Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#N)=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4](Cl)=O.ClC1C(C#N)=C2C(C(=O)C(C(O)=O)=CN2C2CC2)=CC=1F.C(C1C(F)=C(C=C(F)C=1F)C(F)=O)#N.FC1C=C(C)C=C(C)C=1>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[CH3:4]
Reactant: N#Cc1c(Cl)c(F)cc(C(=O)Cl)c1Cl
Agent: Cc1cc(C)cc(F)c1
Agent: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: N#Cc1c(F)c(F)cc(C(=O)F)c1F
Product: Cc1cc(F)c(Cl)c(C)c1Cl

Procedure:
An alternative process for the preparation of the intermediate compound 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride, which serves as a starting material for the preparation of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (EP-A-0 276 700) and which can converted into 3-cyano-2,4,5-trifluoro-benzoyl fluoride, starts from 5-fluoro-1,3-xylene: 5-fluoro-1,3-xylene is dichlorinated in the nucleus under ionic conditions in the presence of a catalyst to give 2,4-dichloro-5-fluoro-1,3-dimethylbenzene and this is then chlorinated under free-radical conditions in the side chains to give 2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene. This is hydrolysed via 2,4-dichloro-5-fluoro-3-dichloromethylbenzoic acid to give 2,4-dichloro-5-fluoro-3-formyl-benzoic acid and then reacted to give 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid. By treatment with thionyl chloride, 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride is obtained, which can additionally be reacted by means of a chlorine/fluorine exchange to give 3-cyano-2,4,5-trifluoro-benzoyl fluoride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[N:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]=[C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)[NH:20][C:15]=2[CH:14]=1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: Nc1ccc(Br)cc1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2nc(-c3n[nH]c4ccccc34)[nH]c2c1

Procedure:
Starting with 643 mg of 1H-indazole-3-carboxaldehyde, 816 mg of 4-bromo-1,2-phenylenediamine, and 836.5 mg of sodium metabisulphite in 15 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a chromatography under pressure on silica, 939 mg of 5-bromo-2-(1H-indazol-3-yl)-3H-benzimidazole are obtained in the form of a brick-red powder.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:11]1[C@@H:16]2[C@H:17]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25](=[O:27])[CH3:26])[N:23]=3)[CH2:18][C@@:12]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:13]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[CH2:14][CH2:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH2:4]([N:11]1[C@@H:16]2[C@H:17]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25]([OH:27])([CH3:1])[CH3:26])[N:23]=3)[CH2:18][C@@:12]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:13]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:42])([F:43])[F:41])[CH:31]=1)[CH2:14][CH2:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: CC(=O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Solvent: C1CCOC1
Product: CC(C)(O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 0 °C
Yield: 38.3 %

Procedure:
Methylmagnesium bromide (3.0M solution in THF, 0.7 ml, 2.1 mmol) was added dropwise to a −78° C. solution of (1R*12R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[2-(2-oxopropyl)-2H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Compound 3i in Table 3; 1.1 g, 1.7 mmol) in THF (25 ml). The mixture was warmed to 0° C. for 30 minutes then quenched by addition of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2.5, 5 and 10% ethyl acetate/iso-hexanes to yield the title compound (0.43 g, 39%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[Br:13])=[O:5])C.[OH-].[Na+]>O>[Br:13][C:7]1[S:8][C:9]([CH2:11][CH3:12])=[CH:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(CC)sc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(C(=O)O)c(Br)s1
Temperature: 140 °C
Yield: 70.6 %

Procedure:
2-Bromo-5-ethyl-thiophene-3-carboxylic acid ethyl ester (0.7 g, 2.65 mmol) was dissolved in IMS (4 mL) and aqueous sodium hydroxide (1 M, 6 mL) was added. The reaction was heated to 140° C. using microwave irradiation for 10 minutes. Water (5 mL) was added and the white precipitate formed was isolated by filtration, washed with water and then dried under vacuum to give the title compound (0.44 g). 1H NMR (400 MHz, CHCl3-d): δ 7.1 (s, 1H), 2.7 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[C:9]#[N:10].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(O)(=O)C>O1CCCC1>[C:9]([C:8]1[CH:11]=[CH:12][C:13]([OH:14])=[C:6]([NH:5][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:7]=1)#[N:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#Cc1ccc(O)c(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C#N)ccc2O)CC1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
Polymer supported sodium cyanoborohydride (3531 mg, 7.20 mmol, 2.04 mmol/g) was added to a solution of 3-amino-4-hydroxybenzonitrile (D19, 477 mg, 3.56 mmol), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (709 mg, 3.56 mmol) and acetic acid (1 mL, 17.5 mmol) in tetrahydrofuran (10 mL). The mixture was heated by microwave at 100° C. for 30 min and then for a further 30 min before being filtered and concentrated by rotary evaporation to give 1,1-dimethylethyl 4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate (D32, 982 mg, 3.09 mmol, 87% yield) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][C:14]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([CH3:20])[N:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH3:13])=[N:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)n1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)n1
Yield: 69.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (1.1 g) and 1-(3,5-dimethylpyrazin-2-yl)piperazine hydrochloride (915 mg) described in Preparation Example 59, the title compound (1.1 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21](=O)[CH:20](Br)[CH2:19][CH2:18][CH2:17][C:7]=2[N:8](C(OC(C)(C)C)=O)[CH:9]=1)=[O:4].[C:24]([NH2:27])(=[S:26])[CH3:25]>CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21]3[N:27]=[C:24]([CH3:25])[S:26][C:20]=3[CH2:19][CH2:18][CH2:17][C:7]=2[NH:8][CH:9]=1)=[O:4]
Reactant: CC(N)=S
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Solvent: CO
Product: COC(=O)c1c[nH]c2c1-c1nc(C)sc1CCC2
Yield: 64.1 %

Procedure:
A mixture of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4-H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(880 mg, 2.27 mmol) and Thioacetamide(426 mg, 4.54 mmol) in MeOH(20 mL) is refluxed for 20 h and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (50% EtOAc/Hex to 10% MeOH/CH2Cl2) to yield 382 mg of 2-Methyl-4,5,6,7-tetrahydro-3-thia-1,7-diaza-cyclopenta[e]azulene-9-carboxylic acid methyl ester as a yellow foam(64%). 1H NMR (CD3OD) 2.18 (quint, 2H), 2.61 (s, 3H), 2.70 (t, 2H) 2.78 (t, 2H), 3.73 (s, 3H), 7.29 (s, 1H)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[O:12](C1C=CC(N)=CC=1)C1C=CC(N)=CC=1.NC1C=C(C=CC=1)OC1C=CC=C(OC2C=CC=C(N)C=2)C=1.C1(=O)OC(=O)C2=CC=CC=C12>CN1CCCC1=O>[CH:8]1[CH:7]=[C:3]([C:4]([NH2:5])=[O:6])[C:2]([C:1]([OH:11])=[O:12])=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1ccc(Oc2ccc(N)cc2)cc1
Agent: Nc1cccc(Oc2cccc(Oc3cccc(N)c3)c2)c1
Agent: O=C1OC(=O)c2ccccc21
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The following example illustrates the synthesis of a phthalimide-terminated imide oligomer with theoretical number average molecular weight of 12,000 g/mole. 4,4'-Oxydianiline (4,4'-ODA) (20.00 mmole, 4.0049 g) and 1,3-bis(3-aminophenoxy)benzene (APB) (20.00 mmole, 5.8467 g) were dissolved in N-methylpyrrolidinone (NMP) (~35 mL) in a flask equipped with a mechanical stirrer, condenser and nitrogen inlet. Pyromellitic dianhydride (PMDA) (38.596 mmole, 8.4187 g) and phthalic anhydride (PA) (2.808 mmole, 0.4159 g) were added to the solution with enough NMP to total 74.8 g (20% solids). The reaction was stirred at 25° C. for 6 h to form the phthalamide acid-terminated polyamide acid. The inherent viscosity (ηinh) of the phthalamide acid-terminated polyamide acid was 0.50 dL/g in NMP at 25° C. To imidize, toluene (40 mL) was added and the reaction was heated at 160° C. for 24 h. After cooling, a powder precipitated which was washed twice in water and dried ~230° C. in a vacuum to afford a yellow solid in high yield. The resulting phthalimide-terminated polyimide was insoluble in NMP and had a glass transition temperature 243° C. A film cast from the polyamide acid solution and dried 1 hour each at 100, 225, and 371° C. had a Tg of 252° C. and was brittle.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])=[CH:5][CH:4]=1.COC1C=C[C:27]([NH2:28])=CC=1.BrCC(Br)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH:11]([CH3:12])[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:27]2=[NH:28])=[CH:5][CH:4]=1
Reactant: COc1ccc(NCC(C)Nc2ccc(OC)cc2)cc1
Reactant: COc1ccc(N)cc1
Agent: CC(Br)CBr
Product: COc1ccc(N2CC(C)N(c3ccc(OC)cc3)C2=N)cc1
Yield: 32.7 %

Procedure:
1,2-Bis(4'-methoxyphenyl-amino)-propane, applied as starting substance, is obtained with a yield of 32.7% by reacting 4-methoxyaniline with 1,2-dibromopropane as described by McKay and Tarlton (loc. cit.). The compound melts at 82°-84° C.
Reaction SMILES: I[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.C([Mg]Cl)(C)C.C([Mg]Cl)(C)C.[Li+].[Cl-].[Cl:29][C:30]1[C:35](I)=[CH:34][N:33]=[CH:32][N:31]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:29][C:30]1[C:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:34][N:33]=[CH:32][N:31]=1
Reactant: Ic1ncnc2c1ncn2C1CCCCO1
Reactant: Clc1ncncc1I
Agent: [Pd]
Agent: CC(C)[Mg]Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Clc1ncncc1-c1ncnc2c1ncn2C1CCCCO1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
6-Iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (620 mg, 1878 μmol) was dissolved in THF (1 mL) in a 15 mL microwave tube and sealed. The solution was flushed with argon and then cooled to −40° C. A solution of isopropylmagnesium chloride (2254 μl, 2254 μmol) (LiCl complex, 1 N in THF) was added in dropwise slowly. The reaction was allowed to stirred at −40° C. for 15 min, LCMS showed incompletion of Mg—I exchange. The mixture was warmed to rt, LCMS indicated Mg—I exchange was still not completed, and then the mixture was cooled to −40° C. again and a solution of isopropylmagnesium chloride-LiCl complex (1 N in THF, 1 mL) was added again in dropwise via a syringe. The reaction mixture was stirred at this temperature for 20 min (LCMS showed all starting material consumed). Under −40° C., a solution of zinc chloride, 0.5 M in THF (4883 μl, 2441 μmol) was added in dropwise. Another 2 mL of the zinc chloride solution was added in to counter the additional Mg reagent. The mixture was stirred at this temperature for 1 hr and gradually warmed to RT. This solution was poured into a solution of 4-chloro-5-iodopyrimidine (429 mg, 1784 μmol), tris(dibenzylideneacetone)dipalladium(0) (103 mg, 113 μmol), and tri-2-furylphosphine (105 mg, 451 μmol) (TFP) in THF (15 mL) flushed with argon. This reaction mixture was heated to 60° C. under argon for 16 hours. The reaction mixture was cooled to rt and quenched with NH4Cl (aq., sat., 10 mL) and partitioned between H2O and EtOAc, 40 mL each. The organic was collected, and filtered through a layer of silica gel. The silica layer was rinsed with THF (80 mL). The filtrate was combined and concentrated. The residue was loaded on silica gel and purified via flash column on silica (A: hexane, B: 1:1 THF/EtOAc, B:A=5-40%). Desired fractions were collected and concentrated to give a dark brown gel. This brown gel was precipitated with hexane:EtOAc=1:1 to give a light brown solid. This solid was washed with the same solvent once and then dried in the air to give 6-(4-chloropyrimidin-5-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine. MS Found: (ESI pos. ion) m/z 317 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)(C)(C)C.C(#N)C>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Solvent: CC(C)(C)O
Product: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Yield: 54.9 %

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (1.71 g) in t-butanol (30 ml) was added slowly to a solution of 1-nitro-2,2-bis methylthioethylene (1.66 g) in acetonitrile (20 ml) at room temperature. The solution was heated under reflux for 3 hours, evaporated to dryness and chromatographed on a column of silica gel with elution by anhydrous ether (250 ml) followed by acetone (500 ml). The acetone eluate was concentrated to low bulk to give 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-ethylene (1.58 g), m.p. 151°-153°. A sample recrystallised from acetonitrile had m.p. 152°-153°.
Reaction SMILES: CCl.[OH-].[K+].[C:5]1(C)C=CC=CC=1.[CH3:12][C:13]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH2:26])=[O:25]>O>[CH3:12][C:13]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH:26][CH3:5])=[O:25]
Reactant: CO/N=C(/C(N)=O)c1ccccc1COc1cc(C)ccc1C
Reactant: Cc1ccccc1
Agent: CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Methyl chloride (0.45 g, 9.0 mmol), 85% potassium hydroxide (0.30 g, 4.5 mmol) and toluene (9 ml) were added to (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (0.94 g, 3.0 mmol). The mixture was stirred at 100° C. for 1 hour. After completion of the reaction, water (100 ml) was added. The mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.88 g, Yield: 90.2%) as colorless crystals. mp 136°-137° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:41]=[C:40]4[C:36]([C:37]([NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])=[N:38][N:39]4COCC[Si](C)(C)C)=[CH:35][C:34]=3[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:56]1([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][C:33]=2[C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:28][CH:29]=2)[NH:39][N:38]=[C:37]3[NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccccc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccccc3)cc12
Yield: 83.3 %

Procedure:
10.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[6-[4-(phenylmethoxy)phenyl]-5-phenyl-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 40 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 100 cm3 of saturated sodium hydrogen carbonate solution and with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 2 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is dried (90 Pa; 45° C.) to give 650 mg of N-[5-phenyl-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][CH2:13]1.C(OCC)(=O)C>ClCCl>[CH:16]12[O:9][CH:15]1[CH2:14][CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[CH2:18][CH2:17]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CCC=CCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2OC2CC1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
18 g m-chloroperbenzoic acid was added to 10 g benzyl 2,3,6,7-tetrahydro-1H-azepine-1-carboxylate in 250 ml dichloromethane at 0° C. in several portions. The mixture was allowed to warm to RT over 2 h. 1 L ethyl acetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. The organic layer was evaporated and the residue was purified by chromatographie on silica gel (ethyl acetae/hexanes 1:5) to yield 10.4 g of the desired product.
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(C)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
To a tetrahydrofuran (2 mL) solution of 4-benzyloxy-phenyl-acetohydroximoyl chloride (63 mg, 0.23 mmol) described in Manufacturing Example 1-1-3 and 3-ethynyl-6-methyl-pyridin-2-ylamine (20 mg, 0.15 mmol) described in Manufacturing Example 170-1-5 was added triethylamine (42 μL, 0.30 mmol) at room temperature, which was stirred for 4 hours at 50° C. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (26 mg, 34%) as a trifluoroacetic acid salt.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:20][CH:19]=1>CC(O)C.C(N(CC)CC)C>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)=[O:26])=[CH:22][CH:23]=2)[N:11]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: NCc1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(C)c1nc(NCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2)nc2ccccc12
Yield: 15.1 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (42 mg, 0.2 mmol) and biphenyl-4-carboxylic acid (4-aminomethyl-phenyl)-amide hydrochloride (49 mg, 0.14 mmol) in 2-propanol (1 mL) and triethylamine (200 μL) was stirred at reflux for 2 days. The resulting mixture was concentrated and purified by column chromatography (silica gel, CH2Cl2 to 10% 2 M NH3/MeOH in CH2Cl2) to give biphenyl-4-carboxylic acid {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-amide (10 mg, 15%) as a white solid.
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[CH3:32])=[CH:19][CH:18]=3)=[O:16])[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:34]N1C(=O)CCC1=O>C(OCC)(=O)C>[Cl:34][C:2]1[S:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[CH3:32])=[CH:19][CH:18]=3)=[O:16])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3ccsc3-c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3cc(Cl)sc3-c3ccccc32)cc1
Reaction time: 8 h

Procedure:
To a solution of 0.457 g (1.0 mmol) of N-[4-[(4,5-dihydro-6H-thieno[3,2-d][1]benzazepin-6-yl)carbonyl]phenyl]-2-methyl-3-fluorobenzamide in 25 ml of ethyl acetate is added 1.0 mmol of N-chlorosuccinimide. The mixture is stirred overnight and filtered. The filtrate is washed with water, 1N HCl, 1M NaHCO3, H2O and dried (Na2SO4). The solvent is removed to give the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1cccc(F)c1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 3-Fluoro-phenylamine to produce 4-Chloro-N-(3-fluoro-phenyl)-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.