Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[N+:17]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:20])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[NH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNc1ccc(C#N)cc1N
Yield: 53.8 %

Procedure:
N-(4-Cyano-2-nitrophenyl)glycine tert-butyl ester (17.337 g) was hydrogenated using 7.5% palladium carbon (1.73 g) in tetrahydrofuran (173 ml) at atmospheric pressure for 2 hours and by adding 7.5% palladium carbon (3.84 g) for one more hour. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. The obtained residue was washed with diisopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (8.324 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([NH2:30])(=[O:29])=[O:28].[OH-].[Na+]>ClCCCl.C(N(CC)CC)C>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([NH:30][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9])(=[O:29])=[O:28]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: NS(=O)(=O)c1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cn1cc(C(=O)NS(=O)(=O)c2cccs2)cn1
Temperature: 55 °C
Yield: 63.8 %

Procedure:
3.8 g of 1-methylpyrazole-4-carboxylic acid and 4.9 g of carbonyldiimidazole in 100 ml of 1,2-dichloroethane are heated at 55° C. for 3.5 h. 4.9 g of 2-thienylsulfonamide and 5.4 ml of triethylamine are added and then the mixture is heated at 55° C. for 13 h. After cooling, 40 ml of 10% strength aqueous NaOH solution are added and then the pH of the aqueous phase is adjusted to 1. The precipitate is removed and dried under reduced pressure. 5.2 g of N-(2-thienylsulfonyl)-1-methylpyrazole-4-carboxamide with a melting point of 174°-180° C. are obtained (active ingredient Example No. 103).
Reaction SMILES: [NH2:1][Cu:2].C(=O)([O-])[O-].[Na+].[Na+].[N:9]1[C:16]([Cl:17])=[N:15][C:13](Cl)=[N:12][C:10]=1[Cl:11]>>[Cl:17][C:16]1[N:9]=[C:10]([Cl:11])[N:12]=[C:13]([NH:1][Cu:2])[N:15]=1
Reactant: N[Cu]
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1nc(Cl)nc(N[Cu])n1

Procedure:
The preferred starting point for the further reaction of the amino copper complex formazan compound is the synthesis solution of (b), which is at pH 4, by reacting the solution with thorough stirring at a temperature of 0° to 5° C. and at a pH between 3 and 4, which is maintained by means of an aqueous sodium carbonate solution, with 16.6 parts of cyanuric chloride to give the 2,4-dichloro-s-triazin-6-ylamino copper complex formazan compound in the course of 3 to 4 hours.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=3[N+:24]([O-])=O)=[N:11][N:10]=2)=[CH:5][CH:4]=1>[Pd].O1CCCC1>[NH2:24][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:14]=1[C:12]1[O:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:27])[F:1])=[CH:4][CH:5]=2)=[N:10][N:11]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A mixture of methyl 4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]-3-nitrobenzoate (0.500 g), 5% palladium on carbon (0.500 g) and tetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere at room temperature and normal pressure for 30 min. Palladium on carbon was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1, volume ratio) to give methyl 3-amino-4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (0.36 g, yield 77%). Recrystallization from hexane-ethyl acetate gave yellow prism crystals. melting point: 237–238° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=2)=[O:11])[CH3:8].Br[CH:27]([CH3:30])[C:28]#[N:29]>CN(C=O)C>[CH2:7]([O:9][C:10]([C:12]1[N:13]([CH:27]([C:28]#[N:29])[CH3:30])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=2)=[O:11])[CH3:8]
Reactant: CC(Br)C#N
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C#N)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A mixture of K2CO3 (7.93 g, 57.0 mmol) and 1H-indole-2,6-dicarboxylic acid diethyl ester (5.0 g, 19.14 mmol) in DMF (30 mL) was stirred at room temperature for 0.5 h. Then 2-bromo-propionitrile (3.4 mL, 38.3 mmol) in DMF (10 mL) was added. The reaction was warmed to 80° C. and kept at this temperature for 6 h. Then the reaction was cooled down to the room temperature. Most of the DMF solvent was removed in vacuo and the crude residue was extracted several times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated. The crude product was triturated with MeCN to give 3.9 g of 1-(cyano-methyl-methyl)-1H-indole-2,6-dicarboxylic acid diethyl ester as a white fluffy solid. The filtrate was concentrated and purification by silica gel chromatography provided 1.6 g of 1-(cyano-methyl-methyl)-1H-indole-2,6-dicarboxylic acid diethyl ester, yield 91%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([NH2:12])=O)[CH:7]=[CH:6][S:5]2.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]#[N:12])[CH:7]=[CH:6][S:5]2
Reactant: Cc1nc2sccn2c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1nc2sccn2c1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a mixture of 6-methylimidazo[2,1-b][1,3]thiazole-5-carboxamide (544 mg, 3.0 mmol) produced above, pyridine (0.7 mL, 9.0 mmol) and tetrahydrofuran (10 mL) was added dropwise under ice-cooling trifluoroacetic anhydride (0.6 mL, 4.5 mmol). After stirring at room temperature for 1 day, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→50/50). The obtained solution was concentrated under reduced pressure to give the title compound (433 mg, 86%) as a pale-brown solid.
Reaction SMILES: [O:1]([CH2:3][C:4]([OH:6])=[O:5])[NH2:2].C(N(CC)CC)C.[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.O1CCCC1.C(OCC)(=O)C>[CH2:14]([NH:21][C:22](=[O:23])[NH:2][O:1][CH2:3][C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C=NCc1ccccc1
Reactant: NOCC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)CONC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To the solution of 2-(aminoxy)acetic acid 5 g (46 mmol) and triethylamine 3.17 ml (23 mmol) in dichloromethane 60 ml and tetrahydrofuran 60 ml, benzyl isocyanate 5.43 ml (44 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 400 ml and washed with water 300 ml and brine 200 ml. The organic phase was basified with 1N-sodium hydride 60 ml. The aqueous phase was acidified with 1N-hydrochloric acid 70 ml and extracted with ethyl acetate 300 ml. The organic phase was washed with brine 200 ml and dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and precipitated by addition of ether 50 ml and n-hexane 150 ml to obtain the title compound 3.2 g (33%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C[Al](C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: C1COCCN1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(N2CCOCC2)nc2c1ccc(=O)n2-c1ccccc1C

Procedure:
Following the general procedure outlined in Example 193, the product of Example 121 (100 mg, 0.22 mmol), morpholine (58 mg, 0.66 mmol) and trimethylaluminum (0.33 mL, 0.66 mmol) were reacted to give the desired product, 61 mg (64%). LC-MS: 431.2 (MH+, m/z), 2.46 (Rt, min).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:25]1([O:24][C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
The mixture of 2-(2-cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (8) (250 mg, 0.64 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and the solution acidified with conc. HCl until pH˜3 to yield a precipitate. The precipitate is filtered to give a pure product (9) as white solid (190 mg, 81%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.O.[OH-].[Na+]>C(O)(=O)C.[Zn]>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][CH:2]=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2csc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Temperature: 120 °C
Yield: 48.6 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (2.0 g, 4.37 mmol) in the 50 ml of acetic acid was added Zn dust (2.0 g). The reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3×150 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.8 g, 50%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[C:32]([N:36]=[C:37]=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[F:27][C:3]([F:2])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][N:20]([C:37]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(OC(F)F)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]azetidine hydrochloride (175) (100 mg, 0.24 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 280 mg, 0.72 mmol), molecular sieves and tert-butyl isocyanate (29 μL, 0.24 mmol). After shaking at ambient temperature for 2 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (20 mL) and evaporation afforded the desired product (90 mg, 78%).
Reaction SMILES: [Na].[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)#N.C(C1C=CC=CN=1)#N>C1(C)C(C)=CC=CC=1.O>[N:21]1[CH:22]=[CH:23][C:18]([C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[OH:9])=[CH:19][CH:20]=1
Reactant: N#Cc1ccncc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: N#Cc1ccccn1
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Yield: 95 %

Procedure:
Sodium (16.6 grams, 0.72 mole) metal and xylene (150 ml) were charged into a 1 liter round bottom three-neck flask equipped with a mechanical stirrer, reflux condenser and two dropping funnels. The mixture was brought to reflux and the addition of benzophenone (54.6 grams, 0.3 mole) was begun. When about 1/4 to 1/3 of the benzophenone had added during 15-30 minutes, the addition of a solution of 4-cyanopyridine (38.2 grams, 0.37 mole) in xylene (200 mL) was begun at a rate so that about 1/2 of the cyanopyridine solution had been added when the addition of benzophenone was complete. The remaining cyanopyridine solution was added during another 30 minutes. Upon work-up with water (300 mL), 4-pyridyl diphenyl carbinol was obtained in about 95% yield.
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C[Al](C)C.[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20](OCC)=[O:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[CH3:2][C:1]([NH:10][C:20]([C:16]1[S:15][CH:19]=[CH:18][N:17]=1)=[O:21])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)(N)c1ccccc1
Reactant: CCOC(=O)c1nccs1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(NC(=O)c1nccs1)c1ccccc1
Yield: 67.1 %

Procedure:
7.13 ml (50.0 mmol) of cumylamine and 156 ml of toluene are placed in a 1-liter three-necked flask with stirring and under an inert atmosphere. 24.8 ml (49.6 mmol) of trimethylaluminium are then added dropwise, and white fumes are evolved. After waiting until the medium has clarified, a solution of 3.9 g (24.8 mmol) of ethyl 2-thiazolecarboxylate (2) in 195 ml of toluene is added. The mixture is stirred for 15 minutes and then refluxed. After heating for 15 hours, the reaction medium is poured into 300 ml of 1M citric acid solution diluted with 200 ml of water and the whole is filtered through Celite®. The Celite® is washed with 100 ml of ethyl acetate and the aqueous phase is extracted with twice 100 ml of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, and after evaporating under reduced pressure, the residue is purified by flash chromatography (msilica=200 g; eluent: dichloromethane). 4.1 g of N-(1-methyl-1-phenylethyl)thiazole-2-carboxamide are obtained in the form of a brick-red solid. Rf(dichloromethane)=0.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.S(Cl)([Cl:19])=O.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:19])=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: OCc1ccc(Br)cc1OC1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: ClCc1ccc(Br)cc1OC1CCCCC1
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
To a solution of (4-bromo-2-cyclohexyloxyphenyl)methanol (5.46 g) in dichloromethane (16 ml) was added thionyl chloride (3.42 g) dropwise at 5° C. under nitrogen, and the mixture was stirred at the same temperature for 1.5 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated and dried in vacuo to give 4-bromo-1-chloromethyl-2-cyclohexyloxybenzene (5.59 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH2:9].C([O-])([O-])=O.[Na+].[Na+].[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:18]([CH2:16][CH3:17])(=[O:20])=[O:19]
Reactant: NCc1ccncc1Br
Reactant: CCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)NCc1ccncc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
To a solution of (3-bromopyridin-4-yl) methanamine (720 mg, 3.9 mmol) in DCM (20 mL) is added Na2CO3 (1.2 g, 11 mmol). Then ethanesulfonyl chloride (740 mg, 5.8 mmol) is added dropwise under N2 atmosphere at 0° C. The mixture is stirred at room temperature for 16 hrs and it is diluted with DCM. The mixture is washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash column chromatography to give 600 mg of ethanesulfonic acid (3-bromo-pyridin-4-ylmethyl)-amide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:33]4[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.226 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70 mg, 0.338 mmol). The product was collected as a white solid (82 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br. s., 1H) 8.48 (t, J=4.93 Hz, 1H) 8.30 (s, 1H) 8.26 (s, 1H) 8.04 (s, 2H) 7.81 (s, 1H) 5.90 (s, 1H) 5.22 (quin, J=7.14 Hz, 1H) 4.39 (s, 1H) 4.38 (s, 1H) 3.87-3.92 (m, 3H) 2.23 (s, 3H) 2.14-2.19 (m, 1H) 2.13 (s, 4H) 1.96-2.05 (m, 2H) 1.84-1.94 (m, 2H) 1.66-1.76 (m, 2H). LC-MS (ES) m/z=445.2 [M+H]+
Reaction SMILES: [C:1]([C:4]1[C:5]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[OH-].[Na+]>C(O)C.C1COCC1.O>[C:1]([C:4]1[C:5]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CCOC(=O)C(C)(C)NC(=O)N1CCn2nc(-c3ccc(F)c(Cl)c3)c(C(N)=O)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(NC(=O)N1CCn2nc(-c3ccc(F)c(Cl)c3)c(C(N)=O)c2C1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of Intermediate 213A (500 mg, 1.106 mmol) in ethanol (20 mL) and THF (20 mL) was added a solution of NaOH (89 mg, 2.213 mmol) in water (10 mL) and the reaction mixture was stirred at RT for 8 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was dissolved in water and the pH of solution was adjusted to 4 using a 1.5N aqueous solution of HCl which was then stirred for 10 min. The precipitate was filtered, dried and triturated with diethyl ether to afford Intermediate 213B as pale brown solid (400 mg, 85%). MS(ES): m/z=424 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (s, 1H), 7.89-7.84 (m, 1H), 7.73-7.67 (m, 1H), 7.50-7.44 (m, 1H), 7.35 (s, 1H), 7.20 (br. s., 1H), 6.93 (s, 1H), 4.74 (s, 2H), 4.16-4.10 (m, 2H), 3.85 (d, J=5.5 Hz, 2H), 1.38 (s, 6H).
Reaction SMILES: C(O[C:9]1[C:14]([F:15])=[C:13]([O:16]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[NH:24][C:25](=[O:39])[C:26]1[CH:31]=[C:30]([F:32])[C:29]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)=[CH:28][C:27]=1[F:38])C1C=CC=CC=1>[C].[Pd].C1COCC1>[CH:35]1([CH2:34][O:33][C:29]2[C:30]([F:32])=[CH:31][C:26]([C:25]3[O:39][C:9]4[C:14]([F:15])=[C:13]([OH:16])[CH:12]=[CH:11][C:10]=4[N:24]=3)=[C:27]([F:38])[CH:28]=2)[CH2:36][CH2:37]1
Reactant: O=C(Nc1ccc(OCc2ccccc2)c(F)c1OCc1ccccc1)c1cc(F)c(OCC2CC2)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1ccc2nc(-c3cc(F)c(OCC4CC4)cc3F)oc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A mixture of N-(2,4-bis(benzyloxy)-3-fluorophenyl)-4-(cyclopropylmethoxy)-2,5-difluorobenzamide (2.50 g), 10% palladium-carbon (containing water (50%), 2.00 g) and THF (20 mL) was stirred at room temperature for 30 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure, and the solid was washed with diethyl ether. To a suspension of the obtained solid, hexachloroethane (2.78 g) and triphenylphosphine (3.08 g) in acetonitrile (20 mL) was added triethylamine (1.96 mL) at 0° C., and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 2 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.34 g).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[OH-].[Na+]>O.O1CCOCC1>[CH2:19]([N:15]1[CH2:16][CH2:17][CH2:18][C:13]2([NH:12][C:11](=[O:27])[C:10]3[CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=[CH:8][C:9]=3[O:26]2)[CH2:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2
Yield: 104 %

Procedure:
A solution of (±)-(E)-3-{1′-benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (240 mg, 0.61 mmol) in water (5 ml) and dioxane (10 ml) was treated with 1 M NaOH (0.80 ml) as described in Example 30, Step A, to give (±)-(E)-3-{1′-benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (hydrochloride salt, 240 mg) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][C:31]([C:35]([F:38])([F:37])[F:36])([OH:34])[CH2:30][CH2:29]2)=[C:22]([Cl:39])[CH:21]=1>>[Cl:39][C:22]1[CH:21]=[C:20]([NH:19][C:10](=[O:12])[C:9]#[C:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][C:2]=2[Br:1])[CH:25]=[CH:24][C:23]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][C:31]([OH:34])([C:35]([F:37])([F:38])[F:36])[CH2:30][CH2:29]1
Reactant: Nc1ccc(CCN2CCC(O)(C(F)(F)F)CC2)c(Cl)c1
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br
Product: O=C(C#Cc1ccc(-c2ccccc2)cc1Br)Nc1ccc(CCN2CCC(O)(C(F)(F)F)CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 2.3.f. from (3-bromobiphenyl-4-yl)propynoic acid and 1-[2-(4-amino-2-chlorophenyl)ethyl]4-trifluoromethylpiperidin-4-ol. Yield: 36 mg (10.5% of theory); C29H25BrClF3N2O2 (M=605.87); calc.: molecular ion peak (M+H)+: 605/07/09; found: molecular ion peak (M+H)+: 605/07/09.