Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][CH:9]2C#N)=O)=[CH:4][CH:3]=1.F[B-](F)(F)F.[H+].[C:27]([C:33]([O:35][CH3:36])=[O:34])#[C:28][C:29]([O:31][CH3:32])=[O:30]>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[N:8]3[C:9]([S:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=43)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:27]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:19][CH:20]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#CC1Sc2ccccc2N1C(=O)c1ccc(F)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(4-fluorobenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile (8.1 g, 28.0 mmol) in dichloromethane (50 mL) was added dropwise 8 mL of tetrafluoroboric acid (HBF4). The solution was stirred for 3 h at room temperature. The brown precipitates appeared were collected by filtration and the filter cake was washed with ether. The solid salt was added to a solution of dimethyl acetylenedicarboxylate (12.2 g, 84.0 mmol) in DMF (40 mL) and then warmed at 35° C. for 14 h. The reaction mixture was concentrated in vacuo and the residue was crystallized from methanol to give dimethyl 1-(4-fluorophenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate, 2.5 g (23%); mp 186-187° C. 1H NMR (DMSO-d6) δ 3.63 (3H, s, COOMe), 3.83 (3H, s, COOMe), 6.78-6.80 (1H, m, ArH), 7.28-7.30 (1H, m, ArH), 7.30-7.44 (3H, m, 3×ArH), 7.62-7.66 (2H, m, 2×ArH), 8.03-8.05 (1H, m, ArH). Anal. Calcd. for (C20H14FNO4S): C, 62.65; H, 3.68; N, 3.65; S, 8.36. Found: C, 62.68; H, 3.46; N, 3.62; S, 8.76.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:24][Si](C(C)(C)C)(C)C)[C:20]([O:22][CH3:23])=[O:21])[C:3]=1[CH3:32]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[C:3]=1[CH3:32]
Reactant: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(O)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetate (537.8 mg, 1.01 mmol) was dissolved in 4.0 mL TFA and heated to 60° C. The reaction was monitored by HPLC and turned dark quickly after addition of TFA. The reaction was completed after 1 h by HPLC, was removed from heat and diluted with toluene (20 mL) and concentrated in vacuo. This dilution/concentration was repeated twice more and the color was observed to diminished on each cycle. Purification via column chromatography using silica gel with EtOAc and heptane gave rise to desired product (297.9 mg, 0.71 mmol). 1H-NMR: (400 MHz, CDCl3): δ 10.34 (s, broad, 1H); 8.40 (d, J=8.0 Hz, 1H); 7.60-7.56 (m, 1H); 7.52-7.46 (m, 2H); 7.38-7.35 (m, 1H); 7.32-7.28 (m, 2H); 5.26 (s, 1H); 3.74 (s, 3H); 2.62 (s, 3H).
Reaction SMILES: ClCCl.C[O:5][C:6]1[C:15]2[C:10](=[C:11]([CH2:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.B(Br)(Br)Br>O>[CH2:16]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][CH:7]=[C:6]2[OH:5])[CH3:17]
Reactant: CCc1cccc2c(OC)cccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCc1cccc2c(O)cccc12
Temperature: 0 °C
Yield: 75 %

Procedure:
Anhydrous dichloromethane (20 mL) was added to 8 (870 mg, 4.6 mmol). After cooling to 0° C., BBr3 (boron tribromide 1.0M in dichloromethane) (14 mL, 14 mmol) was added dropwise. The reaction mixture was heated to reflux for 5 h. After cooling, a large amount of water was slowly added and the mixture was extracted three times with dichloromethane. The organic layer was evaporated and the residue was purified on MPLC to afford compound 9c, 75% yield; MS-ESI− (m/z, %): 171 (M+−1 , 100), 172 (M+, 45); 1H NMR δ 1.37 (3H, t, J=7.8 Hz, CH3CH2—), 3.10 (2H, q, J=7.8 Hz, CH3CH2—), 5.19 (1H, s, OH), 6.82 (1H, d, J=7.8 Hz, H-2), 7.31-7.45 (3H, m, H-3, 6, 7), 7.65 (1H, d, J=8.7 Hz, H-4), 8.06 (1H, d, J=8.1 Hz, H-8).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=O)[C:11]=2[CH2:10][CH2:9]1.[OH-].[Na+].P(Cl)(Cl)([Cl:27])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([Cl:27])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-oxo-6-methyl-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(16 g) was dissolved in phosphoryl chloride (100 ml) and heated at reflux for 5 hours. After cooling, the solution was poured onto ice, made alkaline with aqueous sodium hydroxide solution, and extracted with dichloromethane, which was dried and evaporated. Crystallisation from ethyl acetate gave 1-(2-methylphenyl)-4-chloro-6-methyl-2,3-dihydropyrrolo-[3,2-c]quinoline, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11]([OH:16])[CH2:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18].F[C:23]1C(C)=C(C=C(N=[N+]=[N-])C(OCC)=O)C=CC=1.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11]([O:16][CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCCC3O
Reactant: CCOC(=O)C(=Cc1cccc(F)c1C)N=[N+]=[N-]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCCC3OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The ethyl 5,6,7,8-tetrahydro-11-chloro-8-hydroxy-4H-azocino[3,2,1-hi]indole-2-carboxylate (1.90 g, 6.17 mmol) obtained in Example 23, (a) was added to a mixture of methanol (19 ml) and concentrated sulfuric acid (1.89 g) which had been cooled to 0° C. The reaction mixture was heated to 40° C. and stirred for 1 hour. The reaction mixture was poured into ice water and extracted twice with ethyl acetate, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/99) to obtain 1.96 g of ethyl 5,6,7,8-tetrahydro-11-chloro-8-methoxy-4H-azocino-[3,2,1-hi]indole-2-carboxylate as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:14][CH:15]=1
Reactant: N#CC(C#N)=Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
Then, 2.61 g of (4-(trifluoromethoxy)benzylidene)malononitrile was dissolved in 20 ml of tetrahydrofuran, and while stirring at room temperature, a suspension of 0.11 g of sodium borohydride in 5 ml of ethanol was added dropwise, followed by stirring at room temperature for 30 minutes. Then, 10% hydrochloric acid was added, and the mixture was extracted with diethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.20 g of (4-(trifluoromethoxy)benzyl)malononitrile (the intermediate (7)).
Reaction SMILES: C[Mg]Br.[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12].Cl.[C:15](=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH3:15])([CH3:12])[OH:13]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C([O-])O
Agent: C[Mg]Br
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccccc1N
Temperature: 25 °C

Procedure:
To a 0° C. solution of methylmagnesium bromide (45 mL of a 1.4M solution in toluene, 63 mmol) under nitrogen atmosphere was added a solution of ortho-aminoacetophenone (2.9 g, 21.5 mmol) in THF (20 mL). The mixture was warmed to ambient temperature for 45 min, cooled to 0° C., and poured into ice-water. The mixture was acidified with 6N HCl, adjusted to ca. pH 6 with saturated sodium bicarbonate solution, and then extracted with ether (2×100 mL). The combined ether fractions were dried (MgSO4), filtered and the solvent was removed under reduced pressure to give the oily product, 2-aminophenyldimethyl carbinol.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1c(Cl)nc2c(F)cccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2nccs2)nc2c(F)cccc2c1Cl

Procedure:
Prepared according to Procedure E using 2,4-dichloro-8-fluoro-3-methylquinoline (250 mg, 1.087 mmol), 2-tributylstannylthiazole (0.34 mL, 1.087 mmol) and tetrakis(triphenylphosphine)palladium(0) (126 mg, 0.109 mmol) in toluene (4 mL) and heating at reflux overnight. After purification 2-(4-chloro-8-fluoro-3-methylquinolin-2-yl)thiazole was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[CH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:4]=2[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1O.N>>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:17]1[C:15]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]([CH3:1])=[N:3][C:4]=2[CH:16]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1-c1ccccc1
Reactant: Nc1ccccc1O
Agent: N
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1-c1ccccc1
Temperature: 160 °C
Reaction time: 20 h
Yield: 67.7 %

Procedure:
A 2-neck flask (20 mL) equipped with reflux condenser was charged with 2-methyl-1-phenylbenzimidazole-5-carboxylic acid (see Synthesis Example 1-3) (0.15 g, 0.59 mmol), 2-aminophenol (0.09 g, 0.82 mmol) and polyphosphoric acid (approx. 2 g), and this was heated to 160° C. and stirred under those conditions for 20 hours. After being allowed to cool to room temperature, ice was added and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. The precipitated crystals were filtered off, these were washed with distilled water (approx. 3 mL, 2 times), and then dried to yield the title compound (0.13 g, 68% yield) as greenish pale yellow crystals.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C@H:12]2[C@H:17]([CH2:18][C:19]([O:21]C)=O)[CH2:16][CH2:15][N:14]([CH3:23])[CH2:13]2)=[CH:6][C:5]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)(Cl)=O>C(O)C.O>[Br:3][C:4]1[C:5]([O:24][CH3:25])=[CH:6][C:7]2[C@@H:12]3[C@H:17]([CH2:16][CH2:15][N:14]([CH3:23])[CH2:13]3)[CH2:18][C:19](=[O:21])[C:8]=2[C:9]=1[O:10][CH3:11]
Reactant: COC(=O)C[C@@H]1CCN(C)C[C@H]1c1cc(OC)c(Br)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: COc1cc2c(c(OC)c1Br)C(=O)C[C@H]1CCN(C)C[C@H]21
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
2 ml of 1N NaOH solution were added to a solution of 0.726 g (1.87 mmol) of methyl trans-[3-(4-bromo-3,5-dimethoxy-phenyl)-1-methyl-piperidin-4-yl]-acetate in 3 ml of ethanol and the mixture was stirred at 50° for 30 minutes. The solution was evaporated and the residue was dried in a high vacuum. The thus-obtained sodium salt was suspended in 5 ml of acetonitrile. After the addition of 278 mg (2 mmol) of potassium carbonate the suspension was treated at 0° with 0.913 ml (10 mmol) of phosphorus oxychloride and the mixture was subsequently stirred at 50° for 2 hours. Subsequently, the mixture was poured into 10 ml of water, adjusted to pH=12 with 28% NaOH and extracted three times with 15 ml of ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 95:5) yielded 0.385 g (58%) of trans-8-bromo-7,9-dimethoxy-2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with m.p. 226-228°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])[N:6]=[CH:5]2>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[C:13]([CH2:14][OH:15])[CH:17]=[CH:18][CH:19]=1)[N:6]=[CH:5]2
Reactant: O=C(O)c1cccc(-n2ncc3cc(I)ccc32)c1
Solvent: C1CCOC1
Product: OCc1cccc(-n2ncc3cc(I)ccc32)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
Crude 3-(5-iodo-1H-indazol-1-yl)benzoic acid (144c, 3.5 g, 9.6 mmol) was dissolved in THF (70 mL, dried over 4 Å MS) under argon atmosphere and cooled in an ice bath. Borane-THF complex (1M, 12 mL, 12 mmol) was added during 2 min. The cooling bath was removed and the mixture was stirred at r.t. for 15 min, then heated at reflux for 35 min. Additional borane reagent was added and the heating was continued for 20 min, at which time all starting material had been consumed. Sat. aqueous NR4Cl (25 mL) was added followed by ethyl acetate. The phases were separated and the organic phase was washed trice with water and finally with brine. Evaporation left a residue that was subjected to chromatography (SiO2, 10-80% EtOAc in Heptane) to afford a material that was crystallized from ethyl acetate-Heptane to give (3-(5-iodo-1H-indazol-1-yl)phenyl)methanol (1.69 g) as off white crystals. From the mother liquor was obtained in the same way additional 223 mg of the title compound. Total yield 60% over two steps.
Reaction SMILES: N1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[O:3]C1=O.C[N:14](C)C=O.NCCN1CCC(NC2N(CC3C=CC(F)=CC=3)C3C=CC=CC=3N=2)CC1>O>[C:4]([NH2:14])(=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O
Product: NC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
To a stirred and hot (50° C.) mixture of 4.1 parts of 2H-3,1-benzoxazine-2,4(1H)-dione and 31.5 parts of N,N-dimethylformamide was added dropwise a solution of 9.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine in 31.5 parts of N,N-dimethylformamide at 50° C. Upon completion, stirring was continued for 3 hours at 50° C. Water was added and the product was extracted with 4-methyl-2- pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 9.8 parts (80%) of 2-amino-N-[2-[4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide; mp. 171.7° C. (58).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH2:21][CH:20]=3)=[CH:18][C:13]=2[O:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][N:28]([CH2:4][C:3]5[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=5[Cl:1])[CH2:27][CH2:26]4)[CH2:21][CH:20]=3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: ClCc1ccccc1Cl
Reactant: C1=C(c2ccc3c(c2)OCO3)CCC(N2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccccc1CN1CCN(C2CC=C(c3ccc4c(c3)OCO4)CC2)CC1

Procedure:
The title compound was prepared from 2-chlorobenzyl-chloride (0.16 g, 1 mmole), 1-[4-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl]piperazine (0.29 g, 1 mmole), and excess powdered K2CO3 as described in example 45 to give the product (78%, mp: 115-116° C.). Calc'd for C24H27ClN2O2 : C, 70.14%; H, 6.62%; N, 6.82%. Found: C, 70.25; H, 6.69%; N, 6.83%.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](=O)[CH3:30])=[CH:28][C:23]=2[CH2:22][CH2:21]1>O1CCCC1>[Br:19][C:15]1[CH:14]=[C:13]([C:29]([C:27]2[CH:26]=[CH:25][C:24]3[O:20][CH2:21][CH2:22][C:23]=3[CH:28]=2)=[CH2:30])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc2c(c1)CCO2
Reaction time: 0.33 h

Procedure:
A 1.6 M solution of n-butyllithium in hexane (22.3 mL, 35.7 mmol, 1.16 eq.) was added dropwise to a solution of 1,3-dibromobenzene (8.0 g, 33.9 mmol, 1.1 eq) in 30 mL of dry tetrahydrofuran at −78° C. under nitrogen, and the mixture was stirred for 20 min. After this time, a solution of 1-(2,3-dihydro-benzofuran-5-yl)-ethanone (5.0 g, 30.8 mmol, 1.0 eq, prepared as shown in Scheme 4) in 20 mL of dry tetrahydrofuran was added over 10 minutes and the resulting solution was further stirred for 45 min. The reaction mixture was examined LCMS which showed complete conversion to the desired product. 20 mL of a saturated aqueous solution of ammonium chloride was added and the cooling bath was removed. The mixture was poured into 100 mL of a 1:1 diisopropyl ether/water mixture. The organic fraction was dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in 10 ml, of acetic acid. 0.3 mL of 98% sulfuric acid were added and the dark solution was stirred at room temperature. After 30 min LCMS showed complete conversion to the desired product. Crushed ice was poured in the reaction mixture which was then extracted with dichloromethane. The organic fraction was collected, washed with water, sodium bicarbonate solution and dried with over sodium sulfate. The crude product was purified by flash chromatography eluting with cyclohexane. 3.5 g of clean product was obtained as colorless liquid (yield: 38%)
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH2:18][CH:17]([C:32]([O:34]C)=[O:33])[CH2:16]2)=[O:14])[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1>CO>[N:7]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=3)[CH2:18][CH:17]([C:32]([OH:34])=[O:33])[CH2:16]2)=[O:14])[CH2:8][CH2:9][S:10][CH2:11][CH2:12]1
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
20.4 g (182 mmol) of potassium tert-butoxide were added at RT to a solution of 7.85 g (18.2 mmol) of the compound from Example 24A in methanol (650 ml). The mixture was stirred at 60° C. overnight. For workup, the methanol was removed under reduced pressure, the residue was admixed with water and the mixture was acidified (pH 1) with aqueous 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried with magnesium sulphate, filtered and concentrated under reduced pressure. The reaction led to an 85:15 cis/trans isomer mixture. Yield: 7.70 g (99% of theory)
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[BrH:11]>C1C=CC=CC=1>[Br:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCCCCO
Reactant: Br
Solvent: c1ccccc1
Product: OCCCCCCCCBr
Yield: 71 %

Procedure:
1,8-Octanediol (14.62 g, 0.1 mole) was dissolved in benzene (200 mls) and 12.5 mls of conc (46.48%) aqueous HBr added. The mixture was then heated overnight at reflux whilst removing the water using a Dean & Stark apparatus. About 12 mls of water were rapidly removed within the first 4 hours. The crude mixture was washed with 6N NaOH (100 mls), 10% aq HCl (100 mls), water (2×200 mls) and brine (150 mls). The solvent was removed to give a colourless liquid, (14.8 g, 71%) 1-bromooctan-8-ol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7](Cl)[N:6]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[OH-].[Na+]>O>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([OH:16])[CH:18]=2)[N:6]=1
Reactant: Nc1cccc(O)c1
Reactant: OCCNc1nc(Cl)nc(NCCO)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCNc1nc(NCCO)nc(Nc2cccc(O)c2)n1

Procedure:
70.1 g (0.3 mol) of 2,4-bis-(2-hydroxyethylamino)-6-chloro-1,3,5-triazine, 32.8 g (0.3 mol) of 3-hydroxyaniline and 400 ml of water are placed in a 2 l flask equipped with a stirrer, a dropping funnel, a reflux condenser and a thermometer. The mixture is heated under reflux, with stirring. In the course of this, a solution of 12 g of sodium hydroxide in 60 ml of water is added dropwise slowly at such a rate that a slightly alkaline reaction mixture results. 300 ml of water are then added, as well as active charcoal for the removal of colour. The hot solution is then filtered and cooled. The resulting, virtually colourless crystals are filtered off with suction, washed free from chloride with a little water and dried. The product has a melting point of 142°-143° C. The yield is 70.8 g (=77% of theory).
Reaction SMILES: P(O)(O)(O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][O:12][NH2:13])=[CH:9][C:8]=1[OH:16].C(=O)(O)[O-].[Na+].[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=O)[C:31]([OH:33])=[O:32])[N:29]=1)=[O:23]>O.C(O)C>[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:13][O:12][CH2:11][C:10]2[CH:14]=[CH:15][C:7]([Br:6])=[C:8]([OH:16])[CH:9]=2)[C:31]([OH:33])=[O:32])[N:29]=1)=[O:23]
Reactant: NOCc1ccc(Br)c(O)c1
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=CNc1nc(C(=NOCc2ccc(Br)c(O)c2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
The solution of 4-bromo-3-hydroxybenzyloxyamine phosphate (17.4 g.) in water (200 ml.) and ethanol (200 ml.) was stirred at room temperature and adjusted to pH 7.0 with sodium bicarbonate. 2-(2-Formamidothiazol-4-yl)glyoxylic acid (10.0 g.) was added to the solution and the resulting suspension was adjusted to pH 4.0 to 4.5. After stirring the solution at room temperature for 2 hours, ethanol was removed from the resultant solution in vacuo. Ethyl acetate was added to aqueous residue and adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. The solution was concentrated in vacuo to give 2-(2-formamidothiazol-4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetic acid (syn isomer, 14.8 g.).