Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:25][CH3:26])=[CH:11][C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 93.6 %

Procedure:
A mixture of 5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 25, 265 mg, 0.54 mmol), iron (179 mg, 3.21 mmol) and NH4Cl (20.05 mg, 0.37 mmol) was heated at reflux in ethanol (6 mL) and water (2 mL) for 1 h. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were concentrated in vacuo to give the title compound (235 mg, 94%) as a yellow solid which was used without further purification; 1H NMR: 2.13 (6H, s), 3.07 (1H, s), 3.50 (2H, t), 3.66 (3H, s), 4.00 (3H, t), 4.05 (2H, s), 6.28 (1H, s), 6.79 (1H, s), 7.10 (1H, t), 7.3-7.39 (1H, m), 8.33 (1H, s), 8.37 (1H, s), 8.80 (1H, d), 8.93 (1H, s); m/z: ES+ MH+ 465.25.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30])([O-:21])=[O:20]>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N+:19]([O-:21])=[O:20])[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccccc1[N+](=O)[O-])Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-nitrophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.30 (d, J=7.7, 1H), 8.09-7.95 (m, 4H), 7.94-7.87 (m, 1H), 7.73 (dt, J=7.6, 3.8, 1H), 7.63 (d, J=6.7, 1H), 7.59 (dd, J=11.2, 4.4, 1H), 4.13 (s, 2H), 3.86-3.79 (m, 4H), 3.14-3.04 (m, 4H); MS (ESI+) M/Z 410 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:7](=[O:21])[O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[O:19][CH3:20])[CH:10]=1)=[O:4]>O=O>[CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[O:19][CH3:20])[C:7]([OH:21])=[O:8])=[O:4]
Reactant: COC(=O)NC1=CC(c2cccc(OC)c2OC)OC1=O
Agent: O=O
Product: COC(=O)NC(CCc1cccc(OC)c1OC)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-methoxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one (500 mg, 1.7 mmoles) in oxygen free methanol (0.25 M) is placed into a Parr hydrogenator, the catalyst (RR)-EtDiPhos(COD)OTs (1.5 μmoles) is added and the mixture is stirred for 1.5 hr at room temperature under hydrogen pressure (30 psi).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:29]1(B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[C:29]1([C:14]2[N:15]=[C:11]([C:10]3[C:2]([CH3:1])=[N:3][N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=34)[S:12][C:13]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C1=CCCCC1
Yield: 95.8 %

Procedure:
Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (220 mg, 0.5 mmol) produced in Example 15(i), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (620 mg, 3.0 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (72 mg, 0.088 mmol), cesium carbonate (620 mg, 1.9 mmol), water (0.5 mL) and 1,2-dimethoxyethane (15 mL) as starting materials and in the same manner as in Example 13(iii), the title compound (176 mg, 95%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH2:8]([O:10][C:11]([C:13]1[C:14](=[O:33])[C:15]2[CH:20]=[N:19][C:18](S(C)(=O)=O)=[N:17][C:16]=2[N:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[C:14](=[O:33])[C:15]2[CH:20]=[N:19][C:18]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[N:17][C:16]=2[N:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN(C)CCCN
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCN(C)C)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from N′,N′-dimethyl-propane-1,3-diamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 35 Step E, 20 mg, 0.05 mmol). 8-Cyclohexyl-2-(3-dimethylamino-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (17 mg, 85%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C21H31N5O3: 402.24 (M+H). Found: 402.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:27])[CH2:25][NH2:26])[CH2:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:27])[CH2:25][NH:26][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=3)[CH2:19]2)=[CH:15][CH:14]=1
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1ccc(F)c(F)c1)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The chloroform (0.4 mL) solution of 3,4-difluorobenzoyl chloride (0.060 mmol) was added to the chloroform (1.0 mL) solution of the (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, and then mixed with a (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol). The mixture was stirred at room temperature for 12 hours, and filtered. The resin was washed with dichloromethane (0.5 mL). The filtrate and the washings were combined and mixed with dichloromethane (4 mL). The solution was washed with a 2M NaOH aqueous solution (0.5 mL), and then concentrated to obtain the (R)-1-(4-chlorobenzyl)-3-[{N-(3,4-difluorobenzoyl)glycyl}amino]pyrrolidine (Compd. No. 69) (7.8 mg, 38%): the purity was determined with RPLC/MS (>99%); ESI/MS m/e 408.0 (M++H, C20H20ClF2N3O2).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[N:16]([CH:19]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:20](OCC)=[O:21])=[C:17]=[O:18]>>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([N:14]3[C:20](=[O:21])[CH:19]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:16][C:17]3=[O:18])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: CCOC(=O)C(CC(C)C)N=C=O
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(C)C)C2=O)cn1
Yield: 50 %

Procedure:
Prepared as in Example 10-41 from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 10-41a) and ethyl 2-isocyanato-4-methylpentanoate. Yield: 50%. 1H NMR (CDCl3, 400 MHz): δ 1.01-0.98 (m, 8H), 1.87-1.82 (m, 1H), 2.19 (s, 3H), 2.41 (s, 3H), 4.13-4.12 (t, 1H), (5.05 (s, 2H), 5.70 (bs, 1H), 7.90 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.0 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[C:9]([CH2:11][CH3:12])[N:10]=[C:4]2[CH:3]=1.[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH:33]=[O:34])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]>>[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH:33]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]4=[N:10][C:9]=3[CH2:11][CH3:12])[OH:34])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: CCc1nc2cc(Cl)ccn2c1I
Product: CCc1nc2cc(Cl)ccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 88.8 %

Procedure:
[step 3] Using 7-chloro-2-ethyl-3-iodoimidazo[1,2-a]pyridine (700 mg, 2.28 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (335 mg, 1.14 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[(7-chloro-2-ethylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (480 mg, 89%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:30])[CH2:10][CH2:9]1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:30])[CH2:12][CH2:13]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 41.8 %

Procedure:
To a solution of 540 mg (1.22 mmol) of 3-[1-(3-nitrobenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)quinazolinone in 50 mL of ethanol was added 826 mg (3.66 mmol) of SnCl2.2H2O, and the mixture was stirred for 12 hours at 60° C. After being cooled, the reaction mixture was filtered through cerite, and the filtrate was concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:19 methanol:chloroform) to give 210 mg (0.51 mmol) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1.[I-:10]>>[I:10][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(N)cc1
Reactant: [I-]
Product: COc1ccc(I)cc1

Procedure:
diazotizing p-anisidine to produce a diazotization product and reacting the diazotization product with an aqueous iodide solution to produce 4-iodoanisole;
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:5](NN)=[N:6][C:7]([F:10])=[CH:8][CH:9]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:4]([F:3])=[CH:9][CH:8]=[C:7]([F:10])[N:6]=1
Reactant: BrBr
Reactant: NNc1nc(F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Fc1ccc(F)c(Br)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
Bromine (0.30 mL, 6 mmol) was added dropwise to a stirred solution of (3,6-difluoro-pyridin-2-yl)-hydrazine (435 mg, 3 mmol) in CHCl3 (6 mL) at room temperature. The mixture was stirred at 60° C. for 1 hour. The mixture was cooled at 0° C. and a saturated solution of NaHCO3 was added dropwise. DCM was added, the organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield 2-bromo-3,6-difluoro-pyridine (600 mg, 88% yield) as a dark oil.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.C(O[CH2:21][CH3:22])(=O)C>CO.C(O)C>[N:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:21]=1[CH:22]=[N:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[N:3]=1
Reactant: CCOC(C)=O
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Solvent: CO
Solvent: CCO
Product: FC(F)(F)c1cccc(N2CCC(N=Cc3ccccn3)=N2)c1
Reaction time: 8 h

Procedure:
3-Amino-1-(3-trifluoromethylphenyl)-2-pyrazoline in methanol (23 ml) was stirred together with 2-pyridylaldehyde at room temperature for 2 hours and then under reflux for a further 2 hours. Thin layer chromatography (SiO2, ethyl acetate) indicated that the reaction was substantially complete. After standing overnight, additional 2-pyridylaldehyde (0.5 g) was added and heating was continued for 2 hours. TLC again indicated that no further reaction had occurred. The reaction mixture was evaporated in vacuo to yield an orange-coloured solid which was stirred for 45 minutes in aqueous ethanol (3:1) and 3-(2-pyridylmethyleneamino)-1-(3-trifluoromethylphenyl)-2-pyrazoline was collected, m.p. 155.6°.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[NH:13][C:14]2[C:15]3[C:22]([CH3:23])=[C:21]([C:24]([OH:26])=O)[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3][CH2:2]1.[NH3:27]>CO>[CH:1]1([O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[NH:13][C:14]2[C:15]3[C:22]([CH3:23])=[C:21]([C:24]([NH2:27])=[O:26])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC3)c12
Reactant: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCC3)c12

Procedure:
Prepared analogously to example 1.4 from 4-(2-cyclobutoxy-4-fluoro-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (127 mg) and 7 M ammonia in MeOH (1 ml).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[F:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Oc1cccc(F)c1
Product: CCCCOC(=O)c1nc(Oc2cccc(F)c2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 3-Fluoro phenol in analogy to Example D-20 d); MS-(+)-ion: M+1=356.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:22]5[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.C(OO)(=[O:32])C>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:22]5[CH:23]=[N+:24]([O-:32])[C:25]([CH3:28])=[CH:26][CH:27]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: Cc1ccc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Reactant: CC(=O)OO
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.4 %

Procedure:
To a stirred solution of Example 48 (0.08 g, 0.19 mmol) in DCM (10 ml) was added peracetic acid (0.14 mL, 32 wt % in AcOH, 0.59 mmol). The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.014 g, 22%) as a white solid. δH (CD3OD) 8.53 (1H, d, J 1.5 Hz), 8.40 (1H, d, J 2.1 Hz), 7.69 (1H, dd, J 8.1 and 1.7 Hz), 7.55 (1H, d, J 8.3 Hz), 7.34 (1H, dd, J 8.7 and 2.3 Hz), 7.10 (1H, d, J 8.5 Hz), 4.46-4.37 (2H, m), 4.19-4.13 (2H, m), 2.92 (2H, s), 2.58 (3H, s), 1.41 (6H, s,). LCMS (ES+) 423.0 (M+H)+, RT 2.48 minutes (Method 1).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46](O)=[O:47])[CH:41]=1.CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:46]([C:42]2[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=2)=[O:47])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: O=C(O)c1cccnc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)c5cccnc5)ccc4[nH]3)c2F)c1
Yield: 22.3 %

Procedure:
The title compound (0.011 g, 19%) was prepared from 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.050 g, 0.086 mmol), 3-pyridinecarboxylic acid (0.011 g, 0.086 mmol), DIPEA (0.075 mL, 0.43 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.065 g, 0.257 mmol) in a similar manner as described in the general procedure. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.66 (s, 1H), 10.38 (s, 1H), 9.16 (s, 2H), 8.80 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 7.72-7.97 (m, 1H), 7.32-7.97 (m, 7H), 7.19 (s, 1H), 4.58 (d, 2H). MS: m/z 574 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]Cl)=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].[OH-].[Na+]>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(CCCl)cc1
Reactant: CCOC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CCN(CCc2ccc(SC)cc2)CC1
Yield: 91.4 %

Procedure:
Under nitrogen, 59.6 g of 4-methylmercaptophenylethyl chloride are heated with 75.7 g of 1-ethoxycarbonylpiperazine for 1.5 hours at 130°. A further 25.2 g of 1-ethoxycarbonylpiperazine are added thereto, and after 1.5 hours a further 25.2 g of 1-ethoxycarbonylpiperazine are added. After a total of 4.5 hours, the solution is poured onto ice-water, rendered strongly alkaline with concentrated NaOH and extracted with ether. Concentration by evaporation yields a mobile oil, which is purified by chromatography over silica gel (eluant: dichloromethane and dichloromethane/acetone 8:2). 90 g of the 1-[(4-methylmercaptophenyl)ethyl]-4-ethoxycarbonylpiperazine so obtained are boiled under reflux for 17 hours with 700 ml of concentrated HCl. The solution is diluted with ice-water, rendered alkaline with concentrated NaOH, extracted with ethyl acetate, concentrated by evaporation and recrystallised from ether/petroleum ether. The 1-[2-(4-methylmercaptophenyl)ethyl]piperazine melts at 52°-54°.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.C(N(CC)CC)C.Cl.CN>C(#N)C>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][CH:10]([C:12]([NH:23][CH3:21])=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Yield: 114.6 %

Procedure:
To a solution of 7.5 g (28 mmole) of 1-(diphenylmethyl)azetidine-3-carboxylic acid in 75 ml of acetonitrile was added 6.0 g (37 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated at 60° C. for two hours and successively treated with 3.11 g (30.8 mmole) of triethylamine and 2.08 g (30.8 mmole) of methylamine hydrochloride. The reaction was stirred at 60° C. for an additional hour, the solvent evaporated in vacuo, and the residue dissolved in chloroform. After washing with water and drying over magnesium sulfate, the chloroform layer was evaporated in vacuo to give 9.0 g of 1-(diphenylmethyl)-N-methyl-3-azetidinecarboxamide, mp 103-107° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].[Br:14]Br>CC(O)=O>[C:1]([C:4]1[CH:9]=[C:8]([Br:14])[CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1C(C)=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)cc1C(C)=O
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
Under N2, a pale yellow suspension of crude N-(2-acetylphenyl)acetamide (28 g, 158 mmol) in AcOH (300 mL) was stirred for about 5 min, and Br2 (12.95 mL, 253 mmol) was added within 1 h at room temperature. The resulting mixture was then stirred at room temperature for 75 min. After the reaction went to completion as monitored by LC-MS, the reaction mixture was quenched with H2O (200 mL). The mixture was filtered through Buchner funnel, and the solid was collected as N-(2-acetyl-4-bromophenyl)acetamide (35 g, yield 86%). MS (m/z): 216 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:23][Mg]Br.[Cl-].[NH4+]>CCOCC>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]([OH:22])([CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: C[Mg]Br
Reactant: COc1cc(OC)cc(C(=O)CCCCC#C[Si](C)(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cc(OC)cc(C(C)(O)CCCCC#C[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
[7-(3,5-Dimethoxyphenyl)-7-oxo-1-heptynyl]trimethylsilane (1 equiv.) was dissolved in anhydrous ether (0.5 M), the solution was cooled in an ice-bath under argon and methylmagnesium bromide (2 equiv., 3M solution in diethyl ether) was added dropwise. The light gray solution was allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was poured into saturated ammonium chloride solution, the organic phase was separated and the aqueous phase was extracted with diethyl ether. The combined organic extracts were dried and ether removed to afford pure [7-(3,5-dimethoxyphenyl)-7-hydroxy-1-octynyl]trimethylsilane as a viscous oil after passing through a short silica gel column, in 95% yield.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([CH2:14][NH:15][C:16]3[C:17]([F:29])=[CH:18][C:19]([F:28])=[C:20]([CH:27]=3)[C:21]([NH:23][CH:24]3[CH2:26][CH2:25]3)=[O:22])=[CH:12][N:13]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl>[CH:24]1([NH:23][C:21](=[O:22])[C:20]2[CH:27]=[C:16]([NH:15][CH2:14][C:11]3[S:10][C:9]([NH:8][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[N:7]=4)=[N:13][CH:12]=3)[C:17]([F:29])=[CH:18][C:19]=2[F:28])[CH2:26][CH2:25]1
Reactant: CN1CCNCC1
Reactant: O=C(NC1CC1)c1cc(NCc2cnc(Nc3cccc(Br)n3)s2)c(F)cc1F
Solvent: ClCCl
Product: CN1CCN(c2cccc(Nc3ncc(CNc4cc(C(=O)NC5CC5)c(F)cc4F)s3)n2)CC1
Temperature: 120 °C
Yield: 55 %

Procedure:
A mixture of 5-{[2-(6-bromo-pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-N-cyclopropyl-2,4-difluoro-benzamide (96 mg, 0.20 mmol) in neat N-methyl piperazine (0.4 mL) was heated to 120° C. in a sealed tube for 5 h. The reaction mixture was cooled to RT, diluted with methylene chloride (5 mL), and washed with water (2×5 mL). The organic layer was dried over Na2SO4, concentrated, and the residue was purified by silica gel eluted with 2-10% MeOH/CH3Cl to give the title compound (53 mg, 55%) as a light yellow solid. (M+H)+=500.