Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O.CN(C=O)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:5]([OH:6])[CH2:4][CH2:3][C:2]([F:9])([F:8])[F:1])=[CH:19][CH:18]=1
Reactant: O=C(O)CCC(F)(F)F
Reactant: Brc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CCC(F)(F)F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4,4,4-trifluorobutanoic acid (1.0 g), oxalyl dichloride (0.820 mL) and bromobenzene (3.71 mL) was added DMF (0.008 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aluminum chloride (1.408 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water at 0° C., the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a mixture of the residue, ethanol (15 mL) and THF (5 mL) was added sodium borohydride (0.266 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water at 0° C., the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.49 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>COC(OC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd]
Agent: COC(C)OC
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 127.3 %

Procedure:
12.50 g (61.9 mmol) of 1-bromo-4-nitrobenzene were added to 358 mg, (310 μmol, 0.5 mole %) of tetrakis (triphenyl-phosphine) palladium in 200 ml of dimethoxy-ethane. After stirring for 10 minutes, 11.3 g (92.8 mmol) of phenylboronic acid and 100 ml of ethanol were added. After a further 10 minutes, 263 ml, (526 mmol, 8.5 equiv) of 2M aqueous sodium carbonate were added and the suspension was heated at reflux for 20 minutes, then allowed to cool to room temperature. The mixture was taken into 250 ml of EtOAc and 200 ml of H2. The aqueous layer was extracted with 200 ml of EtOAc and the combined organics were washed twice with 250 ml of water and 100 ml of brine, dried over MgSO4, filtered and evaporated to obtain 15.7 g of the desired product as a solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([C:15]2[NH:16][C:17]([CH2:22][OH:23])=[C:18](CO)[N:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.COC(O)C>O1CCOCC1>[C:9]1([C:15]2[NH:16][C:17]([CH2:22][OH:23])=[C:18]([Cl:1])[N:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1nc(-c2ccccc2)[nH]c1CO
Agent: COC(C)O
Solvent: C1COCCO1
Product: OCc1[nH]c(-c2ccccc2)nc1Cl
Temperature: 50 °C
Yield: 30 %

Procedure:
2.34 Grams (17.5 mmol) of the N-chlorosuccinimide was added to a solution consisting of 3.26 g (16 mmol) of the 2-phenyl-4,5-bis(hydroxymethyl) imidazole, 24 ml of methoxyethanol and 37 ml of dioxane maintained at a temperature of 50° C. with stirring. The mixture was then reacted at the same temperature for 24 hours with stirring, and the reaction solution was concentrated under reduced pressure. The obtained reaction product was washed with water and was recrystallized from propyl alcohol to obtain a 2-phenyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 1.0 g (yield 30%).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH2:19]([O:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][CH2:36]Cl)=[O:23])[CH3:20].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:19]([O:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][CH2:36][S:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)n1c2ccccc2c(=O)n1CCCCl
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)n1c2ccccc2c(=O)n1CCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C

Procedure:
A mixture of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 66 mg, 0.25 mmol), 2-(3-chloro-propyl)-3-oxo-2,3-dihydro-indazole-1-carboxylic acid ethyl ester (alkylating agent G-01d, 70 mg, 0.25 mmol), a few crystals of potassium iodide and K2CO3 (69 mg, 0.5 mmol) in acetone (1 ml) is refluxed overnight. Evaporation of the solvent under a stream of air affords a residue that is purified by flash-chromatography on silica-gel (AcOEt/heptane, 3:2), yielding the title compound as a colourless oil: tR=2.75 min (LC-2), ESI-MS (pos.): m/z 511.15 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.37 (s, 9H, tBu), 1.37 (t, 3H, CH3), 2.14 (quint., 2H, CH2CH2N), 3.28 (m, 2H, SCH2), 4.30-4.40 (m, 4H), 4.69 (s, 2H, CH2CO2), 7.10 (m, 3Harom), 7.26 (t, 1Harom), 7.55 (m, 2Harom), 7.81 (t, 2Harom).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([CH:20]([OH:24])[CH2:21][CH2:22][CH3:23])=[C:16]([CH2:18][CH3:19])[N:17]=2)[CH:12]=[CH:13][N:14]=1.C([Mg]Cl)CC.C(OCC)C.CO.C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[C:16]([CH2:18][CH3:19])[N:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CCCC(O)c1c(CC)nc2c(-c3ccc(Cl)cc3Cl)nccn12
Agent: CCC[Mg]Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(=O)c1c(CC)nc2c(-c3ccc(Cl)cc3Cl)nccn12
Temperature: -78 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
Part A: 8-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxybutyl)imidazo[1,2-a]pyrazine: The aldehyde (1.6 g, 5.0 mmol, Part D of Example 1) was dissolved in anhydrous THF (25.0 mL) and cooled to −78° C. under nitrogen. To this mixture was added dropwise 2.0 M n-PrMgCl in diethyl ether (6.7 mL, 14.4 mmol) and stirred at −78° C. for 4 h. TLC (1:10 MeOH/CH2Cl2) revealed absence of starting material spot (Rf=0.88) and showed a new spot at Rf=0.05. The reaction mixture was quenched with saturated NH4Cl (30.0 mL), stirred the mixture for 10 min., extracted with EtOAc (3×100 mL), dried (MgSO4) and concentrated in vacuum to afford yellow oil. The residue was purified by flash column chromatography on a silica gel using 2.5% MeOH/CH2Cl2 to afford 1.63 g (84%, mp 159-160° C.) of desired product as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:20])[OH:19])[CH2:12]3)=[C:5]2[NH:4][C:3]1=[O:21].Br[CH2:23][C:24]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:25]=1[C:26]#[N:27]>>[C:24]([O:20][C:18](=[O:19])[NH:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[N:2]([CH3:1])[C:3](=[O:21])[N:4]([CH2:23][C:24]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:25]=4[C:26]#[N:27])[C:5]=23)[CH2:12]1)([CH3:31])([CH3:25])[CH3:23]
Reactant: Cn1c(=O)[nH]c2c(N3CCC[C@@H](NC(=O)O)C3)ccnc21
Reactant: N#Cc1cc(Cl)ccc1CBr
Product: Cn1c(=O)n(Cc2ccc(Cl)cc2C#N)c2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccnc21
Yield: 109.8 %

Procedure:
The specific operation referred to the step (5) described in Example 1 for details. 347 mg (R)-1-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperidin-3-yl carbamic acid ter.-butyl ester (1 mmol) and 251 mg 2-(bromomethyl)-5-chlorobenzonitrile (1.1 mmol) were charged. A column chromatography was performed to afford 300 mg titled product with a yield of 60.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=[CH:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1)=[CH:6]2.[C:26]1(=[O:32])[NH:30][C:29](=[O:31])[CH:28]=[CH:27]1>>[N+:20]([C:18]1[CH:19]=[C:14]([CH:13]2[CH:28]3[C:29](=[O:31])[NH:30][C:26](=[O:32])[CH:27]3[C:6]3[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[CH2:12]2)[CH:15]=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1)([O-:22])=[O:21]
Reactant: COc1ccc2[nH]c(C=Cc3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)cc2c1
Reactant: O=C1C=CC(=O)N1
Product: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C3
Yield: 89 %

Procedure:
The reaction of 5-Methoxy-2-[2-(3,5-dinitrophenyl)ethenyl]-1H-indole (II; Ar=3,5-dinitrophenyl) (40) prepared as described in example 46 with maleimide using the procedure described in example 69 gave 4-(3,5-Dinitrophenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-dione (IV; Ar=3,5-dinitrophenyl, R10═H) (41) in a 89% yield as a glassy solid which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:17])=[N:5][C:6]2[C:11]([C:12]=1[Cl:13])=[CH:10][C:9]([N+:14]([O-])=O)=[CH:8][CH:7]=2)#[N:2]>C1COCC1>[NH2:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([Cl:17])[C:3]([C:1]#[N:2])=[C:12]2[Cl:13]
Reactant: N#Cc1c(Cl)nc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: C1CCOC1
Product: N#Cc1c(Cl)nc2ccc(N)cc2c1Cl

Procedure:
The compound was obtained by reducing 3-cyano-2,4-dichloro-6-nitroquinoline as described in Example 3. UV (THF): λmax /ε=415.2 (3,189), 304.6 (7,675), 274.0 (43,425).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][NH:21][CH3:22])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:23]=[C:24]1[NH:28][CH:27]=[C:26]([C:29]([OH:31])=O)[O:25]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O.O>[Cl:8][C:6]1[CH:5]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][CH2:20][N:21]([CH3:22])[C:29]([C:26]3[O:25][C:24](=[O:23])[NH:28][CH:27]=3)=[O:31])[CH2:17][CH2:18]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CNCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1c[nH]c(=O)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(CCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1)C(=O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture containing (E)-3-(3,5-dichlorophenyl)-1-(4-(2-(methylamino)ethyl)piperidin-1-yl)prop-2-en-1-one (step 5) (118 mg, 0.346 mmol) and 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (step 7) (2.59 ml, 0.2M solution in DMF, 0.519 mmol) and DIPEA (0.483 ml, 2.77 mmol) in DMF (3.458 ml) was added T3P® (50% solution in EtOAc) (2.421 ml, 4.149 mmol). The reaction mixture was stirred at RT for 1 h. Water was added to quench the excess T3P® and the solvent was removed under reduced pressure. The residue was passed through an Isolute SCX-2 cartridge (10 g) and washed with excess MeOH. The solvent was removed under reduced pressure to afford a yellow oil which was dried using a high vacuum oven. The crude material was purified using preparative HPLC with water (+0.1% TFA) and acetonitrile (+0.1% TFA) and the product fractions were concentrated under high vacuum to afford the title compound as a clear film;
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:33]C)=[C:10]([CH:32]=1)[C:11]([NH:13][C:14]1[C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([F:26])[C:20]=2[F:27])[S:17][CH:18]=1)=[O:12]>ClCCl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:33])=[C:10]([CH:32]=1)[C:11]([NH:13][C:14]1[C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([F:26])[C:20]=2[F:27])[S:17][CH:18]=1)=[O:12]
Reactant: COC(=O)c1c(NC(=O)c2cc(Cl)ccc2OC)csc1-c1ccc(C)c(F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)c2cc(Cl)ccc2O)csc1-c1ccc(C)c(F)c1F
Reaction time: 1 h
Yield: 93 %

Procedure:
Under an atmosphere of argon, BBr3 (1 mL of a 1 M solution in dichloromethane) was added dropwise to ester 394 (82 mg, 182 μmol) at −78° C. The reaction was stirred for 1 h then quenched with a saturated solution of NaHCO3 (1 mL). The mixture was extracted with dichloromethane (3×5 mL) and combined extracts dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 395 (74.1 mg, 93%) as a solid: LRESIMS m/z 438.0 [M+H]+, calcd. for C20H15Cl1F2N1O4S1 438.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([NH:7][NH2:8])=[O:6].C(Cl)Cl.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=S)=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]2[O:6][C:5]([C:4]3[CH:3]=[C:2]([NH2:1])[C:11]([NH2:12])=[CH:10][CH:9]=3)=[N:7][N:8]=2)=[CH:22][CH:23]=1
Reactant: NNC(=O)c1ccc(N)c(N)c1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nnc(Nc3ccc(C(F)(F)F)cc3)o2)cc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 30 mL vial was added 0.5 g (3.01 mmol) of 3,4-diaminobenzhydrazide, 25 mL of DCM, and 0.61 g (3.01 mmol) of 4-trifluoromethyl-phenyl isothiocyanate. Allowed to stir at r.t. for 72 h. The pink suspension was concentrated in vacuo and used directly in the next reaction. MS (m/z) 370.0 M (+1), tR=1.10, Meth 10. To 20 mL scint vial was added 1.03 g (2.61 mmol) of the crude, 10 mL of DMF, and 0.55 g (2.87 mmol) of EDCI. Allowed to stir at 60° C., for 3 h. Added water, and filtered off solid. Used directly in next reaction. MS (m/z) 336.0 M (+1), tR=1.24, Meth 10
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]=[CH:10][C:9]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(O)ccc1C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(OCc2ccccc2)ccc1C(=O)OCC

Procedure:
A solution of 5.3 g (12.3 mmol) of N-(2,4-dimethoxy-benzyl),N-(2-ethoxycarbonyl-5-hydroxy-benzyl)glycine ethyl ester, 1.8 mL (15.4 mmol) benzylbromide, and 4.4 g (13.5 mmol) cesium carbonate in 35 mL of anhydrous DMF was stirred for 18 hours. The reaction mixture was partitioned between diethyl ether and water, and the organic fraction washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered through a pad of silica gel, and concentrated under reduced pressure to 6.4 g of the title compound. MS (ESI+) 522.5 e/z (M+1)
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5](=[O:18])[CH:6](Cl)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][SH:30])=[CH:24][CH:23]=1.COC(=O)C(SCCC1C=CC(F)=CC=1)CC1C=CC(C(C)(C)O[SiH2]C(C)(C)C)=CC=1>>[Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5](=[O:18])[CH:6]([S:30][CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cl)Cc1ccc(CCO)cc1
Reactant: Fc1ccc(CCS)cc1
Agent: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Product: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CCO)cc1)SCCc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-chloro-3-[4-(2-hydroxy-ethyl)-phenyl]-propionic acid 2,2,2-trichloro-ethyl ester (2.57 g, 7.14 mmol) and 2-(4-fluoro-phenyl)-ethanethiol (1.23 g, 7.85 mmol) as described for 3-[4-(tert-butyl-dimethyl-silanyloxy-methyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid methyl ester. After purification by flash chromatography with n-heptane/EtOAc 5:1 as the eluent the product was obtained as an oil (1.0 g, 29.2%). 1H NMR (300 MHz, CDCl3): δ 7.10-7.14 (m, 6H), 6.93-6.99 (t, 2H), 4.65-4.76 (q, 2H), 3.82-3.86 (t, 2H), 3.55-3.60 (dd, 2H), 3.17-3.25 (dd, 2H), 2.81-3.00 (m, 7H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[CH:33]5)[CH:27]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K35) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an orange solid (261 mg).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:15][NH:16][CH2:17]CC2C=CC=CC=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[CH3:14][O:13][C:10]1([CH2:15][NH:16][CH3:17])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COC1(CNCCc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCC1(OC)CCNC1

Procedure:
8.4 g (20 mmol) of 80% strength 1-benzyl-3-benzylmethylaminomethyl-3-methoxypyrrolidine are dissolved in 100 ml of methanol, 4.4 ml of concentrated hydrochloric acid are added and the mixture is hydrogenated on 4 g of 10% strength Pd/active carbon at 80° C. and 120 bar. The catalyst is filtered off, the solution is concentrated, a solution of 3 g of KOH in 50 ml of methanol are added, KCL is filtered off and the solution is concentrated. The residue is taken up in CHCl3 again, the mixture is filtered, the solution is concentrated and the residue is distilled.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[CH:6][CH:5]=1.[OH-:18].[K+]>O>[CH:3]([C:4]1[C:9]([C:10]([NH2:11])=[O:18])=[CH:8][N:7]=[CH:6][CH:5]=1)=[CH:2][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: N#Cc1cnccc1CC(O)c1ccccc1
Agent: [K+]
Solvent: O
Product: NC(=O)c1cnccc1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
4(2-hydroxy-2-phenyl-ethyl)-nicotinonitrile (2.0 g, 8.92 mmol) was dissolved in KOH (1M solution in MeOH, 36 mL, 35.67 mmol) and then stirred at room temperature for about 4 hours under the nitrogen atmosphere. The mixture was added with 100 mL of distilled water and extracted twice with 150 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, filetered, and then concentrated. A silica gel column chromatography (10% MeOH/MC) was performed on the resulting residue and obtained 1.66 g (83%) of 4-styryl-nicotinamide in white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([F:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH:6]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([F:25])=[C:20]([C:21]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:22])[CH:24]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(F)c(C(=O)O)c3)nc12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(F)c(C(=O)N4CCOCC4)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-2-fluorobenzoic acid (75 mg, 0.22 mmol 0 in DMF (3 mL) was added EDCI (46 mg, 0.24 mmol), HOBt (33 mg, 0.24 mmol), and morpholine (21 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed 1× with saturated sodium bicarbonate, 2× with brine, dried over MgSO4, filtered and evaporated to dryness to provide 92 mg of 7-(cyclopropylamino)-5-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=410)
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1.Cl.[N:24]1C=CC=C[CH:25]=1>>[C:25]([C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1)#[N:24]
Reactant: c1ccncc1
Reactant: Brc1cc(-c2ccccc2)cc2c(-c3ccccc3)coc12
Agent: Cl
Product: N#Cc1cc(-c2ccccc2)cc2c(-c3ccccc3)coc12

Procedure:
A mixture of 64 g. (0.18 mole) of the product of step B, 17.8 g. (0.2 mole) of cuprous cyanide and 35 ml. of pyridine is heated under a nitrogen atmosphere at 150° to 160° C. for one day. The mixture is poured into 1 liter of 3 N hydrochloric acid, extracted with 1 liter of dichloromethane, and the extracts are dried. Evaporation provides a residue which is chromatographed on silica gel, eluting with dichloromethane, to provide 7-cyano-3,5-diphenylbenzofuran as a pale yellow solid. The structural assignment is supported by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:30]([O:32][C:33](=[O:46])[C@@H:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:46])[C@@H:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:10][CH2:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:38][CH:37]=1)[CH3:31]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OCC=C(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccccc2)c2ccccc2)cc1)OCC
Yield: 67.4 %

Procedure:
Reaction of 3,3-diphenyl-prop-2-en-1-ol (210 mg, 1.0 mmol), tributylphosphine (303 mg, 1.50 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (250 mg, 1.05 mmol) and azodicarboxylic dipiperidide (378 mg, 1.50 mmol) in an identical manner to example 3 gave the title compound (290 mg, 67%).