Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1.CCN(CC)CC>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.CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:37]5[CH:36]=[N:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cn1
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2cnc3sc(-c4ccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c(OC)c4)nn23)cn1
Temperature: 120 °C
Yield: 13.2 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.169 mmol, 1 eq), 2-methoxy-5-pyridineboronic acid (39 mg, 0.253 mmol, 1.5 eq), EtOH (5 ml), Et3N (0.070 ml, 0.507 mmol, 3 eq) and Pd(PPh3)2Cl2 (12 mg, 0.0169 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). The solvents were removed under reduced pressure and the residue was treated with Et2O. The filtrate was evaporated and the residue was purified by HPLC to give the desired product (12 mg; 13%) as a colourless oil. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.30 min, [M+H]+ m/z 538.3; 1H NMR (300 MHz, CD3COCD3) δ 8.87 (m, 1H), 8.28 (dd, J=8.7, 2.5 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J=2.1 Hz, 1H), 7.54 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.89 (dd, J=8.7, 0.7 Hz, 1H), 4.71 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.75 (m, 2H), 3.32 (m, 2H), 1.98 (m, 2H), 1.70 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](O)[CH2:9][CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)O)=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O.[C:33]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][CH2:10][C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:41]2[C:40]2[CH:42]=[CH:43][C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:38][CH:39]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O[C@H](CC[C@@H](O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2[C@H](c3ccc(Br)cc3)CC[C@H]2c2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of the product from Example 69A (0.60 g, 1.500 mmol) in anhydrous CH2Cl2 (15 mL) at 0° C. was added Et3N (0.627 mL, 4.50 mmol), and the resulting mixture was stirred at 0° C. for 10 min until a homogenous solution was obtained. To the cooled solution was added methanesulfonyl chloride (0.292 mL, 3.75 mmol) dropwise, and the resulting mixture was stirred at 0° C. for 1.5 h until the reaction was complete as determined by TLC (1:1 EtOAc:hexanes). Solvent was removed in vacuo to give a solid, which was dried in vacuo. The solid was dissolved in anhydrous DMF (5 mL), and 4-tert-butylaniline (2.39 mL, 15 mmol) was added. The resulting mixture was stirred at 40° C. for 4 h and then was partitioned between 1N aq. HCl (30 mL) and EtOAc (30 mL). The organic layer was washed with H2O and dried over Na2SO4. The drying agent was filtered off, the solvent was removed in vacuo, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-20% EtOAc in hexanes. The title compound was obtained as a colorless solid (0.71 g, 92%). 1H NMR indicated this material was a 87:13 mixture of trans:cis pyrrolidine isomers.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:11][Si:12]([CH3:15])(O)O.N(CCO)(CCO)CCO>C(O)CCCO>[C:1]([O:10][SiH:12]([CH3:15])[CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: C[Si](C)(O)O
Solvent: OCCN(CCO)CCO
Solvent: OCCCCO
Product: C[SiH](C)OC(=O)c1ccccc1O

Procedure:
Capillisil is available from Exsymol S.A.M. of Monaco and is a 20% solution of dimethylsilanediol salicylate in butylene glycol with triethanolamine. It is obtained by mild hydrolysis of dimethylsilyl salicylate.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[Cl:1][CH2:2][C:3]([C:20]1[CH:21]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[F:22])([OH:14])[CH:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: Fc1ccc(F)c([Mg]Br)c1
Reactant: C[C@@H](COC(=O)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(COC(=O)C(C)(C)C)C(O)(CCl)c1cc(F)ccc1F
Reaction time: 0.08 h

Procedure:
A solution of 0.66 g (3.0 mmol) of (S)-1-chloro-3-methyl-4-pivaloyloxybutan-2-one in 4 mL of THF was cooled to 0° C., and 3.9 mL (3.3 mmol) of a 0.86 M solution of 2,5-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 5 minutes. After the completion of the dropwise addition, stirring was continued for another 1 hour, 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.50 g of 1-chloro-2-(2,5-difluorophenyl)-3-methyl-4-pivaloyloxybutan-2-ol as a diastereomeric mixture (yield: 50%) ((2S,3S):(2R,3S)=72:28) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=6/4, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 18 minutes (2S,3S), 20 minutes (2R,3S)). The resulting compound was dissolved in 10 mL of THF, and 1.02 g (5.25 mmol) of a 28% solution of NaOMe in methanol was added thereto under ice cooling. The reaction was performed for 5 hours. A reaction product was extracted with ethyl acetate (10 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.28 g of the title compound (yield: 88%) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=3/7, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 17 minutes (2R,3S), 18 minutes (2S,3S)). 1H-NMR (400 MHz, CDCl3) (2R,3S) δ: 0.97 (d, 3H, J=6.6 Hz), 2.25 (q, 1H, J=6.6 Hz), 2.88 (d, 1H, J=4.4 Hz), 3.21 (d, 1H, J=4.4 Hz), 3.51 (d, 2H, J=6.1 Hz), 6.99-7.01 (m, 2H), 7.13-7.17 (m, 1H); (2S,3S) δ: 1.27 (d, 3H, J=6.6 Hz), 2.14 (q, 1H, J=6.6 Hz), 2.83 (d, 2H, J=4.4 Hz), 3.17 (d, 1H, J=4.4 Hz), 3.60 (d, 2H, J=5.9 Hz), 6.99-7.01 (m, 2H), 7.13-7.17 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([C:22]#[CH:23])[CH:9]=1)(=[O:5])=[O:4].CC(C)([O-])C.[K+].O.CCCCCCC>CN1CCCC1=O>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:23]=[CH:22]2)(=[O:4])=[O:5]
Reactant: C#Cc1cc(CCS(=O)(=O)NC)ccc1NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: O
Solvent: CN1CCCC1=O
Product: CNS(=O)(=O)CCc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 82.5 °C
Reaction time: 0.5 h

Procedure:
2-(4-benzylamino-3-ethynyl-phenyl)-ethanesulfonic acid methylamide (100 g) was dissolved in N-methylpyrrolidone (1500 ml) at 25° C. Potassium tert-butoxide (67 g) was added and the reaction mass was heated to 80-85° C. for 120-150 minutes. The reaction mass was cooled gradually to 25° C., water (3500 ml) was added and stirred for 30 minutes. The solution was extracted with ethyl acetate (4000 ml). The organic layer was dried over sodium sulfate and distilled under vacuum to obtain a residue. The residue was treated with heptane (500 ml) to obtain a solid which was filtered, washed with heptane and dried at 50-55° C. under vacuum to obtain the title compound. (Yield: 76 g, HPLC Purity: 98%)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([N+:29]([O-])=O)=[CH:4][N:3]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([NH2:29])=[CH:4][N:3]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3c(C)sc4c([N+](=O)[O-])cnc(N)c34)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(-c3c(C)sc4c(N)cnc(N)c34)cc2)c1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A suspension of Example 66E (0.44 g, 1.01 mmol), NH4Cl (0.054 g, 1.01 mmol), and iron powder (0.45 g, 8.1 mmol) in ethanol (16 mL) and water (4 mL) was heated at 80° C. for 3 hours, cooled to room temperature, and filtered through diatomaceous earth (Celite®). The pad was washed with ethyl acetate and ethanol and the filtrate was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 0.15 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.29 (s, 3H), 4.48 (s, 2H), 4.59 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25-7.29 (m, 3H), 7.30 (s, 1H), 7.31 (s, 1H), 7.60 (d, J=8.81 Hz, 2H), 8.67 (s, 1H), 8.86 (s, 1H); MS (ESI(+)) m/e 404 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=1)#[N:2].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>CO.[Ni]>[C:23]([O:22][C:20]([NH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=1)=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2ccccc2C#N)s1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)c1ccc(-c2ccccc2CNC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a slurry of ethyl 5-(2-cyanophenyl)thiophene-2-carboxylate (1.09 gm 4.24 mmol) in MeOH (8 mL) was added (BOC)2O (1.11 g, 5.08 mmol) and Raney Nickel (3.6 mL). The reaction mixture was allowed to stir at rt under an atmosphere of hydrogen overnight and then filtered through celite. The filtrate was concentrated and the residue was purified by column chromatography to give ethyl 5-(2-{[(tert-butoxycarbonyl)-amino]methyl}phenyl)thiophene-2-carboxylate (1.32 g, 86%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]([C:26]2[CH:35]=[C:34]([O:36][CH3:37])[C:29]3[O:30][CH2:31][CH2:32]O[C:28]=3[C:27]=2[F:38])[C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:22]=[CH:21][S:20][C:19]=3[C:23]([OH:25])=[O:24])[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].COC(=O)N=C(SC)C(=NC1C=CC(C#N)=CC=1)C1C=C(OC)C2OCCC=2C=1F>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@@H:11]([C:26]2[CH:35]=[C:34]([O:36][CH3:37])[C:29]3[O:30][CH2:31][CH2:32][C:28]=3[C:27]=2[F:38])[C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:22]=[CH:21][S:20][C:19]=3[C:23]([OH:25])=[O:24])[N:13]=2)=[CH:8][CH:9]=1)(=[NH:3])[NH2:2]
Reactant: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCO2
Agent: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)c2c(c1F)CCO2
Product: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCC2

Procedure:
The same procedure was carried out as in Examples (168b) to (168d), except that [2-(4-cyanophenylimino)-2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (161b)) was used instead of [2-(4-cyanophenylimino)-2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-methylsulfanylethylidene]carbamic acid methyl ester in Example (168b), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]6[O:30][CH2:31][C:32]([CH3:35])([CH3:34])[N:33]=6)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:36])=[CH:6][C:5]=12.C(C1C=C(NC(NC(C)(C)CO)=[S:47])C=CC=1/N=C/N(C)C)#N.N1C=NN2C=CC(OC3C=CC(N)=CC=3C)=CC=12>C(OC(C)C)(=O)C.C(O)(=O)C>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([NH:33][C:32]([CH3:35])([CH3:34])[CH2:31][OH:30])=[S:47])[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:36])=[CH:6][C:5]=12
Reactant: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(C)CO4)cc23)ccc1Oc1ccn2ncnc2c1
Reactant: CN(C)/C=N/c1ccc(NC(=S)NC(C)(C)CO)cc1C#N
Agent: Cc1cc(N)ccc1Oc1ccn2ncnc2c1
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)O
Product: Cc1cc(Nc2ncnc3ccc(NC(=S)NC(C)(C)CO)cc23)ccc1Oc1ccn2ncnc2c1

Procedure:
The synthesis of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described in WO 2007/059257. Generally, N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine may be prepared by coupling (E)-N′-(2-cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido)phenyl)-N,N-dimethylformimidamide with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in isopropyl acetate:acetic acid (65:35 v/v) at 45° C. to yield 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea. The 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea may then be agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the addition of p-toluenesulfonyl chloride. Water may then be charged to yield N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine as a mixture of polymorphs (generally a mixture containing one or more of Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P). The final crystallizations or isolations will determine the polymorphic form, which are further detailed in the Examples section.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:5]=3[N:4]([CH3:20])[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: Cc1cccc2c1N(C)C(=O)C(N)N=C2c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3)c3cccc(C)c3N(C)C2=O)c1
Reaction time: 0.33 h

Procedure:
Equimolar amounts of 3-(R,S)-amino-1,3-dihydro-1,9-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 3-methoxyphenylisocyanate and triethylamine were mixed in THF at 0° C. and stirred 20 minutes. Removal of THF in vacuo, dissolution of the residue in CH2Cl2 and flash chromatography on silica gel (12% Et2O in CH2Cl2) gave the title compound which was crystallized as a white fluffy solid from Et2O: m.p. 215°-217° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]=1[C:20](O)=[O:21].C(OCC)(=O)C.O>O1CCCC1>[CH3:7][C:8]1[C:9]([CH2:20][OH:21])=[C:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(-c2ccccc2)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.6 %

Procedure:
To an ice-cooling suspension of lithium aluminium hydride (1.79 g) in tetrahydrofuran (50 ml) was added dropwise a solution of 4,-methylbiphenyl-2-carboxylic acid (5.0 g) in tetrahydrofuran (30 ml). The mixture was stirred for 17 hours at room temperature. To the reaction mixture were added ethyl acetate (10 ml) and water (50 ml), and insoluble materials were removed by filtration through celite. The filtrate was concentrated to dryness, and the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel to afford the title compound as colorless syrup (3.95 g, 84%).
Reaction SMILES: CC1C=CC(S([O:11][C@H:12]2[CH2:15][C@@H:14]([C:16]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[O:17])[CH2:13]2)(=O)=O)=CC=1.[C:29]([O-])(=[O:31])[CH3:30].[K+]>CN(C=O)C.C(Cl)Cl>[C:29]([O:11][C@H:12]1[CH2:13][C@H:14]([C:16]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([CH:25]3[CH2:26][CH2:27][CH2:28]3)[CH2:20][CH2:19]2)=[O:17])[CH2:15]1)(=[O:31])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1C[C@H](C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 110 °C

Procedure:
To a stirred solution cis-3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutyl 4-methylbenzenesulfonate (73 mg, 0.18 mmol) in DMF (3 ml) at RT was added potassium acetate (108 mg, 1.1 mmol). The mixture was heated at 110° C. overnight and then cooled to RT and diluted with DCM. The resulting mixture was washed with 1:1 H2O/brine and the organic phase dried (Na2SO4), filtered and concentrated at reduced pressure to yield the title compound (50 mg, 94%), which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.O.CO>C(O)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: BrBr
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)cc(C(=O)O)c1O
Reaction time: 24 h

Procedure:
To a mixture of 2-hydroxy-3-methylbenzoic acid (2.1 g, 13.5 mmol) in acetic acid (30 mL) was added bromine (0.7 mL, 13.7 mmol) slowly over 5 minutes. After 24 h, water was added slowly to the reaction mixture and the reaction stirred for 30 min. The resulting precipitate was collected by filtration and washed several times with water. The product was dried overnight under high vacuum to afford 2.8 g (90%). LC/MS: tR=2.86 min, 229.14 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-phenylacetamide (0.052 g, 0.12 mmol), ethanol (3.5 ml), and 4-dimethylaminobenzaldehyde (0.025 g, 0.17 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 50% dichloromethane in ethyl acetate and then 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.011 g, 17%); 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 2.99 (s, 6H, N(CH3)2), 3.23 (s, 2H, NCH2CO), 3.71 (br s, 4H, piperazine N(CH2)2), 6.81 (d, J=9.15 Hz, 2H, 3,5-C6H4NMe2 or 2,6-C6H4—NMe2), 7.06 (t, J=7.52 Hz, 1H, p-ArH), 7.32 (t, J=7.52 Hz, 2H, m-ArH), 7.68 (d, J=7.52 Hz, 2H, o-ArH), 8.02 (d, J=8.90 Hz, 2H, 3,5-C6H4NMe2 or 2,6-C6H4—NMe2), 8.16 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.82 (s, 1H, CONH), 13.20 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20](F)=[C:19]([O:27][CH2:28][CH3:29])[CH:18]=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1.C(OC1C=C(C=C(OCC)C=1[N:47]1[CH:51]=[CH:50][CH:49]=[CH:48]1)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20]([N:47]4[CH:51]=[CH:50][CH:49]=[CH:48]4)=[C:19]([O:27][CH2:28][CH3:29])[CH:18]=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1F
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), 5-methoxy-N-piperidin-4-yl-isophthalamic acid methyl ester (example 143) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 536.5 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH:9]=[CH:8]2.[H][H].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.CN(C=O)C>[CH2:25]([O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:10]2[CH:9]=[CH:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=3)[CH:11]=2)=[CH:17][CH:18]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc2cc(Nc3ccc(O)cc3)ccc2c1
Reactant: [H][H]
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(Nc3ccc(OCc4ccccc4)cc3)ccc2c1
Yield: 97.1 %

Procedure:
The oil was removed from 100 mg (50% in oil, 2.1 mmol, Alfa) of sodium hydride dispersion by washing with three portions of petroleum ether then the residue was covered with 10 ml of dry THF. A total of 530 mg (2.00 mmol) of 4-[(6-methoxy-2-naphthyl)amino]phenol (prepared as described in Example 2) was added to the resulting mixture in several portions. The deep purple reaction mixture was stirred for an additional 10 minutes until hydrogen evolution ceased then 1 ml of sieve-dried DMF was added, followed by 240 ul (2.02 mmol, Aldrich) of benzyl bromide. The solution was heated to 50° for 1 hour, cooled, added to 50 ml of H2O and extracted with 50 ml of ethyl acetate. The organic extract was washed with two additional portions of H2O, dried (MgSO4) and concentrated in vacuo to give 690 mg (97%) of crude title compound as a lavender solid, m.p. 155°-157°.