Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:53]([N:56]1[C:64]2[C:59](=[CH:60][C:61]([O:66][CH3:67])=[C:62](Br)[CH:63]=2)[CH2:58][CH2:57]1)(=[O:55])[CH3:54].[CH3:68][C@H:69]1[CH2:74][NH:73][CH2:72][C@@H:71]([CH3:75])[NH:70]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:53]([N:56]1[C:64]2[C:59](=[CH:60][C:61]([O:66][CH3:67])=[C:62]([N:73]3[CH2:72][C@H:71]([CH3:75])[NH:70][C@H:69]([CH3:68])[CH2:74]3)[CH:63]=2)[CH2:58][CH2:57]1)(=[O:55])[CH3:54]
Reactant: COc1cc2c(cc1Br)N(C(C)=O)CC2
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)N(C(C)=O)CC2
Yield: 63.2 %

Procedure:
A mixture of palladium (II) acetate (830 mg, 3.7 mmole), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3.46 g, 5.5 mmole) and cesium carbonate (18.1 g, 56 mmole) in dry degassed 1,4-dioxane (200 ml) under argon was sonicated at 28° C. for 0.5 h producing a pink heterogeneous mixture. This was treated with D1 (10 g, 37 mmole) followed by cis-2,6-dimethylpiperazine (12.6 g, 110 mmole) and heated with rapid stirring at reflux for 96 h. The mixture was allowed to cool, filtered through Kieselguhr and then concentrated under vacuum. The residue was treated with EtOAc and 2M HCl acid, shaken well and the aqueous layer separated, basified by addition of K2CO3 and extracted with DCM. The extract was dried (Na2SO4) and concentrated under vacuum to afford the title compound as a pale orange solid (7.1 g, 63%). MH+ 304.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12]O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:15]>ClCCl>[Br:15][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: OCc1nc(-c2ccccc2)cs1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1nc(-c2ccccc2)cs1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 177 %

Procedure:
A solution of (4-phenylthiazol-2-yl)methanol (Example 4C, 0.530 g, 2.77 mmol) in dichloromethane (10 mL) was cooled to 0° C. (ice bath) and treated with PBr3 (0.118 mL, 1.247 mmol) added dropwise over 2 min. A heavy white gum was immediately formed. After 10 min, the bath was removed and the solution was stirred at 22° C. for 4 h. The reaction mixture was quenched with ice (˜10 g) and poured into a mixture of ethyl acetate (150 mL) and saturated sodium bicarbonate (50 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid residue was chromatographed on silica gel (2.5×6 cm, elution toluene) to give the title material (0.561 g, 80%) as a light yellow oil which solidified in the fridge to a pale yellow solid. LC (Method C): 2.062 min. HRMS (ESI) calcd for C10H9BrNS [M+H]+ m/z 253.9634, found 253.9655. 1H NMR (CDCl3, 400 MHz) δ ppm: 4.81 (s, 2H), 7.34-7.39 (m, 1H), 7.41-7.47 (m, 2H), 7.52 (s, 1H), 7.86-7.92 (m, 2H).
Reaction SMILES: [C:1]1([NH:7]/[C:8](=[C:27]2\[C:28](=[O:39])[NH:29][C:30]3[C:35]\2=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)/[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3C(=O)C4=CC=CC=C4C3=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([NH:7]/[C:8](=[C:27]2\[C:28](=[O:39])[NH:29][C:30]3[C:35]\2=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)/[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccccc1)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccc(/C(Nc2ccccc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 140 from (Z)-3-[1-phenylamino-1-(4-phthalimidomethyl-phenyl)-methylidene]-5-nitro-2-indolinone and hydrazine hydrate solution in ethanol.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:30][CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)[CH3:31]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CCN1CCC[C@H]1c1nnc2ccc(F)cn12
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 28.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 107 mg, 2.68 mmol) in DMF (2.00 mL) was added Intermediate A (110 mg, 0.67 mmol) and the reaction stirred for 20 min. Intermediate 61b (150 mg, 0.67 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave the title compound (72.0 mg, 28%). LCMS (Method 4): Rt 0.29 min, m/z 378.2 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: Cc1ncc(C2(CN)CCOCC2)cn1
Product: Cc1ncc(C2(CNC(=O)c3c(F)cccc3Cl)CCOCC2)cn1

Procedure:
From 2-chloro-6-fluorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=364.1, tR (minutes, Method F)=1.57
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][O:6][CH2:7][CH2:8]Br.[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:18][C:19]#[N:20]>CN1C(=O)CCC1.CCOCC>[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:18]1([C:19]#[N:20])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: BrCCOCCBr
Reactant: N#CCc1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#CC1(c2cccc(F)c2F)CCOCC1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
A mixture of sodium hydride (2 mL, 88 mmol) in 120 mL NMP was stirred at 0° C. and treated with a mixture of bis(2-bromoethyl)ether (9 mL, 40 mmol) and 2-(2,3-difluorophenyl)acetonitrile (6.12 g, 40 mmol) in 20 mL ether. The reaction was stirred at room temperature for 4 hours, carefully quenched with 20 mL H2O, and neutralized to pH=5 with concentrated HCl. The mixture was further diluted with 200 mL water, and the precipitate was collected by filtration. The solid was redissolved in 200 mL ether, washed with 20 mL saturated NaCl, dried over anhydrous Na2SO4, and concentrated to give 6.55 g of the title compound as a white solid. MS m/e: (M+H)+ 224.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:26])[CH2:10][C:11]([C:17]2[CH:22]=[C:21]([Br:23])[C:20]([F:24])=[C:19]([Br:25])[CH:18]=2)(O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[CH3:8].S(Cl)(Cl)=O.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:26])[CH:10]=[C:11]([C:17]2[CH:22]=[C:21]([Br:23])[C:20]([F:24])=[C:19]([Br:25])[CH:18]=2)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=O)CC(O)(c2cc(Br)c(F)c(Br)c2)C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C=C(c2cc(Br)c(F)c(Br)c2)C(F)(F)F)cc1Cl
Temperature: 5 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
To a stirred solution of 1-(3-chloro-4-methylphenyl)-3-(3,5-dibromo-4-fluorophenyl)-4,4,4-trifluoro-3-hydroxy-butan-1-one (1.40 g) in toluene (3 mL) at 80° C. was added thionyl chloride (0.68 g) and pyridine (0.46 g). The mixture was stirred at same temperature for 2 hours. The resulting mixture was then cooled to 5° C. and water (3 mL) was added, and the mixture was allowed to stir and warm to ambient temperature. The layers were separated, and the organic phase was poured into 2N aqueous sodium hydroxide solution (3 mL). After stirring 0.5 hour at room temperature, the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford the crude title compound as a yellow oil (1.37 g), which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C([O-])=O.[NH4+]>CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:12]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)ccc1[N+](=O)[O-]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)ccc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(3-methyl-4-nitrophenyl)morpholine-4-carboxylate (2.21 g) in methanol (100 ml) was added ammonium formate (6.48 g). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% Palladium on activated charcoal (219 mg) was then added and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was then filtered through celite and concentrated in vacuo. The residue was taken up in EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford tert-butyl (RS)-2-(4-amino-3-methylphenyl)morpholine-4-carboxylate (1.99 g, 99%) as a colourless oil. MS (EI): 292 (M+), 235 ([M-C4H9]+), 219 ([M-C4H9O]+), 191, 136, 57 ([C4H9]+).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:19])[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].O[Li].O>C1COCC1.O>[C:15]([O:14][C:12]([N:6]1[C:5]([CH3:19])([C:3]([OH:4])=[O:2])[CH2:9][O:8][C:7]1([CH3:11])[CH3:10])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a stirring solution of 4 (9.392 g, 34 mmol) in THF (65 mL) and H2O (35 mL) under an inert atmosphere was added solid LiOH.H2O (1.426 g, 34 mmol) in one portion. The reaction mixture was heated to 90° C. and stirred 8 hours at which point the reaction mixture was cooled to room temperature. The crude reaction mixture was washed with Et2O (3×50 mL) and the Et2O extracts were discarded. The aqueous solution was then acidified with 2M KHSO4 until a white precipitate began to form on addition, pH=5. The acid was added dropwise until the precipitate persisted and the aqueous solution was extracted with Et2O (50 mL). After extraction, two addition drops of acid were added to the aqueous layer and it was again extracted with Et2O (25 mL). The Et2O extracts were combined and quickly back extracted with 1M NaOH (15 mL). The organic phase was then dried over sodium sulfate and concentrated in vacuo to give 5 (7.458 g, 85%) as a white solid which was used without further purification. Compound was observed as an uneven mixture of rotomers.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH:11]=[O:12])[C:8](=[O:13])[C:7]1[C:14]([OH:22])=[C:15]([CH2:19][CH2:20][CH3:21])[C:16]([OH:18])=[CH:17][C:6]=1[O:5]2.C1COCC1.[BH4-].[Na+]>CCO.O.C(OCC)(=O)C.Cl>[OH:12][CH2:11][C:10]1[N:9]2[C:4]([O:5][C:6]3[CH:17]=[C:16]([OH:18])[C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:7]=3[C:8]2=[O:13])=[CH:3][CH:2]=1
Reactant: CCCc1c(O)cc2oc3cc(Cl)c(C=O)n3c(=O)c2c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1c(O)cc2oc3ccc(CO)n3c(=O)c2c1O
Yield: 150.8 %

Procedure:
To 40 mg (0.11 mmol) of 2-chloro-6,8-dihydroxy-9-oxo-7-propyl-9H-pyrrolo[2,1-b][1,3]benzoxazine-1-carboxaldehyde made by the process of Example 9 in 4 mL of EtOH and 4 mL THF was added 20 mg of sodium borohydride. After 15 min the mixture was diluted with H2O and ethyl acetate and 1 mL of 1 N HCl with vigorous bubbling. The mixture was extracted with ethyl acetate and the organic layer dried (Na2SO4) and concentrated to give 48 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8](Br)[CH:9]=1)=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([SH:22])[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([S:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Sc2cccc(OC)c2)c([N+](=O)[O-])s1
Temperature: 50 °C
Yield: 91.6 %

Procedure:
To a cooled (ice bath) solution of 4-bromo-5-nitrothiophene-2-carboxylic acid methyl ester (0.5 g, 1.88 mmol) from above step c, in dimethylformamide (DMF) was added 3-methoxybenzenethiol (0.29 g, 2.1 mmol) and Cs2CO3 (0.67 g, 2.1 mmol). The resulting mixture was heated at 50° C. for 3 h. DMF was removed under vacuum and the residue was partitioned between EtOAc and 10% HCl. The EtOAc layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography (EtOAc:hexane) to give 0.56 g (91%) of 4-(3-Methoxy-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. This ester was dissolved in CH2Cl2 (6 mL) and treated with m-chloroperoxybenzoic acid (MCPBA, 1.1 g) and heated at reflux for 6 h. The resulting mixture was diluted with CH2Cl2 (10 mL) and washed with sat. sodium thiosulfate, 1N NaOH and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:hexane) to give an oil. This oil was dissolved in DMF (5 mL) and cooled in an ice bath. To this solution sodium thiomethoxide (126 mg, Aldrich Chemical Company) was added and the mixture was stirred for 5 h. The reaction was quenched with 10% HCl and the solvents were removed in vacuo. The residue was dissolved in EtOAc, washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin-layer chromatography to give 171 mg of 4-(3-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester, which was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:13]1[N:14]=[C:15]3[C:21]([C:22]([OH:24])=O)=[CH:20][N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:16]3=[N:17][CH:18]=1)=[N:5][N:6]2[CH3:12].C1C=C[C:36]2N(O)N=[N:39][C:37]=2[CH:38]=1.C(N)(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)CCl>[CH:37]([NH:39][C:22]([C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:4]3[C:3]4[C:7](=[CH:8][C:9]([F:11])=[CH:10][C:2]=4[F:1])[N:6]([CH3:12])[N:5]=3)[N:14]=2)[N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[CH:20]=1)=[O:24])([CH3:38])[CH3:36]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2c(F)cc(F)cc21
Reactant: On1nnc2ccccc21
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.5 %

Procedure:
To a solution of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (75 mg, 0.16 mmol), HOBt (63 mg, 0.38 mmol) and EDC (72 mg, 0.38 mmol) in DMF was added isopropylamine (84 ul, 0.98 mmol). The reaction mixture was stirred at room temperature for 1.5 h then additional HOBt, EDC, and isopropylamine were added. The reaction mixture was stirred at room temperature overnight then diisopropylethylamine (170 ul, 0.98 mmol) was added. The reaction was stirred for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with 10% citric acid, sat NaHCO3, sat LiCl, and brine then dried over MgSO4 and concentrated. The residue was chromatographed over silica gel with 20% to 100% EtOAc/heptane to afford 30 mg (37%) of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([OH:22])[C:13]([NH:19][CH:20]=[O:21])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][CH2:35]Br>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]4[N:19]([CH:20]=[O:21])[CH2:35][CH2:34][CH2:33][O:22][C:12]=4[C:11]=3[O:10][C:9]=2[CH:23]([CH3:25])[CH3:24])=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: CC(C)c1oc2c(O)c(NC=O)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(Cl)cc1)N(C=O)CCCO3
Temperature: 60 °C

Procedure:
A stirred mixture of N-[3-(4-chlorophenyl)-8-hydroxy-2-isopropyl-4-oxo-4H-chromen-7-yl]formamide (0.122 g, 0.34 mmol), cesium carbonate (0.444 g, 1.36 mmol, 4 eq.) and 1,3-dibromopropane (0.069 g, 0.34 mmol) in anhydrous N,N-dimethylformamide (3 ml) is heated at 60° C. under a nitrogen atmosphere for 2 h. The mixture is cooled to room temperature and filtered through Celite filter aid. The pad of Celite is washed with ethyl acetate and methylene chloride, and the combined filtrates are evaporated in vacuo to afford a brown solid. This is purified by flash chromatography (cyclohexane/ethyl acetate=9:1 to 4:1) to furnish the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4](I)[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([O:21][CH3:22])[CH:13]=1>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=2[O:21][CH3:22])[CH:3]=1
Reactant: CNc1cnc(Cl)cc1I
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnc(Cl)cc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (6-chloro-4-iodo-pyridin-3-yl)-methyl-amine (prepared according to WO2006013050) and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Off-white solid (81%). MS (ESI): m/z=267.07 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[NH:21][C:22]([C@@H:24]([NH2:29])[CH2:25][CH2:26][S:27][CH3:28])=[N:23][C:19]=2[CH:18]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[NH:21][C:22]([C@@H:24]([NH:29][C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:15][CH:14]=3)[CH2:25][CH2:26][S:27][CH3:28])=[N:23][C:19]=2[CH:18]=1
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Reactant: CSCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)c1ccc(N2CCCC2=O)cc1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 27 from 4-(pyrrolidin-2-on-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine, PfTU and TEA in DMSO at ambient temperature and subsequent Boc cleaving with TFA analogously to Example 1g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].[OH2:9]>>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:9])=[O:1]
Reactant: O
Reactant: O=CCCCCCO
Product: O=C(O)CCCCCO
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
5.27 Grams (45 mmols) of 6-hydroxyhexanal was charged to a 100 milliliter Schlenk flask and dissolved in 45 milliliters of deionized water by heating to 85-95° C. in a water bath. The resulting solution was charged to the Parr autoclave, placed under 1500 psi air and heated to 120° C. Samples were taken every 30 minutes throughout the reaction. After 1.5 hours, reaction conversion was 89% and 6-hydroxycaproic acid was formed in 91% selectivity.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:27])[CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[CH3:28][Mg]Br>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([CH2:9][C:8](=[O:27])[CH3:28])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:12]=2)[CH:15]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Sc2ccccn2)cc1
Reactant: C[Mg]Br
Product: CC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-thioacetic acid S-pyridin-2-yl ester 1c and methyl magnesium bromide (MeMgBr) using a similar procedure described above. 1H NMR (400 MHz, CDCl3) δ 2.14 (s, 3H), 2.31 (s, 3H), 2.38 (s, 3H), 4.08 (s, 2H), 7.03 (d, J=9.1 Hz, 1H), 7.25 (d, J=7.7 Hz, 2H), 7.54 (m, 4H). Mass spectrum m/e 279 (M+).
Reaction SMILES: CN([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH:28]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)C.[CH3:30][NH:31][NH2:32]>C(O)(=O)C>[CH3:30][N:31]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[CH:26]=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:11][CH:12]=2)=[N:5][CH:4]=[N:32]1
Reactant: CN(C)C=NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: CNN
Solvent: CC(=O)O
Product: Cn1ncnc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 6.7 %

Procedure:
In the same manner as Example 48, employing N-(dimethylaminomethylene)-4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzamide (1.56 g) from Example 46 in glacial acetic acid (75 ml) and methylhydrazine (0.32 g), the title compound (0.10 g) was obtained as a solid, m.p. 155-158° C.; MS, m/z: 369 (M)+.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-piperazin-1-yl-quinoline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish solid.
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2.[C:24](OC)(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:27].Cl>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(Cl)Cl>[OH:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:24]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[O:32]
Reactant: Nc1cccc2[nH]ccc12
Reactant: COC(=O)c1ccccc1O
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1O
Temperature: 25 °C

Procedure:
92 ml of a solution of 1.1 mol/l of triisobutylaluminum in toluene were added slowly with stirring under an inert atmosphere to a solution of 6.6 g of 4-aminoindole in 250 ml of chloroform. 9.6 ml of methyl salicylate were then added and the mixture was refluxed for 20 hours and then cooled to room temperature. 300 ml of N hydrochloric acid and 300 ml of methylene chloride were added and the organic phase was washed with water, dried, and evaporated to dryness under reduced pressure at 50° C. The residue was made into a paste with ether, filtered and dried at 60° C. under reduced pressure to obtain 9.4 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide melting at ≃232° C.