Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH:19][CH2:20][CH2:21][CH2:22][CH:23]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:24][C@@H:25]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[NH:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:19][CH2:20][CH2:21][CH2:22][CH:23]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:24][C@@H:25]([C:46]([O:48][C:49]([CH3:51])([CH3:52])[CH3:50])=[O:47])[NH:26][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)C(CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCC(C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
At 0° C. triethylamine (0.31 mL, 2.2 mmol) and 4-methylbenzenesulfonyl chloride (0.141 g, 0.74 mmol) were added to a solution of di-tert-butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.239 g, 0.427 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at 0° C. for 2 h and for 16 h at room temperature. The solution was concentrated and the crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert-butyl 4-{3-{[(4-methylphenyl)sulfonyl)oxy]propyl}-N-trityl-L-glutamate (0.255 mg, 67%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers. The isomers were separated by chiral HPLC (Chiralpak AD-H 5 μm 250×20 mm, hexane/2-propanol 9:1, 25 mL/min):
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]([CH2:34][CH3:35])[C@@H:22]([CH2:32][CH3:33])[CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]([CH2:34][CH3:35])[C@@H:22]([CH2:32][CH3:33])[CH2:23][NH2:24])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCC(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)[C@@H](CC)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)[C@@H](CC)CN
Temperature: 0 °C
Yield: 29 %

Procedure:
tert-Butyl (2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentylcarbamate was dissolved in 5 mL DCM and cooled to 0° C. TFA (5 mL) was added and the mixture was allowed to warm to ambient temperature over 1 hour. The reaction mixture was evaporated to dryness, and the residue was dissolved in 30 mL DCM and washed with 1N NaOH. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography followed by preparative TLC to give the desired product (42.5 mg, 29%). MS ESI (+) m/z 376.1 (M+1) detected.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>ClC(Cl)C>[C:20]([C:23]1[N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[C:9]([C:10](=[O:11])[N:12]=1)=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)([CH3:22])([CH3:21])[CH3:19]
Reactant: COc1ccc(C(N)=O)c(Nc2ccccc2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC(Cl)Cl
Product: COc1ccc2c(=O)nc(C(C)(C)C)n(-c3ccccc3)c2c1

Procedure:
To a solution of 2-anilino-4-methoxybenzamide (150 mg) in 5 mL dichloroethane was added pivaloyl chloride (0.229 mL), and the reaction was heated at reflux for 7 h. The reaction was cooled and partially concentrated, then diluted with ethyl ether, and the resulting precipitate was isolated by filtration to give 180 mg of a solid product. This material was dissolved in CH2Cl2 and washed with 10% sodium carbonate. The organic solution was dried (Na2SO4) and concentrated to give the titled compound.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH3:14])=[C:6]([N:15]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)[S:16]([C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+:43]>C(O)C>[CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH3:14])=[C:6]([N:15]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:40])([F:41])[F:39])=[CH:35][CH:36]=3)[S:16]([C:19]3[CH:29]=[CH:28][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[N:5]=2)[CH2:2][CH2:3]1.[Na+:43]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc(C3CC3)c3ccccc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)[O-])cc2)nc(C2CC2)c2ccccc12
Yield: 95.3 %

Procedure:
A mixture of ethyl 4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (92.0 mg, 157 μmol) prepared in Example 9, 2 mol/L aqueous sodium hydroxide solution (79 μl, 157 μmol) and ethanol (1.57 ml) was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether and pentane to give sodium 4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (86.6 mg, 95%) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.O1CCOCC1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[F:27])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Reactant: OB(O)c1ccccc1F
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(-c3ccccc3F)cnc2n1C
Temperature: 80 °C
Yield: 95.5 %

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (350 mg) and 1,4-dioxane (5 ml), 2-fluorophenylboronic acid (150 mg), tripotassium phosphate (600 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (25 mg), and tris(dibenzylideneacetone)palladium(0) (14 mg) were sequentially added, heated to 80° C., and stirred with heating for 8 hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 349 mg of 2-(2-ethylsulfanylphenyl)-6-(2-fluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 58).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:3](=[O:5])[CH3:2])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (16 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol) in dichloromethane (1 mL) was added acetic anhydride (4.0 μL, 0.043 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.4 mg, 13%). LCMS calculated for C19H25N4O2S (M+H)+: m/z=373.2. Found: 373.1.
Reaction SMILES: Br[C:2]1[C:3]([CH3:18])=[C:4]([C:7]([O:14][CH:15]([CH3:17])[CH3:16])=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[C:10]([C:8]1[C:7]([O:14][CH:15]([CH3:17])[CH3:16])=[C:4]([C:3]([CH3:18])=[C:2]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[CH:9]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1c(Br)cc(C(C)(C)C)c(OC(C)C)c1C=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: Cc1c(C#C[Si](C)(C)C)cc(C(C)(C)C)c(OC(C)C)c1C=O

Procedure:
Following General Procedure D and using 3-bromo-5-tert-butyl-6-isopropoxy-2-methyl-benzaldehyde (Intermediate 141, 0.43 g, 1.37 mmol), triethyl amine, copper(I)iodide (0.021 g, 0.11 mmol), trimethylsilyl acetylene (1 mL), and dichlorobis(triphenylphosphine)palladium(II) (0.077 g, 0.11 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 2% ethyl acetate in hexane as the eluent, the title compound was obtained (0.45 g,˜100%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.N1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23](B([O-])[O-])[C:22]=2C=C1.BrC1C=CC=CC=1.[OH-].[Na+]>C1COCC1.[Pd]>[C:22]1([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: [O-]B([O-])c1cccc2[nH]ccc12
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Brc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)1H-indole (pinacole 4-indoleboronate (2 g, 8.2 mmol) and 3-bromobenzene (0.87 mL, 8.3 mmol) in THF (28 mL) were added Palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 mL of water). The system was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with hexanes:EtOAc 9:1 to give 1.38 g (78%) of 4-phenyl-1H-indole as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([CH:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:27])[C:24](O)=[O:25])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[CH2:10]([CH:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:27])[C:24]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[O:25])[CH2:21][CH2:22]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 4-amino-benzonitrile (Aldrich) and (4-benzyl-piperidin-1-yl)-oxo-acetic acid according to the method described in Example 2. Melting Point: 166-169° C. (diethylether)
Reaction SMILES: [C:1]([NH:5][NH2:6])(=O)[CH2:2][OH:3].[CH3:7][N:8]=[C:9]=[S:10].CO.[Na]>C(O)C>[OH:3][CH2:2][C:1]1[N:8]([CH3:7])[C:9]([SH:10])=[N:6][N:5]=1
Reactant: NNC(=O)CO
Reactant: CN=C=S
Agent: [Na]
Solvent: CCO
Solvent: CO
Product: Cn1c(S)nnc1CO
Yield: 35.9 %

Procedure:
A mixture of 9 g of glycolic acid hydrazide, 7.3 g of methyl isothiocyanate, 50 ml of methanol and 50 ml of ethanol was heated under reflux for 5 hours. Following the addition of 2.3 g of sodium metal, the mixture was further refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 150 ml of water and adjusted to pH 2.5 with phosphoric acid. The resultant crystals were collected by filtration and recrystallized from ethanol. By the above procedure there were obtained 5.2 g of the captioned compound. m.p. 199°-201° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccnc(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccnc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 2-phenylisonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 417.21 g/mol.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:19][CH:20]=3)[CH:15](O)[C:14]([CH3:30])([CH3:29])[CH2:13]2)=[CH:8][CH:7]=1>C1C=CC=CC=1>[Cl:3][CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:17]=2)[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)[CH2:13][C:14]1([CH3:30])[CH3:29]
Reactant: CN(C)CCOc1ccc2c(c1)C(O)C(C)(C)CC2c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CN(C)CCOc1ccc2c(c1)C(Cl)C(C)(C)CC2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (3 ml) was added dropwise to a stirred solution of 4-(4-chlorophenyl)-1-hydroxy-2,2-dimethyl-7-(2-dimethylaminoethoxy)tetralin (2.0 g) in benzene (50 ml), the temperature being maintained at 5°-10°. After being stirred at room temperature for 16 hr., the solution was taken to dryness in vacuo, the residue shaken with ether-sodium carbonate solution and the ether extract dried (MgSO4). Addition of ethereal hydrogen chloride solution precipitated a viscous oil, which was separated by decantation and redissolved in ethanol. Addition of ether and cooling gave 1-chloro-4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)tetralin as the hydrochloride salt, m.p. 185°-210° approx. (0.93 g, 41%).
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:3]=1[N:4]=[C:5]([O:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=O.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:13]([O:12][C:5]1[CH:6]=[C:7]([OH:9])[C:15]2[C:3](=[C:2]([F:1])[C:18]([F:19])=[C:17]([F:20])[CH:16]=2)[N:4]=1)[CH3:14]
Reactant: CCOC(=O)CC(=Nc1ccc(F)c(F)c1F)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOc1cc(O)c2cc(F)c(F)c(F)c2n1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
A solution of 2,3,4-trifluoro-N-[1-ethoxy-2-(ethoxycarbonyl)ethylidene]aniline (122 g) in phenyl ether (120 cc) is introduced dropwise in the course of 25 minutes and with stirring into phenyl ether (600 cc) at a temperature in the region of 250° C. while the ethanol formed is removed by distillation. After stirring for 15 minutes at the same temperature, the solution is cooled to approximately 20° C. and treated with n-hexane (750 cc). The precipitate formed is drained and washed with n-hexane (3×200 cc). 2-Ethoxy-6,7,8-trifluoro-4-hydroxyquinoline (69.5 g) is obtained in the form of a beige solid, m.p. 171° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33](O)=[O:34])[C:27]=2[O:26][CH2:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:32]3[C:27]4[O:26][CH2:25][O:24][C:28]=4[CH:29]=[CH:30][CH:31]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2c1OCO2
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with benzo[1,3]dioxole-4-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=481.1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:54])[C@H:21]([NH:33][C:34]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[C:46](=[O:47])[NH:45][C:44]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)=[N:43]4)[CH2:38][CH2:37]3)=[O:35])[CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:54]=[C:20]([N:17]1[CH2:16][CH2:15][CH:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][CH2:18]1)[C@H:21]([NH:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[C:46](=[O:47])[NH:45][C:44]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:43]2)[CH2:38][CH2:37]1)=[O:35])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=1
Reactant: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCC(N2CCN(Cc3ccccc3)CC2)CC1)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCC(N2CCNCC2)CC1)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1

Procedure:
A solution of 80 mg (0.11 mmol) 4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carboxylic acid [(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide in 10 mL MeOH was hydrogenated in the presence of 10 mg Pd/C (10%) at 50° C. and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the solvent eliminated under reduced pressure and the residue purified by chromatography on silica gel. The product fractions were evaporated down under reduced pressure and dried.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.[F:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=S)=[O:32])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:31](/[N:33]=[C:34]2/[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:21])[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:16][CH2:15]3)[C:3]3[CH:4]=[C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:32])=[CH:36][CH:37]=1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Reactant: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c(N)cn1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To an ice-bath cooled solution of cis-4-(5-amino-2-(2-methoxyethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (156 mg, 0.445 mmol) in THF (0.8 mL) was added 4-fluorobenzoyl isothiocyanate (161 mg, 0.890 mmol) as a solution in THF (2 mL). The mixture was stirred 15 minutes, and then stirred another 30 minutes at RT. DIPEA (0.194 mL, 1.113 mmol) and EDC (213 mg, 1.113 mmol) were added, and the mixture was heated to 60° C. for 1 hour. The mixture was evaporated, and the residue was dissolved with 5% IPA/EtOAc (5 mL), washed with 1:1 aqueous NH4Cl (sat)/water, [1 mL total volume (×2)], brine, and the organic layer was dried over Na2SO4 and filtered. The mixture was purified via flash chromatography using a linear gradient of 0% to 5% of 1% NH4OH in MeOH in DCM. The title compound was collected as a white solid (110 mg, 50% yield). M/Z calc'd for C26H32FN5O4: 497.56. found 498 [M+H].
Reaction SMILES: [Na+].[F:2][C:3]([F:8])(Cl)C([O-])=O.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[NH:25][C:24]2=[O:32])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br-].[Li+].[H-].[Na+].[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[N:25]([CH:3]([F:8])[F:2])[C:24]2=[O:32])=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Br-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1n(-c2ccc(OCc3ccccc3)cc2)c2ncccc2n1C(F)F
Yield: 18.1 %

Procedure:
Difluorochloroacetic acid sodium salt (1.922 g) was added to a solution of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2 g), lithium bromide (1.095 g) and NaH (0.290 g) in DMF (20 mL) at 0° C. The mixture was stirred at 140° C. under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-(difluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (420 mg) as a white solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[NH:28][C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:20]([CH3:27])=[C:21]([NH2:26])[CH:22]=[C:23]([F:25])[CH:24]=5)[C:13]=4[CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CN(C)C1C=CC(C(Cl)=O)=CC=1.[C:41]([C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>>[C:41]([C:45]1[CH:46]=[CH:47][C:48]([C:49]([NH:26][C:21]2[CH:22]=[C:23]([F:25])[CH:24]=[C:19]([C:18]3[C:13]4[CH:12]=[C:11]([C:8]5[CH2:9][CH2:10][C:5]6([O:1][CH2:2][CH2:3][O:4]6)[CH2:6][CH:7]=5)[NH:28][C:14]=4[N:15]=[CH:16][N:17]=3)[C:20]=2[CH3:27])=[O:50])=[CH:52][CH:53]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Agent: CN(C)c1ccc(C(=O)Cl)cc1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12

Procedure:
Example 27 was prepared analogue to Example 15 by replacing Intermediate 6 with Intermediate 18 and 4-dimethyaminobenzoyl chloride with 4-tert-butylbenzoyl chloride.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:24][CH2:25][C:26]#[CH:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:24][CH2:25][C:26]#[C:27][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2ccccc2n1Cc1ccccc1
Product: C(#Cc1ccccn1)CCc1nc2ccccc2n1Cc1ccccc1
Yield: 24.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (38 mg, 0.18 mmol) and 1-benzyl-2-(but-3-ynyl)-1H-benzo[d]imidazole (49 mg, 0.18 mmol). The crude residue was purified over silicagel, chromatography (prepacked 2 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 15 mg of 1-benzyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a yellow oily solid (Yield: 23%).