Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH2:9]([C:7]1[N:6]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)[C:5]2[CH:20]=[CH:21][C:2]([C:2]3[CH:21]=[CH:20][CH:5]=[CH:4][CH:3]=3)=[CH:3][C:4]=2[N:8]=1)[CH3:10]
Reactant: CCc1nc2cc(Br)ccc2n1-c1ccc(CCO)cc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CCc1nc2cc(-c3ccccc3)ccc2n1-c1ccc(CCO)cc1
Temperature: 95 °C
Reaction time: 11 h
Yield: 53.3 %

Procedure:
To a solution of 2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4, 116 mg, 0.57 mmol) in 1,2-dimethoxyethane (DME, 6 ml) was added PhB (OH)2 (141 mg, 1.16 mmol), K2CO3 (240 mg, 1.75 mmol) and Pd(PPh3)4 (67 mg, 0.06 mmol). This mixture was stirred at 95° C. for 11 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (4×10 ml). The organic layer was dried (MgSO4) and concentrated to give brown oil. This mixture was purified by SiO2 preparative TLC (hexane/ethyl acetate=1/5) to afford 52 mg (27%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH3:8].C(O)(=O)C.N1C=CC=CC=1>Cl>[CH2:7]([O:9][C:10](=[O:14])[C:11]([C:12]#[N:13])=[CH:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH3:8]
Reactant: CC(C)(C)C=O
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=CC(C)(C)C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
A mixture of pivaldehyde (5.00 g, 58 mmol), ethylcyanoacetate (6.60g, 58.3 mmol), acetic acid (3.50 g, 58.3 mmol) and pyridine (4.60 g, 58.2 mmol) was heated at reflux for 1 h. A second portion of pivaldehyde (5.00 g, 58 mmol) was added. The refluxing of the mixture was continued for 18h. After cooling, the mixture was poured into 1N aqueous HCl (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers, were washed with 1N aqueous HCl, dried (MgSO4) and concentrated to give a colorless oil. The oil was purified by flash chromatography on SiO2 using hexane-EtOAc (9:1) as the eluant to give 2-cyano-4,4-dimethyl-2-pentenoic acid ethyl ester as a colorless oil (7.69 g, 73 % yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: CC(=O)Nc1cc(-c2ccc(F)c(F)c2)cc([N+](=O)[O-])c1
Yield: 76 %

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (0.7 g, 2.69 mmol) in 1,2-dimethoxyethane (15 ml) was degassed by N2 bubbling for 5 min. 3,4-Difluorophenylboronic acid (0.5 g, 3.23 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.44 g, 0.54 mmol, 0.2 eq.) and aqueous sodium carbonate (0.86 g, 8.07 mmol, 3.0 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 25% ethyl acetate in hexane) to give the product in 76% yield (0.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:18]=[O:19]>O1CCCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[N:11][CH:10]=2)[CH2:15][CH:18]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1ccncc1NC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2cnccc2CC1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-tert-butoxycarbonylamino-4-methylpyridine (step a, 1.47 g, 7.06 mmol) in tetrahydrofuran (50 ml) was cooled to -70° C. and treated with n-butyllithinum (6.2 ml, 2.5M in hexane, 15.5 mmol) at such a rate as to keep the temperature below -60° C. On complete addition the mixture was warmed to -20° C. and stirred for 30 minutes. The mixture was cooled to -30° C. and treated with dimethylformamide (0.66 ml, 8.47 mmol). The mixture was allowed to warm to 20° C., quenched with water (50 ml) and extracted with ethyl acetate (50 ml and 2×25 ml). The combined organic fractions were washed with saturated brine (50 ml), dried (Na2SO4), filtered and concentrated to residue in vacuo. The residue was purified by chromatography on silica gel (75% ethyl acetate/25% hexane) to afford the title compound as a colourless oil; yield: 1.26 g (81%) 1H NMR (CD2Cl2 /TMS): δ=1.6 (9H, s), 2.96 (1H, d, J=18 Hz), 3.35 (1H, dd, J=8 Hz & 18 Hz), 5.05 (1H, br.s), 5.98 (1H, br.s), 7.16 (1H, d, J=5 Hz), 8.15 (1H, d, J=5 Hz), 8.75 (1H, br.d).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[O:16][CH:17]=[CH:18][N:19]=1)CCC>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:15]2[O:16][CH:17]=[CH:18][N:19]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: COc1cccc(Br)c1
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ncco2)c1
Reaction time: 8 h

Procedure:
A suspension containing 1.16 ml of 1-bromo-3-methoxybenzene (9.2 mmol), 2.12 ml of 2-(tributylstannanyl)-1,3-oxazole (5.9 mmol) and 276 mg (0.2 mmol) of tetrakis[triphenylphosphine]palladium in 50 ml of toluene is stirred overnight at reflux under argon. The toluene is evaporated off using a rotary evaporator, and the residue is then suspended in ethyl acetate. After filtering the suspension, the filtrate is evaporated to dryness and the crude product is purified by chromatography over silica gel, eluting with CH2Cl2 and then with CH2Cl2/acetone 98/2 to yield the title product in the form of an oil.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: Cc1cnc(-c2cc3c(O)cccc3s2)o1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cnc(-c2cc3c(OC[C@@H]4CO4)cccc3s2)o1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 4-hydroxy-2-(5-methyloxazol-2-yl)benzo(b)thiophene (2.20 g), (S)-glycidyl nosylate (2.38 g) and potassium carbonate (3.18 g), a crude product of the title compound was quantitatively obtained as pale-yellow crystals.
Reaction SMILES: C1(C=CC=C(O)C=1)O.BrC1C=CC=CC=1C(O)=O.[CH:19]1[C:24](O)=[CH:23][C:22]2[C:26]([O:28][C:29]3[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:30]=3[C:21]=2[CH:20]=1)=[O:27]>>[CH:19]1[CH:20]=[C:21]2[C:30]3[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=3[O:28][C:26](=[O:27])[C:22]2=[CH:23][CH:24]=1
Reactant: O=c1oc2cc(O)ccc2c2ccc(O)cc12
Agent: O=C(O)c1ccccc1Br
Agent: Oc1cccc(O)c1
Product: O=c1oc2cc(O)ccc2c2ccccc12
Yield: 61.6 %

Procedure:
Urolithin B was prepared in one step by coupling resorcinol and 2-bromobenzoic acid following the procedure for the preparation of Urolithin A. The pure compound was obtained as a off-white powder with a yield of 61.6%.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[NH:2]1.C(N(CC)C(C)C)(C)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([N:2]1[C:1](=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3]1=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=O)c2cnccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: O=C1c2ccncc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (5.00 g) and N,N-diisopropylethylamine (20.00 mL) in acetone was added benzyl bromide (5.0 mL). The reaction mixture was heated to reflux for 5 h, then cooled to rt and filtered. The filtrate was poured into water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to give the title compound as a brown solid (4.00 g, 50.00%), HPLC: 92.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 239.2 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 4.92 (s, 2H), 7.26-7.34 (m, 3H), 7.45 (m, 2H), 7.60 (m, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.96 (d, J=10.4 Hz, 1H) ppm.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21](=[O:23])[NH2:22])[CH:11]=[N:10]1)([CH3:8])[CH3:7])(=O)C.[OH-].[Na+].O.Cl>CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:9]([C:6]([CH3:8])([CH3:7])[CH2:5][OH:4])[N:10]=[CH:11][C:12]=2[C:21]([NH2:22])=[O:23])=[CH:15][CH:16]=1
Reactant: CC(=O)OCC(C)(C)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CO)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of the compound (95 mg, 0.30 mmol) obtained in step 1 in methanol (3 mL) was added 6N aqueous sodium hydroxide solution (0.05 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added water and 6M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure to give 5-(4-fluorophenyl)-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-4-carboxamide (60 mg, 0.216 mmol, 73%) as a white powder.
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]1[N:16]2[CH:17]=[C:18]([O:21][C@H:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@@H:25]([NH2:32])[CH2:24][CH2:23]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:32][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([N:8]5[CH2:9][CH2:10][CH2:11][C@H:7]5[CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:33]([CH3:35])[CH3:34])[CH:36]([CH3:38])[CH3:37])=[N:13][N:14]=4)[CH:17]=3)[CH2:23][CH2:24]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OC[C@@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@H]5CO[Si](C(C)C)(C(C)C)C(C)C)n4c3)c3ccccc32)cc1
Yield: 65 %

Procedure:
A solution of Intermediate 28c (40 mg, 0.074 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 45 mg, 0.112 mmol) and DIPEA (38 mg, 0.296 mmol) in DMF (2 mL) was stirred at 60° C. for 30 min. The reaction mixture was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-7% [2M NH3 in MeOH] in DCM, gave the title compound as a viscous yellow oil (38 mg, 65%). LCMS (Method 1): Rt 4.72 min, m/z 791 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[F:16])[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[F:16])[CH2:7][Br:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)Oc1cccc(Cl)c1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1F
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A solution of 3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.41 g, 5.45 mmol) in carbon tetrachloride (30 mL) was treated with N-bromosuccinimide (1.07 g, 6.01 mmol) and benzoyl peroxide (0.15 g). The reaction was then warmed to reflux for 5 h. At this time, the reaction was cooled to 25° C. and then placed in the freezer over the weekend. At this time, the reaction was removed from the freezer and allowed to thaw. The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded impure 4-bromo-3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.59 g, 86%) as a white solid. The material was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:12][CH2:11][CH2:10][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCc1ccccc1
Reactant: CCc1ccncc1
Product: CC(CCCc1ccccc1)c1ccncc1
Yield: 55.5 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 1.86 g (9.35 mmol) of 1-bromo-3-phenylpropane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.17 g of the desired compound (yield: 55.5%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][O:39][CH3:40]>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][O:39][CH3:40])[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: COCCCl
Product: COCCN1C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N(c2ccccc2C)C1C

Procedure:
The title compound, MS: m/e=542.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloroethyl-methyl ether.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH:18]([P:20](=[O:23])([CH3:22])[CH3:21])=[CH2:19].C(N(CC)CC)C>>[C:2]1([C:1]2[CH2:19][CH:18]([P:20](=[O:23])([CH3:22])[CH3:21])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: C=CP(C)(C)=O
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: CP(C)(=O)C1CC(c2ccccc2)=NO1
Yield: 57.7 %

Procedure:
Preparation is carried out in analogy to Example 1 by starting from 60.6 g (0.5 mol) of benzaldoxime, 73.45 g (0.55 mol) of N-chlorosuccinimide, 57.3 g (0.55 mol) of vinyldimethylphosphine oxide and 76.5 ml (0.55 mol) of triethylamine. After the usual working up, the product is recrystallized from. tert.butyl methyl ether. 64.4 g of pure product of melting point 153° C. are obtained.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(NS(=O)(=O)[O:33][CH2:34][C@@H:35]1[C@@H:42]2[C@@H:38]([O:39][C:40]([CH3:44])([CH3:43])[O:41]2)[C@H:37]([N:45]2[CH:53]=[N:52][C:51]3[C:46]2=[N:47][CH:48]=[N:49][C:50]=3Cl)[O:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C(O)C>[C@@H:3]1([N:2]([CH3:1])[C:50]2[N:49]=[CH:48][N:47]=[C:46]3[C:51]=2[N:52]=[CH:53][N:45]3[C@H:37]2[C@@H:38]3[O:39][C:40]([CH3:44])([CH3:43])[O:41][C@@H:42]3[C@@H:35]([CH2:34][OH:33])[O:36]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(=O)(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: CN[C@H]1CCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@H]21)[C@H]1CCc2ccccc21
Temperature: 150 °C
Yield: 55 %

Procedure:
A suspension of (1S)-N-methylindan-1-amine (67.8 mg, 0.461 mmol), [(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl tritylsulfamate (200 mg, 0.309 mmol) and DIPEA (0.160 mL, 0.919 mmol) in ethanol (3.0 mL) was heated at 150° C. for 600 s using microwave irradiation. The residue was purified via flash chromatography (0 to 100% EtOAc/DCM) to afford the title compound as a brown oil (74.3 mg, 55%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:16](Cl)=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:26]>Cl>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:15]2[C:16](=[O:26])[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: OC1(c2cc3ccccc3nc2Cl)CCN(Cc2ccccc2)CC1
Agent: Cl
Product: O=c1[nH]c2ccccc2cc1C1=CCN(Cc2ccccc2)CC1

Procedure:
3-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-chloroquinoline (11.0 g, 31.1 mmol) was refluxed in 6 N hydrochloric acid for 8 h. The solution was cooled and water (100 mL) added. The precipitated solid was collected and dried to give the title compound, 7.9 g. MS 317 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.97 (s, 1H), 7.70 (d, J=7 Hz, 1H), 7.60 (m, 2H), 7.55 (m, 4H), 7.35 (d, J=9 Hz, −1H), 7.27 (t, J=8 Hz, 1H), 6.50 (m, 1H), 4.49 (ABq, J=13 Hz, Δν=16 Hz, 2H), 3.92 (m, 2H), 3.76 (dt, J=12,4 Hz, 1H), 3.40 (m, 1H), 2.96 (m, 2H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=[C:12]([CH3:27])[N:11]=1)([CH3:9])[CH3:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=[O:35])[CH:29]=1>C1COCC1>[CH3:9][C:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=[C:12]([CH2:27][CH:34]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[OH:35])[N:11]=1)([CH3:6])[CH3:8]
Reactant: O=Cc1cccnc1
Reactant: COCCOCOc1c(C(C)(C)C)nc(C)nc1C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)nc(CC(O)c2cccnc2)nc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
n-Butyllithium (1.5 mL of 1.6M solution in hexane, 2.4 mmol) is added dropwise to a solution of 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-methylpyrimidine (750 mg, 2.4 mmol) in dry THF (12 mL) at 0° C. under an atmosphere of dry nitrogen. The reaction mixture is stirred at room temperature for 30 minutes and then cooled to -78° C. A solution of pyridine 3-carboxaldehyde (250 mg, 2.4 mmol) in dry THF (1 mL) is added dropwise. The reaction mixture is stirred at room temperature for 3 hours and then is quenched by the addition of saturated aqueous ammonium chloride. The product is extracted into ether. The organic layer is dried (MgSO4) and evaporated to give crude 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-α-(3- pyridinyl)- 2-pyrimidineethanol (500 mg, 50%) which is not further purified, but used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.Cl.[CH3:18][S:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]N)=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(N(C(C)C)CC)(C)C.P(=O)(O)(O)O>O1CCCC1.CO>[Cl:1][C:2]1[N:11]=[C:10]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:29][CH:28]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nc(Cl)nc(Cc3ccc(S(C)(=O)=O)cc3)c2cc1OC
Temperature: 25 °C

Procedure:
A mixture of commercially available 2,4-dichloro-6,7-dimethoxyquinazoline (200 mg, 0.772 mmol, 1 eq), 4-methylsulfonylbenzylamine hydrochloride (180 mg, 0.810 mmol, 1.05 eq) and diisopropylethylamine (0.40 mL, 2.32 mmol, 3 eq) in tetrahydrofuran (7.7 mL) was heated at reflux for 15.25 h. The reaction mixture was then cooled to rt and concentrated in vacuo. The resultant solid was slurried in methanol (10 mL) collected by filtration, washed with methanol and dried to provide 282 mg (89%) of A1.1 as an off-white solid. LC/MS: 408 [M+H]+; HPLC: 98% at 3.19 min (Phenomenex 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 254 nm); 1H NMR (400 MHz, DMSO-d6): δ 8.98 (m, 1 H), 7.91 (d, J=8.3 Hz, 2 H), 7.69 (s, 1 H), 7.62 (d, J=8.3 Hz, 2 H), 7.11 (s, 1 H), 4.84 (apparent d, J=5.7 Hz, 2 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.19 (s, 3 H).
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cn1nccn1
Yield: 43 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 58, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (120 mg, 43%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.73 (s, 2H), 7.57-7.49 (m, 2H), 7.34-7.12 (m, 4H), 7.03-6.89 (m, 4H), 5.46 (q, 2H), 4.51-4.44 (m, 1H), 3.85-3.76 (m, 1H), 2.77-2.60 (m, 3H), 2.17-1.85 (m, 3H). MS (EI) for C28H26FN5O3. found 500.0 (MH+).