Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:37]=4)=[N:20][N:21]3S(C3C(C)=CC(C)=CC=3C)(=O)=O)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[O:46][CH3:47])C1C=CC=CC=1.C(OC1C=CC(C2C=C3C(C(C4C=CC5C(=CC=CC=5)C=4)=NN3)=CC=2)=CC=1OC)C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:44]=[CH:45][C:36]=1[C:19]1[C:18]2[C:22](=[CH:23][C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:46][CH3:47])[CH:11]=3)=[CH:16][CH:17]=2)[NH:21][N:20]=1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
Agent: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1OCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1O

Procedure:
6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole was converted to 6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole as described in Example 1(a), step (ix). Rf sm 0.40, p 0.17 (ethyl acetate-hexane 3:7); 1H NMR (CDCl3) δ 8.40 (s, 1H), 8.12 (d, 1H, J=8.5 Hz), 8.10 (dd, 1H, J=1.6, 8.4 Hz), 7.93 (d, 1H, J=8.3 Hz), 7.88 (m, 2H), 7.61 (m, 1H) 7.56 (s, 1H), 7.43 (m, 5H), 7.30 (m, 3H), 7.15 (d, 1H, J=2.0 Hz), 7.08 (dd, 1H, J=2.1, 8.3 Hz), 6.91 (d, 1H, J=8.3 Hz), 5.16 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[C:23]1[N:27]2[CH:28]=[C:29](F)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1>CN(C=O)C>[Cl:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[C:17]=1[C:23]1[N:27]2[CH:28]=[C:29]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1
Reactant: Fc1ccc2nnc(-c3c(Cl)cccc3Cl)n2c1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4c(Cl)cccc4Cl)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
Intermediate 1d (404 mg, 2.48 mmol) was added to a stirred solution of sodium hydride (60% in mineral oil, 298 mg, 7.44 mmol) in anhydrous DMF (15 mL) at RT under an argon atmosphere. The reaction mixture was stirred at RT for 15 min, then Intermediate 26c (0.70 g, 2.48 mmol) was added, and stirring at 60° C. was continued for 1 h. After cooling, the reaction mixture was quenched by careful addition of a saturated aqueous solution of NH4Cl and water (1:1) and extracted with EtOAc (×3). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 followed by brine, dried and concentrated in vacuo. The resultant residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM to afford the title compound (345 mg, 33%) as a brown residue. LCMS (Method 3): Rt 2.34 min, m/z 425, 427. [MH+].
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44])[O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:25]3[CH:24]=[C:23]([CH2:26][O:27][Si](C(C)(C)C)(C)C)[N:22]=[CH:21][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:35]([NH2:37])=[O:36])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C@@H:10]([O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:25]3[CH:24]=[C:23]([CH2:26][OH:27])[N:22]=[CH:21][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:35]([NH2:37])=[O:36])[CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2c(cn1)ncn2-c1cc(O[C@@H](CO[Si](C)(C)C(C)(C)C)c2ccccc2Cl)c(C(N)=O)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1sc(-n2cnc3cnc(CO)cc32)cc1O[C@@H](CO)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 236 mg of 3-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(2-chlorophenyl)ethoxy]-5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide in 15 ml THF is cooled to 0° C. At 0° C. 0.26 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for one hour. The solvent is evaporated under reduced pressure and the residue is treated with 15 ml dichloromethane and 10 ml saturated aqueous NaHCO3 solution. The phases are separated; the aqueous phase is extracted with 10 ml dichloromethane. The combined organic phase is dried over Na2SO4, filtered and concentrated to dryness. The raw product is purified by flash chromatography over silica gel Flash NH2 [eluent: dichloromethane/methanol, with a gradient of 100/0 to 90/10 (v/v)]. The title product is obtained after a second purification in preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 80/20 to 30/70 (v/v)).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCCCC1.[Br:20]N1C(=O)CCC1=O>C(OC(=O)C)C>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][Br:20])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)c1ccc(CBr)s1
Yield: 98.6 %

Procedure:
To 5-Methyl-thiophene-2-carboxylic acid tert-butyl ester (10.8 g, 54.5 mmol) was added cyclohexan (100 mL) and N-bromosuccinimide (9.7 g, 54.5 mmol) and was heated at reflux overnight. The suspension was to added ethylacetate (200 mL) and the organic solution was washed with water (4×100 mL). The solvent was removed in vacuo to yield 14.9 g of 5-bromomethylthiophene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[O:27][C:26]([NH:28]CC5C=CC(OC)=CC=5)=[N:25][N:24]=4)[CH:21]=3)[N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH:15]=2)[N:9]=1.FC1C=CC=CC=1C1C=CN=C(C2C3C(=CC=C(C4OC(N)=NN=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)N=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[O:27][C:26]([NH2:28])=[N:25][N:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[N:9]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(-c5ccccc5F)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(-c4ccccc4F)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2ccc3[nH]cc(-c4nccc(-c5ccccc5F)n4)c3c2)o1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a solution of 5-(3-(4-(2-fluorophenyl)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (250 mg, 0.38 mmol) in TFA (1.25 mL) was heated to 100° C. in a microwave for 30 min. The mixture was cooled to RT and TFA was removed in vacuo to give the crude material after washing with Et2O. MS (ESI, pos. ion) m/z: 527 (M+1). To a solution of crude 5-(3-(4-(2-fluorophenyl)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (250 mg, 0.47 mmol) in p-dioxane (2.5 mL) was added aq. 10% NaOH (1.25 mL) and the reaction was heated at 100° C. for 2 h. The reaction was quenched with ice cold H2O and the resulting precipitate was filtered, washed with ice cold H2O and dried. The crude product was recrystallized with 10% MeOH/CHCl3 to give 5-(3-(4-(2-fluorophenyl)pyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (40 mg, 23%) as an off yellow solid. MS (ESI, pos. ion) m/z: 373.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 9.08 (s, 1H), 8.92 (m, 1H) 8.47 (d, J=2.8 Hz, 1H) 8.33-8.30 (m, 1H), 7.72-7.76 (m, 6H), 7.51-7.53 (m, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:21][CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: ICC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CC4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and iodomethylcyclopentane.
Reaction SMILES: [CH3:1][N:2]([C@H:49]1[CH2:53][CH2:52][N:51](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:50]1)[C:3]([C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:12]([CH3:35])[C@@H:13]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]3[C:15]=2[C:16]([O:18]CC2C=CC([N+]([O-])=O)=CC=2)=[O:17])[CH2:7][N:6]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:4].[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][N:2]([C@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1)[C:3]([C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:12]([CH3:35])[C@@H:13]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH2:7][NH:6]1)=[O:4]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)[C@H]4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N(C)[C@H]4CCNC4)C3)[C@H](C)[C@H]12

Procedure:
500 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-(N-methyl-N-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]carbamoyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.45 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 700 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 30 mg of the title compound as a powder.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C.C(N=CC1CCCCC1)CCC.C[O:25][C:26](=[O:35])[C@H:27]([CH2:33]O)[N:28](Cl)[C:29](=O)[CH3:30]>C(COC)OC>[CH2:29]1[C:30]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:33][CH:27]([C:26]([OH:25])=[O:35])[NH:28]1
Reactant: CCCCCC
Reactant: COC(=O)[C@H](CO)N(Cl)C(C)=O
Agent: CCCCN=CC1CCCCC1
Agent: [Li]CCCC
Solvent: COCCOC
Product: O=C(O)C1CC2(CCCCC2)CN1
Reaction time: 1 h

Procedure:
6.4 g of butyllithium (in the form of a hexane solution) were added to 16.7 g of butyliminomethylcyclohexane in 300 ml of anhydrous dimethoxyethane at -76° C. under protective gas (argon). 15 min. after completion of addition, 18 g of N-acetylchloroserine methyl ester in 100 ml of DME were added dropwise, with efficient cooling. The mixture was stirred for a further 1 hour at a low temperature, allowed to warm up and evaporated to a small volume in vacuo. The crude mixture was acidified with 200 ml of 2N HCl and heated to reflux for 45 min. The mixture was evaporated in vacuo, the residue was taken up in glacial acetic acid, 1 g of Pt/C (10% Pt) was added and hydrogenation was carried out under normal pressure. The mixture was filtered, evaporated and chromatographed over a silica gel column with the system chloroform/methanol/glacial acetic acid/water 25:15:2:2. The amino acid crystallized from the appropriate eluate after evaporation.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[N:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[N:15][CH:14]=1>>[N:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)[CH:16]=[N:15][CH:14]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: OB(O)c1cncnc1
Product: O=Cc1cnc2ccc(-c3cncnc3)cn12
Yield: 50 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and pyrimidin-5-ylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:28])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[F:27])=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:42](OC(=O)C)([F:44])[F:43]>O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:42]([F:44])[F:43])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[F:27])[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Cl)cc1F
Temperature: 80 °C
Reaction time: 96 h

Procedure:
A mixture of [3-(4-chloro-2-fluorobenzyl)-2-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.20 g), N,N-dimethylformamide (3.0 mL), potassium carbonate (0.20 g) and acetic acid chlorodifluoromethyl ester (0.15 mL) was stirred at 80° C. for 4 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:4 by volume) gave title compound, 0.071 g.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=1>>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][N:22]2[C:9](=[O:11])[C:5]3[S:6][CH:7]=[CH:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:18]=1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1sccc1N=C=S
Product: Cc1cn(CCCn2c(=S)[nH]c3ccsc3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 3-isothiocyanatothiophene-2-carboxylate (0.107 g. 0.53 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.075 g, 0.53 mmol) as described above.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.FC(F)(F)S(O[C:15]1[C:16]2[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[CH:24][CH:23]=2)[N:20]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:15]2[C:16]3[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:32][CH:31]=[N:30][CH:29]=4)=[CH:26][CH:27]=3)[N:20]=2)[CH2:2]1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: OCC1CCCNC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N3CCCC(CO)C3)c2C1
Yield: 34.6 %

Procedure:
1-(4-(3-(hydroxymethyl)piperidin-1-yl)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (25.7 mg, 34.6%) was prepared from piperidin-3-ylmethanol and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][O:12][CH2:13][C@@H:14]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]#[N:16])[CH:8]=[CH:9][CH:10]=1)=[O:4].[I-].[Li+]>CC(=O)C(C)(C)C.C(OCC)(=O)C>[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][O:12][CH2:13][C@@H:14]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]#[N:16])[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(=O)C(C)(C)C
Product: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)N[C@@H](C#N)COCc2cccc(C(=O)O)c2)c1
Temperature: 25 °C

Procedure:
A solution of N-[2-[(3-(methoxycarbonyl)phenyl)methoxy]-1(S)-cyanoethyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide (0.34 g, 0.58 mmol) in pinacolone (20 mL) is degassed with bubbling nitrogen for 10 minutes. Lithium iodide (0.78 g, 5.80 mmol) is then added, and the solution is refluxed in the dark for 24 hours, after which time it is cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with 5% aq. sodium thiosulfate (2×50 mL), water (1×50 mL) and brine (1×50 mL). The organic layer is then dried over MgSO4, evaporated, and the residue is chromatographed (silica, 3% MeOH/CH2Cl2/0.05% acetic acid) to yield a clear glass, which is crystallized with an EtOAc/hexane (1:50) mixture to yield N-[2-[(3-carboxyphenyl)methoxy]-1(S)-cyanoethyl]-3-methyl-Nα-(diphenyacetyl)-L-phenylalaninamide as a white solid, m.p. 160-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21]C3C=CC(C(OC)=O)=CC=3)[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N(CC(O)C(F)(F)F)C(=O)NN=2)=CC=1.BrC[C:54]1[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:16])[F:17])[C:11](=[O:20])[N:10]([CH2:21][C:54]3[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=3)[C:57]([O:59][CH3:60])=[O:58])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Product: COC(=O)c1cccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)c1

Procedure:
In the same way as for the compound from Example 24A, 267 mg (0.87 mmol) of the compound from Example 19A were reacted with 199 mg (0.87 mmol) of methyl 3-(bromomethyl)benzoate. This gave 302 mg (76% of theory) of the target compound.
Reaction SMILES: [Na:1].C(O[C:5](=O)[CH2:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[CH2:16](Br)[CH:17]=C.[OH-].[K+]>C(O)C.O>[Na:1].[C:8]1([C:7]([CH2:6][CH2:5][CH:16]=[CH2:17])=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: C=CCBr
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCCC(=O)c1ccccc1
Yield: 98 %

Procedure:
A sodium solution of alcohol was prepared by dissolving 33 g of sodium in 1000 mL of ethanol. To the warm solution, 260 mL of benzoyl-acetic acid-ethylester was added and then 130 mL of allyl bromide was slowly dropped into the solution. The mixture was refluxed for 4 hrs. and then the solid removed in a vacuum. The resulting solid was then combined in an aqueous solution of potassium hydroxide prepared by combining 145 g of potassium hydroxide with 500 mL of water. This mixture was heated under reflux for 4 hrs. The mixture was then neutralized and extracted three times with 150 mL of diethylether. The organic layer was separated, washed twice with water, and dried. The solvent was removed in a vacuum to produce a 98 percent yield of phenyl-(but-3-enyl) ketone.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[N+:27]([O-:29])=[O:28])=[CH:21][CH:20]=1>C(OCC)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([CH:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:17])[CH2:26][N+:27]([O-:29])=[O:28])=[CH:23][CH:24]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(C(=O)c1ccccc1)[C@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: 23 °C

Procedure:
To a solution of 1,3-diphenyl-1,3-propanedione (1a) (0.3 mmol, 3 eq) and 1-chloro-4-((E)-2-nitrovinyl)benzene (2g) (0.1 mmol, 1 eq) in diethyl ether (0.3 mL) was added catalyst VI (Q-NH2) (0.015 mmol, 0.15 eq). The resulting mixture was stirred at room temperature (23° C.). After the reaction was complete (monitored by TLC), the product 3g was isolated and purified by centrifuge/washing with diethyl ether (0.3 mL). All the catalyst VI (0.15 equiv) and 2 equivalents of the excess the dione 1a were retained in the filtrate. The combined ethereal filtrate was evaporated to 0.3 mL before the dione 1a (1 eq) and 2g (1 eq) were added again to the solution for the next round of the Michael reaction. This was to ensure that the reaction condition for each cycle was almost the same as the previous one. The excellent yields (96% in average) and enantioselectivities (98-94% ee) were achieved in seven cycles.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CCNCC
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: CCN(CC)CCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and Diethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-diethyl-amine, MS: 446 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]=[CH:9][C:8]2=[O:15].CO>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][C:8]2=[O:15]
Reactant: O=c1ccoc2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCOc2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc21
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a stirred solution of 6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chromen-4-one (0.10 g, 0.2315 mmol) in ethyl acetate (2.5 mL) was added 10% Palladium on C (20 mg, 20% w/w) followed by methanol (2.5 mL). After stirring for 18 h under hydrogen atmosphere, the reaction mixture was filtered through celite and concentrated to furnish the crude product, which was further purified by Preparative HPLC to yield the title compound (41 mg)