is left under stirring at the temperature of -20° C. for 3 hours and 30 minutes. An excess of ice is added and the mixture is made alkaline with concentrated ammonia. The organic phase is separated, dried over anhydrous sodium sulfate and evaporated to dryness. The residue thus obtained is purified by flash-chromatography using a mixture of methylene chloride/methanol 9/1 for the elution. The 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)ethanol, thus obtained in the form of basis, is dissolved in a mixture of 10 ml of isopropyl alcohol and 30 ml of ethyl ether. To the resulting solution there is added a saturated solution of hydrogen chloride in isopropyl alcohol to obtain the 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)-ethanol hydrochloride, designated by its code number SR 58339 A, which, after crystallization from 20 ml of absolute ethanol, melts at 113°-115° C. Yield: 30% of the theoretical value.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:17]3[N:18]=[C:19]([CH:21]4[CH2:23][CH2:22]4)[O:20][C:16]=3[C:15]([C:24]([O:26]C)=O)=[CH:14][C:13]=2[N:28]=1.[F:29][C:30]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:31]=1[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:17]3[N:18]=[C:19]([CH:21]4[CH2:23][CH2:22]4)[O:20][C:16]=3[C:15]([C:24]([NH:32][C:31]3[CH:33]=[C:34]([C:37]([F:38])([F:39])[F:40])[CH:35]=[CH:36][C:30]=3[F:29])=[O:26])=[CH:14][C:13]=2[N:28]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Yield: 17.5 %

Procedure:
To a solution of methyl 7-((2-chloro-6-fluorophenyl)amino)-2-cyclopropyl-8H-imidazo[4′,5′:5,6]-benzo[1,2-d]oxazole-4-carboxylate (Intermediate-59, 0.050 g, 0.125 mmol) in dry toluene (5.0 mL) was added 2-fluoro-5-trifluoromethylaniline (0.022 g, 0.125 mmol) and trimethyl aluminium (2M solution in toluene) (0.009 g, 0.125 mmol). The reaction mass was refluxed for 1 h. The reaction mass was quenched with water and extracted with 10% DCM: MeOH. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.23 (m, 4H), 2.33 (m, 1H), 7.40-7.47 (m, 3H), 7.62 (m, 2H), 7.75 (s, 1H), 8.68 (s, 1H), 9.42 (s, 1H), 9.89 (s, 1H), 11.69 (s, 1H); MS [M+H]+: 547.81.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[C:6]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1.[NH2:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[C:34]([NH:41][CH2:42][CH2:43][NH2:44])[N:33]=1>>[NH2:31][C:32]1[N:33]=[C:34]([NH:41][CH2:42][CH2:43][NH:44][C:9]2[N:10]=[C:5]([O:4][C:3]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:2]=3[Cl:1])[C:6]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][C:7]=3[N:8]=2)[CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39]
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(Oc3ccc(Cl)cc3Cl)c2C1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Oc3ccc(Cl)cc3Cl)c2C1

Procedure:
Following Example 7, treatment of tert-butyl 4-(2,4-dichlorophenoxy)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate with 2-amino-3-nitro-6-(2-aminoethylamino)pyridine gave tert-butyl 2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenoxy)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.