Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][CH2:25][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])([CH3:28])[CH3:27])[C:21]([Cl:34])=[CH:20][N:19]=1>>[Cl:34][C:21]1[C:22]([NH:24][CH2:25][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])([CH3:28])[CH3:27])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CC(C)(CNc1nc(Cl)ncc1Cl)NS(C)(=O)=O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NCC(C)(C)NS(C)(=O)=O)n3)cc2CC1

Procedure:
N-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-1,1-dimethyl-ethyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-1,1-dimethyl-ethyl]-methanesulfonamide in an analogous manner to Example 304. Product isolated as a white foam (120 mg, 71%). LCMS (m/e) 497 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.34-7.26 (m, 2H), 7.04 (d, 1H, J=7.8 Hz), 6.96 (s 1H), 5.80-5.71 (m, 2H), 3.65 (d, 1H, J=6.4 Hz), 3.55 (d, 2H, J=5.7 Hz), 3.38 (s, 3H), 2.95 (s, 3H), 2.98-2.88 (m, 4H), 2.80-2.68 (m, 6H), 1.45 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:20](=O)[CH3:21])C>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)=[C:20]([CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Solvent: O
Product: COC(=O)COc1ccc(F)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.50 g), 2-(4-chlorobenzyl)-3-oxobutyric acid ethyl ester (7.4 g) and polyphosphoric acid (1.1 g) was heated at 130° C. for 2 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1 by volume) to afford title compound, 0.29 g.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][N:12](C)C)=[CH:5][CH:4]=1.O.[NH2:17]N.[OH-].[Na+]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][N:17]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CN(C)CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc(C2=NNCC2)cc1
Temperature: 50 °C

Procedure:
Under N2 atmosphere, 1-(4-chloro-phenyl)-3-dimethylamino-propan-1-one hydrochloride (37.2 g) was dissolved in warm MeOH (75 mL), and slowly added to a solution of hydrazine hydrate (23 mL) and 50% aqueous NaOH (12 mL) in MeOH (30 mL) stirred at 50° C. The mixture was refluxed for 2 hours, and evaporated under reduced pressure. Water was added to the residue, followed by extraction with DCM. The organic phase was washed twice with water, dried and evaporated under reduced pressure, to give 25.0 g of a yellow solid, m.p. 90-100° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH2:28]OS(C)(=O)=O)[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2].[CH3:34][NH2:35].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C@H:18]([CH2:28][NH:35][CH3:34])[CH2:17]2)=[O:14])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](COS(C)(=O)=O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 32 h
Yield: 39 %

Procedure:
The mixture of tert-butyl (2S,4S)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (197 mg, 0.41 mmol, step 1 of Example 17) and 40% monomethylamine aqueous solution (3 mL) in tetrahydrofuran (2 mL) was stirred at 80° C. for 32 h. After cooling to room temperature, the mixture was added to saturated sodium hydrogencarbonate aqueous solution. The organic phase was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographed on a column of NH gel eluting with n-hexane/ethyl acetate (4:1 to 2:1) to give 66 mg (39%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[O:6]=[CH:7][C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9]>C1COCC1.C(OCC)(=O)C>[CH:1]1([CH:7]([OH:6])[C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH3:9])[CH2:3][CH2:2]1
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: Br[Mg]C1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(O)C1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
Cyclopropylmagnesium bromide (32 mL, 16.00 mmol) was added dropwise to a solution of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (1.10 g, 6.35 mmol) in anhydrous THF (Volume: 25.4 mL) at −78° C. The reaction mixture was then allowed to warm to 0° C. and stirred at this temp for 4 hrs before quenching with sat. ammonium chloride solution. The evaporated organic was then purified by column chromatography using hexane:ethyl acetate as eluent to give tert-butyl (2R)-1-cyclopropyl-1-hydroxypropan-2-ylcarbamate (745 mg, 3.46 mmol, 54.5% yield). 1H NMR (500 MHz, CCl3D) δ 4.80 (br. s., 1H), 3.94-3.66 (m, 1H), 3.07-2.90 (m, 1H), 2.87-2.65 (m, 1H), 2.44-2.13 (m, 1H), 1.48-1.37 (m, 9H), 1.24-1.12 (m, 3H), 1.06-0.91 (m, 1H), 0.91-0.78 (m, 1H), 0.64-0.46 (m, 2H), 0.42-0.15 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([Cl:19])[C:13](Cl)=[C:14](Cl)[C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([Cl:19])[C:13]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: Sc1ccccc1
Reactant: CCCCN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN=C(O)c1c(Cl)c(Sc2ccccc2)c(Sc2ccccc2)c(Cl)c1C(=O)O

Procedure:
20 g (58.65 millimols) of tetrachlorophthalic acid N-n-butylimide, 33.64 g (243 millimols) of potassium carbonate, 13.57 g (123 millimols) of thiophenol and 150 ml of tetrahydrofuran are stirred at 25° C. for 18 hours. The mixture is acidified and extracted with methylene chloride. The extracts are dried and evaporated. After recrystallisation from toluene/cyclohexane, 23.88 g (83% of theory) of 4,5-bis-(phenylthio)-3,6-dichlorophthalic acid N-n-butylimide are obtained; melting point 215°-6° C.
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[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: C1CNCCN1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CN2CCNCC2)cc1
Yield: 69.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(piperazin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.105 g; 0.302 mmol), piperazine (0.118 g; 1.36 mmol) and sodium iodide (0.229 g; 1.51 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 2 to 16% methanol in dichloromethane) furnished 0.083 g (69%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH3:15])[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31]([NH:1][C@@H:2]2[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH3:15])[C:3]2=[O:16])=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CN1C(=O)[C@H](N)CCC[C@@H]1c1ccccc1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1CCC[C@H](c2ccccc2)N(C)C1=O

Procedure:
Using a procedure similar to that described in example 3, except using (3R,7R)-3-amino-1-methyl-7-phenylazepan-2-one (3f) (60 mg) to couple with N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (67 mg), the title compound was obtained as a white solid (100 mg, 84%). 1H NMR (300 MHz, CDCl3) δ 1.39 (d, 3H), 1.57 (m, 1H), 1.94 (m, 3H), 2.14 (m, 2H), 2.51 (s, 3H), 3.56 (s, 2H), 4.51-4.56 (m, 1H), 4.92-4.95 (m, 2H), 6.24 (bd, 1H), 6.70-6.75 (m, 1H), 6.83-6.85 (bd, 2H), 7.28-7.39 (m, 6H). MS APCI, m/z=444 (M+1). LC/MS 2.33 min., Method A.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C@H:24]([OH:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:26][C@H:25]2[C@H:29]([C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23][C@H:24]2[OH:30])[CH2:28]1)=[O:12]
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Product: CN(C)c1ccccc1CC(=O)N1C[C@@H]2[C@H](O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Yield: 31.8 %

Procedure:
By carrying out the procedure according to that described in the Example of use 9, using 0.26 g of 2-dimethylaminophenylacetic acid and 0.50 g of (3aR,4R,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride, 0.21 g of (3aR,4R,7aR)-2-[(2dimethylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of a white solid; melting point 204° C., [α]20D =-212° (c =0.5, methanol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]=[CH:7]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred suspension of sodium hydride (NaH, 60% dispersion in mineral oil; 48 mg, 2 mmol) in anhydrous dimethylformamide (5 ml) in an ice bath was added dropwise a solution of 5-bromo 1H indole (1.5 mmol) in anhydrous DMF (10 mL) over a period of 10 min at 0 C. After stirring for 10 min, 1-Bromooctane (1.8 mmol) was added drop wise over 5 min and reaction mixture was allowed to warm to RT and left with stirring for overnight. The reaction was quenched by pouring over ice and extracted twice with ethyl acetate (25 ml). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash silica gel column chromatography with ethyl acetate and Hexane to get 5-bromo 1-octyl 1H-indole as an oil (Yield: 80 to 90%). Product was confirmed by NMR and LC-MS
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[N:32]=[CH:31][NH:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[NH:29][N:30]=[CH:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Nc1nc[nH]n1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ncn[nH]1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-amino-1,2,4-triazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1H-1,2,4-triazol-5-yl)terephthalamide. MS (Q1) 453 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].Cl.[OH:32][CH:33]1[CH2:36][NH:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:35]3[CH2:36][CH:33]([OH:32])[CH2:34]3)=[O:17])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: OC1CNC1
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CC(O)C3)C2)cc1

Procedure:
0.3 g (0.7 mmol) of the compound from Example 12A, 0.2 g (2.18 mmol) of 3-hydroxyazetidine hydrochloride and 0.2 g (1.4 mmol) of potassium carbonate were initially charged in 6 ml of DMF and reacted in a single-mode microwave (Emrys Optimizer) at 150° C. for 30 min. The crude product was purified by preparative HPLC. Yield: 105 mg (40% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([CH3:36])[CH:28]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:35])=[C:29]([CH3:36])[CH:28]=1
Reactant: COC(=O)c1ccc(N=C=O)c(C)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with 3-methyl-4-isocyanato-benzoic acid methyl ester (example 14.1) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 days under reflux conditions to give the title compound as brown solid. MS: m/e=517.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]C2C=CC=CC=2)=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][C:21](=[CH:24][C:25]2[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=2)[O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>CS(C)=O>[F:37][C:35]([F:38])([F:36])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:27]2[CH:26]=[C:25]([CH:41]=[CH:40][CH:39]=2)[CH:24]=[C:21]2[CH2:22][CH2:23][N:18]([C:9]([NH:8][C:5]3[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:10])[CH2:19][CH2:20]2)=[N:30][CH:31]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1ccc(Br)nc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Br)nc1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of phenyl 6-bromopyridin-3-ylcarbamate (1.03 g, 3.5 mmol) in DMSO (5 mL) was added 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (1.3 g, 3.51 mmol) followed by triethylamine (0.98 mL, 7.01 mmol). The reaction was stirred at 60° C. overnight and then allowed to cool to RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4 and concentrated. Purification by silica gel column chromatography (0-5% MeOH/CH2Cl2) afforded the title compound as an oil, which foamed up on the pump (1.76 g, 94% yield). MS (APCI 10V) AP+2 535.08; 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (t, 2H) 2.59 (t, 2H) 3.50 (t, 2H) 3.59 (t, 2H) 6.40 (s, 1H) 6.47 (br. s., 1H) 6.97-7.03 (m, 3H) 7.08 (d, 1H) 7.36-7.41 (m, 2H) 7.87-7.92 (m, 2H) 8.20 (d, 1H) 8.43 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>CN(C)C=O.[Cu](I)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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Reactant: C#Cc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C#Cc2ccncc2)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In 20 mL of dimethylformamide, 1.0 g (3.7 mmol) of 4-bromo-3-(trifluoromethyl)nitrobenzene was dissolved, and 0.502 g (3.7 mmol) of 4-ethynylpyridine, 43 mg (3 mol %) of copper iodide, 78 mg (3 mol %) of dichlorobis(triphenylphosphine)palladium and 2.06 mL (0.56 mmol) of triethylamine were added thereto and the mixture solution was stirred overnight at 50° C. in an argon atmosphere. The reaction solution was partitioned between water and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by a silica gel column (n-hexane:ethyl acetate=3:1) to obtain 1.3 g (quantitative) of a target product as an pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:12])[C:8]([CH3:21])=[C:7]2[C:3]=1[C:4]1[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=1[NH:6]2.[CH:27]1([NH:30][C:31]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:31]([C:33]2[CH:38]=[C:37]([C:2]3[CH:10]=[C:9]([C:11]([NH:13][CH:14]4[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]4)=[O:12])[C:8]([CH3:21])=[C:7]4[C:3]=3[C:4]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=3[NH:6]4)[CH:36]=[CH:35][CH:34]=2)=[O:32])[CH2:28][CH2:29]1
Reactant: O=C(NC1CC1)c1cccc(B(O)O)c1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(Cl)c3c2c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(-c4cccc(C(=O)NC5CC5)c4)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide and 3-(cyclopropylcarbamoyl)phenylboronic acid using an analogous procedure to that described in the preparation of compound 88. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.82 (m, 4H) 1.53 (qd, J=11.66, 3.41 Hz, 2H) 1.79-1.82 (m, 3H) 1.95 (t, J=10.86 Hz, 2H) 2.15 (s, 3H) 2.27 (s, 3H) 2.59 (s, 3H) 2.74 (d, J=11.12 Hz, 2H) 3.75 (m, 1H) 6.98 (s, 1 H) 7.27 (d, J=7.58 Hz, 1H) 7.49 (t, J=7.96 Hz, 1H) 7.69 (d, J=2.02 Hz, 2H) 7.91 (s, 1H) 8.25-8.30 (m, 2H) 10.37 (s, 1H) 11.92 (br. s., 1H); [M+H] calc'd for C30H33N5O2, 496.3; found, 496.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:22]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:12]=[CH:13][C:14]=1[CH:15]=[CH:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:56]=[O:57].II>O1CCCC1.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:22]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:42])([CH3:43])[CH3:44])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:12]=[CH:13][C:14]=1[CH:15]=[CH:16][C:17]1[S:18][C:19]([CH:56]=[O:57])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCCCN(CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(C=Cc2cccs2)c(OCc2ccccc2)c1
Agent: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCN(CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Temperature: -69 °C
Reaction time: 0.58 h
Yield: 57.6 %

Procedure:
In a stream of argon, in 20 ml of tetrahydrofuran was dissolved 2.02 g (3.0 mmol) of [3-benzyloxy-4-(2-thiophene-2-ylvinyl)phenyl]butyl[4-(tert-butyldiphenylsiloxy) butyl]amine, and 2.8 ml of n-butyllithium (1.6 mol solution in hexane) (4.48 mmol) was added dropwise thereto under cooling at −66 to −72° C. After the mixture was stirred for 35 minutes, 0.3 ml (3.9 mmol) of N,N-dimethylformamide was added dropwise thereto. After the mixture was stirred for 1.5 hours, the bath was removed and the temperature was allowed to rise. At −10° C., 10 ml of water was added dropwise. After the reaction mixture was poured into 100 ml of water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give a reddish orange oily matter. Next, 1.43 g of the oily matter was dissolved in 150 ml of ether and 50 mg of iodine was added thereto. After stirred at room temperature for 30 minutes, the mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. Drying over anhydrous magnesium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 1.21 g of a red oily matter (yield: 57.6%).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)C1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (60%).