Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[P:10](Cl)([Cl:13])([Cl:12])=[O:11].C(N(CC)CC)C.O>C(Cl)(Cl)(Cl)Cl>[P:10]([Cl:13])([Cl:12])(=[O:11])[O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][Br:1])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cccc(CBr)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1cccc(CBr)c1
Reaction time: 0.67 h

Procedure:
To mixture of 17 g of m-bromomethylphenol in 150 ml of carbon tetrachloride under argon was added a solution of 25.5 g of phosphorous oxychloride in 25 ml of carbon tetrachloride. The solution was cooled in a water bath and a solution of 9.18 g of triethylamine in 35 ml of carbon tetrachloride was added dropwise with stirring over 40 minutes. This mixture was stirred in the water bath for 1 hour then overnight at room temperature, filtered through diatomaceous earth and washed with carbon tetrachloride. The mother liquor was taken to dryness giving 23-29 g of the desired compound as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[C:6]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:5]=1.C1COCC1.O[Li].O>CO>[CH3:22][O:21][C:20]1[C:15]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[CH:14]=[N:13][N:12]=[N:11]3)[CH:7]=2)[C:3]([OH:23])=[O:2])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(-c2ncccc2OC)cc(-n2cnnn2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccnc1-c1cc(C(=O)O)cc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
3-(3-Methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester (170 mg, 0.52 mmol) was added to a mixture of THF (20 mL) and MeOH (5 mL) and cooled to ice bath temperature under nitrogen atmosphere. LiOH.H2O (8.8 g, 2.1 mmol) was added, and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure and 10.0 g of water ice and 10 mL of 10% aqueous HOAc were added to the residue. The resulting mixture was filtered, and the filtrate was washed with 10% aqueous HOAc. The collected solid was dried under vacuum at 60° C. for 3 horus to give 140 mg of 3-(3-methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid, MS (M+H)=298.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1C=O.[CH3:35][Mg]Br.[C:38](=[O:41])(O)[O-].[Na+].O>ClCCl>[OH:41][CH2:38][CH2:35][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[N:3]1[C:2](=[O:1])[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4]1
Reactant: O=C([O-])O
Reactant: C[Mg]Br
Reactant: O=Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CCO
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzaldehyde (Example 529, 76 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL) and cooled to −78° C. Methylmagnesium bromide (0.057 mL, 3 M diethyl ether solution, 0.17 mmol, 1 equiv) was added dropwise and the mixture was stirred for 30 minutes at −78° C. Additional methylmagnesium bromide (0.057 mL, 3 M diethyl ether solution, 0.17 mmol, 1 equiv) was added and the mixture was stirred for an additional 30 minutes at −78° C. The mixture was treated with sodium bicarbonate (3 mL, aqueous saturated), warmed to ambient temperature, poured into water (10 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate; then 100:0 to 0:100; ethyl acetate:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.13 (1H, s), 8.45 (1H, d, J=2.4 Hz), 8.18 (1H, d, J=8.0 Hz), 7.83 (2H, d, J=8.6 Hz), 7.78 (1H, d, J=8.8 Hz), 7.73 (1H, d, 1.1 Hz), 7.70 (1H, d, J=7.8 Hz), 7.65-7.60 (1H, m), 7.54 (1H, t, J=7.7 Hz), 7.48 (2H, d, 8.3 Hz), 7.44 (1H, d, J=7.8 Hz), 7.39-7.31 (2H, m), 6.53 (1H, m), 5.78 (2H, s), 5.19 (1H, d, J=4.2 Hz), 4.94-4.88 (1H, m), 1.27 (3H, d, J=6.4 Hz) ppm; high resolution mass spectrometry (ES+) m/z 462.1906 [(M+H)+; calculated for C29H24N5O2: 462.1925].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].[Cu](C#N)[C:16]#[N:17]>CN(C)C=O>[C:16]([C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:17]
Reactant: N#C[Cu]C#N
Reactant: CC(=O)c1ccc(CC(C)C)c(Br)c1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CC(C)C)c(C#N)c1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
3′-Bromo-4′-isobutylacetophenone (182 g) and copper cyanide (95.7 g) were stirred in dimethylformamide (520 ml) at 140° C. for 7 h. The reaction mixture was cooled to room temperature and the solid was filtered off. To the filtrate was added water and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from n-hexane to give 3′-cyano-4′-isobutylacetophenone (70 g), melting point: 71–72° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]3C(C)(C)[O:19][CH2:20][CH:14]3[CH2:13]2)=[CH:4][CH:3]=1.Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH2:20][OH:19])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OCC2CN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CCN21
Agent: Cl
Solvent: O
Product: OCC1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Temperature: 25 °C

Procedure:
A mixture of 34 parts of 7-[4,4-bis(4-fluorophenyl)butyl]hexahydro-3,3-dimethyl-1H-oxazolo[3,4-a]pyrazine and 272 parts of a hydrochloric acid solution 0.5N in water was stirred and refluxed for 2 hours. The reaction mixture was cooled to room temperature and the product was extracted twice with 1,1'-oxybisethane. The aqueous phase was separated, alkalized and salted out with sodium carbonate. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (85:15 by volume), saturated with ammonia as eluent. The pure fractions were collected and the eluent was evaporated, yielding 17.0 parts of 4-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinemethanol as an oily residue (intermediate 100).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:15][NH2:16]>ClCCl.C(O)C>[CH3:15][NH:16][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH:3]=1
Reactant: CN
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: CNCc1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
10 g of 4-Biphenylcarbaldehyde and 40 ml of 33% ethanolic methylamine are stirred overnight at room temperature with a 4 Å molecular sieve. The mixture is filtered and concentrated under vacuum. The residue is treated in 60 ml of ethanol with 2 g of sodium borohydride and stirred for 3 hours. The solvent is removed under vacuum, the residue partitioned between ether and water and the organic phase dried and concentrated. The pure base is obtained as an oil following chromatography on silica gel with dichloromethane/ethanol=9/1 as eluant.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C1COCC1.[OH:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:21]2[C:22]([O:24][C:25](=[O:26])[C:20]=12)=[O:23]>CCOCC>[CH3:8][S:9]([O:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:21]2[C:22]([O:24][C:25](=[O:26])[C:20]=12)=[O:23])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OC(=O)c2c(O)cccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)Oc1cccc2c1C(=O)OC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Triethylamine (0.83 g) and methanesulfonyl chloride (0.89 g) were added to a THF solution (10 mL) of 3-hydroxyphthalic anhydride (1.22 g) under ice cooling and the mixture was stirred at room temperature for 8 hours. After finishing the reaction, ether (20 mL) was added and the mixture was washed consecutively with water and saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crude product was washed with a mixed solvent of ether and n-hexane to obtain 3-methanesulfonyloxyphthalic anhydride (1.75 g) having the melting point of 134–140° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[O:4][NH:3]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[O:4][N:3]1[CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1ccc(C2ONC(C)C=C2C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C2ON(Cc3ccc(OC)c(OC)c3)C(C)C=C2C)cc1

Procedure:
A mixture of 0.5 ml of a 0.05M solution of 3,5-dimethyl-6-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine in dichloromethane. 0.5 ml of a 0.75M solution of 3,4-dimethoxybenzaldehyde in dichloromethane, and 0.5 ml of a 0.75M solution of sodium triacetoxyborohydride in dichloromethane was stirred at ambient temperature for 19 h. Methanol (1.0 ml) was added with stirring and the mixture applied to a methanol washed 500 mg Isolute SCX cartridge (Jones Chromatography). The absorbent was washed with methanol (2.5 ml) and then eluted with 2M ammonia in methanol (2.5 ml). The eluate was concentrated to dryness using a centrifugal evaporator and the residue dissolved in chloroform (2 ml) and added to methylisocyanate-polystyrene (loading 1.0 meq/g, 100 mg). This suspension was shaken gently for 19 h, then filtered and resin washed with chloroform (2×2 ml). Removal of the solvent from the combined filtrates by centrifugal evaporation gave 3,5-dimethyl-2-(3,4-dimethoxybenzyl)-6-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine. 1H NMR (CDCl3) δ 1.23(3H, d), 1.49(3H, s), 3.39(1H, m), 3.62(1H, d), 3.70(3H, s), 3.79(3H, s), 3.83(3H, s), 4.05(1H, d), 4.92(1H, s), 5.61 (1H, d), 6.64 (3 H, m),6.81 (2H, d), 7.22 (2H, d).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])[N:28]=[CH:27][N:26]=[C:25]2[S:37][C:38]1[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=1)[NH2:41].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[C:38]([S:37][C:25]3[C:24]4[C:29](=[CH:30][C:31]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:22]([O:21][CH3:20])[CH:23]=4)[N:28]=[CH:27][N:26]=3)[CH:39]=2)=[O:19])[O:7][N:6]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (86 mg, 0.33 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (97 mg, 0.27 mmol). To this solution was added diisopropylethyl amine (71 μL, 0.41 mmol) and DMAP (5.0 mg, 0.04 mmol). The reaction was concentrated to dryness and partitioned between water and dichloromethane, and extracted twice. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The oil was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane 12-70% over 18 column volumes. The appropriate peak was concentrated to a white solid weighing 18 mg. 1H (DMSO-d6) 10.42 (s, 1H), 9.11 (s, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.55 (m, 1H), 7.45 (m, 1H), 7.34 (m, 3H), 6.16 (s, 1H), 4.33 (m, 2H), 4.00 (s, 3H), 3.76 (s, 2H), 1.70 (s, 3H), 1.63 (s, 3H). LCMS (ESI) m/z 528 (M+H)
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([CH2:25]Cl)[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4].O.O.[Na+].[CH3:33][N:34]([CH3:38])[C:35](=[S:37])[S-:36]>C(#N)C.O>[CH3:1][N:2]([CH3:29])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([CH2:25][S:37][C:35](=[S:36])[N:34]([CH3:38])[CH3:33])[N:24]=1)=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4]
Reactant: COc1cc(CCl)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)n1
Reactant: CN(C)C(=S)[S-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(CSC(=S)N(C)C)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)n1

Procedure:
A mixture of 9.3 g of N-(2-dimethylsulfamoylphenylsulfonyl)-N'-(4-chloromethyl-6-methoxy-pyrimidin-2-yl)-urea and 3.7 g of dimethyldithiocarbamic acid sodium salt dihydrate is stirred in 100 ml of acetonitrile at 20°-25° C. for 3 hours. In further processing, the reaction mixture is diluted with 1 liter of water, and the precipitated product is separated. The yield is 10.0 g (91% of theory) of N-(2-dimethylsulfamoylphenyl-sulfonyl)-N'-(4-methoxy-6-dimethylthiocarbamoylthiomethyl-pyrimidin-2-yl)-urea m.p. 181°-183° C. (decomp.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[C:18](Br)=[CH:19][CH:20]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:13]=3[C:12](=[O:27])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH2:1]([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:13]=3[C:12](=[O:27])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CCN(Cc1ccccc1)C3
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(Cc1ccccc1)C3
Yield: 62.4 %

Procedure:
To a solution of methyl 2-benzyl-9-bromo-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (0.1 g, 0.23 mmol) in MeOH (3 mL) was added Pd/C (0.04 g, 5%, 50% water), and the mixture was stirred at atmosphere of hydrogen for about 2.5 h. Debromination occurred without substantially removing benzyl group under this condition. Then the mixture was filtered, washed with MeOH (50 mL), concentrated and was chromatographed on silica gel to afford the product (0.05 g). MS (ESI) m/e [M+1]+ 349.0.
Reaction SMILES: I[CH2:2][C:3]([O:5][CH:6]([C:9]1[CH:25]=[C:24]2[N:12]([CH2:13][C:14]3[C:15]2=[N:16][C:17]2[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:26])[C:10]=1[CH3:27])[CH2:7][CH3:8])=[O:4].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.[ClH:33]>O>[ClH:33].[N:28]1([CH2:2][C:3]([O:5][CH:6]([C:9]2[CH:25]=[C:24]3[N:12]([CH2:13][C:14]4[C:15]3=[N:16][C:17]3[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:26])[C:10]=2[CH3:27])[CH2:7][CH3:8])=[O:4])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: c1c[nH]cn1
Reactant: CCC(OC(=O)CI)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Agent: Cl
Solvent: O
Product: CCC(OC(=O)Cn1ccnc1)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 13 except using (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one and imidazole. 1H NMR (CDCl3 /MeOH-d4) d 9.17 (s, 1H), 8.60 (s, 1H), 8.34 (d, 1H), 8.04 (d, 1H), 7.95 (m, 1H), 7.75 (m, 1H), 7.61 (s, 1H), 7.51 (br s, 1H), 7.41 (br s, 1H), 5.95 (m, 1H), 5.65 (d, 1H), 5.42 (d, 1H), 5.33 (s, 2H), 2.36 (s, 3H), 2.1-1.9 (m, 2H), 1.07 (t, 3H). Anal. Calcd for C24H22N4O3.2 HCl.11/4 H2O: C, 53.68; H, 5.35; N, 10.43. Found: C, 53.52; H, 5.58; N, 10.29.
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:28][Si](C)(C)C>ClCCl.CN(C)C=O>[CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH2:28])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid (Example 2; 364 mg, 1.20 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) cooled to 0° C. was treated with oxalyl chloride (2.0M solution in dichloromethane, 0.84 mL, 1.68 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (0.90 mL, 4.20 mmol) was added and the cloudy mixture was stirred at 25° C. for 16 h. At this time, the reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to afford rac-2-cyclohexyloxy-2-(3,4-dichloro-phenyl)-acetamide (311 mg, 76% yield) as a colorless oil: FAB-HRMS m/e calcd for C14H17NCl2O2 (M+H)+ 302.0714, found 302.0728.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[N:8]=[C:9](CO)[NH:10][C:11]=1[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][C:24]2[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([Cl:32])[CH:25]=2)[C:17]=1[F:33])=[O:13].[CH3:36][CH2:37][N:38]([CH2:41]C)CC.C(CN)[OH:44]>C(Cl)Cl>[Br:6][C:7]1[N:8]=[C:9]([CH2:41][NH:38][CH2:37][CH2:36][OH:44])[NH:10][C:11]=1[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][C:24]2[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([Cl:32])[CH:25]=2)[C:17]=1[F:33])=[O:13]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(CO)nc3Br)c2F)c1
Reactant: CCN(CC)CC
Reactant: NCCO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(CNCCO)nc3Br)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
MsCl (0.020 mL, 0.26 mmol) was added to a solution of 4-bromo-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(hydroxymethyl)-1H-imidazole-5-carboxamide (0.045 g, 0.09 mmol) and Et3N (0.14 mL, 1.00 mmol) in CH2Cl2 (1 mL). After 1 h, ethanolamine (0.20 mL, 3.31 mmol) was added and the reaction mixture was stirred at RT overnight. Purification was achieved by Reverse-Phase HPLC (water:acetonitrile with 0.1% NH4OH). The title compound (0.010, 21%) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.56 (s, 1H), 7.36-7.43 (m, 2H), 7.27 (br. s., 1H), 7.24 (br. s., 1H), 4.64 (s, 2H), 3.86 (s, 2H), 3.66 (t, J=5.36 Hz, 2H), 2.77 (t, J=5.13 Hz, 2H). ES-LCMS: m/z 556.1, 558.4, 560.0 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:14]>C(OCC)(=O)C.CO>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(CCCBr)s1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCCBr)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.1 %

Procedure:
To a solution consisting of 5-(3-bromopropyl) thiophene-2-carboxylic acid (from procedure above, 24 g, 78 mmol) in ethyl acetate (150 mL) and methanol (15 mL) at 0° C. was added TMS-diazomethane (50 mL, 100 mmol, 2 M) dropwise over one hour. The reaction mixture was then allowed to warm to room temperature and was stirred for 16 hours, The reaction mixture was concentrated under reduced pressure without workup. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (1:80 v/v) afforded the title compound as a white solid (4.95 g; 24% over two steps); TLC Rf 0.45 (solvent system: 15:85 v/v ethyl acetate-hexanes); MS (ESI+) m/z 263, 265 (isotopic bromines, each (M+H)+); 1HNMR (CDCl3) δ 7.5 (d, 1H), 6.7 (d, 1H), 3.75 (s, 3H), 3.3 (t, 2H), 2.9 (t, 2H), 2.1-2.0 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[I-:16].[Na+]>CC(C)=O.C(OCC)C>[I:16][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OCCCI)cc1

Procedure:
Dissolve 4-(3-chloropropoxy)benzoic acid, methyl ester (6.97 g, 30.5 mmol) in anhydrous acetone (100 mL) and add powdered sodium iodide (16.0 g, 107 mmol). Heat at reflux under an argon atmosphere for 38 hours. Dilute with ethyl ether (100 mL) and filter through Celite® filter aid. Wash the filtrate with water and brine, then dry (MgSO4). Evaporate the solvent in vacuo to give 4-(3-iodopropoxy)benzoic acid, methyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Nc1ccnc(Cl)n1

Procedure:
In analogy to compound 1.1, a solution of 0.347 g (2.33 mmol) of 2,4-dichloro-pyrimidine in 15 ml of acetonitrile is reacted with 0.22 ml (2.52 mmol) of isopropylamine in the presence of 0.39 ml (2.83 mmol) of triethylamine. Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%) results in 0.26 g (65% of theory) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:20]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:21][C:22]([CH3:24])=[O:23]>Cl.O.C(O)C>[CH2:27]([O:26][C:20]([C:21](=[N:11][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[C:22](=[O:23])[CH3:24])=[O:25])[CH3:28]
Reactant: O=N[O-]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NNc1ccc(C(=O)O)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
4-Amino-benzoic acid (40 g, 0.28 mol) was dissolved in a mixture of concentrated hydrochloric acid (84 ml) and water (84 ml). To the resulting mixture was added dropwise at 5° C. a solution of sodium nitrite (21.5 g, 0.31 mol) in water (100 ml). The resulting diazonium salt was added to a mixture of sodium acetate (116 g, 0.85 mol), ethanol (300 ml) and ethyl acetoacetate (36.5 ml, 0.28 mol) at room temperature. The resulting mixture was diluted with a 50% aqueous ethanol (1 l) and stirred for 1 h at room temperature. The precipitate was filtered off and washed with water (1 l), 50% aqueous ethanol (1 l) and heptane (2×300 ml) and dried in vacuo at 50 ° C. for 48 h affording 77 g (98%) of 4-[N′-(1-ethoxycarbonyl-2-oxo-propylidene)-hydrazino]-benzoic acid as a solid.