Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13]Br)[C:6]([O:8][CH3:9])=[O:7].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH2:15]([N:22]1[CH2:2][C:3]2[C:12](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
TEA was added at room temperature, in the course of 15 minutes, to a solution of methyl 3,4-bis(bromomethyl)benzoate (9.3 g; 1 equiv.) and benzylamine (4.3 g; 1.4 equiv.) in 83.7 ml of benzene. The resulting reaction mixture was first stirred for 30 minutes at room temperature and then heated for 20 hours at reflux (110-120° C.). When the conversion was complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was taken up in 100 ml of dichloromethane and washed 2× with 5% sodium carbonate solution. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Purification by column chromatography (silica gel, 5% ethyl acetate/hexane) yielded methyl 2-benzylisoindoline-5-carboxylate (2.2 g; 28.3%) in the form of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[N+]=[N-])=[CH:4][C:3]=1[S:13](=[O:20])(=[O:19])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].[ClH:21]>COCCOCCOC>[CH2:15]([N:14]([CH2:17][CH3:18])[S:13]([C:3]1[CH:4]=[C:5]([C:8](=[O:12])[CH2:9][Cl:21])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:20])=[O:19])[CH3:16]
Reactant: CCN(CC)S(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl
Reactant: Cl
Solvent: COCCOCCOC
Product: CCN(CC)S(=O)(=O)c1cc(C(=O)CCl)ccc1Cl

Procedure:
12 g of 4'-chloro-3'-diethylsulfamoyl-diazoacetophenone were reacted as prescribed in Example 66(b) with concentrated HCl in diethyleneglycol dimethyl ether and worked up. Colorless crystals, melting point: 63°-65° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:3]1([N:2]([CH3:1])[C:9]2[N:14]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCC1
Reactant: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(N(C)C4CCCC4)n3)CC2)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To 26 mg (0.26 mmol) N-methyl-cyclopentylamine in 2.5 mL NMP are added 80 mg (0.22 mmol) 2-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-N-ethyl-propion-amide (XII.1) and 110 (0.65 mmol) DIPEA. The mixture is stirred at 100° C. for 1 h and at 120° C. for 1 h under microwave irradiation. After that time, the mixture is directly purified by HPLC (XBridge 100; water, 0.3% NH4OH/MeOH) to yield the desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(F)c3)ccn2c1=O
Yield: 80.4 %

Procedure:
Methyl 8-(3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-fluoro-phenyl-boronic acid (71 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (96 mg, 77%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13][CH2:12]1)=[O:4]>[Pd].CO>[CH3:1][N:2]([CH3:24])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4]
Reactant: CN(C)C(=O)c1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)c1ccccc1N1CCNCC1
Yield: 84.1 %

Procedure:
To a round-bottomed flask equipped with stirring was added N,N-dimethyl{2-[4-benzylpiperazinyl]phenyl} carboxamide (Step 2) (420 mg, 1.3 mmol), MeOH (10 mL), 10% Pd/C (Aldrich) (138 mg), and HCO2NH4 (409 mg, 6.5 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was filtered through Celite®, concentrated in vacuo, and redissolved in CH2Cl2 (20 mL). The reaction mixture was washed with a Na2CO3 (10%, 2×), H2O, brine, dried over Na2SO4, filtered and concentrated in vacuo yielding N,N-dimethyl(2-piperazinylphenyl)carboxamide (255 mg). MS (ESI, pos.ion) m/z: 234 (M+H). Calc'd for C13H19N3O: 233.31.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:16][C:15]3[CH:17]=[C:18]4[C:22](=[CH:23][C:14]=3[N:13]=2)[C:21]([CH3:25])([CH3:24])[C:20](=O)[C:19]4([CH3:28])[CH3:27])[C:4]=1[CH3:29].Cl.[CH3:31][O:32][NH2:33]>CO>[CH3:31][O:32][N:33]=[C:20]1[C:21]([CH3:25])([CH3:24])[C:22]2[C:18](=[CH:17][C:15]3[N:16]=[C:12]([S:11][CH2:10][C:5]4[C:4]([CH3:29])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=4)[NH:13][C:14]=3[CH:23]=2)[C:19]1([CH3:28])[CH3:27]
Reactant: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C1C(C)(C)c2cc3nc(SCc4ncc(C)c(OC)c4C)[nH]c3cc2C1(C)C

Procedure:
5 g of 5,7-dihydro-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one and 40 g of O-methylhydroxylamine hydrochloride in 250 ml of methanol were boiled at reflux for 16 hours under argon. After removing the solvent in vacuo the residue was partitioned between methylene chloride and water and the aqueous phase was extracted three times with methylene chloride. The combined organic extracts were made neutral with saturated sodium bicarbonate solution in the presence of ice and under argon gasification. After repeated extraction with methylene chloride the organic phases were dried over sodium sulfate and evaporated in vacuo. A red impurity was removed by chromatography on silica gel with ethyl acetate. The separation of the reaction product from starting material was carried out on silica gel using toluene/methyl isobutyl ketone/pyridine (80:18:2) as the elution agent. The purity of the fractions was assayed by thin-layer chromatography using the system ethyl acetate/methyl isobutyl ketone/pyridine (80:18:2). By crystallization from acetone/water there was obtained 5,7-dihydro-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one O-methyl oxime of melting point 110°-112°.
Reaction SMILES: [CH:1]([Si:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C:22]1([PH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1CCCCC1>[C:10]1([Si:3]([CH2:1][CH2:2][P:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(Pc2ccccc2)cc1
Solvent: C1CCCCC1
Product: c1ccc(P(CC[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
The vinyl triphenyl silane was reacted with 10% excess of diphenyl phosphine. To maintain a homogeneous reaction mixture, a temperature of 80° C. and cyclohexane solvent ere employed. After the usual u.v. initiated addition, the reaction mixture was allowed to cool to room temperature. This resulted in the crystallization of the triphenylsilyethyl diphenyl phosphine adduct. To obtain it in a pure form, the adduct was filtered and recrystallized from a four to one mixture of cyclohexane and toluene. A white crystalline product having a melting point of 128°-131° C. was obtained.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:34]1([CH2:37]Br)[CH2:36][CH2:35]1>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:37][CH:34]3[CH2:36][CH2:35]3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: BrCC1CC1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCN(C2CCC2)CC1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (73%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[C:27]([NH:31][C:32]1[N:36]2[CH:37]=[CH:38][N:39]=[CH:40][C:35]2=[N:34][C:33]=1[C:41]1[S:42][C:43]([C:46]#[C:47][Si](C)(C)C)=[CH:44][CH:45]=1)([CH3:30])([CH3:29])[CH3:28].Br[C:53]1[CH:57]=[CH:56][S:55][CH:54]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])([O-])=O.[Na+].[Na+].[ClH:82]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C1COCC1.CC(=O)OCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[ClH:82].[C:27]([NH:31][C:32]1[N:36]2[CH:37]=[CH:38][N:39]=[CH:40][C:35]2=[N:34][C:33]=1[C:41]1[S:42][C:43]([C:46]#[C:47][C:53]2[CH:57]=[CH:56][S:55][CH:54]=2)=[CH:44][CH:45]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)Nc1c(-c2ccc(C#C[Si](C)(C)C)s2)nc2cnccn12
Reactant: Brc1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1c(-c2ccc(C#Cc3ccsc3)s2)nc2cnccn12
Temperature: 70 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
94 mg (0.5 mmol) of copper(I) iodide, 129 mg (0.5 mmol) of triphenylphosphine, 1.32 ml (9.5 mmol) of NEt3, 701 mg (1.9 mmol) of tetra-n-butyl-ammonium iodide and 173 mg (0.25 mmol) of bis(triphenylphosphine)-palladium(II) chloride were added to a solution of 699 mg (1.9 mmol) of tert-butyl-[2-(5-trimethylsilanylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine (synthesis described in Example 158, part a) and 402 mg (2.5 mmol) of 3-bromo-thiophene in DMF (20 ml). 2.5 ml (2.5 mmol) of a 1M solution of tetra-n-butyl-ammonium fluoride in THF were added dropwise to the reaction solution over a period of 1 h. The mixture was then stirred at 70° C. for 18 h. After cooling to RT, the mixture was diluted with EA and combined with a 0.5M aq. Na2CO3 solution. The phases were separated and the aq. phase was extracted with EA. The combined organic phases were dried over MgSO4, filtered and evaporated under a vacuum. CC (acetonitrile/EA 1:3) was carried out with the group, 912 mg of slightly contaminated product being isolated. 304 mg (0.73 mmol, 38%) of N-tert-butyl-2-(5-(thiophen-3-ylethynyl)thiophen-2-yl)imidazo[1,2-a]pyrazin-3-amine hydrochloride were obtained by hydrochloride precipitation in accordance with the method described in Example 192.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Fc1cc(F)cc(Sc2ccc(Br)cc2)c1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cc(F)cc(F)c3)cc2)c1C
Yield: 56.3 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-3,5-difluorobenzene (0.176 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(3,5-difluoro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.14 g, 53%) as a solid. MS calcd. for C26H18ClF2O2S [(M−H)−] 467, obsd. 467.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4cc(C)cc(C)c4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4cc(C)cc(C)c4)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(3,5-dimethylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 445 (M++1)
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([O:29][CH3:30])[CH:22]=[C:23](O)[CH:24]=2)[CH2:19]1)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([O:29][CH3:30])[CH:22]=[C:23]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH:24]=2)[CH2:19]1)[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCN1CCc2cc(O)cc(OC)c2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCc2cc(OS(=O)(=O)C(F)(F)F)cc(OC)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Triflic anhydride (0.54 mL, 3.2 mmol) was added dropwise over 15 minutes to a suspension of 2-ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol (328 mg, 1.6 mmol) in pyridine (0.52 mL, 6.4 mmol) and DCM (15 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was diluted with DCM (60 mL), washed with water (100 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The resultant solid was purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in pentane) to afford the title compound as a yellow solid (341 mg, 63%). 1H NMR (CDCl3, 300 MHz): 6.76 (d, J=2.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 4.30-4.10 (m, 2H), 3.87 (s, 3H), 3.50-3.37 (m, 2H), 3.36-3.10 (s, 4H), 1.51 (t, J=7.2 Hz, 3H). LCMS (Method B): RT=2.39 min, M+H+=340.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH2:28][OH:29].C(N(CC)CC)C>CN(C=O)C>[CH3:22][C:23]1[N:24]([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=[N:26][C:27]=1[CH2:28][OH:29]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc[nH]c1CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(CO)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 50.4 %

Procedure:
A solution of triphenylchloromethane (13.1 g) in dry DMF (80 ml) was added dropwise over 30 min. to a stirred solution of 4-methyl-5-imidazolemethanol hydrochloride (7.0 g) and triethylamine (9.52 g) in dry DMF (75 ml) at room temperature under nitrogen, and stirring was continued for 2.5 h. The suspension was poured onto ice (600 ml), stirred for 30 min. and filtered. The resulting solid (12.0 g) was triturated twice with acetone (2×250 ml) to give the title compound (8.4 g), t.l.c. (System A 94.5:5:0.5) Rf 0.19.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[Br:22][CH:23]([CH:26]=O)[CH:24]=O>CCO>[Br:22][C:23]1[CH:24]=[N:1][C:2]2[N:6]([N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[C:3]=2[C:20]#[N:21])[CH:26]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: O=CC(Br)C=O
Solvent: CCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (28 mg, 0.1 mmol), 2-bromomalonaldehyde (15 mg, 0.1 mmol) in EtOH (5 mL) was stirred at RT for 2 hr. Then, the mixture was filtered to give the crude product (20 mg, 62.9%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.89 (d, J=2.0 Hz, 1H), 8.95 (d, J=2.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.52-7.43 (m, 2H), 7.27-7.19 (m, 3H), 7.15 (d, J=7.6 Hz, 2H). MS (ESI, m/e) [M+1]+ 391.9.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[F:13])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:24][CH:12]([F:13])[C:11]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=1)=[O:15]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cscc1NC(=O)C(F)Cl
Product: O=C(O)c1cscc1NC(=O)C(F)Oc1ccc(Cl)c(Cl)c1

Procedure:
In analogy to Example 58, the title compound was prepared using 4-(2-chloro-2-fluoro-acetylamino)-thiophene-3-carboxylic acid methyl ester and 3,4-dichlorophenol. MS (m/e): 362.0 (M−H).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:29])[C:10]2[O:16][C:15]3[C:17]([Cl:25])=[CH:18][C:19]([NH:21][CH2:22][CH2:23]Cl)=[CH:20][C:14]=3[CH2:13][S:12](=[O:27])(=[O:26])[C:11]=2[CH:28]=1)=[O:6]>CO>[CH3:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:29])[C:10]2[O:16][C:15]3[C:17]([Cl:25])=[CH:18][C:19]([NH:21][CH2:22][CH2:23][NH:2][CH3:1])=[CH:20][C:14]=3[CH2:13][S:12](=[O:27])(=[O:26])[C:11]=2[CH:28]=1)=[O:6]
Reactant: CN
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Solvent: CO
Product: CNCCNc1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A 30% methanolic methylamine solution (4 mL) was added to a solution of the carboxylic acid of Example 56k (0.5 g, 1.16 mmol) in methanol, in a pressure reactor vessel under nitrogen atmosphere and kept at 110° C. for 4 h. The reaction mixture was cooled, concentrated partially and the solid that precipitated was filtered, washed with methanol, dried, treated with methanolic HCl solution (10 mL) and stirred at 70° C. for 1.5 h. The reaction mixture was cooled and the solid that precipitated was filtered and washed with methanol to obtain the title compound as an off white solid. Yield: 0.325 g, (65.92%); 1H NMR (DMSO-d6): δ 2.50 (d, 3H, CH3), 2.80 (s, 3H, CH3), 3.10 (t, 2H, CH2), 3.30 (t, 2H, CH2), 3.90 (s, 3H, OCH3), 5.10 (s, 2H, CH2), 6.85-6.90 (m, 2H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 1H, Ar), 9.0 (t, 1H, NH); MS: m/e (ES+) 425 (M+).
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[N:9]([C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[CH:25]=2)[CH:8]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:40]([O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44])[CH3:41]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([C:48]4[CH:49]=[CH:50][C:45]([C:43]([O:42][CH2:40][CH3:41])=[O:44])=[CH:46][CH:47]=4)=[CH:8][N:9]3[C:24]3[CH:25]=[C:26]([NH:30][CH3:31])[N:27]=[CH:28][N:29]=3)=[CH:14][CH:13]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2cc(Br)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cn(-c3cc(NC)ncn3)c3cc(-c4ccc(OC)cc4)ccc23)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
DMF (5 mL) was added to a mixture of 6-(3-bromo-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (200 mg, 0.49 mmol), K3PO4 (312 mg, 0.885 mmol) and 4-(ethoxycarbonyl)phenylboronic acid (143 mg, 0.74 mmol) and then the dissolved gas was removed. After adding Pd(PPh3)4 (85 mg, 0.075 mmol), the mixture was stirred at 100° C. for 4 hours. After adding ethyl acetate and water and filtering using a diatomite pad, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4-1:1). The target compound (70 mg) was obtained as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(O)C=CC=CC=1.FC1C=CC(O)=CC=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1ccc(F)cc1)C(=O)O
Agent: Oc1ccc(F)cc1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](COc1ccccc1)C(=O)O

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(phenoxy)-propionic acid was prepared analogously to (2R)-2-tert-Butoxycarbonylamino-3-(4-fluoro-phenoxy)-propionic acid of example 263 except that phenol was substituted for 4-fluorophenol.