Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[F:8][C:9]1[CH:34]=[CH:33][C:12]([O:13][CH2:14][C@@H:15]2[O:20][C@@H:19]([O:21][CH:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:23][CH2:24]Cl)[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH:22]([O:21][C@H:19]2[CH2:18][CH2:17][CH2:16][C@H:15]([CH2:14][O:13][C:12]3[CH:33]=[CH:34][C:9]([F:8])=[CH:10][CH:11]=3)[O:20]2)[CH2:23][CH2:24][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(OC[C@H]2CCC[C@H](OC(CCCl)c3ccc(F)cc3)O2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OC[C@H]2CCC[C@H](OC(CCn3ccnc3)c3ccc(F)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
A mixture of 56 mg of imidazole and 36 mg of 55% sodium hydride was stirred in 2 ml of dimethylformamide at 60°-70° C. for 30 minutes. The mixture was left to cool at room temperature, and then a solution of 218 mg of trans-6-(4-fluorophenoxymethyl)-2-[3-chloro-1-(4-fluorophenyl)propoxy]tetrahydropyran in 1 ml of dimethylformamide was added, and the mixture was heated, with stirring, at 80°-90° C. for 6 hours. At the end of this time, the mixture was treated and the product purified essentially as described in Example 34(b)(i), to give 110 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=1[Cl:1])=[O:6])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,3-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.83-0.92 (m, 3 H) 1.25-1.37 (m, 2 H) 1.67-1.75 (m, 2 H) 2.50 (s, 3 H) 4.15 (t, 2 H) 6.18 (s, 1 H) 7.37-7.48 (m, 2 H) 7.64-7.69 (m, 1 H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[C:27]=1[CH3:35])[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[O:12])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:34][C:28]1[C:27]([CH3:35])=[C:26]([NH:25][C@@H:10]([C:11]2[O:12][C:15]([C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)=[N:14][N:13]=2)[CH2:9][OH:8])[CH:31]=[CH:30][C:29]=1[C:32]#[N:33]
Reactant: Cc1c(N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@H](CO)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl

Procedure:
To a pre-cooled (−78° C.) solution of (R)—N′-(3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)propanoyl)-4-cyanobenzohydrazide (0.810 g, 1.64 mmol) in THF (160 mL) was added TBAF (1.64 mL, 1.64 mmol, 1M solution in THF) dropwise over 10 min. Upon complete addition, the reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in EtOAc (100 mL) and washed with H2O (80 mL). The biphasic mixture was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (1×70 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes then 100% EtOAc) to provide the title compound as an off-white solid. The resulting solid was diluted with CH2Cl2 (90 mL) and hexanes (70 mL) was added. Upon concentration of the suspension a white solid was provided (460 mg, 74%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.21 (d, J=8.8 Hz, 2H), 8.00 (d, J=9 Hz, 2H), 7.53 (d, J=9 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 5.85 (d, J=8 Hz, 1H), 5.34-5.27 (m, 1H), 4.29 (br s, 2H) and 2.38 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C@H:10]([CH:29]([CH3:31])[CH3:30])[C:11]([N:13]1[CH2:18][CH2:17][C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:15]([CH3:28])([CH3:27])[CH2:14]1)=[O:12])=[O:8])(=[O:3])[CH3:2].[CH3:35][N:36]([CH:38](OC)OC)[CH3:37]>>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C@@:16]2([OH:19])[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C@H:10]([NH:9][C:7](=[O:8])[C:6]3[CH:32]=[CH:33][CH:34]=[C:4]([C:1](=[O:3])/[CH:2]=[CH:35]/[N:36]([CH3:38])[CH3:37])[CH:5]=3)[CH:29]([CH3:30])[CH3:31])[CH2:14][C:15]2([CH3:28])[CH3:27])=[CH:25][CH:24]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)c1
Product: CC(C)[C@@H](NC(=O)c1cccc(C(=O)/C=C/N(C)C)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 105 °C

Procedure:
3-Acetyl-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)benzamide was added DMF-DMA (0.3 mL) and the reaction mixture heated at 105° C. for ˜5 h. The residual DMF-DMA was removed on a rotovap and the crude product was dried on house high vac for ˜3 h to afford N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-((E)-3-(dimethylamino)acryloyl)benzamide.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH2:9])[CH2:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][S:11]([CH3:10])(=[O:13])=[O:12])[CH2:4]1
Reactant: COC1CCCC(N)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC1CCCC(NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of 3-methoxycyclohexanamine (0.200 g, 1.5 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.144 mL, 1.9 mmol). The reaction mixture was stirred at room temperature for 16 hrs and then concentrated. The mixture was diluted with ethyl acetate and washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown oil (0.140 g, 44%). The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=[CH2:10])[CH:5]=[C:4]([CH:11]([OH:13])[CH3:12])[N:3]=1.[H-].[Na+].[CH3:16]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:16])=[C:6]([CH:9]=[CH2:10])[CH:5]=[C:4]([CH:11]([OH:13])[CH3:12])[N:3]=1
Reactant: C=Cc1cc(C(C)O)nc(Cl)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cc(C(C)O)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-vinyl-6-(1-hydroxyethyl)-pyridine (1.46 g, 7.31 mmol) in 12 mL of N,N-dimethylformamide is treated with sodium hydride (292 mg, 60% in oil, 7.31 mmol) and stirred at room temperature for 1 h. The mixture is treated with methyl iodide (0.5 mL, 8.04 mmol) and stirred for 2 h. The reaction is diluted with 125 mL of ethyl acetate and washed with 4×50 mL of saturated sodium chloride. The organics are dried over potassium carbonate and concentrated in vacuo. The crude material is chromatographed over 150 g of silica gel (230-400 mesh), eluting with 25% ethyl acetate/hexanes to give 1.09 g (78%) of 2-chloro-3-methoxy-4-vinyl-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: N.[Cl:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](Cl)[N:6]=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1.C([N:24](C(C)C)CC)(C)C>C1COCC1>[Cl:2][C:3]1[N:4]=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:7]([NH2:24])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1c(Cl)nc(SCc2ccccc2)nc1Cl
Agent: N
Solvent: C1CCOC1
Product: Nc1nc(SCc2ccccc2)nc(Cl)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 52 %

Procedure:
Ammonia solution (14 ml, 0.5 M in dioxane) was added dropwise to a solution of the product of example 2, step (c) (2.0 g) and diisopropylethylamine (3.31 ml) in THF (100 ml) over a 1 h period at RT. After stirring for a further 1 h the reaction was concentrated in vacuo onto silica and purified by column chromatography using 9:1 then 4:1 isohexane/ethyl acetate as eluent to yield the subtitled product as a yellow solid (980 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.Cl.FC1C=C([CH:59]([C:63]([NH:65][C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)=[O:64])[C:60](N)=[O:61])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:60](=[O:61])[CH2:59][C:63]([NH:65][C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)=[O:64])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution of 3-fluoro-4-(6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (15 mg, 0.037 mmol) and 3-(4-fluorophenylamino)-3-oxopropanoic acid (8 mg, 0.04 mmol, Compound A of Example 25) in DMF (1 mL) were added DIEA (0.1 mL, 0.57 mmol) and TBTU (13 mg, 0.04 mmol). The reaction mixture was stirred at room temperature overnight and then purified using preparative HPLC. The fraction containing the desired product was collected and concentrated in vacuo. The residue was neutralized with 1 N NH4OH and concentrated again. The solid that formed was filtered, washed with 1 N NH4OH, dissolved in MeOH/H2O, and lyophilized to give the title compound (8 mg, 37%). 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 10.23 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.06 (s, 1H), 8.00 (d, 1H, J=7.5 Hz), 7.70 (m, 1H), 7.50 (m, 2H), 7.30–7.45 (m, 3H), 7.04–7.17 (m, 3H), 6.85–6.92 (m, 2H), 3.36 (s, 4H), 3.44 (s, 6H); MS(ESI) m/z 586.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16](=[C:17]([C:20]3[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=3)[CH2:18][CH3:19])[C:15]3[CH:27]=[CH:28][CH:29]=[N:30][C:14]=3[CH2:13][O:12][C:11]=2[CH:31]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16](=[C:17]([C:20]3[CH:21]=[C:22]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=[CH:24][CH:25]=3)[CH2:18][CH3:19])[C:15]3[CH:27]=[CH:28][CH:29]=[N:30][C:14]=3[CH2:13][O:12][C:11]=2[CH:31]=1
Reactant: CCC(=C1c2ccc(F)cc2OCc2ncccc21)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=C1c2ccc(F)cc2OCc2ncccc21)c1cccc(NS(C)(=O)=O)c1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Methanesulfonyl chloride (0.34 mL, 4.36 mmol) is added dropwise to a solution of 3-[1-(8-fluoro-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-phenylamine (1.37 g, 3.96 mmol) and pyridine (0.35 mL, 4.36 mmol) in dichloromethane (10 mL) at 0° C. After 2 h, 7% aqueous sodium bicarbonate (20 mL) is added and the mixture stirred for 30 min, decanted, and the layers separated. The aqueous phase is washed with dichloromethane (2×20 mL). The organic phases are collected and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 1.98 g of crude product. The material is purified by flash chromatography, using Biotage® and eluting with hexane:ethanol (9:1) to afford 1.35 g (80%) of the title compound. LCMS m/e 425 [M−H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34]([OH:36])=O)[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:2].[N:59]1([C:65]2[CH:70]=[CH:69][C:68]([OH:71])=[CH:67][CH:66]=2)[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34]([N:62]3[CH2:61][CH2:60][N:59]([C:65]4[CH:66]=[CH:67][C:68]([OH:71])=[CH:69][CH:70]=4)[CH2:64][CH2:63]3)=[O:36])[CH:14]=2)=[C:6]([C:37]2[CH:42]=[C:41]([CH:40]=[CH:39][N:38]=2)[C:43]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:54])([F:53])[F:55])[CH:47]=2)=[O:56])[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: Oc1ccc(N2CCNCC2)cc1
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: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCN(c4ccc(O)cc4)CC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
To a solution of 16-(3-(4-(diethylamino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-4,7,10,13-tetraoxahexadecan-1-oic acid (300 mg, 0.37 mmol), 4-(piperazin-1-yl)phenol (71 mg, 0.40 mmol) and DIPEA (142 mg, 1.1 mmol) in DMF (3 mL) was added HATU (160 mg, 0.42 mmol). After 30 minutes, the solvent was removed under vacuum and the residue was dissolved in DCM (50 mL). This was washed with water (4×25 mL), dried (Na2SO4) and concentrated to give the title compound (379 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21].[K].I([O-])(=O)(=O)=[O:26].[Na+].Cl>O.ClCCl>[CH3:1][C:2]1([CH3:23])[S:6](=[O:26])[C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [K]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 3 h

Procedure:
Penicillin G, potassium salt (349.9 g) was dissolved in 3 liters of water. Sodium periodate (194 g) was added and the mixture was stirred for three hours. Dichloromethane (500 ml) was added and the pH of the water layer was adjusted to 2.3 with 6 N hydrochloric acid with vigorous stirring. The aqueous layer was separated and extracted with four 400 ml portions of dichloromethane. The combined extract was washed with aqueous sodium bisulfite to remove any iodine color, dried over sodium sulfate, filtered, and evaporated. The solid residue was empasted with 400 ml of ethyl acetate and allowed to stand at 0° C. overnight. The solid was isolated by filtration and dried in vacuo to afford 322 g of penicillin G sulfoxide.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][O:30][C:31](=[O:33])[CH3:32]>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:13][NH:14][CH:15]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OCBr
Reactant: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Product: CCCCOc1cccc(C(CNC(COC(C)=O)C(=O)N(C)C)C(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from [2-[2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-N,N-dimethylacetamide and acetic acid bromomethyl ester according to Step 1 of Example 3. Colourless oil (38% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13]>C(O)(C)(C)C>[CH3:16][O:15][C:11](=[O:14])[CH2:12][CH2:13][C:8]([C:9]#[N:10])([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14]
Reactant: C=CC(=O)OC
Reactant: N#CCc1ccc(Cl)cc1
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(Cl)cc1
Yield: 71.4 %

Procedure:
A mixture of 25 g. (0.165 mole) of the known compound (p-chlorophenyl)acetonitrile and 77 ml. of methyl acrylate in 80 ml. of t-butyl alcohol is heated to reflux. The heat is removed and 25 ml. of 40% methanolic Triton B in 37 ml. of t-butyl alcohol quickly added. After about 4 hours of heating at reflux the mixture is allowed to cool and taken up in water and benzene. The organic layer is washed successively with 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is distilled under vacuum, first at 40 mm. of mercury to remove excess methyl acrylate and then at 0.35 mm. to give 38.06 g. (71.4% yield) of dimethyl-4-cyano-4-(4-chlorophenyl)pimelate, having a boiling point of 186° to 191°C. The nuclear magnetic resonance (NMR) spectrum of the compound confirms its expected structure.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:17]1([C:25]2[CH:30]=[CH:29]C=[CH:27][CH:26]=2)[CH:22]=[CH:21][C:20](C=O)=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:25]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:26]=[CH:27][C:9]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(-c3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 13.0 g of ethyl acetoacetate, 5.3 g of NaH 50% dispersion in oil, 60 mL of 1.6M n-butyl lithium in hexane, 16.3 g of 4-biphenylcarboxaldehyde and 300 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 150°-152° C.). 'H NMR (CDCl3) δ2.97 (dd, 2H), 3.60 (dd, 2H) 5.77 (dd, 1H), 7.27-7.68 (m, 9H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15](=O)[CH3:16])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[NH2:18][CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[OH:21].C1C=CC=CC=1.C([BH3-])#N.[Na+]>C(O)(C)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:15]([NH:18][CH2:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[OH:21])[CH3:16])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)COc1ccc(CCOC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(C)O
Product: CC(=O)OCCc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 14.8 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-[4-(2-oxopropoxy)phenyl]ethyl acetate (prepared as described in Preparation 37), 1.45 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 60 ml of dry benzene, 50 ml of absolute isopropanol and 2.06 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, 0.49 g of the title compound was obtained, having an Rf=0.34 (thin layer chromatography over silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=1>>[F:22][C:23]1[CH:24]=[C:25]([N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc(I)c1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1cccc(F)c1

Procedure:
The product is prepared according to the procedure described in Example 12, using 140 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 0.66 ml of 1-fluoro-3-iodobenzene. After purification by silica chromatography (gradient of 5% to 15% of the eluent CH2Cl2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 60 mg of (88)-9-(3-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.[CH3:13][C:14]([CH2:18]O)([CH2:16]O)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]2[O:9][CH2:15][C:14]([CH3:18])([CH3:16])[CH2:13][O:10]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: CC(C)(CO)CO
Product: COc1ccc(Cl)cc1B1OCC(C)(C)CO1
Yield: 86 %

Procedure:
The title compound (86%, oil) was prepared from 5-chloro-2-methoxyphenylboronic acid and neopentylglycol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[F:34][CH:35]([F:38])[CH2:36][NH2:37].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:37][CH2:36][CH:35]([F:38])[F:34])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: NCC(F)F
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NCC(F)F
Yield: 79.2 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (250 mg, 0.50 mmol), 2,2-difluoroethylamine (81 mg, 1.00 mmol), WSC hydrochloride (288 mg, 1.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol), to obtain 223 mg of the title compound as a white solid (79%).