Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=3)=[CH:41][C:40]=2[N:53]2[CH:57]=[CH:56][C:55]([CH3:58])=[N:54]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][NH:14][C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=3)=[CH:41][C:40]=2[N:53]2[CH:57]=[CH:56][C:55]([CH3:58])=[N:54]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(C)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(C)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1

Procedure:
A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (from Step 3, Example 1m, 220 mg, 0.3 mmol) in EtOAc (5 mL) was hydrogenated using Method A by using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtOAc/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C>CN(C=O)C.[H-].[Na+]>[OH:31][CH2:30][CH2:29][N:10]1[C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:2]1=[O:1]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccn2ncc(-c3ncc4c(n3)n(C3CCOCC3)c(=O)n4CCO)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaH dispersion in mineral oil (6 mg, 0.15 mmol) was added. The resulting solution was stirred at room temperature for 10 min. Then (2-bromoethoxy)-tert-butyldimethylsilane (0.074 mL, 0.34 mmol) was added and the reaction was stirred at 50° C. for 14.5 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using hexanes/EtOAc mixtures of increasing polarity as eluent, to afford 55 mg of the desired compound (76% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]([C:19]([O:21]CC)=[O:20])[N:16]([CH3:18])[CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]([C:19]([OH:21])=[O:20])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:3][C:2]=1[F:1]
Reactant: CCOC(=O)c1nc(NC(=O)Nc2ccc(C)c(F)c2)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(NC(=O)Nc2cn(C)c(C(=O)O)n2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
690 mg (2.15 mmol) of ethyl 4-({[(3-fluoro-4-methylphenyl)amino]carbonyl}amino)-1-methyl-1H-imidazole-2-carboxylate are suspended in 5 ml of ethanol and 12 ml of tetrahydrofuran. While cooling in ice, 2 ml (25 mmol) of 50% strength aqueous sodium hydroxide solution are added. The reaction mixture is stirred at room temperature overnight and then, while cooling in ice, acidified with 1N hydrochloric acid. The solution is extracted with dichloromethane. The organic phase is concentrated in vacuo.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31]C1C=CC(C=O)=CC=1>>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:4]1[CH:5]=[CH:6][C:7]([F:31])=[CH:2][CH:3]=1)[CH2:17][C:16]2=[O:18]
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2ccc(F)cc2)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(4-fluorophenyl)chroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of 2′,5′-dihydroxyacetophenone and 1.6 ml of 4-fluorobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (400 MHz, d6-DMSO) δ: 7.59 (m, 2H), 7.27 (m, 2H), 7.14 (d, 1H, J 3.1 Hz), 7.05 (dd, 1H, J 8.9, 3.1 Hz), 6.96 (d, 1H, J 8.9 Hz), 5.56 (dd, 1H, J 13.2, 2.8 Hz), 3.18 (dd, 1H, J-16.9, 13.2 Hz), 2.77 (dd, 1H, J −16.9, 2.8 Hz).
Reaction SMILES: O=C1N([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)CC(C(N2CCC(C(O)=O)CC2)=O)O1.Cl.[O:31]1CCCC1>>[N:10]1([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:11][CH2:12][C:7](=[O:31])[CH2:8][CH2:9]1
Reactant: C1CCOC1
Reactant: O=C(O)C1CCN(C(=O)C2CN(C3CCN(c4ccncc4)CC3)C(=O)O2)CC1
Agent: Cl
Product: O=C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 79.7 g of the ketal prepared in a) in 2 l tetrahydrofuran is admixed with 1 l 6 n hydrochloric acid and the reaction mixture is stirred for 2 h at room temperature. Subsequently the tetrahydrofuran is removed in a vacuum on a rotary evaporator, the hydrochloric acid is made alkaline with semi-concentrated ammonium hydroxide solution and extracted four times with 100 ml methylene chloride each time. After drying the combined organic extracts over sodium sulfate and removing the solvent, the residue is purified by means of column chromatography on silica gel. 64.2 g (100% yield) 2,3,5,6-tetrahydro-[1,4']bipyridinyl-4-one is obtained in this manner as a grey powder. m/e=176; f.p.=102° C.
Reaction SMILES: C(O[C:6](=[O:24])[NH:7][CH2:8][CH:9]1[S:13](=[O:15])(=[O:14])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2([C:48]([F:51])([F:50])[F:49])[O:37][N:36]=[C:35]([C:38]3[CH:46]=[CH:45][C:41](C(O)=O)=[C:40]([CH3:47])[CH:39]=3)[CH2:34]2)[CH:29]=[C:30]([Cl:32])[CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2([C:48]([F:50])([F:49])[F:51])[O:37][N:36]=[C:35]([C:38]3[CH:46]=[CH:45][C:41]([C:6]([NH:7][CH2:8][CH:9]4[S:13](=[O:14])(=[O:15])[N:12]([C:16]5[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=5)[CH2:11][CH2:10]4)=[O:24])=[C:40]([CH3:47])[CH:39]=3)[CH2:34]2)[CH:29]=[C:30]([Cl:32])[CH:31]=1
Reactant: COc1ccc(N2CCC(CNC(=O)OC(C)(C)C)S2(=O)=O)cc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Product: COc1ccc(N2CCC(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)cc3C)S2(=O)=O)cc1
Yield: 37.5 %

Procedure:
The compound obtained in Step C (94 mg) was deprotected and coupled with 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.125 g) (prepared according to WO 2009/080250) as described in Example 4, Steps B and C to afford the title compound as a brown solid (65 mg). LCMS (Method F) 2.02 min, M−H 654/655.
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH2:21][NH2:22]>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:22][CH2:21][C:20]1[CH:19]=[C:18]([Cl:17])[CH:25]=[C:24]([Cl:26])[CH:23]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2cc(Cl)cc(Cl)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A mixture of 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5 mmol, Example 1), 3.5-dichlorobenzylamine (0.88 g, 5 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature overnight, and then was processed as in Example 2, Step 4. Recrystallization (twice) of the crude product from methanol gave 1.095 g of the title compound as a whte solid: mp 281°-283° C. (dec). MS (m/z) 326/328/330 (M+). HPLC indicates a major component (99.2%).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6]2[S:12][CH:13]=[CH:14][C:5]1=2)[CH2:2][CH3:3].C([Li])CCC.CCCCCC.[CH3:26][Sn:27](Cl)([CH3:29])[CH3:28].O>C1COCC1>[CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([Sn:27]([CH3:29])([CH3:28])[CH3:26])[S:11][C:7]=2[C:6]2[S:12][C:13]([Sn:27]([CH3:29])([CH3:28])[CH3:26])=[CH:14][C:5]1=2)[CH2:2][CH3:3]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCn1c2ccsc2c2sccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCn1c2cc([Sn](C)(C)C)sc2c2sc([Sn](C)(C)C)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1.1 g (5.0 mmol) of 4-propyl-4H-dithieno[3,2-b;2′,3′-d]pyrrole (32) in 17 ml of dry THF are added 6.9 ml (11.0 mmol) of a 1.6 M n-butyllithium/hexane solution at −78° C. After the mixture has been stirred at −78° C. for 1 h, the cooling bath is removed and the mixture is stirred at room temperature for a further hour. A precipitate forms during this time. The suspension is cooled −78° C. and a solution of 2.2 g (11.0 mmol) of trimethylstannyl chloride dissolved in 3 ml of THF is added. The mixture is stirred −78° C. for 1 h and then the cooling bath is removed to stir at room temperature for a further 3 h. 50 ml of n-hexane are added and hydrolysis is effected with water. The organic phase is washed three times with 50 ml of water and dried over sodium sulfate. After the solvents have been distilled off, the residue is dried under reduced pressure and the crude product (2.26 g, 88%) is used in the next stage without further purification. 1H NMR (CDCl3): 7.01 ppm (s, 2H), 4.16 (t, 2H), 1.94 (qa, 2H), 0.98 (t, 3H), 0.40 (s, 18H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20][C@@:19]2([CH3:33])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:34])[CH2:16][C@@:15]2([CH3:35])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[N-:36]=[N+:37]=[N-:38].[Na+].O>CS(C)=O>[N:36]([C@H:21]1[CH2:20][C@@:19]2([CH3:33])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:34])[CH2:16][C@@:15]2([CH3:35])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3][C@@H:2]1[OH:1])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OS(=O)(=O)c5ccc(C)cc5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N=[N+]=[N-])C[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 53.8 %

Procedure:
3α-hydroxy-2β-toluene-p-sulphonyloxy-5α-pregnane-11,20-dione (500 mg) was dissolved in dimethylsulphoxide (20 ml) and sodium azide (1.5 g) added to the solution. The mixture was heated on a steam bath for 30 hours, cooled and poured into water. The precipitate formed was filtered off, dissolved in ether and the solution dried over anhydrous sodium sulphate. The dried solution was evaporated to a foam (300 mg) which was purified by preparative T.L.C. using ethyl acetate/petrol (1/1). The main band (Rf 0.2-0.3) giving title compound (200 mg) as a foam, [α]D + 104° (c 0.93), identical with the above compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:23](=[O:24])[C:22]2[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH3:19])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(N)cc1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: c1ccncc1
Product: COc1cccc(OC)c1C(=O)Nc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
N-(tert-butoxycarbonyl)-2-(4-nitrophenoxy)ethylamine (5.91 g) was dissolved into methanol (200 ml) and subjected to hydrogeration reaction at ambient pressure by adding 10% palladium carbon catalyst (0.5 g). After completion of hydrogeration reaction, excess catalyst was removed by filtration. Filtrate was concentrated under vacuum to obtain N-(tert-butoxycarbonyl)-2-(4-aminophenoxy)ethylamine (5.07 g) as color-less oily substance. (1-3) N-(tert-butoxycarbonyl)-2-(4-aminophenoxy)ethylamine (1.00 g) was dissolved into pyridine (5 ml) and 2,6-dimethoxybenzoic acid chloride (0.87 g) was added into the solution. After being stirred for one hour, the reaction mixture was concentrated under vacuum and residue was dissolved into chloroform (30 ml). The solution was washed with 1N sodium hydroxide aqueous solution (30 ml) followed by saturated sodium chloride (30 ml). Solvent was distilled out and residue was purified by silica-gel column chromatography (ethyl acetate:hexane=1:1) to obtain 4′-[2-(tert-butoxycarbonylamino)ethoxy]-2,6-dimethoxybenzanilide (1.17 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[C:15]([CH:19]=1)[C:16]([O:18][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)=[O:17]
Reactant: Clc1cccc(CBr)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1cccc(Cl)c1)c1cc(Br)ccc1OCc1cccc(Cl)c1
Temperature: 56 °C
Reaction time: 24 h

Procedure:
3-Chlorobenzyl bromide (568 mg, 2.76 mmol) was added dropwise to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (200 mg, 0.92 mmol) and potassium carbonate (255 mg, 1.84 mmol) in acetone (40 ml) over 1 min. The reaction mixture was stirred at 56° C. for 24 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3×30 ml) and evaporated in vacuo to yield the title compound as an off white solid. 427 mg.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][C:20]1[CH:31]=[CH:30][C:23]2[O:24][C:25]([C:27](=[O:29])[CH3:28])=[CH:26][C:22]=2[CH:21]=1>CC#N>[C:27]([C:25]1[O:24][C:23]2[CH:30]=[CH:31][C:20]([NH:19][C:2]3[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:21][C:22]=2[CH:26]=1)(=[O:29])[CH3:28]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Solvent: CC#N
Product: COCCN1C(=O)C(Nc2ccc3oc(C(C)=O)cc3c2)=C(c2ccccc2)C1=O
Temperature: 150 °C
Yield: 17.1 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.26 mmol, 70 mg) and 1-(5-aminobenzo[b]furan-2-yl)ethan-1-one (0.53 mmol, 92 mg) was dissolved in dry CH3CN (2 mL) and the reaction mixture was subjected to microwave heating single node 150° C. for 15 min and purified on SiO2 (EtOAc:heptane, 1:1) to give 18 mg (15%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.53 (bs, 1H), 7.40 (d, 1H), 7.24-7.09 (m, 5H), 7.06 (dd, 1H), 6.92 (d, 1H), 3.98 (t, J=5.6 Hz, 2H), 3.78 (t, J=5.6 Hz, 2H), 3.52 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH2:6][C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]>C(O)C>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:4]=1
Reactant: COC(=O)CCCCC(=O)CCl
Reactant: NC(N)=S
Solvent: CCO
Product: COC(=O)CCCCc1csc(N)n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 70.2 %

Procedure:
Thiourea (15.7 g) and methyl 7-chloro-6-oxoheptanoate (39.7 g) are mixed in ethanol (200 cc). The mixture is stirred for 20 hours at a temperature of about 20° C.; gradual dissolution of the reactants is observed. The solution is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. The residue is stirred in a mixture of methylene chloride (250 cc) and N sodium hydroxide solution (250 cc). The insoluble product is filtered off, washed with water and recrystallised by dissolving it in boiling water (350 cc) and cooling to 5° C. The resulting crystals are washed with water (3×30 cc), ethanol (3×30 cc) and diethyl ether (2×50 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield methyl 5-(2-aminothiazol-4-yl)valerate (31 g), as a white solid, m.p.=131° C.
Reaction SMILES: [H-].[Na+].O.[N:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)=[O:5].[CH3:22]I>CN(C)C=O>[CH3:22][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]([N:4]=[O:5])[C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]1=2
Reactant: O=NN1c2ccccc2NC(=O)c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)c2ccccc2N(N=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.4 g, 50% oil dispersion) was added in small portions to a water cooled solution of 10,11-dihydro-5-nitrosodibenzo[b,e][1,4]diazepin11(5H)-one (13.5 g) in dimethylformamide (200 ml) such that the temperature did not exceed 20° C. After the addition was complete the mixture was stirred at room temperature for 30 minutes and then treated with methyl iodide (7.0 g) added in one lot. The resulting mixture, after being stirred at room temperature for 2 hours, was poured into an excess of ice and water, and extracted with methylene chloride. The methylene chloride extract was washed with water, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue, which contained some dimethylformamide, was repeatedly triturated with water until it turned to a crystalline solid. It was filtered off, washed with water and air-dried to yield the title compound, m.p. 95°-98°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][N:12](C)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[CH:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].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.O>[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:8]2[CH:23]=[CH:22][CH:21]=[C:10]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:9]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=O)cc2)c1
Temperature: 90 °C
Yield: 60 %

Procedure:
307 ml (615 mmol) of an aqueous potassium carbonate solution (2M) are added dropwise to a mixture of 61.5 g (205 mmol) of tert-butyl (3-bromobenzyl)-N-methylcarbamate, 46 g (307 mmol) of 4-formylbenzeneboronic acid and 500 ml of toluene. The reaction medium is subsequently degassed with argon and 7 g (6.2 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. After heating at 90° C. for 24 hours, the reaction medium is poured into water and extracted with ethyl acetate. The organic phase is separated by settling, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (70/30). After evaporating the solvents, 67 g of tert-butyl (4′-formylbiphenyl-3-yl)methylcarbamate are collected. Yield=60%.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH:14]=O)[CH:10]=[CH:11][CH:12]=1.[OH-].[K+]>C(OCC)C.C(O)C.C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][CH2:1][C:2](=[O:5])[CH:3]=[CH:4]2)[CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(C)=O
Reactant: O=CC(c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C=CC(c2cccc(Cl)c2)(c2cccc(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Butenone (11.3 cc) is added to a solution of bis-(3-chlorophenyl)acetaldehyde (36.9 g) in ethyl ether (200 cc) and then, after cooling to 0° C., a solution of potassium hydroxide (3.1 g) in ethanol (20 cc) is added dropwise. The reaction mixture is stirred for 2 h at 0° C. and then for 16 hours at 25° C. and diluted with ethyl acetate (100 cc) and water (200 cc). The aqueous phase is washed with ethyl acetate (100 cc). The combined organic phases are washed with saturated sodium chloride solution (3×100 cc), dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 7 cm, height 42 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume). 4,4-bis-(3-Chlorophenyl)cyclohexenone (27.7 g) is obtained in the form of yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24]C(=O)C)[CH2:21][O:20]C(C)(C)[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[SH:37].C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O>[NH2:24][C:16]([CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:37][C:31]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=3[F:29])=[CH:3][C:4]=2[F:28])=[CH:9][CH:10]=1)([CH2:21][OH:20])[CH2:17][OH:18]
Reactant: Cc1ccc(S)c(F)c1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)c(F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (225 mg) of Reference Example 10, 2-fluoro-4-methylbenzenethiol (71 mg), diisopropylethylamine (129 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14.9 mg) in 1,4-dioxane (2 mL) was heated under reflux for 6 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (4 mL). Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration. The crude crystals were purified by preparative HPLC to give the title compound (44 mg) as white crystals.