Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:18])[C@@H:10]([CH:11]=[C:12]([Br:14])[Br:13])[C@H:9]1[C:15](Cl)=[O:16].[O:19]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][OH:32])[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1C=CC=CC=1>[CH3:7][C:8]1([CH3:18])[C@@H:10]([CH:11]=[C:12]([Br:14])[Br:13])[C@H:9]1[C:15]([O:32][CH2:31][C:29]1[N:30]=[C:26]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:27][CH:28]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Reactant: OCc1csc(Oc2ccccc2)n1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)OCc2csc(Oc3ccccc3)n2)[C@@H]1C=C(Br)Br
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
1.6 ml of pyridine was added dropwise at 0° C. to a solution of 1.7 g of (1R,3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylicacid chloride and 1 g of the product of Step B in 20 ml of benzene and the mixture was stirred for 2 hours at 20° C. and was poured into aqueous N hydrochloric acid solution. The decanted organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 9-1 hexane-ethyl acetate mixture to obtain 1.87 g of (2-phenoxy-4-thiazolyl)-methyl (1R,3R)2,2-dimethyl-3-(2,2-dibromoethenyl)-cyclopropane-1-carboxylate melting at ≃50° C. and having a specific rotation of [α]D20 =-9°±1° (c=1% in benzene).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]3=[O:11])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1CCCCN1CCCCl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1CCCN1CCN(c2ccc(F)cc2)CC1
Reaction time: 14 h

Procedure:
A mixture of 1-chloro-3-[2-oxopiperidin-yl]propane (2.1 g, 12 mmol), 1-(4-fluorophenyl)piperazine (2.16 g, 12 mmol), anhydrous Na2CO3 (0.618 g, 6.2 mmol) and Nal (0.18 g, 1.2 mmol) in dry DMF (10 ml) was stirred at 800.English Pound. for 14 hrs. The reaction mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHCl3 (2×35 ml). The extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl)piperazin-1-yl]-3-[2-oxopiperidin-1-yl]propane as an oil which was purified by column chromatography over silica gel using chloroform as eluent, yield 2.40 g (63.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-:12].[K+]>CO.O>[OH:12][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:9]=1[C:8]([OH:7])=[O:11]
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)C(=O)OC2
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(CO)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
A colorless, homogeneous solution of 6-methylisobenzofuran-1(3H)-one (0.95 g, 6.41 mmol), KOH (0.576 g, 10.26 mmol) in methanol (20.52 mL) and water (5.13 mL) was refluxed. After two hr, the reaction was cooled to room temperature, concentrated in vacuo, and acidified with 1 M aqueous KHSO4 to pH ˜3. The mixture was extracted with EtOAc (4×50 mL). The combined extract was dried over MgSO4 and concentrated in vacuo to give the desired product (0.632 g, 3.81 mmol, 59.4% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH:14]1[CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC2CCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
A mixture of methyl 3-bromo-4-hydroxybenzoate (Description 64, 2.3 g, 10 mmol), bromocyclobutane (2.0 g, 15 mmol) and potassium carbonate (2.42 g, 17.5 mmol) in DMF (25 ml) was stirred at room temperature for 3 days then at 70° C. for 6 h. The mixture was cooled, diluted with water (150 ml) and extracted with ethyl acetate (4×25 ml). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 25 ml), dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a gum (1.15 g). 1H NMR (CDCl3) δ 1.66-1.77 (1 H, m), 1.88-1.93 (1 H, m), 2.22-2.31 (2 H, m), 2.46-2.60 (2 H, m), 3.89 (3 H, s), 4.75 (1 H, app. pent, J 7.0 Hz), 6.74 (1 H, d, J 8.6 Hz), 7.91 (1 H, dd, J 8.6, 2.1 Hz), and 8.23 (1 H, d, J 2.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(C)(C)C>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][Br:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Br)c1
Agent: CC(C)(C)OOC(=O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5 ml (36.8 mmol) 5-bromo-m-xylene and 6.55 g (36.8 mmol) N-bromo-succinimide in 35 ml tetrachloromethane is added 0.138 ml (0.74 mmol) tert-butyl-perbenzoate. The mixture is irradiated using a heating lamp and stirred for 3 hrs at reflux temperature. The mixture is cooled to room temperature, filtered and evaporated. The product is isolated by chromatography on silica gel (flashmaster, hexane) to give the title compound as white crystals.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].N1C=CC=CC=1>O>[C:31]([O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)(=[O:33])[CH3:32]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.58 g) are added acetic anhydride (8.0 ml) and pyridine (2.0 ml). The mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the precipitated crystal is collected by filtration, and recrystallized from ethyl acetate/n-hexane to give 5-acetyloxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.56 g) as white powder, m.p. 193°-194° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[CH2:19]1)=[O:17].[CH3:38][N:39]=[C:40]=[O:41]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:22][CH:21]([OH:23])[CH:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)[CH2:28][CH2:29]3)[CH2:19]2)=[O:17])=[C:9]([NH:8][C:40]([NH:39][CH3:38])=[O:41])[CH:14]=1
Reactant: Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reaction time: 1 h
Yield: 11 %

Procedure:
A mixture of (3R,4R; 3S,4S)-(2-Amino-4-chloro-phenyl)-{3-[4-(4-chloro-benzyl)-piperazin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-methanone trifluoroacetate (22 mg, 0.05 mmol) was dissolved in DMF and methyl isocyanate (5.8 uL, 0.1 mmol) was added. The reaction mixture was shaken for 1 h and directly used for LC-MS purification to yield 3.4 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 506.2 (100).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[NH:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[NH:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:10]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Sc2cccc(Br)c2)c2ccc(Cl)cc2n1-c1ccccn1
Reaction time: 0.17 h

Procedure:
3-(3-Bromo-phenylsulfanyl)-6-chloro-2-methyl-1H-indole (0.500 g, 1.4 mmol) along with K2CO3 (0.488 g, 3.5 mmol) and 2-fluoropyridine (87 μL, 2.1 mmol) were dissolved in DMF (2 mL) and reacted in a microwave at 200° C. for 20 minutes. The reaction was returned to the microwave at 200° C. for an additional 10 minutes. Standard workup followed by silica gel chromatography (0-100% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.[CH3:16][O:17][C:18]1[C:23](B(O)O)=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[C:12]([C:4]1[CH:3]=[C:2]([C:23]2[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=[CH:6][C:5]=1[O:8][CH:9]([F:11])[F:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(Br)ccc1OC(F)F
Reactant: COc1ncccc1B(O)O
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: ClCCl
Solvent: CO
Product: COc1ncccc1-c1ccc(OC(F)F)c(C(C)(C)C)c1
Temperature: 115 °C
Yield: 57.5 %

Procedure:
step 2—A sealed tube containing 20 (129 mg, 0.464 mmol), 2-methoxy-3-pyridine boronic acid (37, 108 mg, 0.706 mmol, CASRN 163105-90-6), Pd(PPh3)4 (39 mg, 0.034 mmol) and Na2CO3 (147 mg, 1.387 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was heated in a microwave synthesizer at 115° C. for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 5% EtOAc) to afford 82 mg (58%) of 3-(3-tert-butyl-4-difluoromethoxy-phenyl)-2-methoxy-pyridine (22) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[Br:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.[BH4-].[Na+]>CCO.CO>[Br:11][C:12]1[S:16][C:15]([CH2:17][NH:10][C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: Nc1cc(F)c(F)cc1F
Reactant: O=Cc1ccc(Br)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Fc1cc(F)c(NCc2ccc(Br)s2)cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of 2 g (13.6 mmol) of 2,4,5-trifluorophenylamine and 2.66 g (13.9 mmol) of 5-bromothiophene-2-carbaldehyde in 30 ml of EtOH, 9.4 g of molecular sieves (0.3 nm) were added and the mixture was refluxed for 20 hours. After this time the reaction mixture was cooled to room temperature, filtered and the solvent was evaporated in vacuo. The oil obtained was dissolved in 30 ml of MeOH and 0.51 g (13.6 mmol) of NaBH4 were added in small portions, maintaining the temperature of the reaction at room temperature. The mixture was stirred at this temperature for 20 more hours. After this time the solvent was evaporated in vacuo and the residue was treated with 100 ml of water and extracted twice with ether. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and evaporated to dryness to give 3.2 g of an oil. This 3.2 g were combined with 3.5 g obtained in a subsequent preparation and the total product obtained (6.7 g) was purified by chromatography on silica gel using mixtures of hexane/AcOEt 5:1→1:1 as eluent Appropriate fractions were combined to give 0.95 g of the title product as an oil. (global yield 8.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(Cl)c1ccccc1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5ccccc5)c4)CC3)cccc2n1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and benzoyl chloride.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[Br:38][C:39]1[CH:40]=[CH:41][C:42]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:43]([CH:46]=1)[CH:44]=O.Cl>C1COCC1>[CH2:48]([O:47][C:42]1[CH:41]=[CH:40][C:39]([Br:38])=[CH:46][C:43]=1[CH:44]=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: Brc1ccc(OCc2ccccc2)c(C=Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a stirred suspension of benzyl triphenylphosphonium bromide (7.44 g, 17.2 mmol) in freshly distilled THF (60 ml), under argon, was added a solution of LiN(SiMe3)2 (18.2 ml, 1N). The resulting red solution was allowed to stir for 30 minutes, then a solution of 5-bromo-2-benzyloxybenzaldehyde (5.0 g, 17.2 mmol) in freshly distilled THF (15 ml) added. The reaction was stirred at ambient temperature for 60 hours, treated with 1N aqueous HCl (60 ml) and extracted with ethyl ether (2×). The combined etherial extracts were washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant:hexane) to give β-(2-benzyloxy-5-bromophenyl)styrene as a white solid (5.5 g, 88%).
Reaction SMILES: [CH2:1]([C:3]1([C:6](Cl)=[O:7])[CH2:5][CH2:4]1)[CH3:2].[C:9]([Cu])#[N:10]>C(#N)C.ClC=C(Cl)Cl>[CH2:1]([C:3]1([C:6]([C:9]#[N:10])=[O:7])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(C(=O)Cl)CC1
Reactant: N#C[Cu]
Solvent: ClC=C(Cl)Cl
Solvent: CC#N
Product: CCC1(C(=O)C#N)CC1
Yield: 77.3 %

Procedure:
90.5 g of 1-ethylcyclopropanecarboxylic acid chloride is stirred in 100 ml of acetonitrile:trichloroethylene (1:1) with 79.3 g of CuCN for 12 hours at 80° C. The cooled suspension is filtered, the filtrate is evaporated to dryness and the residue is distilled to yield 65 g of colourless 1-ethylcyclopropylcarboxylic acid cyanide having a boiling point at 60 millibars of 88° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[C:21]2[CH:34]=[C:33]3[C:24]([N:25]4[C:30]([CH2:31][O:32]3)=[N:29][NH:28][C:27](=[O:35])[C@H:26]4[CH3:36])=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[F:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]=1[C:21]1[CH:34]=[C:33]2[C:24]([N:25]3[C:30]([CH2:31][O:32]2)=[N:29][NH:28][C:27](=[O:35])[C@H:26]3[CH3:36])=[CH:23][CH:22]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4N4CCN(C(=O)OC(C)(C)C)CC4)ccc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4N4CCNCC4)ccc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4-[3-fluoro-2-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-7-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (enantiomer 1, 0.070 g, 0.141 mmol) in DCM (3 mL) was added TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo to give (R)-7-(2-fluoro-6-piperazin-1-yl-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.06 g, 85%) as a solid. 1H NMR (CD3OD, 400 MHz): δ 7.36 (m, 1H), 7.27 (m, 2H), 7.18 (s, 1H), 6.96 (m, 2H), 4.87 (m, 1H), 4.66 (d, J=13.0 Hz, 2H), 3.08 (s, 8H), 1.51 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.684 min; MS m/z: 396 [M+H]+. SFC (Table 1, Method 33) Rt=4.921 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:4]=2[O:3][CH2:2]1.[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)C2C(=C(C)C(OC)=CC=2)N=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)[C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[C:9]=2[N:10]=1)[CH3:12]
Reactant: Nc1cccc2c1OCO2
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)OCO3

Procedure:
The title compound (14) was prepared from benzo[1,3]dioxol-4-ylamine following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=566 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/I)[CH3:12].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/[C:9]#[C:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:10])[CH:5]=1)[CH3:12]
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)/C=C/I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)/C=C/C#Cc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1,3-dichloro-5-ethynyl-benzene (1.52 g, 8.9 mmol) in triethylamine (32.4 mL) was added PdC12(PPh3)2 (57.15 mg, 0.08 mmol), (E)-3-iodo-prop-2-enoic-acid ethyl ester (1.84 g, 8.1 mmol) and copper(l)iodide (7.7 mg, 0.04 mmol). The reaction mixture was stirred for 2 h at 50° C., whereafter the reaction mixture was cooled to room temperature, water (30 mL) added and the mixture extracted with diethyl ether (3×20 mL). The combined and dried organic phases were evaporated to give crude (E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester in 1.1 g yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:23][O:24][C:25](=[O:35])[CH2:26]P(OCC)(OCC)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>>[CH3:23][O:24][C:25](=[O:35])[CH:26]=[C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2)c1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)C=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(OC)c1
Yield: 25.4 %

Procedure:
(3,4-dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (0.50 g, 4.95 mmol), (diethoxyphosphoryl)acetic acid methyl ester (2.29 g, 9.90 mmol), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 9.90 ml, 9.90 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude yellowish oil was purified via preparative HPLC to give 3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acid methyl ester as a light yellow oil (0.45 g, 25%): 1HNMR (CDCl3) δ 6.89-6.72 (m, 2H, Ar), 6.49-6.36 (m, 4H, Ar), 6.28 (s, 1H, double bond proton), 3.92 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.75 (s, 6H, 2OCH3), 3.64 (s, 3H, OCH3). Anal. Calcd. For C20H22O6+1.06 H2O: C, 63.60; H, 6.45. Found: C, 63.22; H, 5.88.
Reaction SMILES: [CH3:1][O:2]CCO.[H-].[Na+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[C:18](=[O:37])[N:17]2[C:38]([O:40][C:41]2[CH:46]=CC([N+]([O-])=O)=CC=2)=[O:39])=[CH:12][CH:11]=1)#[N:9].O>O1CCCC1>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)[C:18](=[O:37])[N:17]2[C:38]([O:40][CH2:41][CH2:46][O:2][CH3:1])=[O:39])=[CH:14][CH:15]=1)#[N:9]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methoxyethanol (7 μL, 89 μmol) in dry tetrahydrofuran (500 μL) is cooled at 78° C. and treated with sodium hydride (60% in mineral oil, 9 mg, 0.14 mmol). After 30 min, 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 50 mg, 87 μmol) is added and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 8 mg; ESI mass spectrum [M+H]+=514; Retention time HPLC: 0.64 min (X012_S01).