Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13](Br)[CH:14]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:46]=[CH:45][C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[C:30]=2[CH3:44])=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([C:31]3[C:30]([CH3:44])=[C:29]([NH:28][C:26](=[O:27])[C:25]4[CH:24]=[CH:23][C:22]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:46][CH:45]=4)[CH:34]=[CH:33][CH:32]=3)[CH:14]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(N)n2)c1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
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: COCCOC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2cccc(N)n2)c(=O)n(C)c1
Temperature: 95 °C
Yield: 40.4 %

Procedure:
A 48-mL sealed tube equipped with a magnetic stirring bar was charged with 3-(6-amino-pyridin-2-ylamino)-5-bromo-1-methyl-1H-pyridin-2-one (2) (0.054 g, 0.18 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (0.086 g, 0.22 mmol), and Pd(PPh3)4 (0.010 g, 0.010 mmol) in DME (10 mL) and 1N Na2CO3 (5 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (10 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10%, MeOH in dichloromethane/ether (1/1), to afford 0.035 g (40%) of N-{3-[5-(6-amino-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide (3) as a solid; LCMS m/z 482.2018 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:27]([OH:28])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1.[C:29]([O:34]C)(=[O:33])[C@H:30]([CH3:32])O>>[Cl:1][C:2]1[C:27]([O:28][C@H:30]([CH3:32])[C:29]([OH:34])=[O:33])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O)cc12
Reactant: COC(=O)[C@H](C)O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O[C@H](C)C(=O)O)cc12

Procedure:
The phenol from Step 6 (0.38 g, 1.0 mmol) and methyl (S)-lactate (0.16 g, 1.5 mmol) was reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=2[CH3:33])[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=4[CH3:33])[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1C
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: Cc1nccc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)c1C

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K18) (244 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light brown solid (140 mg, 45%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1.[C-]#N.[K+].C(O)C[OH:27]>C(Cl)(Cl)Cl>[OH:27][CH2:21][CH2:20][O:19][C:17]([C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12)=[O:18]
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Reactant: OCCO
Agent: [C-]#N
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CN1Cc2c(C(=O)OCCO)ncn2-c2ccccc2C1=O
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 1.42 g (5 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 100 mg of potassium cyanide and 10 ml of ethyleneglycol is stirred at 130° C. for 6 hours, subsequently diluted with chloroform, washed with water, dried over magnesium sulphate and evaporated. After recrystallisation of the residue from ethyl acetate, there is obtained 2-hydroxyethyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 222°-223° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:31][CH2:30][C:29]1=[O:32]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:31][CH2:30][C:29]4=[O:32])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 35 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (420 mg) described in Preparation Example 112 and 2-azetidinone (70 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (144 mg) was obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18](O)[C:13]=3[C:12]3[CH:22]=[C:23]([F:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>ClC1C=CC=CC=1.ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([Cl:28])[C:13]=3[C:12]3[CH:22]=[C:23]([F:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(F)cnc1n2S(=O)(=O)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: N#Cc1ncc2c(c1Cl)c1cc(F)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A solution of 9-benzenesulfonyl-3-fluoro-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (500 mg, 1.36 mmol) and phosphorus pentachloride (708 mg, 3.4 mmol) in chlorobenzene (1.5 mL) was heated at 110° C. for 1 hour. The reaction mixture was cooled to ambient temperature and then the solvent removed in-vacuo to afford a residue. The resultant residue was dissolved in dichloromethane (50 mL) and then the solution was diluted with ice/water (50 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (50 mL). The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with diethyl ether and dried to afford the title compound as a tan solid (320 mg, 65%). 1H NMR (400 MHz, CDCl3): 9.81 (s, 1H), 8.69 (d, J=2.8 Hz, 1H), 8.50 (dd, J=7.6, 2.8 Hz, 1H), 8.24 (d, J=8.0 Hz, 2H), 7.65 (t, J=7.5 Hz, 1H), 7.53 (t, J=7.8 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14]OS(C)(=O)=O)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][NH2:21].[ClH:22]>>[ClH:22].[CH3:20][NH:21][CH2:14][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1
Reactant: CN
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)C=CCC=C1
Agent: Cl
Product: CNCCC1(c2ccccc2)C=CCC=C1

Procedure:
Methanesulfonic acid 2-(1-phenyl-2,5-cyclohexadien-1-yl)-ethyl ester is reacted with methylamine by an analogous procedure to that described in Example 7. The crude product obtained is converted in the usual manner into the hydrochloride which is recrystallized from isopropanol. There is obtained N-methyl-1-phenyl-2,5-cyclohexadien-1-ethylamine hydrochloride having a melting point of 172°-173° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[N:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:41][S:38]([C:35]3[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=3)(=[O:40])=[O:39])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccncc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccncc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-pyridinesulfonamide (J. Chem. Soc., 1958, 3514: 1H-NMR (CDCl3) δ 8.81 (2H, d, J=5.4 Hz), 7.77 (2H, d, J=5.9 Hz), 7.46-7.18 (9H, m), 6.11 (1H, br.s), 3.44-3.41 (2H, m), 2.84-2.79 (2H, m), 2.31 (3H, s), 2.21 (3H, s).
Reaction SMILES: [C:1](=[O:39])([O:10][CH2:11]/[C:12](/[C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)=[C:13](/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)\[CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9]>C(#N)C.C1(C)C=CC=CC=1>[C:1](=[O:39])([O:10][CH2:11]/[C:12](/[C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:31][CH:30]=1)=[C:13](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)\[CH2:14][OH:15])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCCCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCCBr)=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
To a solution of 24 g of 6-bromohexyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 200 mL of acetonitrile was added 9 mL of PyrHF and the mixture was stirred at 25° C. for 1.5 h. The reaction mixture was diluted with 1 L of toluene, loaded on silica gel and washed with EtOAc. The solvent was evaporated to afford 16.8 g of the titled compound. The crude compound was used directly for the next step.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[Li]CCCC.[Br:25]Br>C1CCCCC1>[Br:25][C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C(O)c1nc(-c2ccccc2)sc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-phenyl-1,3-thiazole-4-carboxylic acid (3.2 g) in abs. THF (190 mL) was added at 78° C. over 10 min n-BuLi (25 mL, 1.6M in hexanes). After addition, Br2 (1.3 mL) in cyclohexane (7.4 mL) was added over 10 min. The reaction mixture was allowed to warm up to RT and was stirred at this temperature for 3 h. The reaction mixture was then cooled to 0° C., carefully quenched with HCl (1M, 32 mL) and extracted with EtOAc (2×). The combined org. phases were washed with aq. sodium thiosulfate (20%), dried over MgSO4 and evaporated to dryness to give 4.5 g of the desired product. The crude was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F-:12].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([F:12])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(Cl)cc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(F)cc1Cl
Temperature: 0 °C
Yield: 68.6 %

Procedure:
A mixture comprising 5.70 g (0.03 mol) of 2,4-dichloro-5-fluorobenzonitrile, 3.48 g (0.06 mol) of spray dried KF and 30 ml of dimethylsulfoxide, was reacted at a temperature of from 140° to 150° C. for 3.5 hours in a glass reactor. After completion of the reaction, the mixture was poured into ice water (50 ml) and extracted with chloroform. The chloroform extract was washed five times with water and then dried. Then chloroform was distilled off. The residue was distilled under reduced pressure to obtain 3.57 g (yield: 68.6%) of 2-chloro-4,5-difluorobenzonitrile. Boiling point: 105°-107° C./37 mmHg; melting point: 35°-37° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:7]=1.C(=O)([O-])O.[Na+].[Cl:35][CH2:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:38](=[O:39])[CH2:37][CH2:36][Cl:35])([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[CH:7]=1
Reactant: O=C(Cl)CCCl
Reactant: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN(C(=O)CCCl)[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine (7.98 g, 16.5 mmol) in a mixture of chloroform (52 ml) and saturated sodium hydrogen carbonate solution (78 ml) was treated dropwise at 0° C. with 3-chloropropanoyl chloride (2.57 g, 19.8 mmol). The reaction mixture was left to warm to room temperature and vigorous stirring continued for 16 hours. For the workup, the layers were separated, the aqueous layer extracted with chloroform (100 ml), thereupon, the combined organic layers dried over sodium sulfate and evaporated at reduced pressure. After chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 60/10 as the eluent, besides recovery of 57% of the starting material, N-[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-3-chloro-N-(4-methoxy-benzyl)-propionamide (intermediate C9A) was obtained as a colourless viscous oil (2.08 g, 22% of theory). MS (ISP): m/z=536.2, 538.3 [M−Cl+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:41][CH:42]([C:48]#[N:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C1COCC1>[C:48]([CH:42]([NH:41][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])#[N:49]
Reactant: O=C(O)c1ccccn1
Reactant: CCOC(=O)C(N)C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C#N)NC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
To a solution of picolinic acid (1.23 g, 10 mmol), EDC.HCl (1.91 g, 10 mmol) and HOBT (1.35 g, 10 mmol) in THF (80 mL) was added DIPEA (3.6 g, 30 mmol) at ambient temperature. The reaction mixture was maintained at the same temperature for 1 hr at which time a solution of ethyl 2-amino-2-cyanoacetate (1.28 g, 10 mmol) in THF (5 mL) was added. The reaction mixture was stirred at ambient temperature for additional 6 hr. It was then concentrated, and the residue was purified by silica gel column chromatography (5:1 PE/EtOAc) to give ethyl 2-cyano-2-(picolinamido)acetate (0.7 g, 30%) as yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]([F:15])([F:14])[F:13])[N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[F:13][C:12]([F:15])([F:14])[C:9]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[NH:11][NH:10]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(F)(F)C1(c2cccc(CBr)c2)N=N1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(C2(C(F)(F)F)NN2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of intermediate 64, 3-(3-bromomethyl-phenyl)-3-trifluoromethyl-3H-diazirine, (140 mg, 0.5 mmol) and potassium phthalimide (95 mg, 0.5 mmol) in dimethylformamide (1.5 mL) was stirred at room temperature for 3 hrs. Dimethylformamide was removed in vacuo. The residue was extracted with CH2Cl2, washed with water, then dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, 1:1 CH2Cl2/pentane) to provide 140 mg (Yield 82%) of the title compound as a solid; 1H NMR (300 MHz, CDCl3) δ ppm: 4.80 (2 H, s) 7.09-7.21 (2 H, m) 7.32 (1 H, t, J=7.9 Hz) 7.41-7.49 (2 H, m) 7.66-7.71 (2 H, m) 7.81-7.85 (2 H, m); LC/MS m/z 346 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.OO.C([O-])([O-])=[O:12].[K+].[K+]>C(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:12])[CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 50 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of 5-bromo-2-methyl-pyridine (1.47 g, 8.54 mmol) in CH2Cl2 (5 mL) was treated with a cold solution of 30% hydrogen peroxide (4.6 mL) in acetic acid (13.8 mL) at 0° C. The reaction mixture was stirred at 50° C. for 18 h and poured into ice water (5 mL). The resulting mixture was adjusted to pH=9 by addition of K2CO3. The mixture was stirred at rt for 15 min and diluted with CH2Cl2 (10 mL). The aqueous layer was extracted three times with CH2Cl2. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 5-bromo-2-methyl-pyridine N-oxide as a white solid (1.6 g, 99%) which was used without further purification.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)=[CH:7][C:6]=1[CH3:31].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:52]>CN(C=O)C>[Br:52][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)=[CH:7][C:6]=1[CH3:31]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one (0.73 g, 1.70 mmol) in DMF (10 mL) were added PPh3 (0.49 g, 1.87 mmol) and CBr4 (0.62 g, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solid was dried and purified by the Simpliflash system (2% methanol in CH2Cl2 as eluent) to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one as a white solid. Yield: 0.39 g (47%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]([CH2:27][CH3:28])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:25]([O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:29])([CH2:27][CH3:28])[CH3:26]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)CC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)Oc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
The mixture of 2-(2-sec-butoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (12) (176 mg, 0.44 mmol) and KOH (500 mg, 8.93 mmol) is dissolved in EtOH (6 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (13) as white solid (162 mg, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH:3]=[N:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].CC(C)(C)C(=O)[C:18]([OH:20])=[O:19]>C(OCC)C>[CH3:14][C:2]([CH3:13])([CH3:1])[C:3](=[N:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)C(=O)C(=O)O
Reactant: C[C@H](N=CC(C)(C)C)c1ccccc1
Solvent: CCOCC
Product: C[C@H](N=C(C(=O)O)C(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 81.2 %

Procedure:
8.9 g (47 mmol) of (S)-(2,2-dimethylpropylidene)-(1-phenylethyl)-amine (J. L. Fauchure, C. Petermann, Helv. Chim. Acta 1980, 63, 824) were dissolved in 10 ml of diethyl ether with the exclusion of moisture. 8.1 g (50 mmol) of trimethylpyruvic acid in 10 ml of diethyl ether were added dropwise to this solution while cooling with ice. Subsequently, the mixture was stirred at 0° C. for a further 2 hours and at room temperature for 6 hours. Colorless crystals form over 2 days and these were suspended in 50 ml of diethyl ether, filtered off and washed twice with 5 ml of diethyl ether each time. After drying in a vacuum there were obtained 8.9 g (81%) of (S)-3,3-dimethyl-2-(1-phenylethylimino)-butyric acid (internal salt) of melting point 135°-136° C. [α]=-14.4 (c=0.16, CH2Cl2).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:6]2.C(O)C>[Pd].O1CCCC1>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[O:13][C:12]([C:10]([N:5]3[CH2:6][CH:7]4[N:2]([CH3:1])[CH:3]([CH2:9][CH2:8]4)[CH2:4]3)=[O:11])=[CH:16][CH:15]=2)=[CH:18][CH:19]=1
Reactant: CN1C2CCC1CN(C(=O)c1ccc(-c3ccc([N+](=O)[O-])cc3)o1)C2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1C2CCC1CN(C(=O)c1ccc(-c3ccc(N)cc3)o1)C2

Procedure:
A mixture of (8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-[5-(4-nitro-phenyl)-furan-2-yl]-methanone free base, palladium on carbon (5%, 0.60 g), ethanol (20 ml) and tetrahydrofuran (20 ml) was stirred under hydrogen (530 ml). The crude mixture was purified by chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as a solid. Mp. 189.7-191.3° C. Yield 1.68 (65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][CH2:27][CH2:26]1>>[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([CH:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]([CH3:19])[CH2:10]2)[CH2:27][CH2:26]1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: c1ccc2c(c1)NCCO2
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCOc4ccccc43)CC2C)cc1OC
Yield: 59 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 3,4-dihydro-2H-1,4-benzoxazine (495 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (320 mg, yield: 59%) as a colorless oil. (cis:trans=1:2.3)