Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C([O-])([O-])=O.[K+].[K+]>>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:9]([CH2:8][C:7]1[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=1[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: BrCCCCCCBr
Reactant: CC(C)(C)Oc1ccccc1CNCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)Oc1ccccc1CN(CCCCCCBr)Cc1ccccn1

Procedure:
Compound 10 was synthesized with 9 (2 g, 8.84 mmol), using 1,6-dibromohexane (30 g, 130 mmol) and K2CO3 (1.22 g, 8.84 mmol) following a procedure analogous to that described for 2. Purification was carried out on a silica gel TLC plate that was developed in with a 1% methanolic NH3 (7 M NH3 in methanol/99% CH2Cl2. The product was isolated as pale yellow oil (73%).δ 1H NMR (CDCl3) δ 8.491 (dd, 1H, Ar), 7.630 (t, 1H, Ar), 7.565 (t, 2H, Ar), 7.120 (t, 2H, Ar), 7.020 (t, 2H, Ar), 3.740 (s, 2H, —CH2—), 3.660 (s, 2H, —CH2—), 3.334 (t, 2H, —CH2—), 2.452 (s, 2H, —CH2—), 1.787 (p, 2H, —CH2—), 1.516 (m, 2H, —CH2—), 1.354 (s, 9H, —C(CH3)3), 1.269 (m, 4H). Mass Spec.=435.18 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=C[CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(CN)CC1>C(O)(=O)C>[CH:2]1([CH2:1][N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:35])[C:10]=3[N:9]=[CH:8]2)[CH2:4][CH2:3]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Agent: NCC1CC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3F)c2ncn1CC1CC1
Yield: 43 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), cyclopropanemethylamine (0.066 ml, 0.76 mmol), and acetic acid (0.1 ml) were used to give 57.1 mg (0.17 mmol, 43% yield) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][O:13][C:14]=2[N:15]=1)([CH3:3])[CH3:2].Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14]=2[N:15]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.9 %

Procedure:
A mixture of the compound obtained in Example 4, step 1 (0.60 g), 4N hydrogen chloride/ethyl acetate (5 mL) and ethyl acetate (5 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane), 0.5M succinic acid/methanol solution was added, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give the title compound (0.032 g, 6%) as a white powder.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:33])[CH2:28][C:29](=O)[CH2:30]Br)[C:24](=[O:34])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[NH2:11]>O1CCCC1.O>[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:33])[CH2:28][C:29]3[N:1]=[C:2]([NH2:4])[S:3][CH:30]=3)[C:24](=[O:34])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[NH2:11]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of thiourea (0.103 g.) and sodium bicarbonate (0.11 g.) in a mixture of tetrahydrofuran (1.3 ml.) and water (1.3 ml.) was gradually added 3-carbamoyloxymethyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (0.55 g.) with stirring at room temperature, and then the resulting solution was stirred for 40 minutes at room temperature. After the reaction, the precipitated crystals were collected by filtration with suction, washed with water, tetrahydrofuran and water in turn, and then dried over phosphorus pentoxide to give 3-carbamoyloxymethyl-7-(2-aminothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid (0.48 g.).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].Br[CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].O>CN(C)C=O>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: Clc1cccc(Cl)c1CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Temperature: 20 °C
Yield: 76.7 %

Procedure:
add 561 mg of anhydrous potassium hydroxide to a solution of 1.54 g of 4-amino-3-nitrophenol in 6 cm3 of N,N-dimethylformamide. Add dropwise, to the purple solution obtained, 2.4 g of 2-(bromomethyl)-1,3-dichlorobenzene in solution in 2 cm3 of N,N-dimethylformamide, without exceeding 20° C. After stirring the reaction mixture for about twenty hours at a temperature around 20° C., the reaction mixture is poured into 200 cm3 of water. The mixture obtained is extracted three times with 100 cm3 of ethyl acetate. The combined organic phases are washed five times with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.2 kPa). The residue is taken up successively in a 50/50 mixture of diethyl oxide and diisopropyl oxide, and finally drained, washed three times with 2 cm3 of diisopropyl oxide, then dried under reduced pressure in the presence of potassium hydroxide. We obtain 2.4 g of 4-[(2,6-dichlorobenzyl)oxy]-2-nitroaniline in the form of a white powder, which has the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:16]>>[CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[C:8]([S:12]([NH2:16])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Br)c(S(=O)(=O)Cl)cc1C(=O)O
Reactant: N
Product: Cc1cc(Br)c(S(N)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
74.1 g of 2-methyl-4-bromo-5-chlorosulphonylbenzoic acid [obtainable by reacting 2-methyl-4-bromobenzoic acid with chlorosulphonic acid] are stirred, at 10° and over a period of 1.5 h, into 170 ml of a 32% aqueous solution of ammonia, and this mixture is subsequently stirred at room temperature for 3 h. After that, the reaction mixture is concentrated, 50 ml of water are added, and this mixture is acidified with conc. HCl. The resulting precipitate is filtered off with suction and recrystallized from methanol. 2-Methyl-4-bromo-5-aminosulphonylbenzoic acid is obtained, m.p. 237°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)o1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (94 mg, 0.179 mmol) and ammonium hydroxide (5 mL), the title compound was obtained as a white solid (30 mg, 33%). 1H-NMR (DMSO-d6): δ ppm 10.34 (br s, 1H), 8.18-8.19 (d, J=5.2 Hz, 1H), 7.65 (br s, 1H), 7.30-7.34 (t, J=7.4 Hz, 2H), 7.21-7.24 (m, 3H), 6.56 (br s, 2H), 6.45 (d, J=5.2 Hz, 1H), 1.40 (s, 9H); MS: 504 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1ccc3nonc3c12

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ8.63-8.59 (m, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.77-7.70 (m, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.6 Hz, 1H), 7.28-7.16 (m, 3H), 7.04 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 5.45 (d, J=16.2 Hz, 1H), 5.28 (d, J=9.6 Hz, 1H), 5.01 (d, J=9.6 Hz, 1H), 4.92 (d, J=16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.1, 163.0, 155.1, 149.4, 148.3, 144.9, 142.2, 137.3, 129.8, 129.7, 123.7, 123.67, 122.8, 121.9, 121.6, 119.4, 110.1, 107.0, 82.0, 57.4, 46.5; MS (ES+) m/z 371.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11]Br>C(O)(=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:11][CH2:9][C:8]([C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1cccnc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CBr)c1cccnc1Br
Temperature: 90 °C
Yield: 73.4 %

Procedure:
A solution of 1-(2-bromopyridin-3-yl)ethanone (2.10 g, 10.5 mmol) in acetic acid (28.0 mL) was treated with bromine (595 μL, 11.5 mmol) and heated at 90° C. for 1 h. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and further extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (10% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) gave the desired product (2.15 g, 73%). LCMS calculated for C7H6Br2NO (M+H)+: m/z=277.9, 279.9, 281.9. found: 277.7, 279.7, 281.8.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:14](=[O:16])[CH3:15])[CH2:9][C:8]=2[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[N:6]1.[Cl:27][C:28]1[CH:42]=[CH:41][C:31]2[N:32]=[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1>CCO>[Cl:27][C:28]1[CH:42]=[CH:41][C:31]2[N:32]=[C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:3][CH:2]([OH:1])[CH2:4][N:5]4[C:13]5[CH2:12][CH2:11][N:10]([C:14](=[O:16])[CH3:15])[CH2:9][C:8]=5[C:7]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)=[N:6]4)[CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)C1
Temperature: 60 °C
Yield: 91.1 %

Procedure:
To a stirred solution of 144 mg (0.39 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone in 4 mL of EtOH was added 100 mg (0.39 mmol) 6-chloro-2-piperazin-1-yl-benzothiazole. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 220 mg (90%) of a white solid. MS (electrospray): exact mass calculated for C29H30ClF3N6O2S: 618.18; m/z found, 619.2 [M+H]+. HPLC (reverse phase conditions 40-90%): tR=8.27 min. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.70 (d, J=8.34 Hz, 1H), 7.62 (m, 2H), 7.57 (d, J=8.59 Hz, 1H), 7.48 (d, J=2.53 Hz, 1H), 7.36 (d, J=8.59 Hz, 1H), 7.16 (dd, J=8.59, 2.53 Hz, 1H), 4.80 and 4.68 (A and B of AB quartet, J=15.92 Hz,1H), 4.58 (s,1H), 4.18-4.08 (m, 2H), 4.01-3.89 (m, 2H), 3.85-3.60 (m, 2H), 3.59-3.47 (m, 4H), 2.94-2.75 (m, 2H), 2.72-2.62 (m, 2H), 2.55-2.47 (m, 2H), 2.46-2.39 (m, 2H), 2.13 (s, 1.5H), 2.08 (s, 1.5H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].CS(O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.O>CN(C)C=O>[CH:6]([C:4]1[N:3]=[CH:2][N:1]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:5]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(C=O)c2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
To 137 mg of imidazole-4-carboxaldehyde diluted in 2 ml of anhydrous dimethylformamide under argon are added portionwise at 0° C. 63 mg of sodium hydride (60% in mineral oil). The reaction mixture is stirred for 45 min at 0° C. then 400 mg of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate are added portionwise, and the solution is brought to 100° C. for 15 h. Water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, washed with sodium chloride saturated aqueous solution, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 2:8 to 100% ethyl acetate) to yield 92 mg of tert-butyl 4-(4-formyl-1H-imidazol-1-yl)piperidine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[NH:5].C([O-])(O)=O.[Na+].[CH2:23]([O:25][C:26](=[O:31])[C:27](=[O:30])[CH2:28]Br)[CH3:24]>CC(O)C>[CH2:23]([O:25][C:26]([C:27]1([OH:30])[CH2:28][N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:4]([C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])=[N:5]1)=[O:31])[CH3:24]
Reactant: CCOC(=O)C(=O)CBr
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)C1(O)CN(c2ccc(Cl)cc2)C(c2ccccc2Cl)=N1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-N-(4-chloro-phenyl)-benzamidine (I-5a), 25.1 g, 95 mmol) and NaHCO3 (84 g, 189 mmol) in 2-propanol (473 ml) was treated with 3-bromo-2-oxo-propionic acid ethyl ester (14.3 ml, 22 g, 113 mmol). The reaction mixture was heated at 80° C. for 17 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was diluted with CH2Cl2 and the organic solution was washed with H2O, dried over MgSO4, and concentrated in vacuo to provide the product, 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester I-5b, as a dark red residue (36 g).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([CH3:27])[CH:26]=1)[NH:23][C:22](=[O:28])[C:21]2=[O:29].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:26][C:25]=3[CH3:27])[C:21](=[O:29])[C:22]2=[O:28])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc2c1NC(=O)C2=O
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccnc1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c1N(C(=O)c1cc(Br)nn1-c1ncccc1Cl)C(=O)C2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (97.6% purity, 13.02 g, 42 mmol) and 5-chloro-7-methylindoline-2,3-dione (K. Tsuji et al., Bioorg. Med. Chem. Letters, 2002, 12(17), pp 2427-2430) (7.82 g, 40 mmol) in dry acetonitrile (50 mL) was added 3-picoline (11.9 g, 127 mmol). The mixture was cooled to 0° C., and then methanesulfonyl chloride (6.87 g, 60 mmol) was added dropwise at 0-10° C. After stirring 5 minutes at this temperature, the mixture was warmed to room temperature for 20 hours. The precipitated solids were filtered, washed with acetonitrile (3×5 mL), and dried under nitrogen to afford the title product, a compound of the present invention, as a yellow powder, 14.90 g (77.6% yield), m.p. 173-177° C. (decomp.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22](O)=[O:23])[C:17]=1[CH3:25].[N:26]1([CH2:32][CH2:33][CH2:34][OH:35])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:29]2[CH2:30][CH2:31][N:26]([CH2:32][CH2:33][CH2:34][OH:35])[CH2:27][CH2:28]2)=[O:23])[C:17]=1[CH3:25]
Reactant: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Reactant: OCCCN1CCNCC1
Product: Cc1c(C(=O)N2CCN(CCCO)CC2)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Yield: 59 %

Procedure:
In analogy to the procedure described in Example 181, 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (Example 16C]) and 1-piperazinepropanol gave after suspending in a small amount of EtOAc and filtration the title compound in 59% yield as light yellow powder. MS: 459.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])=[N:7][C:2]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:33])([CH3:34])[C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CN(CCC#N)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CN(CCC#N)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
Title compound was prepared from 3-{[2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenyl]-methyl-amino}-propionitrile and 8 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Title compound isolated as a white lyophilate (67 mg, 53%). 99% purity, LCMS (510.19 M+H), 1H-NMR (CDCl3, 400 MHz) δ 12.00 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.42-7.37 (m, 3H), 7.02-6.97 (m, 2H), 6.66 (d, J=9.0 Hz, 1H), 3.28 (t, J=6.4 Hz, 2H), 2.73 (s, 3H), 2.53 (t, J=6.6 Hz, 2H), 2.36 (t, J=6.8 Hz, 2H), 2.06 (t, J=6.9 Hz, 2H), 1.27 (s, 6H).
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)C=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20].[CH:28]([C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][C:34]=2[CH:43]=1)=O>>[CH2:41]([O:40][C:38]([C:36]1[O:37][C:33]2[CH:32]=[CH:31][C:30]([CH2:28][NH:20][C:19]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:17]([O:16][CH3:15])[CH:18]=3)=[CH:43][C:34]=2[CH:35]=1)=[O:39])[CH3:42]
Reactant: CCOC(=O)c1cc2cc(C=O)ccc2o1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: COc1cc(C=O)cc(OC)c1OC
Product: CCOC(=O)c1cc2cc(CNc3cc(OC)c(OC)c(OC)c3)ccc2o1
Yield: 99 %

Procedure:
Following the same procedure as described in Example 4, Step 2, but substituting compound 20 and 3,4,5-trimethoxybenzaldehyde for 3,4,5-trimethoxyaniline and compound 27, the title compound was obtained in 99% yield. 1H NMR: (DMSO) δ (ppm): 7.75 (d, J=1.0 Hz, 1H), 7.73 (d, J=1.0 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.6, 1.8 Hz, 1H), 6.11 (t, J=6.1 Hz, 1H), 5.89 (s, 2H), 4.37-4.32 (m, 4H), 3.63 (s, 6H), 3.49 (s, 3H), 1.33 (t, J=7.0, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22].CCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:22][CH2:21][C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 98.8 %

Procedure:
In N,N-dimethylformamide (4 ml) was dissolved the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (101 mg, 0.333 mmol) obtained in Example 5. After addition thereto of t-butyl acrylate (146 μl, 1.00 mmol) and 1,8-diazabicyclo[5,4,0]undece-7-en (151 μl, 1.00 mmol), stirring was conducted at room temperature for 1 week. The reaction mixture was then concentated. The residue thus obtained was subjected to flash chromatoraphy on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated, whereby the title compound (142 mg, 0.329 mmol, 99%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CC1(C)CCCCC1)NC(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(CC(NC(=O)OCc2ccccc2)C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 36 %

Procedure:
A mixture of methyl 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propanoate, 10.00 g of KOH, 100 mL of MeOH, and 20 mL of water was vigorously stirred at rt for 17 h. After methanol was evaporated under reduced pressure, the residue was diluted with water and extracted with Et2O (2×). The aqueous phase was treated with 100 mL of 2 NHCl, extracted with EtOAc (3×), and dried over Na2SO4. The extracts were evaporated under reduced pressure to afford 1.5150 g (36% in two steps) of 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propanoic acid. MS ESI +ve m/z 320 (M+H).