Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C(N([CH2:17][CH3:18])CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[C:18]1[CH:17]=[CH:4][CH:3]=[CH:2][CH:9]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCN(CC)CC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C=O)ccc1-c1ccccc1
Temperature: 25 °C

Procedure:
To an ice-cold solution of 4-hydroxy-3-methoxy-benzaldehyde (1.00 g) in dichloromethane (22 mL) was added triethylamine (1.37 mL). Then trifluoromethanesulfonic anhydride (1.40 mL) was added dropwise, and the resulting mixture was stirred under ice-cooling for 45 minutes. Ice was added and the whole was partitioned between AcOEt (60 mL) and saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer was washed successively with water/brine (3/1, 40 mL) and brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (1.98 g) was dissolved in N,N-dimethylformamide (25 mL). Phenylboronic acid (0.882 g), sodium carbonate (1.39 g), water (5 mL) and tetrakis(triphenyl-phosphine)palladium(0) (0.380 g) were added, and the resulting mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (70 mL) and water (30 mL). The organic layer was washed with water/brine (1/1, 30 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1 to 5/1) to give the title compound (1.12 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[S:37][CH2:38][O:39][CH3:40])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[C:33]4[S:37][CH2:38][O:39][CH3:40])[CH:27]=3)[CH2:23][C:22](=[O:41])[NH:21][C:9]=2[CH:10]=1
Reactant: COCSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccccc3F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCSc1nccn1-c1cccc(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from (2′-fluoro-3-{3-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K71) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (100 mg).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([C:14]1([CH3:17])[CH2:16][CH2:15]1)#[CH:13]>C(N(CC)CC)C.[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>[CH3:17][C:14]1([C:12]#[C:13][C:2]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH2:16][CH2:15]1
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: C#CC1(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C#Cc2cc([N+](=O)[O-])ccc2N)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (430 mg, 2.0 mmol) and 1-ethynyl-1-methyl-cyclopropane (630 mg, 8.0 mmol) in triethylamine (20 mL) was added CuI (76 mg, 0.40 mmol) and Pd(PPh3)2Cl2 (140 mg, 0.20 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2-((1-methylcyclopropyl)ethynyl)-4-nitroaniline (340 mg, 79%). NMR (300 MHz, CDCl3) δ 8.15-8.14 (m, 1H), 7.98-7.95 (m, 1H), 6.63 (d, J=6.9 Hz, 1H), 4.80 (brs, 2H), 1.38 (s, 3H), 1.04-1.01 (m, 2H), 0.76-0.73 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:40])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[CH2:23][CH2:22]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>O.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>[Cl:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:40])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=2)[CH2:23][CH2:22]3)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: N#Cc1c(Cl)cncc1-c1ccc2c(c1)CCN2C(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 54.8 %

Procedure:
To 3,5-dichloro-4-pyridinecarbonitrile (300 mg, 1.74 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (823 mg, 1.908 mmol) in a 5 mL sealable vial was added 1,4-Dioxane (5 mL) and saturated NaHCO3 (2.5 mL). The mixture was then bubbled with N2 gas for 5 minutes then Pd(Ph3P)4 (200 mg, 0.173 mmol) was added. The vial was then capped and heated at 100° C. overnight. The reaction was then diluted with water (10 ml) and extracted with EtOAc (3×20 ml). The organic was combined then washed brine, dried over MgSO4, filtered and concentrated. The crude solid was then dissolved in 3 mL of DMF and loaded on to a 50 g Biotage SNAP column conditioned with hexane and purified by silica gel chromatography with 0 to 60% EtOAc in Hexane over a 30 minute gradient. The fractions with the desired product were pool and concentrated. The semi-solid oil was then treated with 20 ml of 5% DCM/Hexane to induce precipitation. The solid was isolated by filtration to give 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (421 mg, 54.9% yield) as a off yellow solid. LC/MS (ES) m/z=442.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.83 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 7.69 (s, 1H), 7.56-7.67 (m, 3H), 7.51 (d, J=8.08 Hz, 1H), 4.31 (t, J=8.59 Hz, 2H), 4.06 (s, 2H), 3.29 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[CH:9]=[CH:8][C:7]=1[F:18])=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:12]([C:10]1[CH:9]=[CH:8][C:7]([F:18])=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])[CH:11]=1)#[CH:13]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2,2,2-trifluoro-N-{2-fluoro-5-[(trimethylsilyl)ethynyl]phenyl}acetamide (5.3 g, 17 mmol) in THF (400 mL) was cooled to 0° C., and a 1.0 M solution of TBAF in THF (17 mL, 17 mmol) was added dropwise. The resulting mixture was stirred for 10 min. at 0° C. The reaction was quenched with H2O (150 mL), concentrated under reduced pressure, and extracted with DCM. The combined organic layers were concentrated under reduced pressure, and the crude solid was used in the next reaction without further purification. ES-LC/MS m/z=230 [M−H]−.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([O:21][C@@H:22]3[CH:27]4[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]4)[CH2:23]3)=[N:19][CH:20]=2)=[CH:11][C:10]=1[N+:30]([O-])=O)C1C=CC=CC=1>[Pd]>[NH2:30][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[N:17][C:18]([O:21][C@@H:22]3[CH:27]4[CH2:26][CH2:25][N:24]([CH2:29][CH2:28]4)[CH2:23]3)=[N:19][CH:20]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)ccc1OCc1ccccc1
Agent: [Pd]
Product: Nc1cc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)ccc1O

Procedure:
The product of Example 33C (380 mg, 0.88) was hydrogenated under the catalysis of Pd/C (Aldrich, 10 wt. %, 100 mg) according to the procedure of Example 28E. The title compound was obtained as yellow solid (220 mg, yield, 92%). 1H NMR (300 MHz, CD3OD) δ 1.47-1.93 (m, 3H), 1.95-2.35 (m, 2H) 2.70-3.05 (m, 5H), 3.33-3.48 (m, 1H), 5.04-5.30 (m, J=8.8 Hz, 1H), 6.72-6.88 (m, 2H), 6.98 (d, J=1.7 Hz, 1H), 8.70 (s, 2H) ppm. MS (DCI/NH3): 313 (M+H)+.
Reaction SMILES: [C:1](=[S:4])([SH:3])[NH2:2].[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10](=O)[CH2:11]Cl)[CH3:6]>C(O)C>[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10]1[N:2]=[C:1]([SH:3])[S:4][CH:11]=1)[CH3:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)S
Solvent: CCO
Product: CCOC(=O)Cc1csc(S)n1

Procedure:
An ammonium salt (102 g) of dithiocarbamic acid was dissolved in ethanol (700 mL), and a solution of 4-chloro-3-oxobutanoic acid ethyl ester (152 g) in ethanol (200 mL) was added dropwise under ice-cooling over 30 min. The temperature was gradually raised, and the mixture was heated under reflux for 2 hr. The reaction solution was concentrated under reduced pressure, water (1 L) was added thereto, and the precipitated solid was collected by filtration. This solid was dissolved in ethyl acetate (4 L), and the mixture was washed with water (2 L) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (500 mL) was added to the obtained solid, and the solid was washed by suspending and collected by filtration to give the title compound (165 g) as a slightly yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[CH:10]=[N:11][OH:12])=[CH:4][CH:3]=1.[Cl:19]Cl>CCOCC.C(Cl)Cl>[Cl:19][C:10](=[N:11][OH:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[O:7][CH2:6][C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: ON=Cc1ccccc1OCc1ccc(Cl)cc1
Reactant: ClCl
Solvent: ClCCl
Solvent: CCOCC
Product: ON=C(Cl)c1ccccc1OCc1ccc(Cl)cc1

Procedure:
2-(4-Chlorobenzyloxy)benzaldehyde oxime (26.17 g) was dissolved in ether (200 ml) and methylene chloride (50 ml), and chlorine (6.0 ml) was introduced at -10° C. or below, and then the temperature was raised from -10° C. to room temperature over 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give crude α-chloro-2-(4-chlorobenzyloxy)benzaldehyde oxime. The resulting crude product was dissolved in acetonitrile (150 ml), a mixture of imidazole (17.02 g) and acetonitrile (100 ml) was added at room temperature over 15 minutes, and then the resulting mixture was stirred at 65 to 70° C. for 2 hours. After completion of the reaction, water and methylene chloride were added. The resulting crystals were separated by filtration to give 2-(4-chlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde oxime (11.05 g) as colorless crystals. mp. 196°-197° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N+:15]([O-])=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].P(Cl)(Cl)([Cl:38])=O>C(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([Cl:38])[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1c2c(-c3ccccc3)cc[n+]([O-])c2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
5-[3,5-Bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine 10-oxide (compound of Reference Example 10; 400 mg) was added to phosphorus oxychloride (1.5 mL), and the mixture was refluxed for 1 hour while heated. The solvent was removed by distillation to obtain a residue. To this residue, ethyl acetate was added, and then the resulting crystals were collected. As a result, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine was obtained (440 mg, 99%).
Reaction SMILES: Br[Si](C)(C)C.[P:6]([O:12][C@H:13]1[CH2:17][O:16][C@@H:15]2[C@H:18]([O:21][N+:22]([O-:24])=[O:23])[CH2:19][O:20][C@H:14]12)([O:10]C)([O:8][CH3:9])=[O:7].CO>C(#N)C>[P:6]([OH:10])([O:12][C@H:13]1[CH2:17][O:16][C@@H:15]2[C@H:18]([O:21][N+:22]([O-:24])=[O:23])[CH2:19][O:20][C@H:14]12)([O:8][CH3:9])=[O:7]
Reactant: COP(=O)(OC)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: CC#N
Product: COP(=O)(O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromotrimethylsilane (0.191 mL, 1.47 mmol) was added to a stirred room temperature mixture of dimethyl (3S,3aS,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl phosphate (400 mg, 1.34 mmol) in acetonitrile (6 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour. Methanol (5 mL) was added, and the solution was concentrated. The residue was purified by preparative HPLC, eluting with 10-100% acetonitrile/water+0.1% trifluoroacetic acid, to afford the title compound as a white gum. 1H NMR (500 MHz, CD3OD) δ 5.45 (tt, J=5.3, 2.6 Hz, 1H), 5.00 (q, J=5.4 Hz, 1H), 4.74 (ddd, J=9.7, 7.2, 2.8 Hz, 1H), 4.57 (d, J=4.9 Hz, 1H), 4.09 (d, J=10.5 Hz, 1H), 3.97 (dt, J=11.3, 2.5 Hz, 1H), 3.92-3.83 (m, 2H), 3.72 (d, J=11.2 Hz, 3H); LC-MS: m/z 286.0 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11])(=[O:3])[CH3:2].[OH:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.[Na]>>[OH:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)/[CH:19]=[CH:20]\[C:10]1[C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10](/[CH:20]=[CH:19]\[C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([OH:12])[CH:14]=3)[C:5]=2[O:4][C:1](=[O:3])[CH3:2])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Oc1ccccc1S
Reactant: C#Cc1cccc(O)c1
Agent: [Na]
Product: CC(=O)Oc1c(/C=C\c2cccc(O)c2)cccc1Sc1cccc(/C=C\c2cccc(O)c2)c1OC(C)=O
Yield: 78 %

Procedure:
A solution of 2-acetoxythiophenol (10 mmol), 3-hydroxy-phenylacetylene (10 mmol) and sodium (0.01 g atom) was subjected to the General Procedure. The title compound was obtained in 78% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Cl)=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4].Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:7]1[S:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11])[CH3:16]
Reactant: CCOC(=O)CN
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1sc(C(=O)OC)cc1[N+](=O)[O-]
Yield: 89.5 %

Procedure:
A solution of 5-chloro-4-nitrothiophene-2-carboxylic acid methyl ester (6.03 g, 27.2 mmol), glycine ethyl ester hydrochloride (4.18 g, 29.9 mmol) and potassium carbonate (9.4 g, 68 mmol) in acetonitrile (200 mL) was stirred 4 h at 70° C. Quenched in ice/water. The resulting precipitation was collected by filtration, washed with water and dried to give methyl 5-(2-ethoxy-2-oxoethylamino)-4-nitrothiophene-2-carboxylate 19 (7.02 g, 89%). NMR (400 MHz, CDCl3) 1.35 (t, J=7.0 Hz, 3H), 3.87 (s, 3H), 4.11 (d, J=5.5 Hz, 2H), 4.33 (q, J=14.0 and 7.0 Hz, 2H), 8.04 (s, 1H), 8.75 (br s, 1H). (m/z)=289 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:19]([C:22]1[O:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[O:23][CH:24]=[C:25]([C:27]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:28])[N:26]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1nc(C(=O)O)co1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)co1
Yield: 11.6 %

Procedure:
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (600 mg, 2.301 mmol) and 2-acetyloxazole-4-carboxylic acid (428 mg, 2.76 mmol). The product was purified by Flash-chromatography. Yield 11.6%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.68 (s, 3H), 4.26-4.33 (m, 1H), 4.40-4.47 (m, 1H), 4.55-4.68 (m, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.67 (d, 1H), 7.72 (d, 1H), 7.88 (dd, 1H), 7.93 (d, 1H), 8.31 (s, 1H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:21])=O>>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
After heating 11 g of 4-n-octyloxybenzoic acid and an exessive amount of thionyl chloride under reflux for 6 hours, unreacted thionyl chloride was distilled off to obtain 4-n-octyloxybenzoic acid chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C:25]2[C@@H:34]3[C@@H:29]([CH2:30][CH:31]=[CH:32][CH2:33]3)[C:28](=[O:35])[N:27]([C:36]3[CH:41]=[CH:40][C:39]([C:42](N4CCN(C5C=CC=CC=5)CC4)=[O:43])=[CH:38][CH:37]=3)[N:26]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH3:24])[CH3:14]>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:42]([C:39]2[CH:40]=[CH:41][C:36]([N:27]3[N:26]=[C:25]([C:18]4[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH3:24])=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=4)[C@@H:34]4[C@@H:29]([CH2:30][CH:31]=[CH:32][CH2:33]4)[C:28]3=[O:35])=[CH:37][CH:38]=2)=[O:43])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: CCOC(=O)N1CCNCC1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)N1CCN(C(=O)c2ccc(N3N=C(c4ccc(OCC)c(OCC)c4)[C@H]4CC=CC[C@H]4C3=O)cc2)CC1

Procedure:
Prepared from intermediate product A1 and 1-(ethoxycarbonyl)piperazine as described for compound 1. Cystallised from diethyl ether as the free base. M.p. 146–147° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)C=Cc1ccc(Br)s1
Reactant: OB(O)c1ccc(Cl)cc1
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: O=C(O)C=Cc1ccc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.250 g (1.1 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 61.9 mg (0.1 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 5 ml of degassed DME and stirred at room temperature for 10 min. 0.251 g (1.6 mmol) of 4-chlorophenylboronic acid and 1 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The resulting solution was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the resulting solution was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with a saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography. Yield: 0.12 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[K+].O=P(Cl)(Cl)[Cl:19]>C(#N)C.S1(CCCC1)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:19])(=[O:15])=[O:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 75 °C

Procedure:
A round bottom flask, fitted with a magnetic stir bar and a hose adapter connected to a source of nitrogen gas, was charged with a solution of potassium 4-ethoxycarbonylbenzenesulfonate (75.1 g) dissolved in a 3:1 (v/v) mixture of acetonitrile (300 mL) and sulfolane (100 mL). As the solution was stirred, POCl3 (55 mL) was added slowly and the stirring mixture was heated at 75° C. under a nitrogen atmosphere for 3 hours. The heterogeneous reaction mixture was allowed to cool to room temperature and was then concentrated using a rotary evaporator. The flask was then cooled in an ice bath and ice was added to the mixture in the flask. The product crystallized as a white solid and was filtered and washed with cold deionized water. The product was dried under vacuum at room temperature and 3 mmHg for 2 hours to afford 76 g of white solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH2:2][CH3:3].[CH2:10]=[O:11].[K]>C(O)C>[OH:11][CH2:10][N:7]1[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]1=[O:9]
Reactant: C=O
Reactant: CCCC1CNC(=O)C1
Agent: [K]
Solvent: CCO
Product: CCCC1CC(=O)N(CO)C1
Yield: 100 %

Procedure:
A solution of 4-propylpyrrolidin-2-one x1 (30 g, 0.236 mol), aqueous formaldehyde (37%, 3.5 eq, 0.826 mol, 71 ml), and potassium hydroxyde (0.05 eq, 0.012 mol, 0.662 g) in 150 ml of ethanol is refluxed for 24 hours. After evaporation of the solvent under reduced pressure, the crude product is poured in saturated NaHCO3 aqueous solution and then extracted with CH2Cl2. The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure to yield compound 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>>[OH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25]
Reactant: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCCCO)c2ccc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of (7-chloro-thieno[3,2-b]-pyridin-2-yl)-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone 4a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-hydroxy-propyl)-amide 63b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.38 (1H, d, J=5.5 Hz), 7.84–7.74 (2H,m), 7.28 (1H, d, J=2.1 Hz), 6.94 (1H, dd, J=2.1, 8.6 Hz), 6.60 (1H, d, J=5.5 Hz), 4.45–4.42 (1H, m), 3.93–3.91 (2H, m), 3.71–3.60 (8H, m), 3.45 (2H, m), 2.56 (3H, s), 2.02–1.98 (2H, m), 1.72–1.68 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 509. found 509.