Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>CS(C)=O.[Cu]I>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Oc3ccccn3)cc2C1
Temperature: 190 °C
Yield: 32.4 %

Procedure:
A reaction mixture of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.39 mmol, Description 3), 2-bromopyridine (62 mg, 0.39 mmol), caesium carbonate (382 mg, 1.17 mmol), copper(I) iodide (82 mg, 0.43 mmol) and N,N-dimethylglycine (49 mg, 0.47 mmol) in DMSO (1.5 ml) was heated in a microwave at 190° C. for 30 minutes. The resulting mixture was then partitioned between dichloromethane and water and the organic solution was dried (MgSO4) and evaporated under reduced pressure to yield the crude product. The crude product was purified using MDAP. The resulting solution was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic solution was dried (MgSO4) and evaporated under reduced pressure to obtain the title compound as a yellow gum (42 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11](=O)[CH3:12].[BH3-]C#N.[Na+].C(NCC)C>C1(C)C=CC=CC=1.CO>[CH2:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:12]
Reactant: CC=O
Reactant: NCCc1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCNCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCNCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a stirring solution of tyramine (1 mM, 137 mg) and MeOH (5 mL) was added acetaldehyde in excess. Then excess NaBH3CN (1 mM, 62.8 mg) was added and the mixture stirred for 2 hours at r.t. After evaporating the solvent, methylene chloride (5 mL) was added and mixture was washed with H2O (3×5 mL). The mixture was dried over MgSO4, filtered, and evaporated to give the product in 72% yield as an orange oil. TLC (toluene:diethylamine, 4:1 v/v): RF=0.5. 1H NMR, δ: 9.48 (s, 1H), 7.14 (d, 2H), 6.70 (d, 2H), 2.85 (m, 2H), 2.60 (t, 2H), 250 (q, 2H), 2.1 (s, 1H), 1.1 (t, 3H). C NMR, δ: 167.5, 134.3, 130.2, 115.6, 48.2, 44.4, 35.6, 15.6. Anal. calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48%. Found; C, 72.50; H, 9.20; N, 8.50%.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH2:19][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:15]1=[O:29].C1C[O:33]CC1>CCCCCC>[OH:33][CH:16]1[CH2:17][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][N:14]([CH3:13])[C:15]1=[O:29]
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CCC1=O
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CN1CC(c2ccccc2)([N+](=O)[O-])CC(O)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of 118 ul (0.833 mmol) diisopropylamine in 3 ml THF were added 520 ul (0.833 mmol) of a 1.6M n-BuLi solution in hexane at −5° C. The solution was stirred for 15 minutes at 0° C. and then cooled to −70° C. A solution of 150 mg (0.641 mmol) rac-1-methyl-5-nitro-5-phenyl-piperidin-2-one (example A.9, step 1) in 1.5 ml THF was added dropwise. The brown solution was stirred at −70° C. for 45 minutes. 517 mg (1.282 mmol) (oxodiperoxy(pyridine) (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum(IV)) were added portionwise at −70° C. The mixture was stirred at −70° C. for 1 hour and then allowed to warm to 0° C. After 1 hour at 0° C., the mixture was quenched with 2.5 ml of a saturated solution of sodium sulfite. Water and ethyl acetate were added. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 82 mg (51%) of the title compound as a light brown oil. MS (m/e): 251.1 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.[CH3:32][NH2:33]>CCO>[CH2:11]([C:9]1[N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:18][CH:19]=2)[C:6]2=[N:7][C:2]([NH:33][CH3:32])=[CH:3][C:4]([CH3:31])=[C:5]2[N:10]=1)[CH3:12]
Reactant: CN
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCO
Product: CCc1nc2c(C)cc(NC)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 180 °C
Yield: 51.9 %

Procedure:
A mixture of 5-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (74 mg), methylamine (0.6 g), and EtOH (2 mL) was heated in a bomb at 180° C. for 16 hours. Concentration and purification (SiO2, 90/9/1 CH2Cl2 /MeOH/NH4OH) gave 34.4 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][SH:12])[CH2:7]1)=[O:5])[CH3:2].[O-]CC.[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC=CC=1>C(O)C>[CH2:17]([S:12][CH2:11][C@H:8]1[CH2:7][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][S:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)[C@@H]1CS[C@@H](CS)C1
Reactant: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1CS[C@@H](CSCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of trans-4-ethoxycarbonyl-2-mercaptomethyltetrahydrothiophene (compound No. 15-1, 0.3 g) in ethanol (2 ml), sodium ethoxide (0.11 g) is added under nitrogen atmosphere and ice-cooling and the mixture is stirred for 30 minutes. Benzyl bromide (0.28 g) dissolved in ethanol (1 ml) was added to the mixture and the mixture is stirred for 30 minutes under ice-cooling and 1 hour at room temperature. Benzene is added to the reaction mixture. The organic layer is washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue is purified by a silica gel column chromatography to give titled compound (compound No. 25-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10](O)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[Cl:25][C:10]1[C:9](=[O:21])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12](=[O:13])[C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C(O)=C(c2ccccc2)C(=O)N1c1cccc(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
After dissolving compound 6c (2.00 g, 6.67 mmol) in DCM (10 ml) and anhydrous DMF (10 ml), oxalyl chloride (1.69 g, 13.3 mmoL) was added thereto and the agitation for 30 minutes was carried out. After the identification of the reaction progress with TLC, the reaction was terminated. Then, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the column chromatography was carried out with EA/HX ( 1/9). The suspension was carried out with EA/HX (⅓) to obtain compound 7c.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(O)=O.[Na+].[CH3:18][N:19](C=O)C>CC#N>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]#[N:19])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 6-nitroindole (4.9 g 30 mmol) in DMF (24 mL) and CH3CN (240 mL) was added dropwise a solution of CISO2NCO (5.0 mL) in CH3CN (39 mL) at 0° C. After addition, the reaction was allowed to warm to room temperature and was stirred for 2 h. The mixture was then poured into ice-water and basified with sat. NaHCO3 solution to pH 7˜8. The mixture was extracted with ethyl acetate. The organics were washed with brine, dried over Na2SO4 and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:20][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][C:38]([F:39])([F:40])[F:41])[N:28]=2)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C(F)(F)F

Procedure:
Oxalyl chloride (106 μL; 1.25 mmol; 3 eq.), Intermediate 24 (120 mg; 0.42 mmol; 1 eq.), Intermediate 2 (92 mg; 0.42 mmol, 1 eq.) and DIEA (93 μL; 1.25 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 80/20) followed by precipitation from n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:30]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CCOCC>[C:30]([O:34][C:35]([NH:37][CH2:38][C:39]([N:17]([CH:11]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=1)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)C(NCc1ccc(OC(F)(F)F)cc1)c1c(OC)cccc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1c(OC)cccc1OC)N(Cc1ccc(OC(F)(F)F)cc1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-(2,6-dimethoxyphenyl)-2-((4-(trifluoromethoxy)benzyl)-amino)acetate (1.121 g; 2.71 mmol), 2-(tert-butoxycarbonylamino)acetic acid (1.187 g; 6.77 mmol), DIPEA (1.752 g; 13.55 mmol), and HATU (2.577 g; 6.77 mmol) in anh. DMF (20 ml) was stirred at rt, under nitrogen, for 18 h. Et2O (20 ml) and water (20 ml) were then added to the reaction mixture, and the separated aq. layer was further extracted with Et2O (3×50 ml). The mixed organic layers were washed with brine (50 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=50/1) afforded ethyl 2-(2-((tert-butoxycarbonyl)amino)-N-(4-(trifluoromethoxy)benzyl)acetamido)-2-(2,6-dimethoxyphenyl)acetate as a yellow oil. LC-MS (conditions D): tR=1.12 min.; [M+H]+: 571.78 g/mol.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[S:18][CH:19]=[CH:20][N:21]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(-c3nccs3)cc2C1
Agent: Cl
Product: c1csc(-c2ccc3c(c2)CNC3)n1

Procedure:
Prepared in analogy to Example A3(e) from 5-Thiazol-2-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Yellow gum. MS (m/e): 202.8 ([M+H]+, 100%)
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:12]([CH:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
At −60° C., a solution of DMSO (1.73 ml, 24.4 mmol) in CH2Cl2 (20 mL) was added dropwise to a 2M solution of oxalyl chloride (1.28 mL, 14.7 mmol) in CH2Cl2 (7 mL). The mixture was stirred for 20 minutes and then a solution of tert-butyl 4-(hydroxymethyl)azepane-1-carboxylate (2.8 g, 12.2 mmol) in CH2Cl2 (7 mL) was added dropwise. The mixture was stirred for 10 minutes and triethylamine (8.51 ml, 61.1 mmol) was slowly added. The reaction mixture was warmed to ambient temperature and water was added. When the mixture became clear, it was extracted with CH2Cl2, the solvent evaporated to afford crude tert-butyl 4-formylazepane-1-carboxylate (2.78 g, 100%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]2[N:22]=[CH:23][CH:24]=[CH:25][C:15]1=2.CC(C1C=C(C(C)C)C(S([N:41]=[N+:42]=[N-:43])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>C1COCC1>[N:41]([CH:19]1[C:20](=[O:21])[N:14]([CH3:13])[C:15]2[CH:25]=[CH:24][CH:23]=[N:22][C:16]=2[CH2:17][CH2:18]1)=[N+:42]=[N-:43]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CN1C(=O)CCCc2ncccc21
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN1C(=O)C(N=[N+]=[N-])CCc2ncccc21
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A solution of 2.5 eq of diisopropylamine in 50 mL of dry THF was cooled to −78° C. While stirring, 2.4 eq of n-BuLi (2.5 M in hexanes) was added dropwise. The reaction mixture was warmed to 0° C. After stirring for 30 min, the solution was cooled to −78° C. and 1.0 eq of 97 dissolved in 20 mL of dry THF was added. After stirring at −78° C. for 30 min, 1.5 eq of trisyl azide was added. The mixture was stirred, as it warmed to rt. After 17 hrs, 4.5 eq of 17 M glacial acetic acid was added and stirred at rt for 5 hrs. The reaction mixture was rotary evaporated and 30 mL of saturated NaHCO3 was added. The mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and flash chromatographed on silica using EtOAc as eluent. After concentration and drying under vacuum of the fractions containing product, a brownish colored solid was obtained as 98.
Reaction SMILES: N#N.[Mg].Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[C:14]([CH:21]=[O:22])[CH:13]=1.Cl>O1CCCC1.O>[Br:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:19][CH:20]=1)[C:16](=[O:18])[O:22][CH:21]2[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cc(Br)ccc1C(=O)O
Reactant: Brc1ccccc1
Agent: Cl
Agent: N#N
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(c2ccccc2)c2cc(Br)ccc21
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 93.8 %

Procedure:
A tricol of 1 L with a condenser and an addition funnel is purged with N2 and magnesium turnings (5 g, 206 mmol) in tetrahydrofuran (80 mL) are added. Bromobenzene (32 g, 206 mmol) in tetrahydrofuran (80 mL) is added dropwise over 1¼ hour by maintaining the mixture temperature at 30° C. The resulting mixture is stirred for 45 min. at 30° C. 4-Bromo-2-formyl-benzoic acid (C3) (18.9 g, 83 mmol) in anhydrous tetrahydrofuran (200 mL) is added dropwise over 45 min. The mixture is stirred for 2 h at 30° C. The mixture is cooled in an ice-water bath and water (120 mL) and 5N HCl solution (80 mL) are added. The mixture is stirred overnight. THF is removed in vacuo and extracted with DCM (3×100 mL). The combined organics are washed with water (2×100 mL), dried over Na2SO4, filtered and the solvent is removed in vacuo to yield 5-bromo-3-phenyl-3H-isobenzofuran-1-one (22.5 g, 94%). Recrystallization: 5-bromo-3-phenyl-3H-isobenzofuran-1-one is dissolved in hot acetone (250 mL) and the mixture cooled in an ice-water bath over night. The resultant solid is filtered, rinsed with cold ACN (2×15 mL), and then vacuum dried over KOH to yield 5-bromo-3-phenyl-3H-isobenzofuran-1-one (D3) (14.4 g, 61%, mp: 189° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl>[CH:19]1([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(NC3CCCCC3)nnc(Cc3ccncc3)c2c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 0.56 %

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.523 g (5.278 mmol) cyclohexylamine is stirred for 8 h at 115° C. The cooled reaction mixture is then distributed between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic solution washed with brine and dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol (19:1). Title compound (with water content of 0.56%) is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV; m.p. 137-139° C.; ESI-MS: (M+H)+=319.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44]([C:46]1[S:47][CH:48]=[CH:49][N:50]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][C:46]4[S:47][CH:48]=[CH:49][N:50]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1nccs1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3Cc2nccs2)cc1
Reaction time: 96 h
Yield: 48.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 2-formylthiazole (0.24 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.22 g) at room temperature and the mixture was stirred for 4 days. To the reaction solution were added 2-formylthiazole (0.24 g), sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet), and the mixture was further stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethanol:ethyl acetate 1:4→1:3), which was recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(thiazol-2-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 86) (113.6 mg) as yellow crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]#[N:7].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To an ice-cold solution of 3-methoxy 4-phenyl-benzonitrile (1.42 g) in dichloromethane (27 mL) was added dropwise boron tribromide (1.27 mL). The resulting mixture was stirred at room temperature for 1 hour and then at 30° C. for 38 hours. Boron tribromide (0.634 mL) was added dropwise and stirring was continued for additional 23 hours. The reaction mixture was poured into ice (40 g) and the whole was extracted with ethyl acetate (75 mL). The organic layer was washed successively with 1 mol/L hydrochloric acid (25 mL), saturated aqueous sodium hydrogen carbonate (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (1.21 g).
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].C[N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[C:24]([F:25])=[CH:23][C:22]([NH:26][C:27]([C:29]4([C:32]([NH:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)=[O:33])[CH2:31][CH2:30]4)=[O:28])=[C:21]([F:42])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[C:9]([CH3:43])=[N:8]1.[CH3:44]S(O)(=O)=O>C1COCC1.CCOCC>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[CH3:44][N:8]1[C:9]([CH3:43])=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[C:24]([F:25])=[CH:23][C:22]([NH:26][C:27]([C:29]4([C:32]([NH:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)=[O:33])[CH2:30][CH2:31]4)=[O:28])=[C:21]([F:42])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH:11]=[N:7]1
Reactant: Cc1nn(C)cc1-c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)cnn1C
Temperature: 25 °C
Yield: 82.5 %

Procedure:
N-(4-(2-(1,5-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide from Example 49 (0.081 g, 0.155 mmol) was dissolved in THF (2.5 ml) and warmed until reflux. Methanesulfonic acid (10.09 μl, 0.155 mmol) was added and the mixture cooled to RT. The mixture was slowly diluted with Et2O (5 ml). A precipitate immediately began to form upon addition. After the addition was complete, the mixture was sonicated for 20 min. The precipitate was filtered off to yield N-(4-(2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide mesylate (79 mg, 82% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 9.72 (s, 1H), 8.52 (d, 1H), 8.20-8.14 (m, 2H), 7.63-7.56 (m, 3H), 7.25 (s, 1H), 7.18-7.14 (m, 2H), 6.99-6.94 (m, 1H), 3.74 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 1.67-1.64 (m, 2H), 1.58-1.55 (m, 214); MS (ESI) m/z: 522.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N)n1
Yield: 78 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 4-trifluoromethyl-phenylamine provided the title compound (78% yield). 1H NMR (DMSO-d6) δ 1.40 (t, 3H, J=6.9 Hz, CH3), 4.15 (q, 2H, J=6.9 Hz, CH2), 6.45 (s, 2H, NH2), 6.84 (s, 1H, Ar), 7.16 (d, 1H, J=8.9 Hz, Ar), 7.43 (dd, 1H, J=8.8 Hz, 2.8 Hz, Ar), 7.61 (d, 2H, J=8.9 Hz, Ar), 7.93 (d, 1H, J=2.8 Hz, Ar), 7.99 (d, 2H, J=8.9 Hz), 9.59 (s, 1H, NH).