Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C.O>[C:1]1([C:7]2[N:12]=[C:11]([OH:13])[C:10]([N+:15]([O-:17])=[O:16])=[C:9]([OH:14])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cc(O)nc(-c2ccccc2)n1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)nc(-c2ccccc2)nc1O
Temperature: 50 °C

Procedure:
To a suspension of 2-Phenyl-4,6-dihydroxy-pyrimidine (12 g) in 35 mL of acetic acid is added 12 mL of 90% nitric acid and the mixture is heated at 50° C. for 45 min. The reaction mixture is diluted with 150 mL of water and the product is collected, washed with water and ethanol and over dried to afford 2-Phenyl-5-nitro-4,6-dihydroxy-pyrimidine as a pink solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (59.6 mg, 0.187 mmol) and triphenylphosphine (49.1 mg, 0.187 mmol) in methylene chloride (468 μL) was cooled to 0° C. and then treated with N-bromosuccinimide (36.7 mg, 0.206 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The orange reaction mixture was then treated with 2-aminopyridine (35.2 mg, 0.374 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was diluted with ethyl acetate (50 mL). The organic layer was washed sequentially with a 10% aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and water (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 9/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide (25.0 mg, 34%) as a cream solid: mp 101–102° C.; EI-HRMS m/e calcd for C20H21F3N2OS (M+) 394.1327, found 394.1321.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].[H-].[Na+].[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>O1CCCC1>[CH2:18]([O:17][C:15]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([CH:11]=[O:12])=[CH:6]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(C(=O)OCc2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-chloro-3-formylindole (5.00 g) in tetrahydrofuran (135 ml) was added sodium hydride (60% oil suspension, 3.53 g). The mixture was stirred for 20 minutes at room temperature. Carbobenzoxychloride (6.64 ml) was added to the mixture. After being stirred for 1 hour at room temperature, the whole was poured into ice water. The mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solution was concentrated to give a residue, which was subjected to silica gel chromatography. Elution with hexane-ethyl acetate (5:1) provided 1-benzyloxycarbonyl-5-chloro-3-formylindol (5.74 g) as a crystal.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)[NH:7][CH:6]=[C:5]2[CH:24]=[O:25]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25]
Reactant: CCOc1cccc(CC2NC=C(C=O)c3cc(O)c(OC)cc32)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (660 mg, 1.95 mmol) in chloroform (30 mL) was addend manganese (IV) oxide (1.99 mg, 19.5 mmol). The reaction mixture was stirred at room temperature for 15 hrs, filtered through a celite® pad, and washed with chloroform. The filtrate was concentrated in vacuo to afford 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (600 mg, 89% yield). The crude product was used without further purification.
Reaction SMILES: Br.N=[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][S:4]1.C([O-])(=[O:17])C.[Na+].C(O)(=O)C.N([O-])=O.[Na+]>O>[C:9]1([CH2:8][N:7]2[CH2:6][CH2:5][S:4][C:3]2=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)[O-]
Reactant: N=C1SCCN1Cc1ccccc1
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1SCCN1Cc1ccccc1
Yield: 42.3 %

Procedure:
To a solution of 2.73 g (0.01 mol) of 2-imino-3-phenylmethylthiazolidine hydrobromide in 10 ml of water 1.36 g of anhydrous sodium acetate and 0.62 ml of glacial acetic acid are added, then 0.75 g of sodium nitrite dissolved in 3 ml of water is dropped to the above mixture at 5° C. under stirring, then the mixture is stirred at 5° C. for additional 3 hours. After standing in a refrigerator overnight, the solution is stirred at room temperature for 3 hours. After rubbing, a precipitate appears which is filtered off, washed with water, dried and then refluxed with five volumes of n-butanol for 2 hours. After evaporating the solvent, the residue is thoroughly rubbed with diisopropyl ether and the product is filtered off. Thus, 0,81 g (42.3%) of the title product is obtained, m.p.: 49°-50° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(4-fluorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=384 (M+ of free base). α[D]589 =-11.40 (c=0.66, methanol).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:28]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: OCc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3cccc(CO)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 58.5 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 250 mg of the target compound.
Reaction SMILES: [F-:1].[K+].[F-].[Cs+].Cl[C:6]1[C:11]([F:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1>S1(CCCC1)(=O)=O.C1OCCOCCOCCOCCOCCOC1>[F:1][C:6]1[C:11]([F:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1
Reactant: [F-]
Reactant: Fc1cc(C(F)(F)F)cnc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(C(F)(F)F)cnc1F
Temperature: 140 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
47.7 g (0.82 mol) of potassium fluoride and 10.0 g (0.065 mol) of caesium fluoride are suspended in 300 ml of sulfolane and the suspension is heated to 140° C. 60 ml of sulfolane are distilled off by decreasing the pressure and subsequently 65.6 g (0.329 mol) of 2-chloro-3-fluoro-5-trifluoromethylpyridine and 1.3 g (0.004 mol) of 18-crown-6 are added. The reaction mixture is stirred for 48 hours at 140° C. and subsequently distilled by introducing steam. The oil is separated and the aqueous phase is extracted twice with a small amount of ether. The organic phases are purified, dried with a small amount of magnesium sulfate and filtered. Distillation affords 54.8 g (91% of theory) of 2,3-difluoro-5-trifluoromethylpyridine, b.p. 100°-102° C. (980 mbar).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.C(N(CC)CC)C.[C:13]1([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:19][CH2:20][CH2:21][C:22]([N:3]2[CH2:4][CH2:5][S:1][CH2:2]2)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: C1CSCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)N1CCSC1
Temperature: 25 °C
Yield: 88 %

Procedure:
5.5 mmol of thiazolidine and 5.5 mmol of triethylamine were dissolved in 10 ml of methylene chloride. To the solution 5 mmol of 4-phenylbutanoyl chloride was added dropwise under ice-cooling with stirring. The mixture was left to raise to room temperature and further heated under refluxing for 2 hours. The resulting reaction mixture was washed with 1N hydrochloric acid, brine, and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated by distillation and the residue was purified by column chromatography on silica gel to obtain 1.14 g of colorless crystals of N-(4-phenylbutanoyl)thiazolidine (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[C:19]([OH:20])=[N:18][C:5]2[CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[S:22]([O:20][C:19]1[C:2]([Br:1])=[CH:3][C:4]2[CH:10]([CH3:11])[CH2:9][N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[CH2:7][CH2:6][C:5]=2[N:18]=1)(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2nc(OS(=O)(=O)C(F)(F)F)c(Br)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
A mixture of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -pyrido[2,3-d]azepin-2-ol (30.0 mg, 85.0 μmol), Tf2O (50 μl), K2CO3 (18 mg) and DCM (1 ml) was stirred for 16 h at room temperature. The mixture was extracted with sat. aq. NaHCO3, dried over Na2SO4, concentrated in vacuo and purified by column chromatography to yield 11.0 mg (26%) of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate. A mixture of methylamine (50 μl), 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate (11.0 mg, 22.7 μmol), and THF (1 ml) was heated to reflux for 15 h. The reaction mixture was parted between sat. aq. NaHCO3 and EtOAc. The organic layer was dried, concentrated in vacuo and purified with column chromatography to give 5.2 mg (62%) of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 486.2 (M+H+). A mixture of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine (5.2 mg, 14.2 μmol), K2CO3 (15 mg), MeOH (1 ml) and H2O (100 μl) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 2.1 mg (55%) of 3-bromo-N,5-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 271.2 (M+H+).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37](=[O:46])[CH2:36][S:35]2)[CH:32]=1)(=[O:26])[CH3:25]>>[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:37](=[O:46])[C:36](=[C:14]3[N:13]([CH3:12])[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15]3)[S:35]2)[CH:32]=1)(=[O:26])[CH3:25]
Reactant: CSc1sc2c([n+]1C)CCCC2
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-ium p-toluenesulfonate with 2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one. MS(ESI): 519 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](N2C=CN=C2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][NH2:23]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:10]([NH:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][NH2:23])[CH2:24][CH2:25][CH3:26])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Cl
Reactant: CCCN(CCN)CCN
Solvent: C1CCOC1
Product: CCCN(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 23.87 g (100.0 mmol) of 1-(3,5-diamino-6-chloropyrazinoyl)imidazole and 58.51 g (300.0 mmol) of N-(2-aminoethyl)-N-propyl-1,2-ethanediamine in 250 ml of tetrahydrofuran was stirred at ambient temperature overnight. The solvent and excess triamine were evaporated and the residue chromatogaphed on silica gel (150 g) using 1.5:98.5 (v/v) methanol: tetrahydrofuran saturated with ammonia gas as eluent. There was obtained 24.64 g (78.0 mmol, 78%) of 3,5-diamino-N-[2-[(2-aminoethyl)propylamino]ethyl]-6-chloropyrazinecarboxamide as a yellow solid; mp 91°-94° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:7]3[CH:8]=[C:3]([CH:4]=[CH:5][CH:6]=3)[C:1]#[N:2])=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: N#Cc1cccc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 3-cyanophenylboronic acid (185 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 135 mg, 0.52 mmol, 82%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.21 (s, 2H), 6.94 (s, 1H), 7.13 (s, 1H), 7.54 (dd, J=8.2, 2.4 Hz, 1H), 7.55-7.60 (m, 2H), 7.70 (d, J=7.9 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 8.21 (d, J=7.9 Hz, 1H), 8.31 (s, 1H), 8.61 (d, J=1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 113.1, 118.6, 119.0, 120.6, 129.7, 130.4, 130.6, 131.0, 131.3, 132.5, 136.0, 137.3, 139.6, 148.77, 148.81, 155.1; MS (ESI): m/z=261.41 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:6]([O:43][CH3:44])=[C:7]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:30][CH2:29]2)=[O:17])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1.C(N(CC)CC)C.[C:52](Cl)(=[O:55])[CH2:53][CH3:54]>ClCCl>[C:11]([C:9]1[CH:10]=[C:5]([NH:4][C:52](=[O:55])[CH2:53][CH3:54])[C:6]([O:43][CH3:44])=[C:7]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:32][CH2:33]2)=[O:17])[CH:8]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCC(=O)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)C4CCCN4C)CC3)c2n1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@@H]5CCCN5C)CC4)c3n2C)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg of 1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(3-amino-5-tert-butyl-2-methoxy-phenyl)-amide trihydrochloride are dissolved in 2 ml of dichloromethane and combined successively with 160 μl triethylamine as well as 25 μl propionyl chloride. The mixture is stirred for 2 hours at ambient temperature, the solvents are eliminated in vacuo and the residue is purified by preparative HPLC (method 3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccnc3c(C(F)(F)F)cccc23)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 99.2 %

Procedure:
4-Chloro-8-(trifluoromethyl)quinoline (500 mg, 2.16 mmol), 4-hydroxybenzaldehyde (264 mg, 2.16 mmol), and cesium carbonate (845 mg, 2.59 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the resulting mixture was stirred at 100° C. for 5 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 70:30 (v/v)), whereby the objective title compound was obtained as a white solid (680 mg, yield: 99%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1F>>[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: Fc1ccc(Br)cc1Br
Agent: [H-]
Agent: [Na+]
Product: Nc1ncccc1Oc1ccc(Br)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
An nitrogen-purged 22 L 5-necked flask was charged with DMF (9 L) followed by slow addition of 2-aminopyridin-3-ol (250.0 g, 2270 mmol) and stirred with mechanical overhead agitator at ambient temperature for 30 minutes to dissolve material. 60% Sodium hydride (87.17 g, 2180 mmol) was added in portions with vigorous stirring and a nitrogen sweep of the reaction vessel. The pot temperature rose from 16° C. to 25° C. during the NaH addition. After the addition was complete, the reaction was stirred at ambient temperature for 60 minutes to ensure all NaH was consumed. 2,4-Dibromo-1-fluorobenzene (225.3 mL, 1816 mmol) was added and heated to 110° C. under nitrogen for 24 hours. The reaction was cooled to 60° C. and transferred to a 20 L flask and the majority of the DMF removed. The resultant sludge was diluted with 1N NaOH (8 L) and EtOAc (8 L) and the mixture was passed through a plug of celite and washed with EtOAc. The layers were separated and the aqueous was extracted with EtOAc (4 L). The combined organic layers were washed with 1 N NaOH (4 L) and 50% saturated brine (4 L), water (2 L) and concentrated until solids started to form. Hexanes (4 L) were added slowly and the mixture was concentrated to around 2 L volume. Hexanes (4 L) were added and the mixture was stirred for 1 hour to allow to cool to ambient temperature. The resulting slurry was filtered, dried on the filter and then dried under high vacuum overnight to afford 3-(2,4-dibromophenoxy)pyridin-2-amine (277.3 g, 44.4% yield).
Reaction SMILES: B(Br)(Br)Br.ClCCl.[O:8]1[CH:12]=[CH:11][C:10]([C:13]([N:15]([C:17]([C:19]2[O:20][CH:21]=[C:22]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][CH:33]=3)[C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=2)=[O:18])[NH2:16])=[O:14])=[CH:9]1>O>[O:8]1[CH:12]=[CH:11][C:10]([C:13]([N:15]([C:17]([C:19]2[O:20][CH:21]=[C:22]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[C:23]=2[C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[O:18])[NH2:16])=[O:14])=[CH:9]1
Reactant: COc1ccc(-c2coc(C(=O)N(N)C(=O)c3ccoc3)c2-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NN(C(=O)c1ccoc1)C(=O)c1occ(-c2ccc(O)cc2)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Boron tribromide (1 M dichloromethane solution: 12.00 ml) was added dropwise to a dichloromethane (5 ml) solution of the compound of Example 84 (0.86 g) at 0° C., and stirred overnight at 25° C. After water was added to the reaction solution, the thus-precipitated crystals were filtered and purified by silica gel column chromatography (eluent: methanol/chloroform=1/9), thereby giving 0.40 g of the desired compound. Melting point: 168-172° C. (Recrystallized from ethyl acetate)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:27][C:26]=1[F:38]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:27][C:26]=1[F:38])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Fc1cc(OC2CCOCC2)ccc1Br
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)cc1F)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-(4-bromo-3-fluoro-phenoxy)-tetrahydro-pyran (Intermediate 31) in analogy to Example 1a): MS (ISP): 498.1 and 500.2 (M+H)+, 442.2 and 444.0 ((M-isobutene)+H)+ (100%).
Reaction SMILES: CN(C)C=O.[I:6]N1C(=O)CCC1=O.[NH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[NH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([I:6])=[CH:17][N:16]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(I)cn1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
N,N-Dimethylformamide (47 ml) and N-iodosuccinimide (10.7 g, 47.6 mmol) were added to 2-amino-4-chloropyridine (4.72 g, 36.7 mmol); and the reaction mixture was stirred overnight. An aqueous solution of sodium thiosulfate and ethyl acetate were added thereto; the organic layer was separated, concentrated, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure; a solvent mixture (ether: hexane=1:1) was added to the residue; and the solid was filtered off to yield the title compound (7.0 g, 27.5 mmol).