Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[I-].[K+]>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCCCCCCCCCCO
Temperature: 80 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
25.9 g (170 mmol) of 4-hydroxy-3-methoxybenzaldehyde and 38.9 g (155 mmol) of 11-bromoundecan-1-ol are dissolved in 200 mL of N,N-dimethylformamide. 23.57 g (170 mmol) of potassium carbonate and 2.47 g (15 mmol) of potassium iodide are added and the suspension is heated to 80° C. After 12 h, the reaction mixture is cooled to room temperature and poured to icy water. The precipitate is filtered off, digested in 500 mL of water and the mixture was neutralized with hydrochloric acid 37%. The precipitate is filtered off, washed with water and dried overnight at 40° C. 48.5 g of 4-[(11-hydroxyundecyl)oxy]-3-methoxybenzaldehyde are obtained as a slightly pink solid (97% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(Oc2nccnc2C2CCNCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a flask containing tert-butyl 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate (230 mg, 0.460 mmol) is added chloroform (5 mL) and 2,2,2-trifluoroacetic acid (0.709 mL, 9.21 mmol). The reaction was stirred at rt 18 h. The solution was concentrated, followed by azeotropic removal of residual trifluoroacetic acid by concentration from toluene (5 mL×2). The crude salt was freebased by dissolving in MeOH and application to a 5 g Bondesil-SCX ion exchange column. Elution of the product with NH3 in MeOH (2.0 M) and concentration of the product containing fractions gives (1H-benzo[d]imidazol-2-yl)(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)methanone as a brown solid. MS (ESI, pos. ion) m/z: 400.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:30])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl (R)-3-amino-pyrrolidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].[CH3:37][O-:38].[Na+]>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[N:11]=[C:12]([O:38][CH3:37])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: C[O-]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Agent: [Na+]
Product: COc1nc(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)c2ccccc12

Procedure:
The compound obtained in Example 275 was reacted with sodium methoxide by a method similar to Example 270 to yield the title compound as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)=[N:22][CH:21]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2ccc(-c3ccc(C4CCNCC4)cc3)cn2)cn1
Reaction time: 18 h

Procedure:
4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (1.02 g, 2.0 mmol) was slurried in 1,4-dioxane/MeOH (5:1, 6 mL) and was treated with HCl (4M in 1,4-dioxane, 2 mL). After 18 hours, added more HCl (4M, 1,4-dioxane, 3 mL) and stirred 2 days. The solvents were removed via rotary evaporation and the crude was dried under vacuum to obtain the hydrochloride salt of the title compound as a sticky yellow solid which was used in the next step without further purification: MS (M+H)+399.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.O=[S:20](Cl)Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:9][S:20][N:8]=2
Reactant: Nc1ccc(Br)cc1N
Reactant: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Brc1ccc2nsnc2c1
Temperature: 25 °C

Procedure:
To a solution of 4-bromobenzene-1,2-diamine (5.236 g, 28.0 mmol) and Hunig's base (19.5 mL, 112 mmol) in dichloromethane (160 mL) was added SOCl2 (4.08 mL, 56 mmol) dropwise at room temperature. The resulting reaction mixture was heated to reflux overnight. The reaction mixture was then allowed to cool to room temperature, and quenched with 10% HCl until pH=2. The resulting mixture was extracted with dichloromethane (200 mL×4), dried over Na2SO4 and concentrated. The crude compound was purified by flash column chromatography (silica gel, chloroform) to afford 5-bromobenzo[1,2,5]thiadiazole as a brown solid which was used directly in the next step. 1H NMR (CDCl3 500 MHz): δ: 8.21 (d, 1H, J=1.5 Hz), 7.87 (d, 1H, J=8.5 Hz), 7.69 (dd, 1H, J=8.5, 1.5 Hz).
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[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=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[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
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(-c2ccccn2)nc2c(F)cccc2c1Cl

Procedure:
Prepared according to general Procedure E using 2,4-dichloro-8-fluoro-3-methylquinoline (1.0 g, 4.35 mmol), tetrakis(triphenylphosphine)palladium(0) (251 mg, 0.22 mmol) and 2-tributylstannylpyridine (1.6 mL, 4.35 mmol) in toluene (15 mL) to give 4-chloro-8-fluoro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[O:11][N:10]=1)(C)(C)C.[Si](I)(C)(C)C.CO>C(Cl)(Cl)Cl>[NH2:7][CH2:8][C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[O:11][N:10]=1
Reactant: CC(C)(C)OC(=O)NCc1noc(-c2ccnc(C#N)c2)n1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#Cc1cc(-c2nc(CN)no2)ccn1
Reaction time: 0.17 h

Procedure:
NEt3 (6.6 ml, 47.3 mmol) was added to a stirred solution of 2-cyanoisonicotinic acid (7.00 g, 47.3 mmol) in toluene (500 ml). The mixture was cooled to 0° C., before being treated with isobutyl chloroformate (6.1 ml, 47.3 mmol). Stirring was continued at 0° C. for 10 min, then the mixture was allowed to warm to rt over 1 h, before being treated with (N-hydroxycarbamimidoylmethyl)carbamic acid tert-butyl ester (7.44 g, 39.4 mmol) and dried 4 Å molecular sieves (40 g). The reaction was heated under reflux for 16 h. On cooling, the mixture was filtered through celite, washing with MeOH. The combined filtrates were concentrated in vacuo, then the residue was dissolved in EtOAc. The EtOAc solution was washed with saturated aqueous Na2CO3 and brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH-EtOAc, 7:3) furnished [5-(2-cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethyl]carbamic acid tert-butyl ester m/z (ES+)=603.2 [2M+H]+. A stirred solution of this carbamate (1.95 g, 6.5 mmol) in CHCl3 (50 ml) was treated with TMS-I (2.2 ml, 15.6 mmol). After 10 min, the reaction was treated with MeOH (2.5 ml, 62.2 mmol), then stirring was continued for a further 10 min. The solvents were evaporated off under reduced pressure, then the residue was dissolved in MeOH and adsorbed onto SiO2. Column chromatography (EtOAc then EtOAc-MeOH, 9:1) afforded the title compound: m/z (ES+)=202.0 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1)=O.C[Mg]Br.[Cl-].[NH4+].[CH2:21]([O:23]CC)C>>[OH:23][CH2:21][CH2:1][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)c1ccc(CCO)cc1

Procedure:
t-Butyl p-formylbenzoate (20 g, 97 mmol) was dissolved in dry diethyl ether (300 ml), followed by the dropwise addition of methylmagnesium bromide ethereal solution, 33 ml) under cooling with ice and stirring. The obtained mixture was stirred for one hour and poured into a saturated aqueous solution of ammonium chloride, and the obtained mixture was extracted with ether. The ethereal phase was washed with water, dried and distilled to remove the solvent. The pale-yellow viscous liquid residue thus obtained was subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/hexane=1:4) to give 21.8 g of t-butyl 4-(hydroxyethyl)benzoate.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)=[N:5][N:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>ClCCl.CO>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[N:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nnc(Cc2ccncn2)c2ccccc12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Clc1ccc(Nc2nnc(Cc3ccncn3)c3ccccc23)cc1

Procedure:
A mixture of 100 mg (0.45 mmol) 1-chloro-4-(4-pyrimidinylmethyl)phthalazine hydrochloride and 149 mg (1.17 mmol) 4-chloroaniline is heated for 1.5 h to 100° C. The reaction mixture is distributed between dichloromethane/CH3OH, 19:1 and sat. NaHCO3solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4), and concentrated by evaporation. Chromatography (SiO2; ethyl acetate/CH3OH, 19:1) and crystallization from ethyl acetate/ether yield the title compound: m.p.: 174-176° C.; FAB MS (M+H)+=348. The starting material is prepared as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10]N1C(=O)CCC1=O>CN(C=O)C>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([OH:9])=[C:4]([F:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1c(F)cccc1F
Solvent: CN(C)C=O
Product: Oc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
To a solution of 2,6-Difluorophenol (10.0 g, 76.86 mmoles) in DMF (60 mll), N-bromosuccinimide (13.68 g, 76.86 mmoles) was added at 0° C. and stirred at RT for 20 h. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as light yellow liquid (15.1 g, 93% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.49(s,1H), 7.35 (d, J=6.2 Hz, 2H).
Reaction SMILES: [Al].[Pb](Br)Br.[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:14](Cl)([Cl:17])([Cl:16])[Cl:15]>CN(C)C=O>[Cl:15][C:14]([Cl:17])([Cl:16])[CH:9]([C:8]1[CH:7]=[C:6]([OH:5])[CH:13]=[CH:12][CH:11]=1)[OH:10]
Reactant: O=Cc1cccc(O)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: Br[Pb]Br
Agent: [Al]
Solvent: CN(C)C=O
Product: Oc1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 52 %

Procedure:
Aluminum (8.06 g, 0.3 mol) and lead bromide (3.7 g, 0.01 mmol) were added to a mixture of 3-hydroxy benzaldehyde (12.3 g, 0.1 mol) was mixed with 200 ml of dimethylformamide. Carbon tetrachloride (61.53 g, 0.4 mol) was slowly added thereto, the mixture was stirred at room temperature for 10 hours, and unreacted solid was filtered to remove therefrom. After sequentially adding 5% HCl, ethylacetate and water thereto, the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and distilled. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:4) to obtain the title compound (12.57 g, 91%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[OH:16][C:17]1[C:22]2[O:23][C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:25][C:21]=2[CH:20]=[C:19]([C:38](Cl)=[O:39])[CH:18]=1>C(Cl)Cl>[OH:16][C:17]1[C:22]2[O:23][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:25][C:21]=2[CH:20]=[C:19]([C:38]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:39])[CH:18]=1
Reactant: O=C(Cl)c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
Piperidine (0.3 ml, 2 mmol) and ethyl diisopropylamine (0.5 ml, 3 mmol) were dissolved in methylene chloride (10 ml). 7-Hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl chloride (353 mg, 1 mmol) dissolved in methylene chloride (3 ml) was added dropwise at room temperature. The reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was extracted with IN aqueous HCl solution, brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue purified by column chromatography on silica gel (20 g, 5% methanol in dichloromethane eluant) to yield the phenol as a white solid (180 mg, 45%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15]([SH:17])[CH3:16].[OH-].[K+]>C(O)C.C(OCC)(=O)C>[CH2:15]([S:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:16]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCSCCCCCCCCCCC(=O)O
Yield: 8.2 %

Procedure:
11-Bromoundecanoic acid (1 g, 3.77 mmol, Aldrich) was added to a solution of ethanethiol (0.279 mL, 3.77 mmol, Aldrich) and potassium hydroxide (0.486 g, 8.66 mmol) in absolute ethanol (40 mL) and refluxed for 5 hr under a nitrogen atmosphere. After cooling and acidification with HCl, solvent was removed under reduced pressure to give a white solid. The solid was dissolved in ethyl acetate and extracted with water. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by silica column chromatography using increasing concentrations of ethyl acetate in hexane for elution. The product eluted at 25% ethyl acetate/hexane. Solvent was removed under reduced pressure to yield 11-(ethylthio)-undecanoic acid (76 mg, 8%), mp 58-61°C.; 1H NMR (300 MHz, CDCl3) δ1.24 (t, 3H, J=7.4, CH3), 1.20-1.40 (bm, 12H, methylene envelope), 1.48-1.67 (bm, 4H, S--CH2 --CH2COO--CH2 --CH2), 2.33 (t, 2H, J=7.5, CH2 --COOH), 2.49 (t, 2H, J=7.4, S--CH2 --CH2), 2.51 (q, 2H, J=7.4, S--CH2 --CH3), 10.5 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCl3) δ14.88, 24.70, 25.98, 28.97, 29.08, 29.24*, 29.38, 29.48, 29.69, 31.73, 34.11, 180.05; MS, m/z 246 (M+, 50), 217 (COOH(CH2)10S+, 7), 199 (100), 181 (7), 167 (7), 149 (6), 117 (7), 101 (9), 97 (9), 87 (14), 83 (18), 75 (54), 69 (29), 62 (18), 55 (37).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)s1
Yield: 81.2 %

Procedure:
A mixture of the title compound of Example 2 (200 mg, 1.37 mmol), thionyl chloride (500 μl, 6.85 mmol) and DMF (20 μl) in dry methylene chloride was refluxed for 2 hours. The solvents were evaporated and the residue dried in vacuo to give 183 mg (81%) of the title product as a brown solid, mp 123-5 C. 1H-NMR (CDCl3): δ 7.74 (m, 1H), 6.64 (m, 1H),). GC-MS (m/e, %) 166/164 (M+, 11), 129(100).
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15](N)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:2].[BrH:22].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.CC#N>[Br:22][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH:4]([N:5]3[CH:9]=[CH:8][N:7]=[CH:6]3)[CH:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[CH:19]=[CH:18][C:13]=2[N:14]=1
Reactant: Br
Reactant: CCC(CC)C(c1ccc2nc(N)sc2c1)n1ccnc1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(CC)C(c1ccc2nc(Br)sc2c1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (260 mg, 0.866 mmol) and water (4 mL) at 0° C. was added aqueous HBr (0.98 mL, 8.66 mmol) and the mixture was cooled to −0° C. A cold (−10° C.) solution of sodium nitrite (75 mg, 1.08 mmol) in water (1 mL) was added to the reaction mixture over a period of 5 min while maintaining the temperature below −5° C. and the reaction was stirred at −10° C. for 15 min. To a cold (−10° C.) solution of CuBr2 (253 mg, 1.08 mmol) in water (4 mL) was added the reaction mixture and stirred for 10 min at 0° C. MeCN was added to the reaction mixture and then the reaction mixture was stirred for 2.5 h while warming to RT. The reaction was basified with sat. aq. NaHCO3 (pH 7) and then 10 N NaOH (pH 8) followed by celite filtration. The aqueous phase was extracted three times with DCM and the organic extracts were combined and dried over MgSO4, filtered and then concentrated. The crude product was purified by preparative TLC using 5% MeOH in DCM as eluent to afford to 2-bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole as white solid. MS (ES+): m/z 364 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:20])=[CH:15][CH:14]=1
Reactant: O=C(Cl)COc1ccc(F)cc1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1ccc(F)cc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and (4-fluoro-phenoxy)-acetyl chloride (471.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 2-(4-fluorophenoxy)-1-(3-phenylpyrrolidin-1-yl)ethan-1-one are collected and the solvent is removed in vacuo to give 495 mg of colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>>[NH2:2][O:1][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: N#Cc1cccc(CON)c1

Procedure:
Prepared by a similar procedure as described for preparation 15, starting from N-hydroxyphthalimide and 3-bromomethyl-benzonitrile. 13C-NMR (CDCl3) δ 139.5, 132.5, 131.7, 131.5, 129.2, 118.7, 112.6, 76.5.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=1[C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[OH:21][C:19]1[CH:20]=[C:15]2[C:16]([C:22](=[O:32])[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:1]([CH3:2])[O:14]2)=[CH:17][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C)oc3cc(O)ccc3c2=O)cc1
Temperature: 115 °C

Procedure:
Acetic anhydride (3 ml, 30 mmol) was added to a suspension of potassium carbonate (4.0 g, 29 mmol) and 1-(2,4-dihydroxy-phenyl)-2-(4-methoxy-phenyl)-ethanone (1.95 g, 7.5 mmol) in DMF (10 ml), and the resulting suspension heated at 115° C. for ˜90 mins. The mixture was allowed to cool and poured into water (200 ml), to give an off-white precipitate. The solids were removed by filtration and washed with water (100 ml) and diethyl ether (2×40 ml), to give 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one as an off-white powder, dried in vacuo, (1.65 g)