Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:13]3[CH2:23][OH:24])[CH2:4][CH2:3]1>O1CCOCC1.O=[Mn]=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:13]3[CH:23]=[O:24])[CH2:4][CH2:3]1
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3CO)CC1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3C=O)CC1
Temperature: 90 °C

Procedure:
To a solution of [4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-1-yl]-methanol (example 257A) (300 mg, 0.745 mmole) in 1,4-dioxane (4 mL) is added MnO2 (320 mg, 3.72 mmole) and the reaction mixture is heated at 90° C. overnight. Another portion of MnO2 (320 mg, 3.72 mmole) is added and the reaction mixture is heated at 90° C. overnight. The reaction mixture is filtered onto celite, cake washed with AcOEt and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (100:0) to (95:5) to give 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carbaldehyde melting at 70° C.
Reaction SMILES: B(Br)(Br)Br.ClCCl.C([O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:28]([CH3:41])[C:29](=[O:40])[N:30]([C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=4[F:39])[C:19]=3[C:18]=2[CH:17]=1)C1C=CC=CC=1.O>FC(F)(F)C(O)=O>[F:39][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:31]=1[N:30]1[C:19]2[C:18]3[CH:17]=[C:16]([OH:15])[C:25]([O:26][CH3:27])=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:28]([CH3:41])[C:29]1=[O:40])[C:35]#[N:36]
Reactant: COc1cc2ncc3c(c2cc1OCc1ccccc1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncc3c(c2cc1O)n(-c1ccc(C#N)cc1F)c(=O)n3C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A boron tribromide solution in dichloromethane (1.0 M, 14.5 ml, 14.5 mmol) was slowly added dropwise with ice-bath cooling in a dry nitrogen atmosphere to a solution of 4-(8-benzyloxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)-3-fluorobenzonitrile (1.45 g, 3.19 mmol) in trifluoroacetic acid (29 ml). When the addition was complete, the mixture were subsequently stirred for a further 30 min. When the reaction was complete (HPLC-MS check), the reaction mixture was carefully added to water (700 ml) and extracted twice with ethyl acetate (290 ml each time). The combined organic phases were washed with water (100 ml) and semi-saturated NaHCO3 solution (150 ml), subsequently dried using Na2SO4 and filtered with suction. The filtrate was evaporated in vacuo, and the residue was chromatographed over flash silica gel (solvent gradient ethyl acetate/0-33% by vol. of ethanol), giving 3-fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (1.10 g, 3.03 mmol), as solid. MS: 365.1 (M+H+), TLC (HPTLC): Rf=0.46 (ethyl acetate/ethanol 2:1, parts by volume).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH2:9].CO[C:13]1[C:22](=[O:23])[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[C:15](=[O:24])[CH:14]=1>C(O)C>[CH3:10][N:5]([CH2:6][CH2:7][CH2:8][NH:9][C:13]1[C:22](=[O:23])[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[C:15](=[O:24])[CH:14]=1)[CH2:4][CH2:3][CH2:2][NH:1][C:13]1[C:22](=[O:23])[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[C:15](=[O:24])[CH:14]=1
Reactant: COC1=CC(=O)c2sc(C)nc2C1=O
Reactant: CN(CCCN)CCCN
Solvent: CCO
Product: Cc1nc2c(s1)C(=O)C=C(NCCCN(C)CCCNC1=CC(=O)c3sc(C)nc3C1=O)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
83.4 mg (0.57 mmol; 0.6 equivalents) of N-(3-aminopropyl)-N-methylpropane-1,3-diamine are added to 200 mg (0.95 mmol) of 5-methoxy-2-methyl-4,7-dioxobenzothiazole in solution in 15 ml of anhydrous ethanol. The reaction mixture is stirred at 60° C. for 2 hours, then the solvent is evaporated off under reduced pressure. The residue is purified on a silica column (eluent: methanol at 3% in dichloromethane) and 30 mg (yield=36%) of expected product is obtained in the form of a red powder. Melting point: 94-96° C.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:15]2[C:14](=O)[C:13]3[CH:12]=[C:11]4[C:17]5[C:22]([C:23](=O)[C:10]4=[CH:9][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:21][CH:20]=[CH:19][CH:18]=5.O.NN.Cl>C(O)COCCO>[CH:21]1[C:22]2[CH2:23][C:10]3[CH:9]=[C:8]4[C:7]5[C:15]([CH2:14][C:13]4=[CH:12][C:11]=3[C:17]=2[CH:18]=[CH:19][CH:20]=1)=[CH:3][CH:4]=[CH:5][CH:6]=5
Reactant: O=c1c2ccccc2c2cc3c(=O)c4ccccc4c3cc12
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc2c(c1)Cc1cc3c(cc1-2)Cc1ccccc1-3
Temperature: 170 °C
Reaction time: 0.17 h

Procedure:
Potassium hydroxide (163.7 g), diethylene glycol (1412 mL, Alfa-Aesar) and indeno[1,2-b]fluorene-6,12-dione (28.23 g) were charged to a suitable vessel under argon. Hydrazine-hydrate (152 mL, Alfa-Aesar) was added and the reaction heated to 170° C. for 18 hours. The reaction mixture was slowly added to a mixture of ice (2 kg) and concentrated hydrochloric acid (1 L) and the resulting slurry stirred for 10 minutes. The solids were collected by vacuum filtration, washed with water (3×500 mL) and dried to give the product as a grey solid. Yield; 24.49 g. 1H NMR (400 MHz, CDCl3); 7.95 (2H, m), 7.80 (2H, m), 7.54 (2H, m), 7.39 (2H, m), 7.30 (2H, m).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:17]3[CH2:18][CH2:13][CH2:14][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.9 %

Procedure:
To a stirred mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.9 g, 22.6 mmol, 1.00 equiv), (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (10 g, 50 mmol, 2.2 equiv) and triphenylphosphine (11.8 g, 45 mmol, 2.0 equiv) in tetrahydrofuran (300 mL) at 10° C. was added a solution of diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) dropwise in 30 min. The resulting mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 3 g (33%) of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[I-].[K+].[C-:19]#[N:20].[K+].O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:19]#[N:20])=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: ClCc1ccc(Br)cc1OC1CCCCC1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)cc1OC1CCCCC1
Temperature: 70 °C
Reaction time: 1.33 h
Yield: 27.9 %

Procedure:
To a solution of 4-bromo-1-chloromethyl-2-cyclohexyloxybenzene (5.58 g) in ethanol (55.8 ml) were added potassium iodide (3.36 g) and potassium cyanide (1.56 g) at room temperature under nitrogen, and the mixture was stirred at 70° C. for 80 minutes. The resulting mixture was poured into water and the aqueous layer was extracted with toluene. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/toluene=2:1 to 1:1) to give (4-bromo-2-cyclohexyloxyphenyl)acetonitrile (1.51 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:15]([CH2:16]O)=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.O=S(Cl)[Cl:22]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:15]([CH2:16][Cl:22])=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(Sc2cc(=O)[nH]c(C)c2CO)c1
Solvent: ClCCl
Product: Cc1cc(C)cc(Sc2cc(=O)[nH]c(C)c2CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of intermediate 15 (275 mg; 1 mmol) in dichloromethane (10 ml) became homogeneous by addition of SOCl2 (2.3 ml) at room temperature. After 2 hours of stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected intermediate 16 in quantitative yield (294 mg).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[C:20]([C:22](OC)=[O:23])[N:21]=2)=[CH:13][CH:12]=1>C1COCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][OH:23])[N:21]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1csc(-c2ccc(F)cc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1csc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49.3 %

Procedure:
DIBAL-H (2.48 mL, 2.98 mmol, 1.2M in toluene) was added dropwise to a solution of methyl 2-(4-fluorophenyl)thiazole-4-carboxylate (300 mg, 1.26 mmol) in dry THF (6 mL) at −30° C. The reaction mixture was allowed to warm up to room temperature and stirred for 10 h. The reaction mixture was quenched carefully with saturated NH4Cl solution, filtered through Celite and diluted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 25% EtOAc in petroleum ether) to afford (2-(4-fluorophenyl)thiazol-4-yl)methanol (130 mg, yield 54%). 1H NMR (300 MHz, CDCl3) δ 7.96-7.91 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.18-7.11 (m, 3H), 4.84-4.82 (d, J=5.3 Hz, 2H), 2.38-2.34 (t, J=6.2 Hz, 1H). MS (ESI) m/z: Calculated for C10H8FNOS: 209.03. found: 209.9 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([CH:8]=[C:9]([C:18]([OH:20])=[O:19])[CH:10]([C:14]([F:17])([F:16])[F:15])[O:11]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Cl:21]Cl>CC(O)=O.[Zn]>[Cl:21][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[CH:1]1[CH2:2][CH2:3]1)[O:11][CH:10]([C:14]([F:15])([F:17])[F:16])[C:9]([C:18]([OH:20])=[O:19])=[CH:8]2
Reactant: O=C(O)C1=Cc2ccc(C3CC3)cc2OC1C(F)(F)F
Reactant: ClCl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)C1=Cc2cc(Cl)c(C3CC3)cc2OC1C(F)(F)F
Reaction time: 0.75 h

Procedure:
To a solution of the product of Example 146 Step 2 (0.28 g, 1.0 mmol) in 5 mL HOAc was added Cl2 in HOAc (3.0 mL, −1.5 mmol). After 0.75 h, the reaction was treated with Zn dust for 1.5 h. The reaction mixture was decanted from the Zn and concentrated under vacuum. The resulting residue was triturated with H2O, filtered, and washed with H2O. The yield of 6-chloro-7-cyclopropyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid was 0.26 g (82%) after drying overnight in a vacuum oven at 50° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH3:28])[NH:26][C:25](=O)[CH2:24][O:23][CH2:22]2)=[CH:17][CH:16]=1.[C-:29]#[N:30].[K+]>O1CCCC1.C(=O)(O)[O-].[Na+].C(O)(=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH3:28])[NH:26][CH:25]([C:29]#[N:30])[CH2:24][O:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: [C-]#N
Reactant: COc1ccc(C2(C)COCC(=O)N2)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C2(C)COCC(C#N)N2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 160 mmol of lithium aluminium hydride (1M in hexane) in 750 ml of tetrahydro-furan is mixed at 0° C. with 7.8 ml of ethyl acetate and stirred at 0° C. for 2 hours. A solution of 20 mmol of 5-(4-methoxyphenyl)-5-methylmorpholin-3-one (Example 3i) in 250 ml of tetrahydrofuran is added dropwise to this solution, and the reaction mixture is stirred at 0° C. for 45 minutes. 600 ml of glacial acetic acid and then 120 mmol of a 4.5M aqueous potassium cyanide solution are added. The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with 1M sodium bicarbonate solution and extracted with ethyl acetate-tetrahydrofuran 1:1 (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is obtained as a pale yellowish oil from the residue by flash chromatography (SiO2 60F). Rf=0.19 (CH2Cl2-MeOH 95:5); Rt=2.41 (gradient I).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=O.II.[CH2:13]([SH:16])[CH2:14][SH:15]>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[S:16][CH2:13][CH2:14][S:15]2)=[CH:5][CH:6]=1
Reactant: SCCS
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: II
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)SCCS1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), iodine (250 mg, 1 mmol), 1,2-ethanedithiol (0.85 mL, 10 mmol) in dry tetrahydrofuran (20 mL) was heated at reflux under an atmosphere of nitrogen for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo and the residue taken up in ether (20 mL). The organic solution was washed with water (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and evaporated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-(4-chlorophenyl)-2-methyl-1,3-dithiolane (24) as a colourless oil (1.11 g, 48%). 1H nmr (300 MHz, CDCl3) 2.13 (s, 3H, CH3), 3.31-3.53 (m, 4H, SCH2CH2S), 7.27 (d, J=8.7 Hz, 2H, 2×ArH), 7.69 (d, J=8.7 Hz, 2H, 2×ArH).
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][S:5][CH:6]=1.[CH2:10]([CH:12]([C:15]1[C:16]2[N:17]([C:22](I)=[C:23]([CH3:25])[N:24]=2)[N:18]=[C:19]([CH3:21])[CH:20]=1)[CH2:13][CH3:14])[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:10]([CH:12]([C:15]1[C:16]2[N:17]([C:22]([C:3]3[C:2]([CH3:1])=[CH:6][S:5][CH:4]=3)=[C:23]([CH3:25])[N:24]=2)[N:18]=[C:19]([CH3:21])[CH:20]=1)[CH2:13][CH3:14])[CH3:11]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1cscc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3cscc3C)c(C)nc12
Yield: 86.9 %

Procedure:
To a 100 mL round bottom flask containing 4-methyl 3-thiophene boronic acid (0.27 g, 1.91 mmol), and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.65 g, 1.91 mmol) in 20 mL of a stock solution (DME:H2O:EtOH=7:3:2) is added 2 M Na2CO3 (1.9 mL). The resulting mixture is degassed by bubbling N2 for 5 min. Then Pd(PPh3)4 (0.11 g, 0.096 mmol) is added. The reaction mixture is refluxed overnight. The reaction is diluted with H2O (20 mL); extracted with EtOAc (3×30 mL); dried (Na2SO4), filtered and purification of the crude material by chromatography gives the title compound (0.52 g, 1.66 mmol, 87%). 1H NMR (CDCl3): δ 0.89 (t, J=7.5 Hz, 6H), 1.75-1.90 (m, 4H), 2.13 (d, J=0.8 Hz, 3H), 2.44 (s, 3H), 2.49 (s, 3H), 3.30-3.39 (m, 1H), 6.64 (s, 1H), 7.08-7.11 (m, 1H), 7.34 (d, J=3.1 Hz, 1H). ES-MS (m/z): calcd for C18H23N3S (M+H)+: 314.5; found: 314.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[C:24]1([S:30]([N:33]2[C:37]3[CH:38]=[N:39][C:40]([C:43]#[N:44])=[C:41](Br)[C:36]=3[C:35]3[CH:45]=[CH:46][CH:47]=[N:48][C:34]2=3)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C.ClCCl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:41]2[C:36]3[C:35]4[CH:45]=[CH:46][CH:47]=[N:48][C:34]=4[N:33]([S:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)(=[O:32])=[O:31])[C:37]=3[CH:38]=[N:39][C:40]=2[C:43]#[N:44])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1ncc2c(c1Br)c1cccnc1n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: B1C2CCCC1CCC2
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cc2c(C#N)ncc3c2c2cccnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 65 °C
Yield: 38 %

Procedure:
A mixture of 4-methylene-piperidine-1-carboxylic acid tert-butyl ester (0.70 g, 3.55 mmol) and 9-borabicyclo[3,3,1]nonane (0.5M solution in THF, 7 mL, 3.5 mmol) were heated at reflux for 1.5 h. The reaction mixture was cooled and added to a degassed mixture of 9-benzenesulfonyl-5-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (0.41 g, 1.0 mmol), [1,1-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.090 g, 0.11 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in water (1 mL) and DMF (10 mL) and the reaction mixture was then heated at 65° C. for 1.25 h. After cooling to ambient temperature the reaction mixture was then diluted with water (5 mL) and dichloromethane (10 mL). The aqueous phase was extracted with dichloromethane (2×15 mL) and the combined organic phase was washed with brine (15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with pentane (10 mL) and the resultant material was purified by flash chromatography (silica, 5 g column, SPE-Si II, 0-2% methanol in DCM) to afford title compound as a yellow solid (202 mg, 38%). 1H NMR (CDCl3, 400 MHz): 9.81 (s, 1H), 8.79 (dd, J=4.8, 1.6 Hz, 1H), 8.33-8.27 (m, 3H), 7.66-7.60 (m, 1H), 7.55-7.46 (m, 3H), 4.22-4.01 (m, 2H), 3.34-3.27 (m, 2H), 2.62-2.50 (m, 2H), 1.97-1.76 (m, 2H), 1.72-1.46 (m, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])=[O:17]
Reactant: Cc1ccccc1CO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: Cc1ccccc1COC(=O)CCC(=O)CN
Reaction time: 96 h

Procedure:
From 2-methylbenzyl alcohol (5.0 g; 41 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 4 days at 100° C. The yield was 0.72 g (44%). Mp 107–109° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[N:2]1.S(=O)(=O)(O)O.[CH3:14][CH2:15]O>>[NH:1]1[C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)c1ccn[nH]1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccn[nH]1
Temperature: 80 °C

Procedure:
To 1H-pyrazole-5-carboxylic acid (8.21 g, 73.2 mmol) in EtOH (100 mL) was added concentrated sulfuric acid (21.6 g, 220 mmol). The reaction mixture was heated to 80° C. for 16 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and 2N NaOH aqueous solution was added until pH=8. The phases were separated and the organic phase was washed with saturated NaHCO3 aqueous solution (50 mL) and brine (20 mL), dried (Na2SO4), and concentrated to give the product (6.36 g).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:28]([CH3:29])[CH2:27][CH2:26][C:25]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:24][C:23]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH3:29])[CH2:27][CH2:26][C:25]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([CH2:39][N:40]([CH3:47])[CH:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[CH:37][CH:38]=4)=[O:31])=[CH:24][C:23]=3[CH:48]=2)=[CH:4][CH:5]=1)[CH3:15]
Reactant: CCOCCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
In a mixture of water ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-(3-ethoxypropoxy)phenyl borate (250 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (450 mg). To the solution was added potassium carbonate (308 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (43 mg), and the mixture was refluxed under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25 g, ethyl acetate:ethanol:triethylamine=100:10:1) and recrystallized from ethanol/hexane to give 7-[4-(3-ethoxypropoxy)phenyl]-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 13) (359 mg, 66%) as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([N:48]([CH3:47])[C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=2[O:44][CH2:45][CH3:46])=[O:33])[CH2:35][CH2:36]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CNCc1ccccc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)Cc2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-methylbenzylamine (MCB) to give the title product. LC-MS (ES+) 768 [(M+H)+].