Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].C(N(CC)CC)C.[C:42]([NH:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][C:54](O)=[O:55])[CH2:48][CH2:47]1)(=[O:44])[CH3:43].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:42]([NH:45][CH:46]1[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][C:54]([NH:1][CH2:2][C:3]([N:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]3[C:24]4[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[C:20]=4[CH:19]=[CH:18][CH:17]=3)[C:8]=2[Cl:34])[CH3:6])=[O:4])=[O:55])[CH2:50][CH2:51]1)(=[O:44])[CH3:43]
Reactant: CC(=O)NC1CCN(CCC(=O)O)CC1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCN4CCC(NC(C)=O)CC4)c3Cl)cccc2n1Cc1ccccn1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred mixture of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.30 g, 0.60 mmol) in anhydrous DMF (15 mL) was added triethyl amine (0.067 g, 0.66 mmol) under nitrogen at 0° C. The mixture was stirred for 30 min and was added 3-(4-acetamidopiperidin-1-yl)propanoic acid (0.257 g, 1.20 mmol) and HBTU (O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) (0.296 g, 0.78 mmol). The mixture was stirred at room temperature overnight, evaporated, mixed with a saturated brine solution and extracted with ethyl acetate. Evaporation gave a crude oil that was purified using silica chromatography eluting with a gradient of 2% to 30% DCM (dichloromethane)/MeOH/NH4OH (10:1:0.1). After drying at 78° C. under high vacuum, 3-(4-acetamidopiperidin-1-yl)-N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide, 8, was isolated as a solid (0.23 g, 55%). LCMS (+ESI) 696 (M+1). 1H-NMR (CDCl3, δ ppm): 8.96 (bs, 1H), 8.59 (m, 1H), 7.58 (t, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.27 (m, 1H), 7.19 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.82 (m, 1H), 5.66 (m, 2H), 5.48 (bd, 1H), 5.28 (s, 2H), 4.20 (s, 3H), 3.85 (m, 2H), 3.54 (dd, J=18, 3.6 Hz, 1H), 3.26 (s, 3H), 2.96 (bd, 2H), 2.62 (m, 2H), 2.37 (m, 2H), 2.14 (m, 2H), 1.97 (s, 3H), 1.96 (m, 3H). Calcd. for C34H39Cl2N7O5+1.4H2O: C, 56.57; H, 5.84; N, 13.58. Found: C, 56.44; H, 5.59; N, 13.48.
Reaction SMILES: O.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([OH:9])[CH3:8].BrCl.C(O)C1[O:17]C=CC=1>O1CCCC1>[CH3:8][C:7]1[O:9][CH:6]=[CH:5][C:4](=[O:17])[C:3]=1[OH:2]
Reactant: OCc1ccco1
Reactant: CC(O)c1ccco1
Agent: ClBr
Solvent: C1CCOC1
Solvent: O
Product: Cc1occc(=O)c1O
Temperature: 0 °C

Procedure:
To a 3-neck round bottom flask is charged a solution of 50 ml of water and 20 ml of tetrahydrofuran and the solution is cooled to 0° C. An addition funnel is charged with a solution of 1(2-furyl)-1-ethanol (0.89 mole) in 25 ml of tetrahydrofuran and this solution is added dropwise to the reaction flask while BrCl (0.30 mole) is added via a gas inlet tube. The rate of addition is such that all the furfuryl alcohol is added in the first 1.3-1.5 equivalents of BrCl while maintaining the temperature below 30° C. The reaction mixture is heated to reflux and the tetrahydrofuran removed by distillation. When the temperature reaches 105° C., a condensor is attached and the reaction mixture heated under reflux for about 2 hours. The reaction mixture is cooled and maltol isolated by the method of Example 1.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[C:14]1([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:21](=[O:22])[CH:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCCBr
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 3-bromopropylamine hydrobromide (2.91 g, 13.3 mmol) in 10 mL of CH2Cl2 was added 2.8 mL of triethylamine (20.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes, followed by addition of diphenyl acetyl chloride (2.56 g, 11.1 mmol) and triethylamine (2.8 mL, 20 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred for 40 minutes at room temperature and then diluted with 200 mL of CH2Cl2. The solution was washed with aqueous 0.5 N HCl (100 mL×3), water (50 mL), NaHCO3 (sat, 100 mL) and NaCl (sat), dried over MgSO4. Removal of solvent gave the crude product as a light yellow solid that was used in the next step without further purification (3.33 g, 91%): 1H NMR (400 MHz, CDCl3) δ 7.56–7.45 (m, 10H), 5.88–5.69 (br, 1H), 4.92 (s, 1H), 3.47–3.39 (m, 2H), 3.35 (t, 2H, J=6.4 Hz), 2.16–1.98 (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2](CCCC1C=CC=CC=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][C@@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:6][CH3:7])[O:8][CH3:9]
Reactant: BrCc1ccccc1
Reactant: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Product: COP(=O)(CC(=O)[C@@H](C)Cc1ccccc1)OC

Procedure:
(S)-(+)-Dimethyl (3-methyl-2-oxo-4-phenylbutyl)phosphonate was prepared in the same manner as the second alternative preparation of (S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) using the same sequence of reactions except that benzyl bromide was used instead of (3-bromopropyl)benzene. The crude product was purified by silica gel chromatography. Elution with ethyl acetate-heptane (80:20 v/v) afforded the title compound (680 mg) as a colorless oil; TLC Rf 0.35 (solvent system: 80:20 v/v ethyl acetate:heptanes; MS (ESI+) m/z 271.1 (M+H)+; 1H-NMR (CDCl3) δ 7.29-7.14 (m, 5H), 3.71 (dd, 6H, J=10.99, 19.04 Hz), 3.12-2.89 (m, 4H), 2.58 (dd, 1H, J=7.69, 13.55 Hz), 1.11 (d, 3H, J=6.96 Hz); [α]Tλ=α/cl, [α]21.9D=0.249/(0.01501 g/1.5 mL)(0.5)=+49.8° (c=1, CHCl3).
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:9][N:10]1[O:22][C:21]2[C:20]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[S:14][C:13]=2[N:12]=[C:11]1[S:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1.C(Cl)(=O)C>C(N(CC)CC)C>[C:2]([N:17]1[CH2:16][C:15]2[S:14][C:13]3[N:12]=[C:11]([S:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:42]=[CH:41][C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=5)[CH2:29][CH2:28]4)[N:10]([NH2:9])[O:22][C:21]=3[C:20]=2[CH2:19][CH2:18]1)(=[O:1])[CH3:3]
Reactant: NN1Oc2c(sc3c2CCNC3)N=C1SCCCN1CCN(c2ccc3ccccc3n2)CC1
Reactant: C1CCOC1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2c(sc3c2ON(N)C(SCCCN2CCN(c4ccc5ccccc5n4)CC2)=N3)C1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 10 ml of tetrahydrofuran, 203 mg of 3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)-propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene trihydrochloride as synthesized in Example 1-59 was added and into which 133 mg of triethylamine was dropped. Acetyl chloride was added to the mixture under cooling with ice, followed by 30 minutes stirring and distillation under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=25:1) to provide 150 mg (83%) of 7-acetyl-3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene.
Reaction SMILES: [CH:1]([OH:9])(O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[ClH:10].C1(C)C=CC=CC=1>O>[Cl:10][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9]
Reactant: CCCCCCC(O)O
Reactant: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCCCCCCl

Procedure:
A mixture of 44 g of heptane diol, 400 ml of concentrated hydrochloric acid, 150 ml of toluene and 50 ml of water was stirred for two and half hours at reflux. The toluene fraction was removed and 200 ml of toluene were added to the aqueous fraction and the mixture was heated for five hours at 85° C. to 90° C. The toluene was removed and 200 ml of toluene and 100 ml of concentrated hydrochloric acid were added to the aqueous phase. The mixture was heated for five hours, then cooled and the organic fraction was combined with the two preceding toluene fractions. The toluene fraction was washed with water, dried and evaporated to dryness under reduced pressure, then distilled at 70° C. under 0.5 mm of mercury to obtain 37 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[NH2:28][NH2:29]>Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[N:28][NH2:29])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NN
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NN
Yield: 61 %

Procedure:
A solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of Step 1, Example 1, 500 mg), concentrated hydrochloric acid (5 drops) and hydrazine hydrate (86 mg) in methanol (20 mL) were heated at reflux for 5 h. The mixture was concentrated and the residue was triturated with water. Filtration yielded the title compound (317 mg, 61%).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].CN(C=O)C.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([OH:30])[C:28]=1[I:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([O:30][CH:2]([CH3:4])[CH3:3])[C:28]=1[I:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)I
Reactant: CCOC(=O)c1cc(O)c(I)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2ccccc2)c(I)c(OC(C)C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Iodopropane (1.47 mL) was added to a DMF (30 mL) suspension of ethyl 3-(benzyloxy)-5-hydroxy-4-iodobenzoate (2.94 g) and potassium carbonate (1.53 g), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.72 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Si:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)Cl)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11][CH2:12][CH2:13][O:14][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl ester (2.5 g) was dissolved in 50 ml DMF and treated with 2.0 ml tert-butyldiphenylchlorosilane, 1.2 ml triethylamine and 95 mg DMAP. After stirring for 12 h equivalent portions of the reagents were added and the mixture stirred for additional 12 h. The mixture was concentrated, the residue was dissolved in ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 2.0 g.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:22])[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:23]([O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32](=[O:33])[NH:21][C:20]1[C:15]([NH:14][C:10]2[CH:9]=[C:8]([CH3:22])[CH:13]=[CH:12][CH:11]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:35])([CH3:24])([CH3:25])[CH3:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cccc(Nc2ncccc2N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2ncccc2NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (1.7 mL, 12.0 mmol) was added to a mixture of N2-m-tolylpyridine-2,3-diamine (600 mg, 3.01 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.03 g, 5.42 mmol), HOAt (740 mg, 5.42 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.04 g, 5.42 mmol) in anhydrous DCM (25 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 min then slowly warmed to RT. Stirring at RT was continued for 16 h. After re-cooling the mixture to 0° C., additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (220 mg, 1.20 mmol), HOAt (160 mg, 1.20 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.20 mmol) and triethylamine (0.41 mL, 3.01 mmol) were added. The reaction mixture was stirred at 0° C. for 15 min then slowly warmed to RT. Stirring at RT was continued for 72 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was extracted with DCM (×3) and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as an off-white foam. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method C): RT 2.70 min [M+H]+ 371.3.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccccn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1ccccn1)NO
Reaction time: 72 h
Yield: 85 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (524 mg, 1.60 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 then 100:8) to furnish III as a colourless oil (425.79 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].I[CH2:13][CH3:14]>>[CH2:13]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[CH3:14]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCOC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (1.5 g), in dimethylfomylamide (30 mL), 60% sodium hydride (0.50 g) was added portion-wise at 0° C. then warmed to ambient temperature. Iodoethane (3.5 mL) was added to the mixture at 0° C. then stirred for 16 h at room temperature. The reaction mixture was filtered then the filtrate was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O (×2) then brine and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAdEt2O (1:1) as eluent to give the subtitle compound as clear, colourless oil. Yield: 1 g
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH2:10][C:11](=[CH:15][Br:16])[CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CON=C(C(=O)OC)C1=CC=CC(=CBr)C1

Procedure:
15 g (72.4 mmol) of m-methylphenylglyoxylic acid methyl ester O-methyl oxime, 13.5 g (75.8 mmol) of N-bromosuccinimide and 0.1 g (0.6 mmol) of azobisisobutyrodinitrile in 150 ml of CH2Cl2 are exposed for 4 hours to a 300 watt UV lamp, the reaction mixture being refluxed. Thereafter, the organic phase is extracted with water, dried over MgSO4 and evaporated down.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[NH:8][C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31])[CH2:2][CH2:3][CH3:4].Cl[CH2:33][O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH2:33][O:34][CH3:35])[C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31])[CH2:2][CH2:3][CH3:4]
Reactant: COCCl
Reactant: CCCCc1c(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c(=O)n(COC)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile (0.88 g), chloro(methoxy)methane (0.19 mL), potassium carbonate (0.58 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.77 g, 79%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Si:23]([O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.7 %

Procedure:
A mixture of (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.7 mmol), imidazole (5.54 g, 81.4 mmol) and t-butyldimethylsilyl chloride (6.6 g, 45 mmol) in DMF (50 ml) was stirred and r.t. for 4 days. The mixture was diluted with EtOAc and washed with H2O and sat. NH4Cl. The organic layer was dried over MgSO4 and concentrated. 14 g of an oil product was obtained and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([NH:18][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccccc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and phenyl isocyanate. m/z (ES+) 264 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12]Br)=[O:5])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(Br)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
2-Bromo-4-bromomethyl-thiazole-5-carboxylic acid ethyl ester (22.1 g, 67.3 mmol) was dissolved in 169 mL of dry N,N-dimethylformamide. N-(2,4-dimethoxy-benzyl)glycine ethyl ester (17.1 g, 67.3 mmol) and potassium carbonate (10.2 g, 74.0 mmol) were added and the reaction was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-70% ethyl acetate in hexanes to produce 19.5 g of a light yellow solid. MS: (+) m/z 501.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(#N)C>[C:13]1([S:19]([NH:1][C:2]2[C:3]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCCc1ncccc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: N#CCCCc1ncccc1NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 3-amino-2-(3-cyanopropyl)pyridine* (5 g, 0.031 mole) in acetonitrile (50 ml) was treated with benzenesulphonyl chloride (4 ml) and pyridine (6 ml). The solution was allowed to stand at room temperature overnight when the solvent was removed in vacuo. The residue was dissolved in dilute sodium hydroxide (100 ml) and was extracted with chloroform (4×100 ml) the chloroform extracts being discarded. The aqueous layer was adjusted to pH=4 and extracted with chloroform (3×100 ml). The combined chloroform extracts were dried over magnesium sulphate, the solvent was removed to give the title compound (7.12 g) as a cream coloured solid. m.p. 80°-81° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([NH:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])=[O:22])=[CH:15]2>>[CH2:28]([CH:24]([NH:23][C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=2)=[O:22])[C:25]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COCOC1CCNCC1
Product: COCOC1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
4-Methoxymethoxy-piperidine (1.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 1:1 ethyl acetate-hexanes: Yield 241 mg, 50%; HPLC (60/40) 7.67 minutes (94%);