Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]2)=[CH:32][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Sodium hydride (60%, oily, 2.55 g) was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (11.61 g), 4-benzyloxybenzyl chloride (15.23 g) and N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for one hour. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-(4-benzyloxybenzyl)-4-phenylpyrrole-3-carboxylate (22.16 g, yield: 97%) was obtained from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 97–98° C.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[CH:16]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.O1CCCC1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCC.O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:24][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[CH:16]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)cc12
Yield: 85 %

Procedure:
To 750 mg (1.62 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 1-(a) were added 2.5 ml of tetrahydrofuran, 0.22 ml of ethylenediamine and 16.5 ml of tetrahydrofuran solution containing 1M tetrabutylammonium fluoride, and the mixture was refluxed for 48 hours. After completion of the reaction, water and hexane were added to the reaction mixture, precipitated solid was collected by filtration, and dried under reduced pressure. The obtained dried material was dissolved in ethanol, poured into water, and precipitated solid was collected by filtration. The obtained solid was washed with water, and dried under reduced pressure to obtain 459 mg of the title compound as a white solid. (Yield: 85%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: OCCCc1ccncc1
Agent: [Pd]
Solvent: CC(=O)O
Product: OCCCC1CCNCC1

Procedure:
4-Pyridinepropanol (10.0 g, 73 mmol) was dissolved in glacial acetic acid (50 mL). 10% Palladium on carbon (1.1 g) was added and the mixture hydrogenated under 50 psi hydrogen gas for 6 days. The mixture was filtered through Celite and the solvent removed by rotary evaporation. The crude product 3-piperidin-4-yl-propan-1-ol (acetic acid salt) was used as obtained. 1H NMR (500 MHz, CDCl3) □ 6.3 (br), 3.65 (2H, t), 3.36 (2H, m), 2.79 (2H, dt), 2.01 (3H, s), 1.85 (2H, m), 1.7-1.3 (7H, m).
Reaction SMILES: C(OC1C=C(C=CC=1OC(C)C)/C=[N:8]/[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)C.[Si:24]([O:31][C:32]1[C:33]([F:42])=[C:34]([CH:37]=[C:38]([CH2:40][CH3:41])[CH:39]=1)[CH:35]=O)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].NC1C=CC(C#N)=CC=1>>[Si:24]([O:31][C:32]1[C:33]([F:42])=[C:34]([CH:37]=[C:38]([CH2:40][CH3:41])[CH:39]=1)/[CH:35]=[N:8]/[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)ccc1OC(C)C
Agent: N#Cc1ccc(N)cc1
Product: CCc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(O[Si](C)(C)C(C)(C)C)c1

Procedure:
According to the procedure for Intermediate 1.1, Intermediate 188.3 (3.72 g, 13.17 mmol) and 4-aminobenzonitrile (1.56 g, 13.17 mmol) afforded 5.10 g of Intermediate 188.4 as an orange oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1)C=C.C1(O)C=CC=CC=1.N1CCCCC1>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1
Reactant: C=CCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Oc1ccccc1
Solvent: C1CCNCC1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3O)nc12
Yield: 9.2 %

Procedure:
A mixture of 5-(2-allyloxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.25 g, 0.0008 mol), phenol (0.145 g, 0.0015 mol), piperidine (0.131 g, 0.0015 mol) and tetrakis(triphenylphosphine)palladium(O) (0.046 g, 0.00004 mol) in absolute ethanol (5 ml) was refluxed overnight under nitrogen. The mixture was allowed to cool, the solvent evaporated under vacuum and the residue dissolved in ethyl acetate (40 ml). This solution was washed with water (3×10 ml), 1M HCl (3×10 ml) and brine (1×10 ml). After drying (Na2SO4) and filtration, the filtrate was evaporated under vacuum to give the crude product. The title phenol (0.021 g, 10%) was obtained after trituration with diethyl ether and crystallisation from ethyl acetate/pentane, m.p. 233°-238° C. Found: C,63.17; H,5.65; N, 19.52. C15 H16N4O2 requires C,63.36; H, 5.67; N, 19.71%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])(C)(C)C>C(Cl)Cl>[NH2:14][C@@H:15]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17]
Reactant: CN(C)C(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 130.4 %

Procedure:
Trifluoroacetic acid (1 mL, 10 mmol) was added to a solution of tert-butyl[(1S)-1-(biphenyl-4-ylmethyl)-2-(dimethylamino)-2-oxoethyl]carbamate (50 mg, 0.1 mmol) in methylene chloride (2 mL). The reaction was stirred for 2 h., and was concentrated under reduced pressure to give the crude product (2S)-2-amino-3-biphenyl-4-yl-N,N-dimethylpropanamide (35 mg, 97%). Analytical LCMS (M+H)+: m/z=269.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](I)=[C:7]([CH:19]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])#[N:2].[C:21]([NH:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([NH:24][C:25](=[CH:30][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C)NC(C)=O

Procedure:
15.3 g (39.5 mmol) of t-butyl [2-(5-cyano-2-iodophenoxy)ethyl]carbamate, 9.05 g (63.2 mmol) of methyl 2-acetamidoacrylate, 11 ml (79 mmol) of triethylamine, 1.3 g of palladium (II) acetate and 7.30 g of tris(2-methylphenyl)phosphine were stirred in 150 ml of acetonitrile overnight. The solvent was distilled off, and the residue was treated by the silica gel chromatography (ethyl acetate/hexane) to obtain the crude product, which was washed with hexane and a mixed solvent of hexane/ethyl acetate, and then vacuum-dried to obtain the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl.[CH2:30]([C:34]1[C:35]([CH2:47]Cl)=[C:36]([Cl:46])[N:37]=[N:38][C:39]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:31][CH2:32][CH3:33].CCCCCC>CC#N.CCOC(C)=O>[CH2:30]([C:34]1[C:35]([CH2:47][N:12]([CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)=[C:36]([Cl:46])[N:37]=[N:38][C:39]=1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1c(-c2ccccc2)nnc(Cl)c1CCl
Reactant: CCOc1cccc(CNCc2ccc3c(c2)OCCO3)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCc1c(-c2ccccc2)nnc(Cl)c1CN(Cc1cccc(OCC)c1)Cc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (0.211 g, 0.7 mmol) and K2CO3 (0.69 g, 3 mmol) is added to a solution of 5-butyl-3-chloro-4-chloromethyl-6-phenyl-pyridazine hydrochloride (0.175 g, 0.6 mmol) in CH3CN (15 mL). The mixture is stirred at 80° C. overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The organic layer is washed with water (15 mL), brine (15 mL), then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Preparative TLC (3:1 Hexane, EtOAc) of the residue provides a light yellow oil. LC-MS (M+1) 558 1H NMR (δ, CDCl3) 7.36–7.48 (m, 5H), 7.18 (t, J=7.2 Hz, 1H), 6.72–6.89 (m, 6H), 4.21 (s, 4H), 4.01 (q, J=7.2 Hz, 2H), 3.80 (s, 2H), 3.56 (s, 2H), 3.50 (s, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.41 (t, J=6.9 Hz, 3H), 0.84–1.02 (m, 4H), 0.58 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][CH2:13][Mg+].[Br-].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH2:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C=O
Reactant: CC[Mg+]
Agent: O=[Cr](=O)([O-])Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)cc1OC
Reaction time: 1 h
Yield: 66.1 %

Procedure:
4-Chloro-2-methoxy-benzaldehyde (0.54 g, 3.2 mmol) in 10 mL of THF was treated with 3.0 M EtMgBr (2 mL, 6.0 mmol) at room temperature. The solution was stirred for 1 hour and quenched with MeOH. The solution was poured into water, treated 10 mL of 10% HCl, extracted with EtOAc several times. The combined organic layers were washed brine, dried (MgSO4), filtered, and concentrated. The residue was diluted with CH2Cl2, treated with PCC (1.33 g, 6.4 mmol) for 2 hours. The reaction mixture was filtered through a pack of silica gel to give 0.42 g of the title compound. MS (DCI) m/e 199 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[O-2].[Mg+2].[CH3:25][O:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][O:32][C:33](N=[N+]=[N-])=[O:34])=[CH:29][CH:28]=1>O1CCOCC1>[CH3:25][O:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][O:32][C:33]([NH:18][C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:34])=[CH:29][CH:28]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)N[C@@H](COCc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
O-Benzyl-L-serine trifluoroacetic acid salt, 3.09 g. in 20 ml. of water containing 0.8 g. of magnesium oxide is treated with 2.28 g. of p-methoxybenzyloxycarbonyl azide in 20 ml. of dioxane. The mixture is stirred at room temperature for four days. It is then filtered and the filtrate diluted with ethyl acetate and the solution washed with cold 0.2 N hydrochloric acid and with saturated sodium chloride solution. The ethyl acetate solution is dried and evaporated to an oil. The crude product is triturated with isopropyl ether and stored in the cold to yield crystalline material. Separation by filtration gives 1.75 g., mp. 70°-72° C. This product is recrystallized from aqueous ethanol to give 1.54 g. and is again recrystallized from ethyl acetate-hexane to yield 1.25 g. of the above named product, mp. 72°-73° C.
Reaction SMILES: CS(N)(=O)=O.[CH:6]1([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:8][CH2:7]1.C([C:15]1([CH2:25][O:26][C:27]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:30]([C:31]([OH:33])=O)=[C:29]([F:39])[CH:28]=2)[CH:22]2[CH2:23][CH:18]3CC(C[CH:16]1[CH2:17]3)[CH2:21]2)#N.C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC1CCCC2>>[C:15]12([CH2:25][O:26][C:27]3[C:35]([CH:36]4[CH2:37][CH2:38]4)=[CH:34][C:30]([C:31]([NH:12][S:9]([CH:6]4[CH2:8][CH2:7]4)(=[O:11])=[O:10])=[O:33])=[C:29]([F:39])[CH:28]=3)[CH2:21][CH:22]1[CH2:23][CH2:18][CH2:17][CH2:16]2
Reactant: NS(=O)(=O)C1CC1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with cyclopropanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.037 g, 37%): 1H NMR (300 MHz, DMSO-d6) δ 11.81 (br s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.87 (d, J=13.1 Hz, 1H), 3.92-3.73 (m, 2H), 3.13-3.01 (m, 1H), 2.10-1.96 (m, 1H), 1.95-1.49 (m, 4H), 1.40-1.03 (m, 8H), 1.03-0.93 (m, 1H), 0.94-0.82 (m, 2H), 0.77-0.59 (m, 3H), 0.41-0.32 (m, 1H); MS (ES+) m/z 408.1 (M+1)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccc(O)cc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and tyramine in DME. ES-MS m/e (%): 332 (M+H+, 100).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH3:6][C:7]1[CH:8]=[C:9](O)[C:10]2[CH:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[N:12]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Br:3][C:9]1[CH:8]=[C:7]([CH3:6])[N:12]=[C:11]2[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=12
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(O)c2cnn(Cc3ccccc3)c2n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(Br)c2cnn(Cc3ccccc3)c2n1

Procedure:
Phosphorus oxybromide (5.31 g, 18.54 mmol) was added to a suspension of 6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.08 g, 12.87 mmol) and toluene (25 mL). The contents were heated to reflux for 1 h, wherein 10 mL DMF were added during this process. The solvent was removed under reduced pressure. The crude residue was suspended in 30 mL water containing ice. The contents were adjusted to pH=10 by addition of sat. NaHCO3. The solid product was filtered and dried under hi-vacuum. The final product was collected as 3.55 g (91%). LCMS E-S (M+H)=302.1/304.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 (s, 3H), 5.65 (s, 2H), 7.16-7.35 (m, 5H), 7.48 (s, 1H), 8.12 s, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[NH:4][C:3]1=[O:14].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[S:32](Cl)(=[O:34])=[O:33]>>[NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([S:32]([C:25]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=2[O:23][CH3:22])(=[O:34])=[O:33])[C:3]1=[O:14]
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Product: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2S(=O)(=O)c1ccc(OC)cc1OC

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and 2,4-dimethoxybenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/ hexane/iso ether mixture. M.p.=196°-198° C.
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)#[C:2][CH3:3].Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:36])([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.CC(C)([O-])C.[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[C:1]([CH:4]1[N:9]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:36])([C:32]([F:33])([F:35])[F:34])[C:28]([F:31])([F:29])[F:30])=[CH:23][CH:22]=2)[CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:5]1)#[C:2][CH3:3]
Reactant: CC#CC1CN(C(=O)OCc2ccccc2)CCN1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC#CC1CN(C(=O)OCc2ccccc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
A 150-mL reaction vessel was charged with benzyl 3-(prop-1-yn-1-yl)piperazine-1-carboxylate (2.88 g, 11.2 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.36 g, 13.5 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine, RuPhos (0.530 g, 1.14 mmol, Sigma-Aldrich, St. Louis, Mo.), RuPhos Palladacycle (0.417 g, 0.572 mmol, Strem Chemical Inc, Newburyport, Mass.), sodium tert-butoxide (2.73 g, 28.4 mmol, Strem Chemical Inc, Newburyport, Mass.) and toluene (35 mL). The mixture was degassed by bubbling Ar through the solution for 10 min. The vessel was sealed and heated at 100° C. for 1.5 h. The reaction mixture was cooled to room temperature and water (100 mL) was added. The aqueous phase was extracted with EtOAc (3×100 mL) and the combined organic phases were washed with saturated aqueous sodium chloride (150 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (100 g of silica, 0 to 50% EtOAc in hexanes) to afford benzyl 3-(1-propyn-1-yl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate as a yellow solid.
Reaction SMILES: [C:1]([C@@H:5]1[NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=[CH:23][C:22]2[CH:30]=[C:18]([CH:19]=[CH:20][CH:21]=2)[C:17]2=[CH:31][C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][O:11][C@H:10]2[CH2:32][N:7]([C@H:8]([C:33]([O:35][CH3:36])=[O:34])[CH2:9]2)[C:6]1=[O:37])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>CO.[Pd]>[C:1]([C@@H:5]1[NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22]2[CH:30]=[C:18]([CH:19]=[CH:20][CH:21]=2)[C:17]2=[CH:31][C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][O:11][C@H:10]2[CH2:32][N:7]([C@H:8]([C:33]([O:35][CH3:36])=[O:34])[CH2:9]2)[C:6]1=[O:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NCCCCC=Cc1cccc(c1)-c1cccc(c1)CO2
Agent: [Pd]
Agent: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NCCCC/C=C/c1cccc(c1)-c1cccc(c1)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NCCCCCCc1cccc(c1)-c1cccc(c1)CO2
Reaction time: 6 h

Procedure:
Pd/C 10% (20% w/w) was added to a 0.025 M solution of methyl (9R,11S,14S,20E)-14-tert-butyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.1 9,12]octacosa-1(26),2(28),3,5,20,22,24-heptaene-11-carboxylate 103 in MeOH containing trifluoroacetic acid (1.0 eq.). The reaction mixture was stirred under a hydrogen atmosphere for 6 h. Solids were filtered off and the resulting solution was evaporated under reduced pressure. The residue was used without further purification in the following step. MS (ES+) m/z 507 (M+H)+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(OCCCCCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,4-Dihydro-2H-pyran (24.7 g) was added drop wise at room temperature to a solution of 4[(6-hydroxyhexyl)oxy]benzoic acid (35 g), toluene-4-sulfonic acid monohydrate (1.8) in diethylether (440 ml) and stirred at room temperature for 18 h. The resulting mixture was filtered over Hyflo Super Cel (FLUKA), organic solvents were removed in vacuum. The residue (60 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (1:1) as eluent, to give after crystallisation from ethyl acetate/hexane (5:40) 4{[6(tetrahydro-2H-pyran-2-yloxy)hexyl]oxy}benzoic acid.
Reaction SMILES: C(OC([NH:11][C:12]1([PH:20]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: NN1CCCC(NC(=O)OCc2ccccc2)([PH](=O)NC(=O)C2CCCCC2)C1=O
Agent: [Pd]
Solvent: CCO
Product: NN1CCCC(N)([PH](=O)NC(=O)C2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium black (50.0 mg) was added to a solution of (3S, P (SR))-3-benzyloxycarbonylamino-1-amino(cyclohexanecarbonylamino)phosphinyl-2-piperidone (250.2 mg, 0.5733 mmol) in ethanol (6 mL), and the resulting mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]3[N:8]([N:11]=[CH:12][N:13]=3)[CH:9]=[N:10][C:5]=2[S:4][CH:3]=1.[Cu][C:15]#[N:16]>CN(C=O)C>[N:13]1[CH:12]=[N:11][N:8]2[C:7]=1[C:6]1[C:2]([C:15]#[N:16])=[CH:3][S:4][C:5]=1[N:10]=[CH:9]2
Reactant: N#C[Cu]
Reactant: Brc1csc2ncn3ncnc3c12
Solvent: CN(C)C=O
Product: N#Cc1csc2ncn3ncnc3c12
Temperature: 150 °C

Procedure:
9-Bromothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (1.16 g, 4.55 mmol) was dissolved in DMF (23 mL), and copper(I) cyanide (817 mg, 9.1 mmol) was added. This mixture was heated to 150° C. for 23 h, whereupon the reaction mixture was concentrated under reduced pressure, and the residue purified by flash chromatography. LCMS method [4], retention time=0.890 min; MS(ESI) 202.0 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.36 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H).