Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:4]2[CH2:3]1.[OH-].[Na+].O.Cl>C(O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ncccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)O)ncn2-c2cccnc2C1=O
Reaction time: 1 h

Procedure:
A mixture of 1.61 g (5.6 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]pyrido[2,3-f][1,4]-diazepine-3-carboxylate, 0.33 g (8.2 mmol) of sodium hydroxide, 9 ml of water and 27 ml of ethyl alcohol is heated to boiling under reflux for 25 minutes. The mixture is treated with 8.2 ml of 1 N hydrochloric acid, the ethanol is removed by distillation, the residue is diluted with water and left to stand in an ice-bath for 1 hour. The precipitated material is filtered off under suction, washed with water and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]pyrido[2,3-f][1,4]diazepine-3-carboxylic acid of melting point 292°-295°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].CN(C=O)C.[Cl-].C(Cl)(=O)C([Cl:27])=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([Cl:27])=[O:17])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CCc1cccs1)CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N(CCc1cccs1)CC(=O)Cl

Procedure:
2-(N-(Ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetic acid (14 g, 54.41 mmol) was dissolved in dry dichloromethane (DCM) (300 mL). To this suspension was added 0.1 mL of DMF, followed by the careful addition of oxayl chloride (10.4 g, 81.93 mmol). The reaction mixture was stirred at room temperature for 1 hour, at which time 0.5 mL of additional oxalyl chloride was added. The solvent was evaporated under vacuum to give 2-(N-(ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetyl chloride. This acid chloride was re-dissolved in dry DCM (300 mL) and AlCl3 (18.1 g, 135.74 mmol) was added at room temperature. The reaction was kept at room temperature for 1 hour then quenched by the slow addition of ethanol (about 10 mL). The mixture was then poured into ice and stirred for 1 hr. The aqueous mixture was extracted with DCM (3×150 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated to give a residue, which was purified by silica gel chromatography to produce ethyl 4,5,7,8-tetrahydro-4-oxothieno[3,2-d]azepine-6-carboxylate (7.4 g, 30.92 mmol).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.O>CN(C)C=O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([O:6][CH2:5][C:4]([NH2:3])([CH3:8])[CH3:7])=[CH:11][CH:12]=1)#[N:15]
Reactant: CC(C)(N)CO
Reactant: N#Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(N)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
4.0 g of 60% sodium hydride was added to a solution containing 8.9 g of 2-amino-2-methyl-1-propanol dissolved in 100 ml of N,N-dimethylformamide in an ice bath. After the reaction mixture was stirred for 30 minutes at room temperature, 13.7 g of 4-chlorobenzonitrile was added to the reaction mixture and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was poured into water. The organic layer of the reaction mixture was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure. The fraction possessing a low boiling point was removed from the residue, thus obtaining 15 g of the desired product (yield: 79%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]2[O:16][CH3:17])=O.[OH:18][CH2:19][C@H:20]([NH:27][C:28]1[S:29][CH2:30][C:31](=[O:33])[N:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:18][CH2:19][C@H:20]([NH:27][C:28]1[S:29]/[C:30](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]3[O:16][CH3:17])/[C:31](=[O:33])[N:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CSC(N[C@@H](CO)c2ccccc2)=N1
Reactant: COc1c(C(N)=O)cnc2ccc(C=O)cc12
Product: COc1c(C(N)=O)cnc2ccc(/C=C3\SC(N[C@@H](CO)c4ccccc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-methoxy-quinoline-3-carboxylic acid amide (example 2b) and 2-((R)-2-hydroxy-1-phenyl-ethylamino)-thiazol-4-one (example 3a) to give 6-[2-((R)-2-hydroxy-1-phenyl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-methoxy-quinoline-3-carboxylic acid amide. LC-MS m/e 449 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:35][CH2:34][C:24]2[N:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:27][C:23]=2[CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2ccccc12)OCC
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)c2ccccc12)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in tetrahydrofuran in the presence of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid as colorless amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH2:24]Br)=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH2:24][N:11]2[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=3[CH:9]=[CH:10]2)=[O:20])=[CH:29][CH:30]=1
Reactant: Cn1ncc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2cccc(C(=O)c3ccc(Cl)cc3)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 3-(4-chlorobenzoyl)benzyl bromide (681 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 2 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl-acetate=1:3) to provide the title compound as white powder (630 mg, yield 83%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:16][CH:15]=1)([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (303 mg, 1.91 mmol, 1.00 eq) and 4-iso-propylphenol (331 mg, 2.43 mmol, 1.27 eq) were dissolved in DMF (6.0 mL). Anhydrous K2CO3 (398 mg, 2.88 mmol, 1.51 eq) was added and the reaction mixture was stirred at room temperature for 24 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as pale yellow solid (490 mg, 1.90 mmol, 99% yield). Rf=0.40 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C14H15N2O3+ [M+H]+ 259.1077. found: 259.1072. 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J=3.4 Hz, 1H, aromatic H), 8.44 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.37-7.28 (m, 2H, aromatic H), 7.12-7.06 (m, 2H, aromatic H), 7.03-6.97 (m, 1H, aromatic H), 2.96 (hept, J=6.9 Hz, 1H, CH(CH3)2), 1.30 (d, J=7.0 Hz, 6H, CH(CH3)2). 13C NMR (101 MHz, CDCl3) δ 167.08, 150.67, 146.49, 145.02, 140.18, 134.81, 127.84, 121.11, 111.24, 33.62, 24.03.
Reaction SMILES: [C:1]([C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[Cl:13])#[N:2].Cl.[NH2:15]C(C)(CC)C#C.[OH-].[Na+]>O>[C:1]([C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([NH2:15])=[O:8])=[CH:5][C:4]=1[Cl:13])#[N:2]
Reactant: C#CC(C)(N)CC
Reactant: N#Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1c(Cl)cc(C(N)=O)cc1Cl
Temperature: 25 °C

Procedure:
To a well stirred mixture of 4-cyano-3,5-dichlorobenzoyl chloride (4.0 g, 0.017 mol) and water (100 ml) at 0° C. (ice-water bath) were added 3-amino-3-methyl-1-pentyne hydrochloride and 50 weight percent aqueous sodium hydroxide (10 ml). The resulting mixture was stirred 1 hour at 0° C., warmed up to room temperature and extracted with ethyl acetate (3×50 ml), the combined organic layers were washed with water (3×50 ml), and then dried over anhydrous sodium sulfate. The solvent was then eliminated in the rotavap, yielding the crude product as a yellow oil (2.79 g). The crude product was purified by Michel-Miller chromatographic column packed with Merck (grade 60) silica gel using ethyl acetate as solvent, yielding 0.75 g of N-[3'-methyl-1'-pentynyl)]-4-cyano-3,5-dichlorobenzamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[F:12])[CH2:9][C:8]2=[O:10]
Reactant: O=Cc1ccccc1F
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2F)Oc2ccc(Br)cc21
Yield: 66.6 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15 g, 70.1 mmol), 2-fluorobenzaldehyde (8.7 g, 70.1 mmol), and borax (26.7 g, 70.1 mmol) in ethanol (90 mL) and H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(2-fluorophenyl)chroman-4-one (15 g, 50%). 1HNMR (CDCl3): 2.8 (d, 1H), 3.0 (t, 1H), 5.7 (d, 1H), 6.7 (d, 1H), 6.9 (t, 1H), 7.2 (m, 2H), 7.3 (m, 2H), 7.5 (m, 2H), 7.9 (t, 1H), 8.1 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][CH:26]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:47][CH2:48][F:49]>O1CCCC1>[F:49][CH2:48][CH2:47][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH2:19]2)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:33][CH:34]=1
Reactant: FCCI
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(OCCF)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 54.3 %

Procedure:
150 mg (0.28 mmol) 4-(3-{(R)-3-[1-(4-hydroxy-phenyl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 3 ml tetrahydrofurane. 179 mg (0.55 mmol) cesium carbonate and 91 mg (0.52 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 60 hours and filtrated. The filtrate was concentrated. Chromatography over 10 g silica gel (dichloromethane ethanol 100/0-90/10) gave 90 mg (50%) tert-butyl 4-{3-[(3R)-3-({1-[4-(2-fluoroethoxy)phenyl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate and 40 mg starting material.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:22])=[N:4][CH:5]=[C:6]([C:12]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:7](OCC)=[O:8].C([NH2:25])=O.CC[O-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:22])=[N:4][CH:5]=[C:6]([C:12]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:7]([NH2:25])=[O:8]
Reactant: NC=O
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1NCc1cccc(F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cnc(Cl)c(Cl)c1NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of ethyl 5,6-dichloro-4-(3-fluorobenzylamino)nicotinate (260 mg, 0.76 mmol) in DMF (1 mL) was added HCONH2 (0.272 mL, 6.84 mmol) and NaOEt (21% in EtOH, 0.425 mL, 1.14 mmol). After stirring at room temperature for 30 min, the mixture was added water, and the precipitate was collected by filtration to give 5,6-dichloro-4-(3-fluorobenzylamino)nicotinamide (170 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]1([C:20]([C:22]2[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=2)=[CH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:14]1([C:20]([C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)=[CH2:21])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=C(c1ccccc1)c1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C=C(c1ccccc1)c1cccc(COc2ccc(CCC(=O)OC)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (0.360 g, 2.00 mmol), [3-(1-phenylvinyl)phenyl]methanol (0.421 g, 2.00 mmol) and tributylphosphine (0.747 mL, 3.00 mmol) in toluene (30 mL) was stirred under ice-cooling, 1,1′-(azodicarbonyl)dipiperidine (0.757 g, 3.00 mmol) was added by small portions under a nitrogen atmosphere, and the mixture was stirred at room temperature for 18 hrs. Hexane (15 mL) was added to the reaction mixture, the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-20% ethyl acetate/hexane) to give the title compound as a colorless oil (0.641 g, yield 86%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:28]=[C:29]([C:7]2[N:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN1CCC(c2c[nH]c3ccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)nc23)CC1
Yield: 90.7 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (160 mg, 0.441 mmol) and 3,5-di(trifluoromethyl)phenylboronic acid (183 mg, 0.71 mmol) were converted to 171 mg of the title compound by the procedure of Example 3. (91%). MS(FD) m/e 427.6 (M+). EA calculated for C21H19F6N3: C, 59.02; H, 4.45; N, 9.84. Found: C, 59.31; H, 4.69; N, 9.83.
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[I:18])[C:9]2[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>CC(O)C>[C:23]([O:27][C:28](=[O:29])[NH:30][CH:31]1[CH2:35][CH2:34][N:33]([C:2]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[I:18])[C:9]3[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[N:5]([CH3:22])[C:4]=3[N:3]=2)[CH2:32]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2I)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1c(=O)c2c(nc(N3CCC(NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2I)n(C)c1=O
Reaction time: 3 h

Procedure:
8-Chloro-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (5A) (100 mg, 0.23 mmol) and (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (216 mg, 1.16 mmol), and triethylamine (0.32 ml, 2.32 mmol) were dissolved in 20 ml of 2-propanol and the mixture was subjected to microwaves (method F, 130° C., 300 W) for three hours. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=12.99 min.). Evaporation of the solvent afforded compound (7A) as white crystals.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[O:20])=[C:11]2Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[O:20])=[C:11]2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(S(=O)(=O)c2ccccc2)c2ccccc12
Product: O=Cc1c(N2CCNCC2)n(S(=O)(=O)c2ccccc2)c2ccccc12
Yield: 45 %

Procedure:
1-Benzenesulfonyl-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-benzenesulfonyl-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (45% yield). ESI/MS 370 (M+H); RT 2.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]#[N:31])[C:9]2[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([C:26]#[N:27])[C:18]([NH:20][C:21](=O)[O:22]CC)=[O:19])=[CH:11][C:10]=2[O:28][CH3:29])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]#[N:31])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:21](=[O:22])[NH:20][C:18](=[O:19])[C:17]([C:26]#[N:27])=[N:16]3)=[CH:11][C:10]=2[O:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1ccc(C(C#N)c2ccc(Cl)cc2)c(OC)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1cc(-n2nc(C#N)c(=O)[nH]c2=O)ccc1C(C#N)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 8.3 parts of ethyl [2-[[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]hydrazono]-2-cyanoacetyl]carbamate, 1.77 parts of anhydrous potassium acetate and 100 parts of acetic acid is stirred for 2 hours at reflux temperature. The reaction mixture is evaporated in vacuo. The residue is stirred in water. The product is filtered off and dissolved in trichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated in vacuo, yielding 2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile.
Reaction SMILES: OS(O)(=O)=O.[C:6]([NH:9][C@@H:10]([CH2:14][S:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:21][C:20]=1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:17])[C:11]([OH:13])=[O:12])(=[O:8])[CH3:7].O.[CH3:44]O>>[C:6]([NH:9][C@H:10]([C:11]([O:13][CH3:44])=[O:12])[CH2:14][S:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:21][C:20]=1[C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:17])(=[O:8])[CH3:7]
Reactant: CC(=O)N[C@@H](CSC(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCc1ccccc1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@H](CSC(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCc1ccccc1)NC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
H2SO4 (0.020 mL, 0.343 mmol) was added to a solution of (R)-2-acetamido-3-((2′,4′-difluoro-3-(benzyloxycarbonyl)biphenyl-4-yloxy)carbonylthio)propanoic acid (54 mg, 0.102 mmol) in MeOH (10 mL). The reaction mixture was stirred at r.t. for 18 h, poured into H2O (30 mL) and extracted with CH2Cl2 (20 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (3% MeOH/CH2Cl2) to furnish (R)-benzyl 4-((2-acetamido-3-methoxy-3-oxopropylthio)carbonyloxy)-2′,4′-difluorobiphenyl-3-carboxylate (yellow-coloured solid, yield: 82%).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:18]O>S(=O)(=O)(O)O.O>[CH2:1]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10]([O:12][CH3:18])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(C(=O)O)ccc1OC
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCc1cc(C(=O)OC)ccc1OC

Procedure:
A crude product of 3-hexyl-4-methoxybenzoic acid and methanol (4 ml) were mixed. To this solution was added conc. sulfuric acid (2 drops), and the mixture was refluxed under heating for 20 hours. Water (10 ml) was added and methanol was evaporated under reduced pressure. The aqueous layer was extracted 3 times with ethyl acetate (20 ml). The organic layers were combined, and washed 3 times with saturated brine (20 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate=10/1) to give methyl 3-hexyl-4-methoxybenzoate (96.2 g) as a colorless oil.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].[N:13]([O-])=[O:14].[Na+]>O>[CH3:11][C:10](=[O:12])[C:9](=[N:13][OH:14])[C:6](=[O:8])[CH3:7]
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)C(=NO)C(C)=O
Yield: 89 %

Procedure:
Variant b): 1225 g of 20% strength sulfuric acid were metered into a solution of 500 g (5 mol) of acetylacetone, 1 l of water and 1305 g of 25% strength aqueous sodium nitrite solution, the pH being adjusted to 3-5 and the internal temperature to 25-17° C. The product of value was isolated as in variant a). This gave 570 g of the title compound (89% yield).