Azzindani/Open_Reaction_Data huggingface dataset:
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[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([OH:33])=O)=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41][CH2:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1.ON1C2C=CC=CC=2N=N1.[Cl-].C(N=C=NCCCN(C)C)C>CN(C=O)C.O.C(N(CC)CC)C>[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[N:24]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:47][C:46]4[CH:45]=[CH:44][C:43]([CH2:42][S:41][C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=5)=[CH:49][CH:48]=4)=[O:33])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: Nc1ccc(CSc2ccccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.50 g) was dissolved in DMF (10 ml), 4-[(2-pyridinylsulfanyl)methyl]aniline (272 mg) and 1-hydroxybenzotriazole (321 mg) were added to the mixture, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chloride (401 mg) and triethylamine (0.44 ml) were added to the mixture, and the mixture was stirred for 16 hours at room temperature. The reaction solution was added to water, and 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 obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 199) (0.36 g).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.B(O)O.[C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+]>>[C:26]([O:25][C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:34][CH:33]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1
Reactant: CCOC(=O)CCCNc1ccc2ncc(Br)n2n1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [K+]
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cnc3ccc(NCCCC(=O)O)nn23)cc1

Procedure:
The ethyl 4-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)butanoate was subjected to Suzuki coupling with N-Boc-benzyl amine boronic acid, using 4.0 equivalents of K2CO3 as the base and procedure described in example 5.6.19 to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].S(=O)(=O)(O)O.[NH4+].[OH-].C(Cl)Cl.[CH2:33](O)[CH3:34]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][CH2:33][CH3:34])=[O:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:20])[F:21]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)acetic acid (3 g, 5.61 mmol) in ethanol (30 mL) was added sulfuric acid (8 mL, 150 mmol) in ethanol (30 mL). The reaction mixture was stirred at 80° C. for 2 hr. Then 30 mL of 25% aqueous NH4OH solution and 50 mL CH2Cl2 were added to the reaction mixture. The organic layer was separated and dried over Na2SO4, and concentrated under reduced pressure to provide ethyl 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)acetate (2 g, 79%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=1.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCCC1>[Cl:9][C:10]1[C:15]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:27])=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]=1
Reactant: O=Cc1ccccc1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Lithium diisopropylamide (3.7 mL, 1.8 M tetrahydrofuran solution, manufactured by Tokyo Chemical Industry Co., Ltd.) was added to a solution of 2-chloro-6-(trifluoromethyl)pyridine (1.0 g, manufactured by Matrix Chemical LLC) in tetrahydrofuran (55 mL, manufactured by Kanto Chemical Co., Inc.) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. Then, benzaldehyde (1.17 g, manufactured by Kokusan Chemical Co., Ltd.) was added thereto at −78° C., and the mixture was stirred overnight while gradually raising the temperature to room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×10 mL), washed with brine (20 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=9:1), to give 1.58 g of the title compound. LC-MS: HPLC retention time 1.68 minutes, m/z 288 (M+H), condition C-1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([NH:18][CH2:19][C:20]1[N:25]=[CH:24][C:23]2[CH2:26][CH:27]([NH:29]C(=O)OC(C)(C)C)[CH2:28][C:22]=2[CH:21]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH2:29][CH:27]1[CH2:26][C:23]2[CH:24]=[N:25][C:20]([CH2:19][NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:21][C:22]=2[CH2:28]1
Reactant: CC(C)(C)OC(=O)NC1Cc2cnc(CNC(=O)OCc3ccccc3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2cnc(CNC(=O)OCc3ccccc3)cc2C1
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (25 ml) was added to t-butyl [6,7-dihydro-3-[[benzyloxycarbonyl]aminomethyl]-5H-cyclopenta[c]pyridin-6-yl]carbamate (55, 4.45 g, 11.2 mmol) at room temperature, and the mixture was stirred for 20 minutes. Excess trifluoroacetic acid was removed under vacuum, and the residue was partitioned between 1:1 tetrahydrofuran/diethylether and 5% sodium hydroxide solution. The aqueous solution was extracted twice more with 1:1 tetrahydrofuran/diethylether, and the combined extracts were washed with brine and dried (Na2SO4). The solvent was removed under vacuum to leave phenylmethyl [[6-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl]methyl]carbamate as an amber oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 84.3 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 4.97 mg (0.0458 mMol) ethyl chloroformate, 11.1 mg (84%) of the title compound were recovered.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[C:6]([OH:10])(=O)[CH:7]=[CH2:8].[C:11](O)(=[O:14])C=C.C(C(CO)(CO)CC)O.C(C1C=C(CC)C2SC3C(=CC=CC=3)C(=O)C=2C=1)C>C(O)C>[CH3:11][O:14][CH:7]([CH2:6][O:10][CH:2]([CH2:1][OH:5])[CH3:3])[CH3:8]
Reactant: C=CC(=O)O
Agent: CCC(CO)(CO)CO
Agent: CCc1cc(CC)c2sc3ccccc3c(=O)c2c1
Solvent: CCO
Product: COC(C)COC(C)CO
Yield: 39.4 %

Procedure:
A slurry obtained by mixing 37.7 g of a borosilicate glass powder, 24.9 g of alumina powder, 6.2 g of an acrylic organic binder containing hydroxyl groups, 3.1 g of ethanol, 3.0 g of trimethylolpropane triacrylate, 1.2 g of 2-methyl-1-[4-(methylthio)phenyl]2-morphorinopropane-1-on, 0.3 g of 2,4-diethylthioxanthone and 0.5 g of dipropyleneglycol monomethyl ether was formed into a sheet by the doctor blade method. The sheet was dried at 100° C. to obtain a photosensitive insulating ceramic green sheet with a thickness of 30 μm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:40])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][C:21]=3[O:35][CH2:36][C:37]([OH:39])=[O:38])[C:6]3=[C:7]([C:11]([OH:13])=[O:12])[NH:8][C:9]([CH:10]=1)=[C:5]23>O1CCOCC1.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:40])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=3[O:35][CH2:36][C:37]([OH:39])=[O:38])[C:6]3=[C:7]([C:11]([OH:13])=[O:12])[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CC2CCc3cc(Cl)cc4[nH]c(C(=O)O)c2c34)c(OCC(=O)O)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(NC(=O)CC2CCc3cc(Cl)cc4[nH]c(C(=O)O)c2c34)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 123.8 %

Procedure:
A solution of 7-chloro-3-[p-tert-butoxycarbonylaminomethyl-o-(carboxymethoxy)phenylcarbamoylmethyl]-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acid acid (189 mg)in a mixture of 1,4-dioxane (4 mL) and 4N HCl in 1,4-dioxane (4 mL) was Stirred for 20 h at room temperature and concentrated in vacuo. The residual solid was rinsed with THF and dried in vacuo to give 104 mg of the title compound (47%): 1H NMR (DMSO-d6) δ13.05 (br, 2H), 11.45 (s, 1H), 9.24 (s, 1H), 830 (br, 3H), 8.04 (d, 1H, J=8.3 Hz), 7.20 (s, 1H), 7.16 (s, 1H), 7.06 (d, 1H, J=8.3 Hz), 6.84 (s, 1H), 4.74 (s, 2H), 3.90 ~3.95 (m,3H), 3.09 (m, 1H), 2.78 (m1H), 2.69 (m, 2H), 2.08 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([NH:14][CH3:15])=[CH:7][C:6]=1[F:16])[CH3:2]>[Ni].C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:14][CH3:15])=[CH:7][C:6]=1[F:16])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)c(NC)cc1F

Procedure:
Prepared analogously to example 14b by hydrogenation of 2-fluoro-4-methylamino-5-nitro-benzoic acid ethyl ester using Raney nickel in THF.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])(=[O:13])=[O:12].C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O>CS(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:14][CH2:15][CH2:16][CH:17]=[O:18])(=[O:13])=[O:12]
Reactant: O=S(=O)(CCCCO)c1ccc2ccccc2c1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCCCS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of the product of step c (524 mg, 1.98 mmol) and triethylamine (0.829 ml, 5.96 mmol) in DMSO (10 ml) was added a solution of sulfur trioxide-pyridine (948 mg, 5.96 mmol) in DMSO (10 ml) and the reaction mixture stirred at ambient temperature for 15 minutes. The reaction mixture was poured into ice-water (150 ml) and then extracted thrice with ethyl acetate (60 ml). The combined organic phases were washed with aqueous citric acid (70 ml) and brine (70 ml), then dried over anhydrous sodium sulfate. The filtrate was evaporated at reduced pressure and the residue purified by flash column chromatography (2:1 ethyl acetate:hexane) to afford the title compound (457 mg, 88%). 1H NMR 9.75 (1H, s), 8.50 (1H, s), 8.05-7.65 (6H, m), 3.26-3.22 (2H, m), 2.71 (2H, t, 6.9), 2.15-2.04 (2H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[C:15]([C:17]1[CH:18]=[C:19]([S:24]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1F)#[N:16].Cl>CN(C=O)C>[C:15]([C:17]1[CH:18]=[C:19]([S:24]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])#[N:16]
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reactant: Oc1ccccc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccccc1I
Temperature: 80 °C
Yield: 88.7 %

Procedure:
To a solution of 2-iodophenol (6.0 mmol, 1320 mg) and K2CO3 (10.5 mmol, 1450 mg) in DMF (15.0 mL) was added 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65, 4.5 mmol, 1280 mg). The reaction mixture was heated at 80° C. for 24 hours. The reaction was cooled to room temperature and the mixture was poured into 1 N aqueous HCl (100 mL) to obtain a white solid. The afforded solid was washed with heptane and the solid was dried in vacuo to furnish 1.932 g of the title compound. LCMS Rt=1.67 minutes MS m/z 485 [MH]+
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)(Cl)Cl>[C:1]1([CH:7]([CH3:11])[C:8]([Cl:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C(=O)Cl)c1ccccc1

Procedure:
(±)-2-Phenylpropionic acid in the amount of 7.50 g (50 mmol) and 7.14 g (60 mmol) of thionyl chloride were heated for 1 hour under reflux in carbon tetrachloride. The solvent and unaltered thionyl chloride were evaporated under reduced pressure to give (±)-2-phenylpropionic acid chloride as a pale yellow oil. To the oil were added 30 ml of benzene, 7.30 g (52.5 mmol) of p-nitrophenol and 4.75 g (60.0 mmol) of pyridine were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with 10 ml of aqueous 10% hydrochloric acid, extracted with ethyl acetate, followed by solvent evaporation from the organic layer, to obtain 13.9 g of a pale yellow solid. Recrystallization of the solid from ethanol gave 10.4 g (38.4 mmol, yield 77%) of (±)-p-nitrophenyl 2-phenylpropionate as colorless crystals.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[NH:6][C:7]([CH3:31])=[C:8]([C:24]([O:26][CH2:27][CH2:28][CH2:29]Cl)=[O:25])[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]>CS(C)=O>[CH3:4][C:5]1[NH:6][C:7]([CH3:31])=[C:8]([C:24]([O:26][CH2:27][CH2:28][CH2:29][C:1]#[N:2])=[O:25])[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCl)C1c1ccccc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCC#N)C1c1ccccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 67.6 %

Procedure:
0.55 g (11 mmol) of sodium cyanide in 15 ml of dimethylsulphoxide are added dropwise at a reaction temperature of 60° C. to a solution of 4.09 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(3-chloropropoxy)carbonyl-pyridine in 10 ml of dimethylsulphoxide. The reaction mixture is then stirred for 2.5 hours at 120° C. and is poured into 150 ml of ice water after it has cooled down. The mixture is extracted with 3×50 ml of ethyl acetate. After dehydration and concentration of the organic phases by evaporation under vacuum, 5.7 g of a brown oil are obtained. This oil is chromatographed on silica gel with dichloromethane/methanol (99:1). After concentration by evaporation under vacuum and recrystallisation of the residue from methanol, the main fraction yields 2.7 g (68%) of yellow crystals, melting point 48°-51° C.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)([NH:16][C:17]2[CH2:18][O:19][CH2:20][C:21]([F:42])([F:41])[C@:22]([C:25]3[CH:26]=[C:27]([NH:32][C:33]4[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=4)[CH:28]=[CH:29][C:30]=3[F:31])([CH3:24])[N:23]=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[NH2:16][C:17]1[CH2:18][O:19][CH2:20][C:21]([F:41])([F:42])[C@:22]([C:25]2[CH:26]=[C:27]([NH:32][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[CH:28]=[CH:29][C:30]=2[F:31])([CH3:24])[N:23]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccc(C#N)cc4)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(c2cc(Nc3ccc(C#N)cc3)ccc2F)N=C(N)COCC1(F)F
Temperature: 23 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of (R)-4-(3-(3-(bis(4-methoxyphenyl)(phenyl)methylamino)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenylamino)benzonitrile (intermediate A13A) (21 mg, 31 μmol) in dichloromethane (1 ml) at 23° C. was added trifluoroacetic acid (370 mg, 250 μl, 3.24 mmol) and the mixture was stirred at 23° C. for 1 h. Poured into sat. Na2CO3-sol., extracted thrice with ethyl acetate, dried the combined organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by preparative HPLC (column: Gemini 5μ C18 110 A° AXIA (50×21.2 mm); flow: 40 ml/min; gradient: water (+0.1% TEA)/acetonitrile (90%-10% 1 min plateau; in 3.5 min to 5%-95%); collection: UV-detector 300 nm) to give the title compound (8.9 mg, 76.6%) after trituration with little diethyl ether/pentane as a white solid. MS (ISP): m/z=375.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:37]1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:37]3[S:38][C:39]4[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=4[N:41]=3)[CH2:14][C@H:13]2[NH:25][CH:26]2[CH2:27][CH2:28]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC2CC2)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC4CC4)C3)sc12
Yield: 71.9 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(cyclopropylamino)piperidine-1-carboxylate obtained in Example (213a) (32.0 mg, 0.078 mmol), 4 N hydrochloric acid-1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (24 mg, 0.085 mmol) and sodium carbonate (82 mg, 0.777 mmol), to obtain 29 mg of the title compound (72%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: OCc1ccc(F)c(Cl)c1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3ccc(F)c(Cl)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3-chloro-4-fluorophenyl)methanol and 7-chloro-1,2-dimethyl-2,3-dihydro imidazo[1,2-c]pyrimidin5(1H)-one.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[C:26]([C:29]1[S:33][C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[N:31][C:30]=1[CH3:44])(=[O:28])[CH3:27].C(N(CC)CC)C.O>CS(C)=O>[C:26]([C:29]1[S:33][C:32]([NH:34][C:35]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:36])=[N:31][C:30]=1[CH3:44])(=[O:28])[CH3:27]
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)c1sc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)nc1C
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine hydrochloride (0.100 g; Example 1a, Step 5), phenyl 5-acetyl-4-methylthiazol-2-ylcarbamate (0.089 g, 1.2 equiv), and triethylamine (0.045 mL, 1.2 equiv) in dimethyl sulfoxide (1 mL, 0.3 M) was heated to 65° C. for 2 h. The reaction was cooled to room temperature. Water was added and then the solution was extracted with ethyl acetate (2×). The organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a 12 g silica gel column using 10-30% ethyl acetate/dichloromethane over 20 minutes as the eluent to give the title compound as a light yellow foam. 0.065 g, 47% yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.44-2.54 (5H, m), 2.61 (2H, t, J=5.7 Hz), 2.66 (3H, s), 3.63 (2H, t, J=5.8 Hz), 3.73 (2H, t, J=5.9 Hz), 6.42 (1H, s), 6.92-7.04 (3H, m), 7.07 (1H, d, J=7.8 Hz), 7.38 (1H, t, J=8.0 Hz), 7.89 (1H, dd, J=8.6, 2.7 Hz), 8.43 (1H, s).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>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.O>[CH3:27][S:24]([C:20]1[CH:19]=[C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:32]4[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=4)=[N:3]3)=[CH:8][CH:7]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(N)nc4)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazoline (0.15 g, 0.00037 mol), 2-aminopyridine-5-boronic acid pinacol ester (0.122 g, 0.0005568 mol), cesium carbonate (0.243 g, 0.00074 mol), DMF (4 mL) and water (2 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.013 g, 0.000018 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 5% MeOH in chloroform) to yield the title compound (125 mg, 74%). LC-MS (ESI): Calculated mass: 461.2; Observed mass: 462.1 [M+H]+ (RT: 0.17 min).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]([O:11][C:12](=[O:14])[CH3:13])[C:9](=[NH:15])[N:8]=[C:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1)(=[O:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[C:1]([NH:4][C:5]1[N:10]([O:11][C:12](=[O:14])[CH3:13])[C:9](=[NH:15])[N:8]=[C:7]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(=N)n1OC(C)=O
Reactant: C1CCNCC1
Solvent: CC#N
Product: CC(=O)Nc1cc(N2CCCCC2)nc(=N)n1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture containing 0.5 g (0.0013 mole) of 6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-(4-toluenesulfonyloxy)pyrimidine in 20 ml of acetonitrile and 0.5 ml of piperidine is stirred at room temperature for 3 hours, then evaporated under reduced pressure. After adding 30 ml of ether to the residue, the crystalline precipitate is filtered, washed with ether and then with water, finally dried to give the aimed product in a yield of 0.24 g (64%), m.p.: 217°-218° C. (with decomposition).