Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH3:22][CH:21]([CH3:23])[CH2:20][C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])=[O:24]
Reactant: CC(C)CC(=O)Cl
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Product: CC1=C2C[C@@]3(C)C(=CC[C@H](OC(=O)CC(C)C)[C@@H]3C)C=C2OC1=O

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with isovaleryl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[F:11])[NH:7][CH2:6][CH2:5]2>C1COCC1.Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1c(F)c(Br)cc2c1NCC2
Agent: O=[Mn]=O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(Br)cc2cc[nH]c12
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a stirred solution of 5-bromo-6-fluoro-2,3-dihydro-1H-indole-7-carboxylic acid (5.8 g, 0.022 mol) in THF (120 mL) was added MnO2 (11.6 g, 0.134 mol). The reaction mixture was stirred at reflux overnight and then filtered (hot) through celite, washing with hot THF (2×75 mL). The filtrate was concentrated, giving a brown solid, which was suspended in 1M HCl (150 mL). The mixture stirred at reflux overnight to remove traces of Mn and then cooled to room temperature. The solid was filtered off, dried, and recrystallised from IPA, giving 3.5 g (61%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([O:27][CH3:28])=[C:16]2[CH:23]3[CH2:24][CH:19]4[CH2:20][C:21]([Cl:26])([CH2:25][CH:17]2[CH2:18]4)[CH2:22]3)[CH:5]=[C:6]([O:8]C(=O)C(C)(C)C)[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([O:27][CH3:28])=[C:16]2[CH:17]3[CH2:18][CH:19]4[CH2:20][C:21]([Cl:26])([CH2:22][CH:23]2[CH2:24]4)[CH2:25]3)[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: COC(=C1C2CC3CC1CC(Cl)(C3)C2)c1cc(Cl)cc(OC(=O)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=C1C2CC3CC1CC(Cl)(C3)C2)c1cc(O)cc(Cl)c1

Procedure:
Crude pivaloate 15 was hydrolyzed at room temperature with K2CO3 (1.45 g, 10.5 mmol) in 10 ml methanol. Evaporation of methanol, followed by standard workup and purification (silica gel, 30% EtOAc/hexanes) afforded 1.095 g (63% over 2 steps) of a slightly yellow oil which solidified upon standing. Trituration of the solid produced white crystalline enol ether phenol 16, mp 130° C.
Reaction SMILES: Cl.O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:9]=1>>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCNCC1COc1cccnc1
Reaction time: 12 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to 4-tert-butyl 1-benzyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (77 mg, 0.18 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure, dissolved in water, and basified with 1 N NaOH in water. The solution was extracted with EtOAc (3×), and the combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 40.5 mg (69%) of the title compound. LC-MS: RT=5.15 min, [M+H]+=328.1.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Cl)=[CH:3][CH:2]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)C=Cc1ccc(C)cc1

Procedure:
0.1122 g (5×10-4 mols) of palladium acetate, 6.61 ml (50 millimols) of p-tolyl chloride, 6.78 ml (62.5 millimols) of ethyl acrylate and 11.91 ml (50 millimols) of tri-n-butylamine in 100 ml of p-xylene are stirred for 3 hours at 120° C. The mixture is extracted by shaking with 50 ml of 2 N HCl, 25 ml of 2 N NaOH and 25 ml of water, and is then dried for 15 minutes with 5 g of magnesium sulphate. The crude product is distilled in vacuo. 6.08 g (64% of theory) are obtained as a colourless liquid. Analysis for C12H14O2 : calculated C 75.77%, H 7.52%; found C 75.73%, H 7.54%.
Reaction SMILES: C([O:3][P:4]([CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([C:28]4[O:29][C:30]([C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=5)=[N:31][N:32]=4)[CH:26]=[CH:27][C:21]=3[N:20]=2)=[C:14]([CH3:40])[CH:13]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[O:29][C:28]([C:25]3[CH:26]=[CH:27][C:21]4[N:20]=[C:19]([C:15]5[C:16]([CH3:18])=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[CH:13][C:14]=5[CH3:40])[NH:23][C:22]=4[CH:24]=3)=[N:32][N:31]=2)=[CH:34][CH:35]=1
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(C)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Cc1cc(CCCP(=O)(O)O)cc(C)c1-c1nc2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [(E)-3-(4-{6-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester (1.44 g, 2.5 mmol) in CH2Cl2 (15 mL) was added trimethylsilylbromide (1.62 mL, 12.5 mmol) and the mixture was stirred at RT for 18 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC using a gradient of 0-80% MeCN/water containing 0.7% NH4OH to give the title compound. MS: m/z 523.1 (M+1). H1-NMR (DMSO-d6): δ ppm 8.46 (s, 0.6H), 8.19 (d, J=8.59 Hz, 2H), 8.0 (d, J=8.21 Hz, 1H), 7.88 (s, broad, 0.4H), 7.72 (d, J=8.59 Hz, 2H), 7.05 (s, 2H), 2.64 (t, 2H), 2.11 (s, 6H), 1.78 (m, 2H), 1.41 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].C([O:14][C@@H:15]1[C@@H:24]([O:25]C(=O)C)[C@@H:23]([O:29][C@@H:30]2[O:47][C@H:46]([CH2:48][O:49]C(=O)C)[C@H:41]([O:42]C(=O)C)[C@H:36]([O:37]C(=O)C)[C@H:31]2[O:32]C(=O)C)[C@@H:22]([CH2:53][O:54]C(=O)C)[O:21][C@H:16]1[O:17][CH2:18][CH2:19]Br)(=O)C.C[O-].[Na+].CO.C=O>CN(C)C=O.O.C(OCC)(=O)C.C(CC(C)(C)C)(C)C>[C@@H:30]1([O:29][C@H:23]2[C@@H:22]([CH2:53][OH:54])[O:21][C@@H:16]([O:17][CH2:18][CH2:19][S:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)[C@H:15]([OH:14])[C@H:24]2[OH:25])[O:47][C@H:46]([CH2:48][OH:49])[C@H:41]([OH:42])[C@H:36]([OH:37])[C@H:31]1[OH:32]
Reactant: Nc1ccc(S)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C=O
Agent: C[O-]
Agent: [H-]
Solvent: CC(C)CC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(SCCO[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
p-Aminothiophenol (205 mg; 1.64 mmol) was dissolved in dimethylformamide (4 ml). Sodium hydride (70 mg; 2.9 mmol) was added and the mixture was stirred under nitrogen for 20 min at room temperature. 2-Bromoethyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-β-D-galactopyranoside 14 (640 mg; 0.86 mmol) in dimethylformamide (7 ml) was added and the reaction mixture was stirred under nitrogen for 2 h (TLC:SiO2, ethyl acetate:isooctane 3:1) and poured into cold water (40 ml). The water solution was extracted with ether (4×20 ml) and the combined ether solutions were washed with water (10 ml) and dried (sodium sulfate). Evaporation gave a residue that contained a series of partly de-acetylated compounds. Evaporation of the water solution gave an additional amount of partly de-acetylated material. The combined residues were de-acetylated (sodium methoxide/methanol) and the product (after evaporation) was filtered through a column (SiO2, ethyl acetate/methanol 2:3) which gave crystalline (needles) 26. Yield: 425 mg (99%). Recrystallization from methanol gave an analytical sample: mp 104°-106°, [α]D 23 -0.8° (c 1.1; H2O); 1H-NMR (DMSO-D6 plus D2O, 50° C., TMS) δ 7.13, 6.58 (d, 2H each, J=8.5 Hz, aromatic H), 4.28 (d, 1H, J=7.0 Hz, H1'), 4.28 (d, 1H, J=7.5 Hz, H1), 2.90 (t, 2H, J=7.0 Hz, CH2 --S) ppm. 13C-NMR (DMSO-D6 plus D2O) δ 149.2, 136.6, 124.7, 119.7 (aromatic C), 107.0, 105.5 (Cl, Cl'), 79.7, 77.8, 76.9, 75.9, 75.5, 74.2, 73.9, 71.4, 70.7, (C2-C5, C2'-C5', CH2O), 63.8, 63.1 (C6, C6'), 37.6 (CH2 --S) ppm.
Reaction SMILES: C(OC([N:8]1[CH:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]2[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:12]=2[S:11](=[O:35])(=[O:34])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O.[OH-].[Na+].C(Cl)Cl.CO>C(Cl)Cl>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[CH2:15][CH:14]1[C:13]2[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:12]=2[S:11](=[O:35])(=[O:34])[CH2:10][CH2:9][NH:8]1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3S(=O)(=O)CCN2C(=O)OC(C)(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2NCCS(=O)(=O)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.5 %

Procedure:
To a stirred solution of 9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9 tetrahydro-5λ6-thia-8-aza-benzocycloheptene-8-carboxylic acid tert-butyl ester (310 mg, 0.61 mmol) in dry CH2Cl2 (3 ml), was added trifluoroacetic acid (372 μL, 4.86 mmol). The resulting mixture was stirred at RT for 20 h under nitrogen. The reaction mixture was combined with water/NaOH 2N, extracted twice with CH2Cl2, and the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH: 9/1) gave the title compound as a pale yellow oil (118 mg, 47%).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[C:14]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([CH:22]1[CH2:27][CH2:26][N:25]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:24][CH2:23]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(N2CCC(C(=O)c3ccccc3)CC2)c2ccccc12
Yield: 7.5 %

Procedure:
The title compound (3 mg, 8% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 4-benzoylpiperidine (89 mg, 0.468 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:26])[C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 (0.190 g, 0.720 mmol) in dichloromethane (3 ml) was added benzoyl chloride (0.0920 ml, 0.792 mmol) and triethylamine (0.220 ml, 1.58 mmol). The reaction was stirred at 25° C. After 2 h, the reaction contents were poured into saturated sodium bicarbonate (6 mL). The aqueous layer was brought to pH 11 with 5 N NaOH and extracted with 10% methanol in dichloromethane (3×15 mL). Silica gel chromatography (gradient elution 30 to 60% EtOAc in hexanes with 2.5% TEA additive) afforded 210 mg of (S)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(phenyl)methanone 5. 1H NMR (CDCl3) δ 9.55 (s, 1H), 9.08 (d, J=5.9 Hz, 1H), 8.00 (d, J=5.1 Hz, 1H) 7.41-7.51 (m, 5H) 4.70 (m, 1H), 4.02 (app d, J=11.7 Hz, 1H), 3.86 (app d, J=12.1 Hz, 1H) 3.62-3.72 (m, 1H), 3.47 (dd, J=13.1, 3.3 Hz, 1H), 3.30 (td, J=12.6, 3.3 Hz, 1H), 1.61 (bs, 1H), 1.57 (d, J=6.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22]>ClCCl.CN(C)C1C=CN=CC=1>[Br:7][C:4]1[S:3][C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:25][CH3:26])=[N:6][CH:5]=1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: Nc1ncc(Br)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)Nc1ncc(Br)s1
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 2-amino-5-bromothiazole (1220 mg, 6.81 mmol) in dichloromethane (10 ml) was added triethylamine (1.235 ml, 8.86 mmol) and 4-dimethylamino pyridine (83 mg, 0.681 mmol), followed by addition of 5-chloro-2-methoxybenzoyl chloride (1397 mg, 6.81 mmol) and stirred overnight. The reaction was concentrated and water was added to the residue. The mixture was sonicated and filtered to obtain the title compound as off-white solid (1.56 g, 66%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.88 (m, 3H) 7.23 (d, J=8.81 Hz, 1H) 7.58-7.67 (m, 3H) 12.32 (s, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=2)[N:14]=[CH:13][N:12]=1.[CH3:22][C:23]1[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:26]2=[N:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=[C:25]2[N:24]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.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>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:29]3[CH:30]=[C:25]4[N:24]=[C:23]([CH3:22])[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:48])[CH3:47])[C:26]4=[N:27][CH:28]=3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: Cc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1COCC[Si](C)(C)C
Reactant: Ic1ccc2ncnc(N3CCc4ccccc4C3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCc6ccccc6C5)c4c3)cnc2n1COCC[Si](C)(C)C
Yield: 72.4 %

Procedure:
0.87 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline, 0.96 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridine, 0.52 g of sodium hydrogencarbonate and 0.29 g of Pd(PPh3)2Cl2 in 17 ml of dioxane and 2 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 3 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 0-30% in 20 min), giving 0.85 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline as white powder (yield 60%, content 86%); MS-FAB (M+H+)=523.2; Rf (polar method): 2.12 min.
Reaction SMILES: [CH2:1]([C:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][N:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([C:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:33][C:32]=3[F:34])=[CH:15][N:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: C=CCC1(c2ccc(F)cc2)CCN(C(C)c2ccc(Br)cn2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CCC1(c2ccc(F)cc2)CCN(C(C)c2ccc(-c3ccc(F)cc3F)cn2)C(=O)O1
Yield: 46 %

Procedure:
A solution of 6-allyl-3-(1-(5-bromopyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.24 mmol), 2,4-difluorophenylboronic acid (56.9 mg, 0.36 mmol), PdCl2(PPh3)2 (10 mg, 10%) and aqueous solution of Cs2CO3 (2 M, 0.2 mL) in 1,4-dioxane (3 mL) was heated to reflux overnight. After the solvents were evaporated, the crude product was purified by preparative TLC to give 6-allyl-3-(1-(5-(2,4-difluorophenyl)pyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (50 mg, 46%). LC-MS Method 3, tR=1.336 min, m/z=453.1. 1H NMR (CDCl3): 2.30-2.40 (m, 1H), 2.39-2.42 (d, 3H), 2.50-2.60 (m, 2H), 2.60-2.70 (m, 2H), 4.10-4.20 (m, 1H), 4.50-4.65 (m, 2H), 5.55-5.70 (m, 2H), 6.40-6.50 (d, 1H), 6.80-7.00 (m, 4H), 7.10-7.15 (m, 1H), 7.22-7.30 (m, 2H), 7.30-7.40 (m, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4([C:27](=[O:36])[NH:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)[CH2:26][CH2:25]4)=[O:23])=[CH:17][C:16]=3[F:37])[C:8]=2[CH:7]=1)=[O:5])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[F:37][C:16]1[CH:17]=[C:18]([NH:21][C:22]([C:24]2([C:27](=[O:36])[NH:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:25][CH2:26]2)=[O:23])[CH:19]=[CH:20][C:15]=1[O:14][C:13]1[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(C(=O)O)cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc21
Reaction time: 8 h
Yield: 77 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(2-fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.069 g, 0.10 mmol, 1.0 eq.), and a 1M tetrabutylammonium fluoride solution (5 ml). The reaction was allowed to stir at overnight. The reaction was diluted with ethyl acetate, washed with (2×) H2O (50 ml), 1M HCl (2×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo, affording 4-(2-fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid as a white solid (0.048 g, 74% yield). MS (ESI) for C30H31F2N5O6Si: 624 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][C:16]1[CH:17]=[C:18]([OH:25])[C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1>CN(C=O)C>[CH2:2]([O:25][C:18]1[C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=[C:16]([Cl:15])[CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Cl)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
1-(Bromomethyl)benzene (7.905 ml, 66.46 mmol) was added to a mixture of cesium carbonate (21.65 g, 66.46 mmol) and 5-chloro-2-nitropyridin-3-ol (11.6 g, 66.46 mmol) in DMF (50 mL). The reaction mixture was stirred overnight at ambient temperature, then partitioned between ethyl acetate and water, washed with water and brine, dried, and concentrated to afford 3-(benzyloxy)-5-chloro-2-nitropyridine (16.0 g, 91.0% yield) as a light yellow powder. 1H NMR (CDCl3) δ 5.25 (s, 2H), 7.41 (m, 5H), 7.53 (s, 1H), 8.04 (s, 1H).
Reaction SMILES: ClC1C=CC(C(OC2CNC2)C2C=CC(Cl)=CC=2)=CC=1.[N-]=C=O.Cl[C:25]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:26]=1[CH:27]([O:35][CH:36]1[CH2:39][N:38]([C:40]([NH:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1)[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH:27]([O:35][CH:36]2[CH2:39][N:38]([C:40]([NH:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:37]2)[C:26]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Agent: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)cc1
Agent: [N-]=C=O
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1

Procedure:
This material was prepared from 3-(4,4′-dichlorobenzhydryloxy)azetidine (36) and the corresponding commercially available isocyanate, using the procedure described for compound (5) (53.0 mg, 45%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[C:29]([CH2:33][OH:34])[CH:30]=[CH:31][CH:32]=3)[N:23]=2)=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]>C(Cl)Cl>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[CH:33]=[O:34])[N:23]=2)=[CH:20][CH:21]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cccc(CO)c3)no2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)Cc1ccc(-c2nc(-c3cccc(C=O)c3)no2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Florosil (400 mg) and pyridinium chlorochromate (195 mg, 0.903 mmol) were added to a solution of {3-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]phenyl}methanol (139 mg, 0.451 mmol) and methylene chloride (2.5 mL) and stirred at ambient temperature for 3 hours. The reaction mixture was filtered through a pad of silica gel. The pad was rinsed with methylene chloride (2×) and 1:1 ethyl acetate:hexanes (2×). The filtrate was concentrated in vacuo to give the desired compound as a crude residue.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]#[N:21]>>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[N:15]([CH3:14])[C:16]([C:20]#[N:21])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)=[O:13]
Reactant: Cn1cccc1C#N
Reactant: CC(C)(C)C(=O)c1ccc(Br)cc1
Product: Cn1c(C#N)ccc1-c1ccc(C(=O)C(C)(C)C)cc1

Procedure:
The title compound was prepared from 1-(4-bromophenyl)-2,2-dimethylpropan-1-one and 1-methyl-2-cyanopyrrole according to the coupling procedure described in example 1. MS m/z 267; HRMS: calcd for C17H18N2O+H+, 267.14919; found (ESI, [M+H]+), 267.1494.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:25]>>[ClH:25].[CH3:24][O:23][CH:20]1[CH2:19][CH2:18][N:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:22][CH2:21]1
Reactant: COC1CCN(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)CC1
Agent: Cl
Product: COC1CCN(c2ccc3c(c2)CNC3)CC1

Procedure:
Prepared in analogy to Example A3(e) from 5-(4-methoxy-piperidin-1-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 233.3 ([M+H]+, 100%).