Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.CCN(CC)CC.Cl.[NH2:21][OH:22]>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[N:21]\[OH:22])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)/C(=N/O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To the solution of 6-methoxy-2,3-dihydro-1H-inden-1-one (6.5 g, 40 mmol) in 100 mL of MeOH was added Et3N (11.1 mL, 80 mmol) and hydroxylamine hydrochloride (3.9 g, 56 mmol). The mixture was stirred at rt for 2 h. The mixture was evaporated and redissolved in EtOAc, the organic phase was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give (E)-6-methoxy-2,3-dihydro-1H-inden-1-one oxime (intermediate 16) (6.6 g, 93%).
Reaction SMILES: CI.[O:3]=[C:4]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:23]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[OH:21])=[O:8].[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:3]=[C:4]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:37])([F:38])[F:36])[CH2:24][CH2:23]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][C:10]=1[O:21][CH3:40])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2)ccc1C(=O)NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.84 %

Procedure:
Methyl iodide (21 mg, 0.009 ml, 0.148 mmol) was added to a stirred solution of 3-hydroxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (prepared by the method as described above) (51 mg, 0.1 mmol) and K2CO3 (20 mg, 0.144 mmol) in DMF (3 mL) and the resulting mixture was stirred at 80° C. for 2 hrs. The mixture was filtered, the filtrate was diluted with cold water and filtered the solid precipitated out, dried to afford 41 mg (78.84% yield) of 3-methoxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. 1H NMR: (DMSO-d6): δ 8.8-8.7 (bs, 1H), 8.04-7.98 (bs, 1H), 7.88-7.74 (dd, 4H), 7.72-7.64 (t, 1H), 7.58-7.46 (m, 3H), 7.46-7.34 (m, 3H), 4.32-4.18 (bs, 1H), 4.04 (s, 3H), 3.8-3.66 (bd, 2H), 3.66-3.54 (bt, 3H), 3.22-3.04 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)(=[O:23])=[O:22].F[C:35](F)(F)[C:36]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:35]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)(=[O:23])=[O:22])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:36]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=497.1 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([NH2:38])=[O:37])=[CH:39][CH:40]=2)=[O:25])[CH2:7]1
Reactant: O=C(NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccc(C(N)=O)cc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CNC(=O)NC[C@@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 74.1 %

Procedure:
Example 55 was prepared in an analogous manner to Example 43 from Intermediate 14 (0.109 g) and 4-aminomethylbenzamide (0.045 g) using N,N-dimethylformamide as solvent to yield the title compound (0.0828 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH:28]1[C:32]2=[N:33][CH:34]=[C:35](B(O)O)[CH:36]=[C:31]2[CH:30]=[CH:29]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:35]4[CH:36]=[C:31]5[CH:30]=[CH:29][NH:28][C:32]5=[N:33][CH:34]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: OB(O)c1cnc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc5[nH]ccc5c4)nc3s2)CC1

Procedure:
5-Chloro-2-((4-methylsulfonylpiperazin-1-yl)methyl)-7-morpholinothiazolo[5,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridin-5-yl boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 15 minutes. Acetonitrile was added and the solution was filtered. The resulting organic layer was purified by reverse phase silica gel chromatography to give the product 116.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1cccc(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1cccc(Cl)c1
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution of 483 mg (1.4 mmol) of 1-[(3-chlorophenyl) methyl]-5-methoxy-2-methyl-1H-indole-3-acetamide and 5.6 mL of 1M BBr3/methylene chloride in 20 mL of methylene chloride was stirred for 5 hours, 2 mL of 1M BBr3/methylene chloride added and stirred 16 hours. The mixture was poured into water, extracted with ethyl acetate, the ethyl acetate solution washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted using a gradient, 50% EtOAc/hexane→4EtOAc, to give 155 mg of starting material, 1-[(3-chlorophenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetamide, and 220 mg (48% yield) of 1-[(3-chlorophenyl)methyl]-5-hydroxy-2-methyl-1H-indole-3-acetamide, mp, 173-177° C.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][N:3]=1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH2:27]>>[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26]/[N:27]=[C:2]1\[NH:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)=[CH:9][C:8]\1=2
Reactant: COC(CN)OC
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)C(Cl)=NCCO3)cc1
Product: COC(C/N=C1\NCCOc2ccc(-c3ccc(C(F)(F)F)cc3)cc21)OC

Procedure:
A solution of 5-chloro-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine (11.7 mmol) in 2,2-dimethoxyethanamine (20 mL) was heated at 100° C. for 1 hour. The reaction mixture was concentrated to give (Z)-2,2-dimethoxy-N-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ylidene)ethanamine as an oil. The crude material was dissolved in toluene (80 mL) and PPTS (6.0 g) was added and the mixture was refluxed for 5 h. The reaction mixture partitioned between ethyl acetate and brine and filtered through celite. The organic layer was dried with sodium sulfate and concentrated before being purified by silica gel chromatography (Rf=0.15 in 2:1 hexanes/ethyl acetate) to give 10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine as a white solid (2.3 g, 60% over three steps). C18H13F3N2O×TFA. 331.1 (M+1). 1H NMR (DMSO) δ 8.53 (d, J=2.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 2H), 7.91 (dd, J=8.0, 2.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.77 (d, J=12.0 Hz, 2H), 7.30 (d, J=8.8 Hz, 1H), 4.65 (m, 4H). 19F NMR (DMSO) δ −59.21 (s, 3F).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)=[CH:10][N:9]=1.C(N(CC)CC)C>O1CCCC1>[Cl:7][C:8]1[N:9]=[C:10]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=2)=[CH:12][N:13]=1
Reactant: COC(=O)CS
Reactant: COC(=O)Cc1ccc(-c2cnc(Cl)nc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CSc1nc(Cl)ncc1-c1ccc(CC(=O)OC)cc1
Reaction time: 4 h

Procedure:
Methyl thioglycolate (0.18 ml) was added to a solution of the product from step (iii) (0.6 g) and triethylamine (0.56 ml) in tetrahydrofuran (10 ml) at room temperature. The mixture was stirred for 4 hours and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 20-30% ethyl acetate in isohexane. Yield 0.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:18]Cl>C(Cl)Cl>[Cl:18][C:6]1[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=1
Reactant: COc1ccc(CCCCCCO)cc1OC
Reactant: ClCl
Solvent: ClCCl
Product: COc1cc(Cl)c(CCCCCCO)cc1OC
Reaction time: 16 h

Procedure:
To 1.40 g of 6-(3,4-dimethoxyphenyl)hexan-1-ol in 25 mL of methylene chloride cooled in a ethanol-dry ice bath was added 4.6 mL of 1.35M chlorine in methylene chloride. The reaction mixture was kept at -75° for 1.5 hours, at -18° for 16 hours and then at 0° for 24 hours. After concentration under reduced pressure, the crude product was purified by HPLC to give 6-(6-chloro-3,4-dimethoxyphenyl)hexane-1-ol as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave a molecular ion at m/z 272 (C14H21ClO3).
Reaction SMILES: Cl[C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C@H:11]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C@@H:12]2[OH:21])[CH2:4][C@@H:3]1[OH:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:28])[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: C[C@]12C[C@H](Cl)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Product: CN1CCN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]43)C[C@@H]2O)CC1

Procedure:
The compound was prepared according to Example 5 from 2β-chloro-3α-,17β-dihydroxy-16β-piperidino-5α-androstane and from N-methyl-piperazine.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:42][C:43]1[CH:44]=[C:45]([NH:50][CH3:51])[C:46]([NH2:49])=[CH:47][CH:48]=1>CN(C=O)C>[Br:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][C:6]([CH:4]2[CH2:3][C:2](=[O:1])[CH2:5]2)=[O:8])=[C:45]([NH:50][CH3:51])[CH:44]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: CNc1cc(Br)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1cc(Br)ccc1NC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a stirred solution of 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N-diisopropylethylamine (4.2 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 min. A solution of 4-bromo-N2-methylbenzene-1,2-diamine (2.0 g) in DMF (2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo, and the residue was diluted with DCM (200 ml) and washed with saturated NH4Cl (100 ml), saturated NaHCO3 (60 ml), water (100 ml) and brine (100 ml). The DCM layer was then dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.7 g) as an off-white solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:21][CH2:20][CH2:19][C:7]3([CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH2:8]3)[CH2:6]2)OCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:17][C:15]([CH3:18])([CH3:16])[CH2:14][CH2:13][CH2:12][CH:9]1[CH2:10][CH2:11][C:7]2([CH2:19][CH2:20][CH2:21][C:5](=[O:1])[CH2:6]2)[CH2:8]1
Reactant: CC(C)(O)CCCC1CCC2(CCCC3(C2)OCCO3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(O)CCCC1CCC2(CCCC(=O)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of 5-(1,4-dioxa-dispiro[4.1.4.3]tetradec-9-yl)-2-methyl-pentan-2-ol (18) (420 mg, 1.42 mmol) in acetone (9 mL) was added H2O (catalytic amount) and p-toluenesulfonic acid (catalytic amount). The reaction mixture was stirred at room temperature overnight and then dried over anhydrous MgSO4. The solution was filtered through silica and the filtrate concentrated under reduced pressure. The resulting residue was purified over silica (isooctane/EtOAc, 7:3) to afford 312 mg (86% yield) of the desired ketone isomer as a colorless oil which was characterized as follows:
Reaction SMILES: C1(C(C)C)C=CC=CC=1.[Na].[O-]O.C1(C(C)C)C=CC=CC=1.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1([CH2:36][CH2:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[C:24]1([CH2:23][CH2:22][CH:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:37][C:38]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)([CH3:40])[CH3:39])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=Cc1ccccc1
Reactant: CC(C)(CCc1ccccc1)c1ccccc1
Agent: [Na]
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: CO
Product: CC(C)(CC(CCc1ccccc1)c1ccccc1)c1ccccc1
Temperature: 135 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A one-liter glass flask equipped with a stirrer, a dropping funnel with a gas introduction conduit, a reflux condenser with a calcium chloride tube, and a thermometer was charged with 240 grams (2.0 moles) of purified cumene, 4.0 grams (0.17 mole) of metallic sodium, and 3.6 grams (0.02 mole) of 80% cumene hydroperoxide while introducing argon gas through the gas introduction conduit, and the resulting mixture was heated to 135° C. A mixture of 69 grams (0.66 mole) of purified styrene and 60 grams (0.50 mole) of purified cumene was dropped thereto with stirring over 2 hours while maintaining the temperature of the reaction system at 135°-140° C. After dropwise addition was completed, the reaction mixture was further stirred while heating for 1 hour and then cooled to room temperature. An excess of metallic sodium was decomposed by dropping methanol in small portions while stirring. Introduction of argon gas was stopped, and the contents were transferred to a separating funnel and washed with water. The aqueous layer was removed, and the remaining oily layer was analyzed by gas chromatography. This gas chromatographic analysis showed that 67.6 grams (0.31 mole) of 1,3-diphenyl-3-methylbutane and 36.5 grams of (0.11 mole) of 1,3,5-triphenyl-5-methylhexane were formed. The total yield (per styrene) was 80 mole %.
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[CH:6][C:5]=1[OH:12].[F:13][C:14](F)([F:22])S(OC(F)F)(=O)=O>C(#N)C.O>[F:13][CH:14]([F:22])[O:12][C:5]1[C:4]([I:3])=[CH:9][C:8]([O:10][CH3:11])=[N:7][CH:6]=1
Reactant: O=S(=O)(OC(F)F)C(F)(F)F
Reactant: COc1cc(I)c(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1cc(I)c(OC(F)F)cn1
Reaction time: 0.03 h

Procedure:
4.8 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 600 mg (purity 93%, 2.22 mmol) of 4-iodo-6-methoxypyridin-3-ol in 4.8 ml of acetonitrile, the mixture was cooled in an ice bath and 863 μl (purity 75%, 3.56 mmol, 1.6 eq.) of difluoromethyl trifluoromethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added with vigorous stirring. The reaction mixture was stirred for 2 min and diluted with 33 ml of water. The aqueous phase was extracted twice with in each case 40 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The crude product was purified by flash chromatography (IR-50SI, petroleum ether/ethyl acetate 12-20%). Yield: 407 mg (purity 90%, 55% of theory)
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(C(=O)OC2CCN(C)C(=O)N2c2nnc(C(C)(C)C)s2)cc1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3 -methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Methoxybenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4 -thiadiazol-2-yl)-3-methyl-6-(4-methoxybenzoyloxy)-2(1 H)-pyrimidinone.
Reaction SMILES: [Mg].C1(S([N:11]2[C:26]([CH2:27][CH3:28])=[C:15]3[CH2:16][CH:17]([N:23]([CH3:25])[CH3:24])[C:18]4[CH2:19][O:20][CH:21]=[CH:22][C:13]([C:14]=43)=[CH:12]2)(=O)=O)C=CC=CC=1>CO.C(Cl)(Cl)Cl>[CH2:27]([C:26]1[NH:11][CH:12]=[C:13]2[CH:22]=[CH:21][O:20][CH2:19][C:18]3[CH:17]([N:23]([CH3:25])[CH3:24])[CH2:16][C:15]=1[C:14]2=3)[CH3:28]
Reactant: CCC1=C2CC(N(C)C)C3=C2C(=CN1S(=O)(=O)c1ccccc1)C=COC3
Agent: [Mg]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC1=C2CC(N(C)C)C3=C2C(=CN1)C=COC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Magnesium (turning) 246 mg was added to compound (55) in methanol 9 ml and the mixture was stirred at room temperature for 3 h. Ice was added to the reaction mixture which was diluted with chloroform. The insoluble materials were filtered off through cerite and the filtrate was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (2:1) to give the titled compound as a pale yellow oil 97.8 mg. Yield 79%. This was treated with 1 eq. oxalic acid to give the salt, which was recrystallized from ether-methanol to give colorless crystals, m.p. 236-237° C. (dec.).
Reaction SMILES: Br[C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:20][C@H:21]3[CH2:25][N:24]([C:26](=[O:44])[C@H:27]([CH:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)[NH:28][C:29]([O:31][CH2:32][C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=[CH2:36])=[O:30])[C@H:23]([C:45]([O:47][CH3:48])=[O:46])[CH2:22]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][C:9]([C:18]#[N:19])=[CH:8]3)[CH:3]=1.[CH:49]([Sn](CCCC)(CCCC)CCCC)=[CH2:50]>C1(C)C=CC=CC=1.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:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:7]([CH:8]=1)=[N:6][C:5]([O:20][C@H:21]1[CH2:25][N:24]([C:26](=[O:44])[C@H:27]([CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[NH:28][C:29]([O:31][CH2:32][C:33]([CH3:37])([CH3:38])[CH2:34][CH:35]=[CH2:36])=[O:30])[C@H:23]([C:45]([O:47][CH3:48])=[O:46])[CH2:22]1)=[C:4]1[C:13]=2[CH:14]=[C:15]([O:16][CH3:17])[C:2]([CH:49]=[CH2:50])=[CH:3]1)#[N:19]
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3cc(C#N)ccc3c3cc(OC)c(Br)cc23)C[C@H]1C(=O)OC)C1CCCC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3cc(C#N)ccc3c3cc(OC)c(C=C)cc23)C[C@H]1C(=O)OC)C1CCCC1

Procedure:
To a degassed solution of the product mixture from Step 2, methyl (4R)-4-[(8-bromo-3-cyano-9-methoxyphenanthridin-6-yl)oxy]-1-[(2S)-2-cyclopentyl-2-({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetyl]-L-prolinate (420 mg, 0.58 mmol) in PhMe (10 mL) was added vinyltributyltin (0.205 mL, 0.70 mmol) and tetrakis(triphenylphosphine)palladium (67 mg, 0.06 mmol). The mixture was then heated to reflux for 18 h. The solvent was then removed in vacuo and the crude material was purified on silica (gradient elution, 10-50% EtOAc/hex) to provide the title compound. LRMS (M+H)+=669.3.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1.[BH4-].[Na+].[Na+].[Cl-]>C1(C)C=CC=CC=1.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:30][CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: NCCc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C#Cc2ccc(CNCCc3ccc(Cl)cc3)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A solution of 4-[(4-butylphenyl)ethynyl]benzaldehyde (2.62 g, 10.0 mmol, intermediate to which may be obtained according to methods disclosed in EP03103780.7) and 2-(4-chlorophenyl)ethylamine (Aldrich, 1.56 g, 10 mmol) was heated at reflux in toluene (50 mL) for 12 hrs with azeotropic removal of water. The mixture was evaporated under vacuum and the residue was taken up in MeOH (60 mL) and chilled at 0° C. NaBH4(567 mg, 15.0 mmol) was added portionwise and the reaction mixture was stirred for 30 min at 0° C. and 3 hrs at rt. The reaction mixture was poured into a saturated solution of NaCl and extracted with Et2O. The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give the crude product. Purification by chromatography on silicagel (EtOAc/c-hex 30/70) gave 2.96 g (54%) of the title compound as a white solid. HPLC, Rt: 5.0 min (purity: 99.9%).