Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)=[CH:4][C:3]=1[CH2:17][OH:18].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)=[CH:4][C:3]=1[CH2:17][O:18][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1
Reactant: O=Cc1ccc(Oc2ccc(Br)c(CO)c2)nc1
Reactant: C1=COCCC1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: O=Cc1ccc(Oc2ccc(Br)c(COC3CCCCO3)c2)nc1
Yield: 100 %

Procedure:
THP protection of 6-(4-bromo-3-(hydroxymethyl)phenoxy)nicotinaldehyde (2.4 g, 7.78 mmol) with 3,4-dihydro-2H-pyran (2.2 mL) catalyzed with (1S)-(+)-10-camphorsulfonic acid in CH2Cl2 (80 mL) at r.t. for 1 h provided the desired 6-(4-bromo-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)nicotinaldehyde as colorless oil (3.07 g, 7.8 mmol, yield 100%) after silica gel column purification (hexane:EtOAc=3:1, v/v).
Reaction SMILES: [CH3:1]N1CCOCC1.Cl[C:9]([O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10].Cl.[NH2:18][C@H:19]([C:23]([NH:25][C@H:26]([C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)=[O:29])[CH3:27])=[O:24])[CH:20]([CH3:22])[CH3:21].O>C(Cl)Cl>[CH:12]1([O:11][C:9]([NH:18][C@H:19]([C:23]([NH:25][C@@H:26]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)=[O:29])[CH3:27])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:1]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: CN1CCOCC1
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)Nc1ccc(C#N)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC1CCCCC1)C(=O)N[C@H](C)C(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47 %

Procedure:
0.6 g of N-methyhnorpholine, and subsequently 0.6 g of cyclopentyl chloroformate were added to a suspension containing 1.0 g of L-valyl-N-(4-cyanophenyl)alaninamide, hydrochloride suspended in 50 ml of methylene chloride at -20° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of a white crystal (yield: 49% ).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]1([NH2:20])[CH2:19][O:18][CH2:17]1.[S:21]1(=[O:33])(=[O:32])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][NH:24][CH2:23][CH2:22]1>>[NH2:20][C:16]1([CH2:15][NH:14][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=3)[N:3]=[C:2]([N:24]3[CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:21](=[O:33])(=[O:32])[CH2:22][CH2:23]3)[N:11]=2)[CH2:19][O:18][CH2:17]1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: NCC1(N)COC1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Product: NC1(CNc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(Cl)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6-trichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 460, 1H NMR (400 MHz, CD3OD) δ ppm 8.00-7.98 (t, J=2.0, 4.8 Hz, 2 H), 7.91-7.89 (d, J=7.2 Hz, 1 H), 7.64-7.60 (t, J=7.2 Hz, 1 H), 7.51-7.44 (m, 2 H), 7.40-7.38 (d, J=9.2 Hz, 1 H), 5.22 (s, 2 H), 4.65-4.62 (t, J=6.4, 5.6 Hz, 4 H), 4.56-4.54 (d, J=6.4 Hz, 2 H), 4.08 (s, 2 H), 3.54-3.51 (t, J=5.2, 4.8 Hz, 2 H).
Reaction SMILES: [C:1]1([C@@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH2:26]Br)[C:22]([O:24][CH3:25])=[O:23]>C(#N)C>[CH3:25][O:24][C:22]([CH:21]1[CH2:26][N:13]1[CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[O:23]
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: COC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CN1C(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of (S)-(−)-1-(1-naphthyl)ethylamine (20.8 g, 120 mmol) in acetonitrile (HPLC grade, 600 mL) is added K2CO3 (52.7 g, 360 mmol) and methyl 2,3-dibromopropionate (30 g, 120 mmol). The solution is stirred overnight at room temperature. The solution is evaporated to dryness, then H2O/EtOAc (1:1) (600 mL) is added, and the mixture is extracted with EtOAc (4×100 mL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1:2) to provide 24 g (78%) of the title compound as a mixture of two diastereomers in an equimolecular ratio. M+H+=256.10.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:14]([CH3:15])=[CH:13][C:12]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(Br)cn1
Reactant: C/C=C/C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C(C)c1ccc(NC(C)=O)nc1
Temperature: 100 °C

Procedure:
A mixture of N-(5-bromopyrid-2-yl)acetamide (31.4 g, Reference Example 23), ethyl crotonate (37.0 mL), triethylamine (33 mL), tetrakis(tri-o-tolylphosphine)palladium(0) and tetrabutylammonium bromide (9.36 g) in dimethylformamide (250 mL) was heated at 100° C. under an argon atmosphere for 48 hours. The reaction mixture was cooled and then evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was washed with brine, then dried over magnesium sulphate and then evaporated. The resulting light brown solid was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3, v/v) to give the title compound (27.3 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[CH2:13][NH:14]C(=O)OCC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:14][CH2:13][C:12]1[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=1[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCc1ccccc1CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1ccccc1CN

Procedure:
To a solution of 750 mg (1.95 mmol) benzyl 2-{2-[(tert-butoxycarbonyl) amino]ethyl}benzylcarbamate in 6.0 mL absolute ethanol was added 150 mg of 10% palladium on carbon catalyst. A balloon of hydrogen was bubbled into the stirring suspension at room temperature over 2 h. The reaction was filtered through celite and the filter pad washed with fresh absolute ethanol (2×). The filtrate was concentrated to dryness in vacuo to give tert-butyl 2-[2-(aminomethyl)phenyl]ethylcarbamate as a colorless oil: 1H NMR (CDCl3, 400 MHz): δ7.31-7.19 (m, 4H), 5.68 (br s, 1H), 3.90 (s, 2H), 3.41-3.34 (br m, 2H), 2.90-2.83 (br t, 2H, J=6.8 Hz), 1.41 (s, 9H); MS (Electrospray): M+NH=251.1; TLC Rf=0.24 (160/10/1 of methylene chloride/methanol/concentrated ammonium hydroxide).
Reaction SMILES: O[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][OH:27].CN(C)CCN(C)C>>[OH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[CH:4][CH:3]=1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(O)ccc(O)c21
Reactant: NCCNCCO
Agent: CN(C)CCN(C)C
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(O)c21
Reaction time: 60 h

Procedure:
A suspension of 5.44 g. of 1,4,5,8-tetrahydroxy-9,10-anthracenedione [P. G. Marshall, J.C.S., 254 (1937)] in a solution of 2.08 g. of 2-(2-aminoethylamino)ethanol in 50 ml. of N,N,N',N'-tetramethylethylenediamine is stirred and heated under reflux for 17 hours, then allowed to cool. The solid is collected by filtration and washed 3 times with N,N,N',N'-tetramethylethylenediamine, then twice with hexane. The first filtrate and the diamine washings are combined and the solution is allowed to stand for 60 hours as a solid separates. This solid is collected and washed as above to give 0.524 g. of a dark blue solid. This solid is purified by dry column chromatography on deactivated (i.e., air-equilibrated) silica gel by the procedure of B. Loev and M. M. Goodman [Chem. and Ind., 2026 (1967)], eluting with chloroform-methanol (3:1) and monitoring the eluate fractions by thin layer chromatography on silica gel with the same solvent mixture. The cuts which showed only the slower of two purple spots were pooled and evaporated to give 0.42 g. of the product of the Example as a dark blue solid, mp. 196°-198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.C(=O)=O.Cl.[CH3:30][NH:31][O:32][CH3:33].O>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]([O:32][CH3:33])[CH3:30])=[O:7])=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=2)(=[O:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNOC
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CON(C)C(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
To a solution of 4-chloro-2-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-benzoic acid (5.0 g, 12.1 mmol) in THF (20 mL) was added N,N′-carbonyldiimidazole (CDI, 2.45 g, 15.13 mmol) in portions (Caution!: CO2↑). The resulting reaction mixture was then heated at reflux. After 4 hours, reaction mixture was cooled to room temperature and charged with N,O-dimethylhydroxylamine hydrochloride (1.3 g, 13.31 mmol) and heated at reflux for 1 hour. Water (100 mL) was added followed by EtOAc (100 mL) with stirring. EtOAc layer was separated and aqueous layer was further extracted with EtOAc (2×50 mL). Combined EtOAc layers were washed with aq. 2N HCl (50 mL), saturated NaHCO3 solution (50 mL), brine (50 mL), dried (Na2SO4) and evaporated. Obtained crude product was purified by automated normal-phase chromatography (50% EtOAc in hexanes) to afford title compound (4.0 g) in 73% yield. MS (ES) M+H expected 457.0, found 456.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]#[CH:18]>C(C(C)=O)C>[CH2:18]([N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7])[C:17]#[CH:16]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCN1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a stirred solution of 5,5-dimethylhydantoin (10 g, 78 mmole) in methyl ethyl ketone (500 mL) at room temperature was added potassium carbonate (13 g, 94.1 mmole), followed by propargyl bromide (14 g, 80% in toluene, 94.1 mmole). The reaction mixture was then refluxed for 2.5 hr. The mixture was cooled to room temperature and the solid was filtered by suction filtration. The filtrate was concentrated on a rotary evaporator to give 12.5 g (96%) of 3-(2-propynyl)-5,5-dimethylhydantoin as a yellow solid, mp=156°-160° C. An NMR spectrum showed the desired product with a purity about 95%. This intermediate was subjected to the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH:8]([CH2:17][C:18](=O)[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)C=C[N:3]=1.[C:24]([O-:27])(=O)[CH3:25].[NH4+:28].C([O-])(O)=O.[Na+].CCOC(C)=O>C(O)(=O)C>[C:19]([C:18]1[NH:28][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:8]([C:6]2[CH:7]=[CH:2][NH:3][C:24](=[O:27])[CH:25]=2)[CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: [NH4+]
Reactant: CC(C)(C)C(=O)CC(C(=O)c1ccccc1)c1ccnc(F)c1
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2cc[nH]c(=O)c2)c(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A solution of 2-(2-fluoropyridin-4-yl)-5,5-dimethyl-1-phenylhexane-1,4-dione (200 mg, 0.6 mmol) and ammonium acetate (329 mg, 3.8 mmol) in acetic acid (3 mL) was heated at reflux for 18 h. Upon cooling to RT the solution was slowly added to a mixture of sat'd aqueous NaHCO3 (40 mL) and EtOAc (40 mL). The mixture was stirred for 15 min. and the organic layer then collected. The aqueous layer was extracted with ethyl acetate (25 mL) and the organic layers combined, washed with sat'd aqueous NaHCO3, H2O and brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography using EtOAc-MeOH (100:0→95:5) as eluant to give the pure product as a cream solid (144 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl>CO>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1cccc2c(Cl)ccnc12
Yield: 81.5 %

Procedure:
In a similar fashion using route 2 general procedure 4, 4-chloro-8-nitroquinoline 463 (3.3 g, 15.8 mmol), SnCl2 (15 g, 79.1 mmol), conc. HCl (cat.) and MeOH (100 ml) to give the title compound (2.3 g, 36%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Br:12]Br.OS([O-])=O.[Na+]>C(Cl)Cl>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A round-bottom flask with stirbar was charged with 2-(trifluoromethyl)phenol (1.7 g, 10.49 mmol) in 10 mL CH2Cl2 was cooled to 0° C. Bromine (0.540 ml, 10.49 mmol) in 2 mL CH2Cl2 was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour, then allowed to warm to ambient temperature over 1 hour. Aqueous NaHSO3 solution was added, and the mixture extracted with CH2Cl2. The organic phase was washed with aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The residues were purified by flash chromatography eluting with 100% CH2Cl2, to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 10.90 (s, 1H), 7.63 (m, 1H), 6.98 (d, 1H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH:29]([OH:31])[CH3:30])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>[Pd].C1COCC1>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([OH:31])[CH3:30])=[CH:22][CH:23]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C#CCCCC(C)O)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCCCC(C)O)cc2)nc1
Yield: 101.8 %

Procedure:
In a reactor equipped with a stirrer and a thermometer, (-)-5-decyloxy-2-[4-(6-hydroxyheptynyl)phenyl]pyrimidine (4.0 g), 5% Pd/C (0.5 g) and THF (50 ml) are charged, and the mixture is reacted at room temperature for 17 hours in a hydrogen atmosphere under ordinary pressure. After filtrating the catalyst off, the reaction mixture is evaporated under reduced pressure. A resulting residue is purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to obtain (-)-5-decyloxy-2-[4-(6-hydroxyheptyl)phenyl]pyrimidine (4.11 g). [α]D =-2.8° (c=1.055, CHCl3).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[SH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([S:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)O)cc1C(C)(C)C
Reactant: O=C(O)c1ccc(S)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Crude 3-(tert.butyl)-4-methoxybenzoic acid, prepared starting with 1.04 g (5 mmoles) of 3-(tert.butyl)-4-methoxybenzoic acid, described in Example 35 of French Patent No. 85 13747 (2.570.377), is dissolved in 15 ml of dichloromethane. The solution is slowly added to a mixture of 771 mg (5 mmoles) of 4-mercaptobenzoic acid and 8 ml of pyridine. The reaction mixture is stirred at ambient temperature for 8 hours, evaporated to dryness, taken up in water, acidified to pH 5 with 1N HCl and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting residue is purified by chromatography on a silica column (eluant: ethyl ether). The solvent is evaporated and 530 mg (32% yield) of 4-[3-tert.butyl-4-methoxybenzoylthio] benzoic acid whose melting point is 220°-221° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][CH3:19])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COCCCCN
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: COCCCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and commercially available 4-methoxybutan-1-amine, the title compound was obtained; MS (Found M+1=345).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][CH:14]=[C:15]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]2)[N:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][CH:14]=[C:15]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]2)[N:16]=1
Reactant: CCOC(=O)c1cnn(Cc2coc(-c3cccc(C(F)(F)F)c3F)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnn(Cc2coc(-c3cccc(C(F)(F)F)c3F)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
A mixture of the compound (0.44 g) obtained in Example 105b, 4N sodium hydroxide (3 mL), ethanol (8 mL) and tetrahydrofuran (2 mL) was stirred at room temperature for 16 hr. The reaction mixture was adjusted to pH 5 with 1N hydrochloric acid, and the precipitate was collected by filtration, dried under reduced pressure and recrystallized from ethanol-hexane to give the title compound (0.32 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.O=S(Cl)Cl.[NH2:16][CH:17]1[CH2:26][CH:25]2[N:20]([CH2:21][CH2:22][C:23]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:24]=32)[CH2:19][CH2:18]1>C1(C)C=CC=CC=1.[OH-].[Na+]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:16][CH:17]1[CH2:26][CH:25]2[N:20]([CH2:21][CH2:22][C:23]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:24]=32)[CH2:19][CH2:18]1)=[O:7]
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)c3ccc(Cl)c(Cl)c3)CCN1CC2
Product: Cl
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A mixture of 3,4-dichlorobenzoic acid (6.5 g) and 25 ml of SOCl2 were refluxed for 3 hours and concentrated in vacuo. The concentrate was dissolved in 10 ml of toluene and added dropwise to a cold mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine (8 g, 0.03 mole) in 200 ml of toluene and 75 ml of 20% NaOH. The mixture was stirred in the cold for 1 hour whereupon the solid material was collected by filtration and chromatographed over silica gel using ethyl acetate-methanol-chloroform (7:2:1) as eluant. This major fraction (6.2 g) was converted to the HCl salt with hydrogen chloride in 2-propanol and methanol, isolated by evaporation of the solvent and recrystallized from methanol-ethyl acetate to yield 3.8 g of the desired product, m.p. (decomposed at 271°-3°). This compound conforms to Formula II where R1 and R2 are --OCH3, R3 is H and R4 is ##STR22##
Reaction SMILES: [OH-:1].[Na+].O.C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[C:20](F)=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=2)[C:13]=1[CH3:14])=[O:8])C.[CH3:26]O>O1CCCC1>[CH3:26][O:1][C:20]1[C:15]([N:12]2[C:13]([CH3:14])=[C:9]([C:7]([OH:6])=[O:8])[CH:10]=[N:11]2)=[N:16][CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ncc(C(F)(F)F)cc2F)c1C
Reactant: CO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)cnc1-n1ncc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4N Aqueous solution of sodium hydroxide (20 ml) and water (20 ml) were added to a solution of 1-[3-fluoro-5-(trifluromethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3 g) in methanol (20 ml) and tetrahydrofuran (20 ml), and stirred at room temperature for five hours. After completion of the reaction, the organic solvent was evaporated, diethylether and water was added to the residue. The aqueous layer was separated, pH was adjusted to 5 by the addition of concentrated hydrochloric acid under ice cooling, and the precipitated solid was collected by filtration dried at 60° C. under air blow to give the titled compound (1.17 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH:8]=[O:9].O.[SH-:12].[Na+].[BH4-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([SH:12])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: [SH-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1c(S)cncc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under argon atmosphere a mixture of 3,5-dichloro-pyridine-4-carbaldehyde (3.00 g, 17.05 mmol) and sodium hydrosulfide hydrate (flakes 70%, 1.37 g, 17.05 mmol) in DMF (20 mL) was stirred at 0° C. for 15 min. NaBH4 (8.52 g, 17.05 mmol) was added. After 30 min at 0° C. the solution was filtered and the solvent was removed in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 176.0 [M+H+].
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6]>CCO>[F:32][C:29]([F:30])([F:31])[C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=1)[CH2:18][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:5]([OH:6])=[O:4])[N:8]=[CH:9]1
Reactant: COC(=O)c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 103.4 %

Procedure:
Add 5N NaOH (200 mL) to a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazole-4-carboxylic acid methyl ester (3.0 g, 7.0 mmol) in EtOH (200 mL). Warm the mixture to 70° C. and stir for 16 h. Then cool to RT and concentrate to 220 mL under reduced pressure. Cool this solution to 0° C. and add conc. HCl to pH 1. Filter the resulting precipitate and dry under vacuum to provide 3.0 g (1100%) of the title compound as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.85 (s, 1R), 7.19–7.34 (m, SR), 7.15–7.02 (m, 2R), 5.20 (s, 2R), 3.20 (br s, 11H); MS/ES 415.2 (M+1).