Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.O[C:7]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][O:10][C:9]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:8]1=2.C(N(CC)CC)C.O>ClCCl>[O:17]=[C:16]1[C:8]2[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][O:10][C:9]=2[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCOC(=O)C1(O)COC2=C1C(=O)CCCC2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1coc2c1C(=O)CCCC2
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (9.7 g, 0.08 mol) was added dropwise to a stirring solution of ethyl 3-hydroxy-4-oxo-2,3,5,6,7,8-hexahydro-4H-cyclohepta[b]furan-3-carboxylate (17 g, 0.07 mol) and triethylamine (30 mL, 0.21 mol) in dichloromethane (100 mL) at 0° C. The mixture was allowed to reach ambient temperature, stirred for 2 hours, then poured into water and extracted with dichloromethane. The organic layer was washed sequentially with aqueous 2N sodium hydroxide, saturated aqueous sodium bicarbonate, and brine, then dried over magnesium sulfate, filtered, concentrated in vacuo, and purified on Silica gel (1:1 ethyl acetate/hexanes) to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:24])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])=[C:14]([Cl:23])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])=[C:14]([Cl:23])[CH:13]=2)/[C:3]([OH:24])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1Cl
Temperature: 47.5 °C
Yield: 99.5 %

Procedure:
A solution of (E)-3-cyclohexyl-2-(3-chloro-4-((methylene)-methylsulfonyl)-phenyl)-acrylic acid methyl ester (887 mg, 2.4 mmol) in ethanol (10 mL) was treated with a 1N aqueous sodium hydroxide solution (8 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (20 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the (E)-3-cyclohexyl-2-(3-chloro-4-((methylene)-methylsulfonyl)-phenyl)-acrylic acid (0.847 g, 99%) as a white solid: mp 105-108° C.; EI-HRMS m/e calcd for C17H21ClO4S (M+) 356.0849, found 356.0844.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:41]1[CH:40]=[C:39]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:19][CH2:18]5)[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:43]=[N:42]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Temperature: 100 °C
Yield: 67.4 %

Procedure:
A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (500 mg, 1.16 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (679 mg, 3.5 mmol), Pd(dppf)Cl2 (47.5 mg, 0.058 mmol), and aqueous solution of Na2CO3 (saturated, 3 mL) in 1,4-dioxane (10 mL) under nitrogen was heated at 100° C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/EtOAc (1/1) as eluting solvents to afford tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (360 mg, 67%). MS (ESI) m/z: 461 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][CH3:19].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:18][CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)serine (10.26 g, 50.00 mmol) in DMSO (500 mL) was added sodium hydride (2.0 g, 50 mmol) at room temperature. After 1 hour, bromoethane (5.45 g, 50.0 mmol) was added and then additional sodium hydride (2.0 g, 50 mmol) was added immediately. After 16 hours, hydrochloric acid (1.0 M in water, 50 mL, 50 mmol) and water (2 L) were added. The mixture was extracted with ethyl acetate, and the organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford N-(tert-butoxycarbonyl)-O-ethylserine which was used without further purification. MS ESI calc'd. for C10H20NO5 [M+H]+ 234. found 234.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.[CH2:12]([OH:16])[CH:13]=[CH:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(OC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:8]([C:4]1[CH:3]=[C:2]([CH:14]([CH3:15])[CH2:13][CH:12]=[O:16])[CH:7]=[CH:6][CH:5]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cccc(Br)c1
Reactant: CC=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(CC=O)c1cccc(C(C)(C)C)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
In a 1 L three-necked round-bottom flask equipped with a mechanical stirrer and a reflux condenser were introduced DMF (200 mL), 1-bromo-3-tert-butylbenzene (54.3 g, 0.25 mol), crotyl alcohol (65 mL, 0.76 mol, 3 eq), sodium carbonate (66.2 g, 0.62 mol, 2.5 eq), tetrabutyl ammonium bromide (69.5 g, 0.25 mol, 1 eq), palladium acetate (5.05 g, 7.5 mmol, 3 mol %) and tri-o-tolyl phosphine (7.6 g, 25 mmol, 0.1 eq). After stirring for 1 h at 90-100° C., the reaction mixture was cooled to ambient temperature. The reaction mixture was filtered over celite. The organic phase thus obtained was diluted with MTBE (500 mL) and washed three times with water (500 mL portions), dried over magnesium sulphate and concentrated. The resulting crude product was distilled with a bulb-to-bulb distillation (3 mBar, 121° C.) to give a colourless oil (34.7 g, gc purity 73%). The crude product was chromatographed on a silica gel column with 5% EtOAc in hexane as elution agent giving 3-(3-tert-butylphenyl)butanal (12.3 g, gc purity 99%; yield 39%).
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=2[N+:25]([O-])=O)[C@H:13]([C:28]([OH:30])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O>C(O)(=O)C.[Fe]>[Cl:24][C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][C:21]=1[Cl:23])[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]1[C:28](=[O:30])[NH:25]2
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cc(Cl)c(Cl)cc2N2CCNC[C@@H]12
Temperature: 60 °C
Yield: 120.2 %

Procedure:
To a solution of 1.5 g (S)-4-carbobenzyloxy-1-(4,5-dichloro-2-nitrophenyl)-piperazine-2-carboxylic acid in 40 mL of acetic acid is added 1.2 g of iron powder. With good stirring, the mixture is heated at 60° C. for 2 hours, then concentrated under reduced pressure (1-2 mm, <40° C.) to a gray-black residue. This material was slurried with 100 mL of ethyl acetate (2×). The combined ethyl acetate filtrates are washed with 100 mL of 1N HCl, 200 mL of water (2×), 100 mL of brine and dried over MgSO4. Filtration and concentration of the solvent gave a semi-solid material that is crystallized from hexane to afford 1.08 g (80.6%) of title compound as a white solid, mp 174-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH:11]1([Mg]Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:7]([C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[OH:8])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C(O)C2CCCCC2)cc1

Procedure:
Referring now to FIG. 2, this alternative synthesis starts from 4-methoxy-benzaldehyde (VI) which is subjected to treatment with cyclohexyl magnesium bromide to yield cyclohexyl-(4-methoxy-phenyl)-methanol (V). This in turn is then oxidised so as to yield cyclohexyl-(4-methoxy-phenyl)-methanone (III).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]4[NH:29][CH2:28][CH2:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=4[CH:34]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>C1COCC1>[CH:1]([N:29]1[C:23]2[CH:22]=[CH:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][O:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)=[CH:34][C:24]=2[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:28]1)=[O:3]
Reactant: CC(=O)O
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2NCC1
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C=O)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.2 ml) was added dropwise formic acid (0.1 ml), under ice-cooling, and the mixture was heated to stir under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (5 ml), and then to the mixture was added dropwise, under ice-cooling, a solution of methyl 7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g) in THF (15 ml). The mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C:7]([C:10]#[N:11])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6](=[O:12])[C:7]([CH3:9])([CH3:8])[CH2:10][NH2:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)C#N
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of cyano-dimethyl-acetic acid tert-butyl ester (5.3 g) and Raney Ni (2 mL in water) in MeOH (400 mL) was stirred at rt under H2 atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celite pad, filtrate was concentrated to give the desired product (5 g). 1H NMR in CDCl3, δ in ppm: 2.8 (br, 2H), 1.45 (s, 9H), 1.17 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23]N=3)=[CH:17][CH:16]=2)=[C:9]([O:31][CH3:32])[CH:8]=1)([CH3:6])[CH3:5].[CH3:34]OC(=O)C(C1C=CC(S)=C(OC)C=1)(C)C>>[CH3:1][O:2][C:3](=[O:33])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:34]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[C:9]([O:31][CH3:32])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)c(OC)c1
Reactant: COC(=O)C(C)(C)c1ccc(S)c(OC)c1
Product: COC(=O)C(C)(C)c1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(OC)c1
Yield: 34 %

Procedure:
Compound 47A was prepared analogously to compound 21D using the product prepared from compound 21C. Yield was 34% after flash column purification. MS m/z 475 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].Br[CH2:28][CH2:29][CH2:30][OH:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: OCCCBr
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(Cl)cc(Cl)c2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1ccc(C[C@@H]2CN(CCCO)CCN2C(=O)c2cc(Cl)cc(Cl)c2)cc1C
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A mixture of (2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazine hydrochloride (300 mg), 3-bromo-1-propanol (121 mg), potassium carbonate (251 mg) and potassium iodide (24 mg) in dried acetonitrile (3 ml) was stirred at 50° C. for 10 hours. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent to give (2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4-(3-hydroxypropyl)piperazine as a syrup. Methanesulfonyl chloride (58 mg) was added to an ice-cooled solution of the alcohol obtained at above procedure (210 mg) and triethylamine (97.6 mg) in dichloromethane (4 ml) over 1.5 hours. After being stirred for 1 hour, the reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated under reduced pressure to give the corresponding mesylate. A mixture of the mesylate obtained by the above procedure, 4-aminomorpholine (59.1 mg) and triethylamine (73.2 mg) in methanol (4 ml) was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4-(N-morpholino-3-aminopropyl)piperazine dihydrochloride.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.[BH4-].[Na+]>C(Cl)Cl.CO>[OH:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(CCNCC(O)c3ccccc3)cc2)cc1
Reaction time: 2 h

Procedure:
4 g (20 mmol) of phenacylbromide are dissolved in 20 ml of methylene chloride and added dropwise to a solution of 4.6 g (20 mmol) of 4'-(2-aminoethyl)-4-methoxy-biphenyl and 3.45 ml (20 mmol) of N,N-diisopropyl-ethylamine and 100 ml of methylene chloride at ambient temperature. After 2 hours, 50 ml of methanol are added and, with slight cooling, 1 g (27 mmol) of sodium borohydride is added in batches. After stirring overnight the mixture is evaporated in vacuo, acidified with dilute hydrochloric acid and stirred for 30 minutes. It is then made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform evaporation residue is purified by column chromatography on silica gel (eluant: chloroform/methanol=10:1). Finally, it is recrystallised from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=O)=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH2:34])[CH3:30].Cl.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH:34][C:24]([C:20]1[S:19][C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([C:4]3[NH:5][C:6]([CH2:7][CH3:8])=[C:2]([Cl:1])[N:3]=3)=[O:10])[C@H:13]([O:27][CH3:28])[CH2:14]2)=[N:22][C:21]=1[CH3:23])=[O:26])[CH3:30]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C
Yield: 86.3 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid obtained in Example (14a) (30 mg, 0.07 mmol), hydrochloric acid glycine ethyl ester (11 mg, 0.08 mmol), WSC hydrochloride (44 mg, 0.23 mmol), HOBT (16 mg, 0.12 mmol), diisopropylethylamine (0.015 mL, 0.08 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 31 mg of the title compound as a white solid (87%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:23]3[CH2:22][CH2:21][NH:20][CH:19]([CH3:18])[CH2:24]3)=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CC1CNCCN1
Product: CC1CN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CCN1
Yield: 91.8 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and 2-methylpiperazine (100 mg, 1.0 mmol) were reacted according to GP4 to give 30 mg of the title compound (160FE38). MS (ESI) 327 (MH+). Purity for MH+ (UV/MS) 100/89.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[OH:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[CH:10]=[CH:9][C:8]([N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]3=[O:17])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:24]=1
Reactant: O=C(O)c1cc(-n2ccccc2=O)ccc1I
Reactant: OCc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(O)c1cc(-n2ccccc2=O)ccc1-n1cnc(CO)c1
Temperature: 130 °C

Procedure:
A mixture of 2-iodo-5-(2-oxopyridin-1(2H)-yl)benzoic acid prepared above (220 mg, 0.65 mmol), 4-hydroxymethylimidazole II-1 (126 mg, 1.29 mmol), 8-hydroxyquinoline (19 mg, 0.13 mmol) and K2CO3 (290 mg, 2.10 mmol) in DMSO (2 mL) was degassed with Ar before being charged with CuI (25 mg, 0.13 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give 2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoic acid (92 mg). MS 312.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[CH2:14]([O:21][CH2:22][C:23](O)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23](=[O:24])[CH2:22][O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: O=C(O)COCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)COc1ccc(NC(=O)COCc2ccccc2)cc1
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a mixture of 4-aminophenoxyacetic acid methyl ester 15 (20 g, 110.5 mmol) and benzyloxyacetic acid (20.4 g, 123 mmol) in anhydrous dichloromethane (200 ml) under nitrogen atm. was added dropwise a solution of 1,3-dicyclohexylcarbodiimide (63.2 g, 306 mmol) in anhydrous dichloromethane (80 ml). The reaction mixture was stirred at room temp. for 12 hrs. The solids were filtered off, the dichloromethane solution was washed with 5% sodium bicarbonate solution (100 ml), water (100 ml), dried over sodium sulphate, and distilled to get crude 66. The crude 66 was purified by column chromatography on silica gel using benzene as eluant to get pure 66 (25 g, 68.9%) as a white powder. M.p: 76-77.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9](C2C=CC=C(F)C=2)=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.[C:19](=N)(OCC)[CH3:20]>CO>[CH3:19][C:20]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH:9]=[O:10])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(C)=N
Reactant: Nc1ccc(C(=O)c2cccc(F)c2)cc1N
Agent: Cl
Solvent: CO
Product: Cc1nc2cc(C=O)ccc2[nH]1
Reaction time: 17 h

Procedure:
(a-1) A mixture of 20 parts of (3,4-diaminophenyl) (3-fluorophenyl) methanone, 27 parts of ethyl ethanimidate hydrochloride and 80 parts of methanol was stirred for 17 hours at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated. The residue was taken up in a potassium carbonate solution 10% and the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 15.6 parts (70.5%) of 3-fluorophenyl) (2-methyl-1H-benzimidazol-5-yl)methanone as a residue (int. 34).