Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]([I:8])=[CH:5]OC.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:19].C[O-].[Na+]>C(O)C>[I:8][C:4]1[C:3](=[O:2])[N:19]=[C:11]2[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]2[CH:5]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: COC=C(I)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1nc2[nH]c3ccccc3n2cc1I

Procedure:
To a mixture of 2-iodo-3-methoxy-acrylic acid methyl ester (1, 1.21 g, 5 mmol), 1H-benzoimidazol-2-ylamine (2, 0.67 g, 5 mmol) and ethanol (30 mL) was added a solution of sodium methoxide (10 mL, 0.5 M in methanol, 5 mmol). The resulted mixture was refluxed for 3 h and concentrated to afford 3-iodo-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-2-one (3). A mixture of (3-tert-butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]carbamic acid tert-butyl ester (4, 490 mg, 1 mmol), 3 (311 mg, 1 mmol), K2CO2 (414 g, 3 mmol), Pd(PPh3)4 (0) (41 mg, 0.05 mmol), ethanol (6 mL), dioxane (2 mL) and water (2 mL) was degassed and heated at 80° C. for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0%-6% MeOH in methanechloride) to give desired product 5 (170 mg, 31%) as light yellow solid. LCMS (EI) m/z: 570 (M+Na+).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([CH3:35])([CH3:34])[CH2:20]2)[N:11]=[C:10]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][C:45]([CH3:48])([CH3:47])[N:44]([O:49][CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[C:43]([CH3:57])([CH3:56])[CH2:42]2)[N:9]=1>>[CH:28]1([O:27][N:22]2[C:23]([CH3:25])([CH3:26])[CH2:24][CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]3[N:11]=[C:10]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]4[CH2:42][C:43]([CH3:57])([CH3:56])[N:44]([O:49][CH:50]5[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]5)[C:45]([CH3:47])([CH3:48])[CH2:46]4)[N:9]=[C:8]([N:7]=[C:2]=[O:3])[N:13]=3)[CH2:20][C:21]2([CH3:34])[CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(CCCCNc2nc(N=C=O)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of oxalyl chloride with the compound prepared in Example 22.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][N:15]=1>N1C=CC=CC=1>[F:13][C:14]1[N:15]=[CH:16][C:17]([C:18]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: N#Cc1cccc(C(N)=NO)c1
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2noc(-c3ccc(F)nc3)n2)c1
Temperature: 25 °C

Procedure:
3-Cyano-N′-hydroxybenzimidamide (0.322 g, 1 mmol) was dissolved in pyridine 10 mL and 6-fluoronicotinoyl chloride (Frontier Scientific, 0.160 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.56-7.52 (m, 1H), 7.85 (t, J=7.9 Hz, 1H), 8.15-8.12 (m, 1H), 8.43-8.41 (m, 1H), 8.49 (m, 1H), 8.8-8.74 (m, 1H), 9.11-9.0 (m, 1H) ppm; MS (DCl/NH3) m/z 267 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:35])[CH:7]([CH:13]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:35])[CH:7]([CH:13]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C(=O)O)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
A solution of KOH (0.067 g, 1.03 mmol) in ethanol (3 mL) was added to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-phenyl-ethyl]-malonic acid diethyl ester (0.44g, 0.96 mmol) in ethanol (3 mL) and methylene chloride (2 mL) at 0° C. The mixture was stirred for 48 h at room temperature. The mixture was concentrated under reduced pressure and ethyl acetate and 0.5 M HCl were added to the residue. The organic layer was washed with brine and dried. Filtration and evaporation in vacuo gave 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-phenyl-ethyl]-malonic acid monoethyl ester (0.37, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Product: Cc1ccc(Cl)c(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=397.2, tR (minutes, Method C)=1.11
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:33])[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1.[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=1>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:33])[CH:15]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)[CH2:43][C:40]1[CH:41]=[CH:42][C:37]([C:36]([O:35][CH3:34])=[O:45])=[CH:38][CH:39]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C(Cc1cccc(-c2ccc(OC(F)(F)F)cc2)c1)c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C(=O)c2ccccc2F)c2cccc(-c3ccc(OC(F)(F)F)cc3)c2)cc1
Temperature: -78 °C

Procedure:
Sodium t-butoxide (67 mg, 0.70 mmol) was added all at once to a THF solution (4 mL) containing the intermediate from Step B (250 mg, 0.668 mmol) stirred at −78° C. After 2 minutes 4-bromomethyl-benzoic acid methyl ester (161 mg, 0.70 mmol) was added all at once. The reaction solution was allowed to warm to room temperature. After stirring for 1 hour the reaction solution was partitioned between aqueous 1N HCl and ethyl acetate. The organic phase was washed with brine and dried over MgSO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.92-7.90 (m, 2H); 7.79-7.75 (m, 1H); 7.51-7.49 (m, 2H); 7.47-7.32 (m, 4H); 7.30-7.27 (m, 2H); 7.24-7.19 (m, 3H); 7.17-7.15 (m, 1H); 7.05 (dd, J=8.3, 11.3 Hz, 1H); 4.88 (t, J=7.4 Hz, 1H); 3.91 (s, 3H); 3.68 (dd, J=7.1, 13.7 Hz, 1H); 3.17 (dd, J=7.6, 13.7 Hz, 1H). LCMS1 4.40 min. (M+H)− 523
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[Cl:23][CH2:24][C:25](=O)[CH2:26]Cl.CN(C)C(=O)C>O>[Cl:23][CH2:24][C:25]1[N:13]=[C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[S:14][CH:26]=1
Reactant: O=C(CCl)CCl
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1cccc2cc(-c3nc(CCl)cs3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.46 g), 1,3-dichloro-2-propanone (0.33 g) and N,N-dimethylacetamide (6 mL) was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.45 g, yield 85%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 153-154° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.Br[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Reactant: Brc1cccc2ccccc12
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1c1cccc2ccccc12

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 1-bromonaphtalene were used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[C:11](=[CH:16][C:17]([F:24])=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:12](OC)=[O:13]>C1COCC1>[F:24][C:17]1[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:10]([CH2:9][OH:8])=[C:11]([CH2:12][OH:13])[CH:16]=1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(F)c(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To 23.6 mmol LiAlH4 in 10 ml THF was added dropwise over 5 min a solution of 3.93 mmol 4-fluoro-5-trifluoromethyl-phthalic acid dimethyl ester in 5 ml THF. The mixture was stirred at room temperature for 2 h, and then heated at 50° C. for 20 min. The reaction mixture was quenched by dropwise addition of 8 ml ethyl acetate, stirred for a further 15 min at 50° C., then cooled to room temperature and acidified to pH 1 by dropwise addition of 5 M aq HCl. The mixture was then partitioned between ethyl acetate and brine and the organic phase was then separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane) to afford the title compound as a colourless oil (57% yield). MS (m/e): 283.1 ([M+OAc)]−, 100%), 223.1 ([M−H]−, 20%).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[OH:1][CH2:2][C:3]#[C:4][CH2:5][N:30]1[C:26](=[O:36])[C:27]2=[CH:35][CH:34]=[CH:33][CH:32]=[C:28]2[C:29]1=[O:31]
Reactant: OCC#CCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC#CCO
Yield: 53 %

Procedure:
1,4-Dihydroxy-2-butyne (430 mg, 5.0 mmol), triphenylphosphine (1.44 g, 5.5 mmol) and phthalimide (1.47 g, 10.0 mmol) were dissolved in 50 mL of dry THF. To this solution, with stirring under dry argon, was added diisopropyl azodicarboxylate (1.09 mL, 5.25 mmol) dropwise. After stirring at room temperature for 6 hours, the reaction mixture was evaporated in vacuo to remove the THF. The residue was dissolved in methylene chloride (25 mL) and ethyl acetate (25 mL), the insoluble phthalimide was filtered off and the filtrate was concentrated in vacuo. The residue was subjected to flash column chromatography (eluent, ethyl acetate-hexane, 1:1) to give 1-hydroxy-4-phthalimido-2-butyne (240) as a white solid (570 mg, 53%). 1H NMR (CDCl3) δ7.88 (2H, dd, J=5.7, 3.1 Hz), 7.74 (2H, dd, J 5.7, 3.1 Hz), 4.49 (2H, t, J=2.0 Hz), 4.24 (2H, dt, J=6.2, 2.0 Hz), 1.92 (1 H, t, J=6.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(OC)=O)=[CH:4][C:3]=1[N:14]1[C:18](=[O:19])[C:17](=[C:20]([CH3:22])[CH3:21])[O:16][C:15]1=[O:23].C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:14]1[C:18](=[O:19])[C:17](=[C:20]([CH3:21])[CH3:22])[O:16][C:15]1=[O:23]
Reactant: COC(=O)Oc1cc(N2C(=O)OC(=C(C)C)C2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)=C1OC(=O)N(c2cc(O)c(Cl)cc2F)C1=O
Yield: 56 %

Procedure:
To a dried methanol solution (100 ml) of 3-(2'-fluoro-4'-chloro-5'-methoxycarbonyloxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (3.44 g, 10 mmol), which was synthesized by a method shown in Reference Example 12 described below, was added potassium carbonate (1.38 g, 10 mmol) and the mixture was heated at reflux for 2 hours. After the reaction was completed, the resulting mixture was quenched with an aqueous solution of ammonium chloride and extracted with ether. The ethereal extracts were dried and evaporated as small a volume as possible. The resulting residue was purified by silica gel column chromatography to give pure 3-(2'-fluoro-4'-chloro-5'-hydroxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.60 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]([O:12][C:13]([CH3:15])=[CH2:14])=[O:11].C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:11])[O:12][C:13]([CH3:15])=[CH2:14])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: Nc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a biphasic solution of 3-fluoroaniline (0.3 mL, 3.12 mmol) in 1:1 EtOAc/water (10 mL) was added isopropenyl chloroformate (0.564 g, 4.68 mmol) and NaHCO3 (1.31 g, 15.6 mmol) and the mixture stirred at RT overnight. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to furnish prop-1-en-2-yl 3-fluorophenylcarbamate (125 mg, 21% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 7.35 (m, 1H), 7.31 (m, 1H), 7.21 (m, 1H), 6.83 (m, 1H), 4.74 (m, 2H), 1.92 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]1)=[O:12].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]([NH:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:27])[F:28])=[O:12])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,1-dimethylethyl {cis-4-[({[2-(trifluoromethyl)phenyl]methyl}amino)carbonyl]cyclohexyl}carbamate in CH2Cl2 (40 ml) at 0° C., a premixed solution of CH2Cl2 (10 ml) and TFA (10 ml) was added. The reaction mixture was stirred at 0° C. for 10 min. The reaction was warmed to room temperature and stirring was continued for 2 h. The solvent was next removed under reduced pressure to yield 2.83 g (69% over 2 steps) of the title compound. MS ES+): m/e 301.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:30])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH:28]=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[C:10]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:11]1[C:10]([O:38][CH2:39][C:40]([F:41])([F:42])[F:43])=[CH:9][C:8]2[N:7]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH:19]=3)[CH2:16][C:15](=[O:30])[NH:14][C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2cc(OCC(F)(F)F)c(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from [2′-fluoro-5-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M24) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:20])[C:10]3[C:15]([C:16]=2[C:17]([OH:19])=O)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:20])[C:10]3[C:15]([C:16]=2[C:17]([N:28]([CH2:27][CH2:26][CH2:25][N:24]([CH3:35])[CH3:23])[CH2:29][CH2:30][CH2:31][N:32]([CH3:33])[CH3:34])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)c(C(=O)O)c2ccccc21
Reactant: CN(C)CCCNCCCN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CN(C)CCCN(CCCN(C)C)C(=O)c1c(COc2ccc(Cl)cc2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-carboxy-1H-indole (0.100 g, 0.317 mmol) was dissolved in 3.2 ml of N,N-dimethylformamide. To this solution were added N,N-bis(3-dimethylaminopropyl)amine (0.074 ml, 0.0623 g, 0.332 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.091 g, 0.475 mmol), and hydroxybenztriazole (0.0642 g, 0.475 mmol). The resulting mixture was then heated for 6 hours and then stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.O.Cl[C:11]([CH3:15])([CH3:14])[C:12]#[CH:13]>[Cu].[Cu]Cl.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11]([CH3:15])([C:12]#[CH:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CCOCC
Solvent: O
Product: C#CC(C)(C)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzenamine (4.0 g, 23 mmol), TEA (4.3 ml, 31 mmol), 2.0 ml of water, copper (0.058 g, 0.91 mmol) and copper(I) chloride (0.058 g, 0.59 mmol) in diethyl ether (9.8 ml, 20 mmol) was added 3-chloro-3-methylbut-1-yne (2.0 g, 20 mmol), dropwise. After stirring overnight, the reaction mixture was transferred to a seperatory funnel containing water and diethyl ether. The aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated. The crude oil was purified with by MPLC (100% DCM to 10% (91/10/1 DCM:MeOH:NH4OH)) to provide the product as an oil. MS m/z: 240 (M+2).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.Br[CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CC(=O)NC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(CCCCl)CC1

Procedure:
A mixture of 4-acetamidopiperidine (1.4 g; preparation 14), triethylamine (3.56 ml) and 1-bromo-3-chloropropane (1.45 ml) in 50 ml of tetrahydrofuran was refluxed overnight, then an additional 3.5 ml of triethylamine and 1.45 ml of 1-bromo-3-chloropropane were added. After a further 3 hours at reflux, the mixture was concentrated to a small volume, treated with chloroform and washed with aqueous saturated solution of potassium carbonate. The organic phase was dried over sodium sulfate, concentrated to dryness and the residue (2.3 g of a green oil) was purified by silica gel chromatography (eluent chloroform/methanol 9:1) to give 0.67 g of the product, m.p. 74-77° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[F:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[F:33]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 425.0448 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:17]=2)=O)=[CH:5][CH:4]=1)#[N:2].O>O1CCCC1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:13]([NH:12][CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[S:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2csc(NC(=O)Cc3ccc(C#N)cc3)n2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2csc(NCCc3ccc(C#N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
610 mg 2-(4-Cyano-phenyl)-N-[4-(4-methoxy-phenyl)-thiazol-2-yl]-acetamide were suspended in 20 ml tetrahydrofuran. 2.1 ml of a one molar solution of borane tetrahydrofuran complex were added at room temperature. The reaction mixture was stirred at room temperature for two hours and then at 50° C. for two hours. The cooled reaction mixture was poured on 50 ml water and extracted five times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. Then the solvents were removed in vacuo to obtain 600 mg 4-{2-[4-(4-Methoxy-phenyl)-thiazol-2-ylamino]-ethyl}-benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[CH:8]2.N[C@H:33]1CCCNC1=O>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:33][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:9]=[CH:8]2
Reactant: N[C@H]1CCCNC1=O
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16; 1.01 g, 2.28 mmol) in dichloromethane (10 mL) was added (S)-3-aminopiperidin-2-one (prepared according to Example 3; 521 mg, 4.56 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with a gradient of 50-100% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxopiperidin-3-yl)-1H-indazole-6-carboxamide (Ib) (1.00 g, 99%). Mass spec: 443 (M+1). 1H NMR (CDCl3) δ 8.58 (br, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.15 (m, 1H), 7.04 (s, 1H), 7.00 (m, 1H), 6.89 (m, 1H), 5.80 (br, 1H), 4.51 (ddd, 1H), 4.22 (d, 2H), 3.38 (m, 2H), 2.70 (m, 1H), 2.36 (m, 2H), 1.99 (m, 2H), 1.70 (m, 1H), 0.93 (d, 6H).