Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][S:5]([CH:8]([C:12]1[C:21]([Cl:22])=[C:20]([Cl:23])[CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([O:26][CH3:27])[C:16]([O:24][CH3:25])=[N:17]2)[CH2:9][CH:10]=C)(=[O:7])=[O:6].[BH4-].[Na+].Cl>ClCCl>[CH3:4][S:5]([CH:8]([C:12]1[C:21]([Cl:22])=[C:20]([Cl:23])[CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([O:26][CH3:27])[C:16]([O:24][CH3:25])=[N:17]2)[CH2:9][CH2:10][OH:1])(=[O:7])=[O:6]
Reactant: O=[O+][O-]
Reactant: C=CCC(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc2cc(Cl)c(Cl)c(C(CCO)S(C)(=O)=O)c2nc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
Ozone was bubbled through a solution of 1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-butenyl methyl sulphone (50 mg, 0.128 mmol) [Example 93(a)] in dry dichloromethane (1.3 ml) at -78° C. until a blue colour developed. The mixture was stirred for 5 minutes and was then purged with a stream of oxygen and then nitrogen. Methanol (1.3 ml) was added and the mixture allowed to equilibrate at -78° C. before sodium borohydride (12 mg, 0.319 mmol) was added in two portions. The mixture was stirred for 5 mins and was then allowed to warm to room temperature. The mixture was poured into 2M hydrochloric acid (20 ml) and extracted with dichloromethane (2×20 ml). The combined extracts were washed with brine (20 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 1:1 hexane:ethyl acetate) to give 1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-hydroxypropyl methyl sulphone (35.6 mg, 70%) as a white foam.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][C:15]=2[NH:14][C:13]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:32]1[C:33]2[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:34]=2[N:35]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:36](=[O:47])[C@H:37]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[N:38]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([C:32]3[C:33]4[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:34]=4[N:35]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=4)[C:36](=[O:47])[C@H:37]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[Cl:46])[N:38]=3)[CH:19]=[CH:20][C:15]=2[NH:14][C:13]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c3c2)OC1(C)C
Reactant: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c4c3)c3cc(Cl)ccc32)cc1
Temperature: 90 °C
Yield: 12.6 %

Procedure:
1-(3-((Tert-Butyldimethylsilyl)oxy)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (0.46 g, 1.06 mmol) and (S)-5,7-dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.5 g, 1.06 mmol) were combined in toluene (4 mL) and saturated aqueous sodium bicarbonate (2 mL) and purged with nitrogen. Tetrakis(triphenylphosphine)palladium (122 mg, 0.106 mmol) was added and the mixture was heated at 90° C. for 7.5 h. After cooling, the mixture was diluted with ethyl acetate and washed twice with water then once with brine then dried (MgSO4). Chromatography, eluting with 10-50% ethyl acetate in hexanes gave the title compound as an orange brown solid (100 mg, 0.134 mmol).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[C:12]([C:10]1[C:9]2[N:18]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:20][C:8]=2[C:7]([OH:27])=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:11]=1)#[CH:13]
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2nc(-c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-4-trimethylsilanylethynyl-thiazolo[4,5-c]pyridine-6 carboxylic acid ethyl ester (113 mg, 0.28 mmole) and glycine (750 mg, 9.99 mmole) in 0.5 M sodium methoxide/methanol (20 ml) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (30 ml) and extracted with dichloromethane (2×40 ml). The remaining aqueous layer was acidified to pH=2 with 1N HCl. The suspension was extracted with ethyl acetate (2×40 ml), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (96 mg). MS: (+) m/z 354.20 (M+1), (−) m/z 352.16 (M−1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([N:20]=CN(C)C)[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CO>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N=CN(C)C)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.8 %

Procedure:
(Z)-N-(2-phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide (130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by the addition of 0.5 ml of 1.8N sulfuric acid. The mixture so obtained was stirred for 3 days at room temperature. The reaction mixture was then added with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and 20 ml of ethyl acetate. The resulting mixture was then allowed to separate into an organic phase and an aqueous phase. The aqueous phase was further extracted twice with 10 ml portions of ethyl acetate. All the organic phases were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, whereby 105 mg of the title compound were obtained (yield: 95%).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH2:12][N:13]([CH3:25])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)=[O:15])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>CO.[C].[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([N:13]([CH3:25])[CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:15])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CN(CCCN(C)C(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CCCN(C)C(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
A solution of the compound (162 mg, 0.461 mmol) obtained in Example 28c in methanol (5 mL) was added to 10% palladium-carbon (dry; 16 mg), and the atmosphere in the system was replaced with a hydrogen atmosphere, and then the mixture was stirred at room temperature for 1.5 hours. The atmosphere in the system was replaced with a nitrogen atmosphere, and the mixture was filtered through celite. The solvent was evaporated under reduced pressure to give the title compound (150 mg; yield, 100%) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:30]2[N:31]=[C:32](S(C)(=O)=O)[O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[CH3:21][C:16]([CH3:22])([CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:32]3[O:33][C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[C:30]=4[N:31]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:23])[C:17]([OH:19])=[O:18]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Cc1cccc2oc(S(C)(=O)=O)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(Cl)Cl
Product: Cc1cccc2oc(Nc3ccc(-c4ccc(C(=O)CC(C)(C)C(=O)O)cc4)cc3)nc12
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (74 mg, 0.24 mmol) in dichloroethane (3 mL), 4-methyl-2-(methylsulfonyl)-1,3-benzoxazole (50 mg, 0.24 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.72 mL, 0.72 mmol) was added, and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.24 mL, 0.24 mmol) and methanol (5 mL) was added to the reaction mixture and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2,2-dimethyl-4-{4′-[(4-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoic acid as a white solid (32.6 mg, 32.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.00–7.80 (m, 8 H), 7.30 (d, 1 H), 7.05 (d, 2 H), 3.30 (s, 2 H), 2.50 (s, 3 H), 1.10 (s, 6 H); LC-MS ret. time 3.77 min (method 2), m/z 429.2 (MH+).
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][O:14][CH3:15])[C:6]=2[CH2:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:3]1.C([O-])(=O)C.[NH4+].[N+:27]([CH3:30])([O-:29])=[O:28]>>[CH3:15][O:14][CH2:13][O:12][C:11]1[C:6]2[CH2:5][C@@H:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:3][C@@H:2]([CH2:30][N+:27]([O-:29])=[O:28])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc2c1CC(c1ccccc1)OC2O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COCOc1cccc2c1C[C@@H](c1ccccc1)O[C@H]2C[N+](=O)[O-]
Yield: 11 %

Procedure:
A solution of 1.81 g (6.3 mmol) of 3,4-dihydro-1-hydroxy-5-methoxymethoxy-3-phenyl-1H-2-benzopyran (the product of Step 2 of Example 89) and 488 mg (1.8 mmol) of ammonium acetate in 30 mL of nitromethane was heated at reflux for 3 days and then concentrated in vacuo, the concentrate was poured into 30 mL of a 1M aqueous hydrochloric acid solution and the cloudy mixture was extracted with 2×150 mL of ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with hexane/diethyl ether (8:1 v/v) to give 230 mg (11% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([C:32]#[N:33])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[CH:28]=[CH:27][C:26]([C:29]3([C:32]#[N:33])[CH2:30][CH2:31]3)=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(C3(C#N)CC3)cc2)cc1
Temperature: 98 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a 25 mL press resistant vial which contained a solution of (R)-2-(4-Hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 2 (293 mg, 1 mmol) and the product from step 1 (340 mg, 1.5 mmol) in anhydrous dioxane (8 mL) were added cesium carbonate (450 mg, 2.5 mmol) and N,N-dimethylglycine.HCl (40 mg, 0.0.24 mmol) at rt. The reaction mixture was flushed with argon and copper (I) iodide (20 mg, 0.1 mmol) was added. The vial was sealed and the reaction mixture was stirred at 98° C. for 72 h. After cooled to rt, the mixture was poured onto 100 mL ice-water solution and this solution was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried over anhydrous Na2SO4. The solvent was removed under vacuo to obtain the crude product which was purified by silica gel flash chromatography to yield the title product, (260 mg, 75%); LCMS; 93%, ESI+ Calcd: 434.5. found m/z: 335.6 (M+1-boc). 1H NMR (400 MHz, CDCl3); δ 1.33-1.39 (m, 2H), 1.47 (s, 9H), 1.66-1.68 (m, 2H), 1.81-2.10 (m, 4H), 3.30-3.45 (m, 2H), 3.75-4.21 (m, 3H), 6.90 (d, J=9.2 Hz, 2H), 6.91-6.94 (m, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.24-7.27 (m, 2H)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1.CO>C(OCC)(=O)C.C1CCCCC1>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:33][C:30]6[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=6)[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: O=Cc1ccncc1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(Cc4ccncc4)C3)ccc1OCC2

Procedure:
Following the procedure for 128, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with pyridine 4-carboxaldehyde, the crude product subjected flash chromatography (SiO2, gradient 0 to 20% MeOH in ethyl acetate) then trituration in cyclohexane to give 166 as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J=5.20 Hz, 2H); 7.95 (s, 1H); 7.86 (d, J=2.20 Hz, 1H); 7.30-7.24 (m, 3H); 7.21-7.12 (m, 1H); 6.88-6.83 (m, 1H); 5.73-5.65 (m, 1H); 4.54 (t, J=5.99 Hz, 2H); 3.89-3.74 (m, 3H); 3.71 (s, 2H); 3.30 (s, 2H); 3.16 (t, J=5.99 Hz, 2H); 1.58 (d, J=6.62 Hz, 6H). LCMS: RT=6.07 min, M+H+=442
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:45])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH2:36][O:37]C3CCCCO3)[N:33]=[C:32]([CH3:44])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:45])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[C:32]([CH3:44])[N:33]=[C:34]([CH2:36][OH:37])[CH:35]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from (RS)-[5-chloro-2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M299) (0.41 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (150 mg, 53%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC[O-].[Na+].Cl>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:9][N:8]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccccn2)noc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccccn2)noc1/C=C/c1ccccc1
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
To a solution of 5-methyl-3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester (3.0 g, 13 mmol) and benzaldehyde (1.32 mL, 13 mmol) in ethanol (20 mL) was added sodium ethylate (0.97 g, 14 mmol) and the reaction mixture was stirred at reflux for 40 min. Aqueous hydrochloric acid (1 M, 14 mL) was added and stirring was continued for 15 min. The precipitate was filtered and dried to afford the title compound (2.3 g, 61%) as an off-white solid. MS: m/e=290.9 [M−H]−.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C@@:5]1([CH2:11][NH:12]C(OC)=O)[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1.[ClH:18]>O1CCOCC1.O>[ClH:18].[NH2:12][CH2:11][C@:5]1([CH2:4][C:3]([OH:17])=[O:2])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1
Reactant: COC(=O)C[C@@]1(CNC(=O)OC)CC[C@@H](C)C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@](CN)(CC(=O)O)C1
Yield: 25 %

Procedure:
[(1R,3R)-1-(Methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid methyl ester (2.60 g, 37 mmol) was refluxed in a mixture of 1,4-dioxane (15 mL) and 6N Hydrochloric acid (30 mL) for 16 hours. The mixture was allowed to cool, diluted with water (80 mL), and washed with dichloromethane (2×200 mL). The aqueous layer was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/methanol (95:5) to give 0.55 g (25%) of ((1R,3R)-1-aminomethyl-3-methyl-cyclopentyl)-acetic acid hydrochloride;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[CH2:15]([C:17]1[CH:18]=[C:19]([CH3:29])[C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:21][CH:22]=1)[CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:20]3[C:19]([CH3:29])=[CH:18][C:17]([CH2:15][CH3:16])=[CH:22][N:21]=3)[CH2:24][CH2:25]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 76.1 %

Procedure:
Using 4-bromo-2-methanesulfonylbenzoic acid (2.76 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (1.85 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.20 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])=[N:25][CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1-c1ncc(CBr)o1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cnc(-c3ccccc3Cl)o2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
113 mg (0.37 mmol) of the compound from Example 5A were reacted with 100 mg (0.37 mmol) of the compound from Example 54A analogously to the preparation of the compound in Example 77. This gave 23 mg (12% of theory) of the title compound.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[CH3:13]>C(O)(=O)C>[Br:1][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[C:5]([CH3:13])[CH:6]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)c(C)c1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.67 mL bromine was added to 2 g 1-(4-fluoro-3-methyl-phenyl)-ethanone in 10 mL conc. acetic acid. The reaction was stirred 3 h at RT. The mixture was added to ice water. The precipitate was filtered, washed with water and dried to give 2.7 g desired product. Rt: 1.10 min (method A), (M+H)+: 231
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:6](Br)[CH:5]=1.[CH3:17][Zn]C.CO>O1CCOCC1.CCOCC>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([CH3:17])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:8]([F:10])[CH:9]=1
Reactant: C[Zn]C
Reactant: COCOc1c(F)cc(C(=O)OC)cc1Br
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: COCOc1c(C)cc(C(=O)OC)cc1F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-5-fluoro-4-methoxymethoxybenzoic acid methyl ester (301 mg) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)(42 mg) in dioxane (5 mL) was added dimethylzinc (2M toluene solution) (2.1 mL). The mixture was stirred at 120° C. for 3 hours under heating and then cooled down to 0° C., and methanol (0.3 mL) was added thereto. The mixture was diluted with ether, washed with 1M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=50:1, v/v) to give the title compound (197 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:6][C:7]([C:9]1([C:12]([F:15])([F:14])[F:13])[CH2:11][CH2:10]1)=[O:8].[Cl:20][C:21]1[C:22]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][O:39][CH3:40])=[CH:23][C:24]([N:30]=[C:31]=[S:32])=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1.CN(C=O)C>[Cl-].[Na+].O>[Cl:19][C:18]1[CH:17]=[CH:16][C:4]([CH2:5][NH:6][C:7]([C:9]2([C:12]([F:13])([F:14])[F:15])[CH2:10][CH2:11]2)=[O:8])=[CH:3][C:2]=1[NH:1][C:31]([NH:30][C:24]1[CH:23]=[C:22]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][O:39][CH3:40])[C:21]([Cl:20])=[CH:26][C:25]=1[N+:27]([O-:29])=[O:28])=[S:32]
Reactant: COC[C@@H]1CCCN1c1cc(N=C=S)c([N+](=O)[O-])cc1Cl
Reactant: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H]1CCCN1c1cc(NC(=S)Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-amino-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (150 mg; 0.51 mmol), (S)-5-chloro-2-isothiocyanato-4-(2-(methoxymethyl)pyrrolidin-1-yl)-nitrobenzene (169 mg; 0.51 mmol) and DMF (3 mL) was stirred at rt overnight. The mixture was poured into brine and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was washed with Et2O to give the sub-title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[NH:12][C:11](=[O:13])[C@@H:10]([CH2:14][CH2:15][C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CCOC(C)=O>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:12]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C@H:10]([CH2:14][CH2:15][C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:11]1=[O:13])[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: CC1(CC[C@H]2C[C@@H](Cc3ccccc3)NC2=O)OCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)[C@@H](CCC2(C)OCCO2)C[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 12-3 (210 mg, 0.7257 mmol) and THF (5 mL) at -78° C. was added NaN(TMS)2 (0.943 mL, 0.943 mmol, 1.0M in THF). After 30 min, ethyl bromoacetate (0.104 mL, 0.9434 mmol) was added and the reaction was warmed to 0° C. After 1.0 hour, the reaction mixture was diluted with EtOAc and then washed with sat NaHCO3, brine, dried (MgSO4), and concentrated to give 12-4 as a yellow oil.