Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[H][H]>>[NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: NC1(C(=O)O)CCN(Cc2ccccc2)C1
Reactant: [H][H]
Product: NC1(C(=O)O)CCNC1

Procedure:
According to a particular variant of embodiment of this synthesis process, 1-benzyl-3-pyrrolidinone is treated with an ammoniacal solution of ammonium chloride and of potassium cyanide to obtain (±)-3-amino-1-benzyl-3-cyanopyrrolidine. This compound is then converted by acid or basic hydrolysis to (±)-3-amino-1-benzyl-3-pyrrolidinecarboxylic acid, and lastly a reduction with hydrogen, preferably a catalytic hydrogenolysis, is carried out to obtain (±)-3-amino-3-pyrrolidinecarboxylic acid or (±)-cucurbitine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20][OH:21])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1
Reactant: CCc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Reactant: NO
Agent: Cl
Product: CCc1ccc(C(=NO)c2ccc(Cl)cc2)c(O)c1

Procedure:
4'-Chloro-4-ethyl-2-hydroxybenzophenone (130.4g) was treated with hydroxylamine hydrochloride (140g) similarly to Example 12, to give the title compound, one isomer only (81.2g), m.p. 159°-161°C,
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:24](O)=[O:25])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25])([O-:20])=[O:19]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)c([N+](=O)[O-])c4)cc23)CC1
Yield: 62.8 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 26.4 mg (0.131 mMol) 3-nitro-4-chlorobenzoic acid, 11.4 mg (63.3%) of the title compound were recovered.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C:16](=[O:17])[N:15]2[C@H:18](C(O)=O)[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:25])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:30]([NH:32][CH:33]([C:42](=[O:53])[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52])[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])C=C.C(NC1C(=O)N2C(C(NC(C(=O)CSCC3C=CC=CC=3Cl)CC(OC(C)(C)C)=O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1>>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:30]([NH:32][CH:33]([C:42](=[O:53])[CH2:43][O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[O:31])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:25])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc1ccccc1Cl
Agent: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)CSCc1ccccc1Cl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)COCc1ccccc1Cl
Yield: 23 %

Procedure:
was prepared from acid 212e and (3S) t-butyl N-(allyloxycarbonyl)-3-amino-5-(2-chorophenylmethyloxy)-4-oxopentanoate (201) using a method similar to that used for compound 224e, to afford 40 mg (23%) of a glassy solid: 1H NMR (CDCl3) δ7.83-7.73 (2H, m), 7.67-7.10 (9H, m), 5.23-5.09 (2H, m), 4.59 (1H, m), 4.45-4.22 (2H, m), 3.7-3.19, 3.08-2.72, 2.71-2.47, 2.05-1.85, 1.72-1.61, 1.45-1.26 (20H, 6 m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][CH:20]([NH:22]C(=O)OC(C)(C)C)[CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(COc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)COc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
tert-Butyl {2-[4-(4-benzyloxyphenoxy)phenoxy]-1-methylethyl}carbamate (837 mg, 1.86 mmol) was treated with 90 percent strength trifluoroacetic acid. The trifluoroacetic acid was distilled off and the aqueous phase was freeze dried. Chromatography was performed on a chiral column (ChiralpakAD-H/91, 250 4.6 mm, eluent: heptane/ethanol=3:1+0.1% DEA) for enantiomer separation (S)-2-[4-(4-Benzyloxyphenoxy)phenoxy]-1-methylethylamine (RF: 11.667 min.), Yield: 230 mg (35%), M+H+: 350.19, (R)-2-[4-(4-benzyloxyphenoxy)phenoxy]-1-methylethylamine (RF: 13.122 min.), Yield: 226 mg (35%), M+H+: 350.19.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CO.C[O:10][C:11]([C:13]1[NH:14][C:15]2[CH:16]=[C:17]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:18]=[C:19]3[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:21]=1[C:20]=23)=O.C(N(CC)CC)C>CN(C)C=O.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]>[C:31]([O:30][C:28](=[O:29])[NH:27][C:17]1[CH:18]=[C:19]2[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:21]3=[C:13]([C:11](=[O:10])[NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[NH:14][C:15]([CH:16]=1)=[C:20]23)([CH3:34])([CH3:32])[CH3:33]
Reactant: CN(C)CCN
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Yield: 76 %

Procedure:
Preparation of example 165 was carried out in a manner analogous to step 5 of Example 147, except that N,N-dimethylethylenediamine was substituted for methanol. Thus CO was bubbled through a mixture of Intermediate 147(d) from Example 147 (1.5 g, 3.97 mmol), triethylamine (1.1 mL, 7.92 mmol), N,N-dimethylethylenediamine (0.7 g, 7.94 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (0.65 g, 0.796 mmol) in N,N-dimethylformamide (30.0 mL). Reaction conditions, work up and silica gel chromatography (eluted with 46:4:25 dichloromethane: methanol: ethyl acetate) were also carried out in an analogous manner and afforded the title compound (1.25 g, 3.02 mmol) in 76% yield.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C([O:42][C:43](=[O:64])[C@H:44]([OH:63])[CH2:45][N:46]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:56]=2[F:62])=[CH:51][CH:50]=1)[NH2:47])C.CCN(C(C)C)C(C)C.CCO.[Li+].[OH-].O>>[Cl:61][C:59]1[CH:58]=[CH:57][C:56]([F:62])=[C:55]([C:52]2[CH:53]=[CH:54][C:49]([CH2:48][N:46]([CH2:45][C@@H:44]([OH:63])[C:43]([OH:64])=[O:42])[NH:47][C:7]([C:4]3[S:3][C:2]([OH:1])=[N:6][CH:5]=3)=[O:9])=[CH:50][CH:51]=2)[CH:60]=1
Reactant: O=C(O)c1cnc(O)s1
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cnc(O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
2-Hydroxy-5-thiazolecarboxylic acid (43.5 mg, 0.3 mmol) and HCTU (124 mg, 0.3 mmol) were stirred in DMF (1.3 mL, 16.4 mmol) for 15 minutes at room temperature. (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (100 mg, 0.3 mmol) and DIPEA (142 μL, 818 μmol) were added, and resulting mixture was stirred at room temperature for 30 minutes. The mixture was then evaporated under reduced pressure. The residue was dissolved in EtOH (955 μL, 16.4 mmol). A solution of 1.0 M LiOH in water (1.4 mL, 1.4 mmol) was added and the resulting mixture was stirred at 40° C. for 3 hours. LC/MS showed completion. The solvent was removed in vacuo and the residue was purified by preparative HPLC to yield the title compound (22 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C20H17ClFN3O5S, 466.06. found 466.0.
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][C:13]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[CH2:22]([O:21][C:13]1[CH:14]=[C:15]([CH2:18][CH2:19][CH3:20])[CH:16]=[CH:17][C:12]=1[OH:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1ccc(O)c(OCc2ccccc2)c1
Yield: 85.7 %

Procedure:
To a solution of 2-(benzyloxy)-4-propylphenyl 4-methylbenzenesulfonate (0.07 mmol; 28 mg) under argon, in a mixture of ethanol (0.2 mL) and water (0.1 mL), was added KOH (0.09 mmol; 5 mg). The reaction was refluxed for 1 hr, then hydrolysed with NH4Cl sat. (3 mL), and extracted with ethyl acetate (3*5 mL). Combined organic phases were washed with saturated NaHCO3 (3 mL), dried over MgSO4, concentrated. The residue was purified by preparative TLC (cyclohexane/dichloromethane) to yield the title compound as a clear oil (16 mg; 0.06 mmol; 86%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[N+:32]([O-])([O-:34])=[O:33].[Na+]>C(O)(C(F)(F)F)=O.O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:15]([N+:32]([O-:34])=[O:33])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine (Example 14, 10 mmol, 4.24 g) in TFA (10 mL) was added sodium nitrate (12 mmol, 1.02 g) at 0° C. The mixture was allowed to warm up to room temperature and stirred for 8 hours. The mixture was then diluted with water/EtOAc, neutralized slowly with NaHCO3 powder. The organic layers were combined, dried, and condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% MeOH) to give a pale-yellow solid, 3-butyl-4-(4-cyclohexyloxy-3-nitro-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine (3.09 g).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(N)CN.O>COCC(O)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: NCCN
Solvent: COCC(C)O
Solvent: O
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 110 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) is placed in a mixture of 1-methoxy-2-propanol (13.0 g) and ethylenediamine (1.3 g, 21.6 mmol, 1.68 equiv) and is heated to 110° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at room temperature in a mixture of ethylenediamine (9.6 g, 159.7 mol, 12.4 equiv) and 1-methoxy-2-propanol (0.8 g) and the solution is added in portions to the thebaine mixture over 1 hour 20 minutes at such a rate that the batch temperature is maintained at ˜110° C. The reaction mixture is held at this temperature for 1 hour then cooled to room temperature and then water (24 g) is added while maintaining the batch temperature at ≦30° C. The resulting slurry (pH 11.4) is filtered and the product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.68 g, 91.3% yield; 99.1 area % purity by HPLC).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]2[CH:7]=[C:8]([NH:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[C:10]([CH2:11][CH3:12])[C:5]=2[O:4][CH2:3]1.[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([N:13]([CH:14]([CH3:15])[CH3:16])[C:8]2[CH:9]=[C:10]([CH2:11][CH3:12])[C:5]3[O:4][CH2:3][C:2]([CH3:1])([CH3:17])[C:6]=3[CH:7]=2)=[CH:24][CH:23]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCc1cc(NC(C)C)cc2c1OCC2(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N(c2cc(CC)c3c(c2)C(C)(C)CO3)C(C)C)cc1
Yield: 31.2 %

Procedure:
Following general procedure E and using 3,3-dimethyl-7-ethyl-5-(isopropyl)amino-2,3-dihydro-benzofuran (Compound 34, 0.43 g, 1.96 mmol), ethyl-4-iodo-benzoate (0.45 g, 1.93 mmol), cesium carbonate (0.88 g, 2.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.020 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.040 g, 0.064 mmol) in 6 mL of anhydrous toluene, the title compound (0.23 g, 32%) was obtained. This reaction was conducted in a sealed tube for 7 days. Some 3,3-dimethyl-7-ethyl-5-(isopropyl)amino-2,3-dihydro-benzofuran (Compound 34) was recovered. 1H NMR (300 MHz, CDCl3): δ 7.82 (d, 2H, J=9.0 Hz), 6.69 (d, 1H, J=2.0 Hz), 6.66 (d, 1H, J=2.0 Hz), 6.51 (d, 2H, J=9.0 Hz), 4.38-4.26 (m, 5H), 2.60 (q, 2H, J=7.5 Hz), 1.33 (t, 3H, J=7.1 Hz), 1.32 (s, 6H), 1.21 (t, 3H, J=7.5 Hz), 1.15 (d, 6H, J=6.5 Hz)
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18](=[O:34])[CH:19]([N:21]4[CH2:26][CH2:25][C:24]([OH:33])([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)[CH3:20])=[CH:17][C:11]=3[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:35]1([C:9]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([OH:34])[CH:19]([N:21]4[CH2:22][CH2:23][C:24]([OH:33])([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:25][CH2:26]4)[CH3:20])=[CH:17][C:11]=3[O:10]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCC(O)(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C(O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCC(O)(c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of sodium borohydride (0.15 g, 3.97 mmol) and ethanol (5 mL) was stirred 10 minutes and then 1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-one (1.70 g, 3.36 mmol in 20 mL of ethanol) was added. The reaction was stirred at ambient temperature over the weekend. The white precipitate was collected, rinsed with ethanol and ether and air dried to afford 1.35 g of crude product. The product was recrystallized from ethanol/ethyl acetate/methylene chloride to give 1.05 g (61%) of 1R*, 2R*)-1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-ol which had: mp 224-224.5° C. Analysis calculated for C33H33NO4: C, 78.08; H, 6.55; N, 2.76. Found: C, 78.16; H, 6.46; N, 2.72.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][C:14]([C:25](O)=[O:26])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N-:28]1C=CN=C1.N.O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][C:14]([C:25]([NH2:28])=[O:26])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: c1c[n-]cn1
Reactant: Cc1cc(C2=NN=C(C(=O)O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: N
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2=NN=C(C(N)=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
4.17 g (10.0 millimoles) of 5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carboxylic acid-imidazolide are suspended in a mixture of 85 ml dichloro methane and 15 ml of a 15% aqueous methanolic ammonia solution. The reaction mixture is sealed and stirred at room temperature for 6 hours. The mixture is cooled with icecold water. The precipitated product is filtered and washed with 20 ml of diethyl ether. Thus 3.11 g of the desired compound are obtained, yield 85%, mp.: 266–268° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[N:11]2)=[N:8][CH:9]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[F:18][C:15]([F:16])([F:17])[C:13]1[CH:12]=[N:11][N:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][N:6]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1cnc(-n2cc(C(F)(F)F)cn2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cnc(-n2cc(C(F)(F)F)cn2)nc1
Reaction time: 8 h
Yield: 170.7 %

Procedure:
A Parr Shaker bottle was charged with Pd/C (10% wet; degussa type; 300 mg) and the 5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (1.18 g, 4.55 mmol) in ethyl acetate (91 mL). Shaked at 40 psi of H2 (g) for 8 hours. Crude mixture filtered through celite and concentrated under reduced pressure to afford 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-amine (1.78 g, 98%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 5.85 (s, 2H) 8.15 (s, 1H) 8.18 (s, 2H) 8.95 (s, 1H); MS (M+1): 230.2.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].II.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18](=[O:26])[C:19](=[O:25])[C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:13][CH2:12]1.[Cl-].[NH4+]>C1COCC1>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18](=[O:26])[C:19]([OH:25])([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12]1
Reactant: CN1CCC(OC(=O)C(=O)c2cccs2)CC1
Reactant: Brc1cccs1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CN1CCC(OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromothiophene (3.2 ml, 33 mmol) in THF (30 ml) is added dropwise to a mixture of magnesium (0.8 g, 33 mmol) and a single crystal of iodine in THF (30 ml). After addition of just under one half of the 2-bromothiophene the addition is suspended until reaction has initiated (judged by an exotherm). The addition is then completed maintaining the reaction temperature to below 40° C. After the addition is completed the reaction mixture is heated to 70° C. for 1 hour. This mixture is then cooled and added to a solution of oxo-thiophen-2-yl-acetic acid 1-methyl-piperidin-4-yl ester (6.48 g, 25.6 mmol) in THF (80 ml). After the addition is completed the reaction mixture is stirred at room temperature for 1 hour and then heated to reflux for 2 hours. After cooling to room temperature saturated aqueous ammonium chloride solution (100 ml) is added. The solution is extracted with diethylether dried over magnesium sulphate, filtered and concentrated. Purification by flash silica column chromatography gives the title product.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)C=CC=CC=1.CC(C)([O-])C.[K+].[C:39]([C:44]1[CH:53]=[CH:52][C:47]([C:48](OC)=[O:49])=[CH:46][CH:45]=1)(=O)[CH2:40][CH2:41][CH3:42].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1C=CC=CC=1.O1CCCC1.[C].[Pd].CO.O>[C:15]1([C:13]2[N:14]=[C:10]([CH2:9][CH:39]([C:44]3[CH:45]=[CH:46][C:47]([CH2:48][OH:49])=[CH:52][CH:53]=3)[CH2:40][CH2:41][CH3:42])[S:11][CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCC(=O)c1ccc(C(=O)OC)cc1
Reactant: c1ccc(-c2csc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C[Al+]CC(C)C
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: CCCC(Cc1nc(-c2ccccc2)cs1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a suspension of triphenyl[(4-phenyl-1,3-thiazol-2-yl)methyl]phosphonium bromide (1.00 g, 1.94 mmol) synthesized according to the method described in Liebigs Annalen der Chemie, 1981, vol. 4, pp. 623-632 and benzene (20 mL) was added potassium tert-butoxide (239 mg, 2.13 mmol), and the mixture was stirred under an argon atmosphere at room temperature for 3 hr. A solution of methyl 4-butyrylbenzoate (319 mg, 1.55 mmol) in benzene (20 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 3 hr, and further heated under reflux for 16 hr. The reaction mixture was allowed to cool to room temperature, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-20:80) to give a yellow oil. A mixture of the obtained oil, tetrahydrofuran (20 mL), methanol (10 mL) and 10% palladium-carbon (50% water-containing product, 200 mg) was stirred under a hydrogen atmosphere at room temperature for 2 days. The catalyst was filtered off, and the obtained filtrate was concentrated to give a colorless oil. To a solution of the obtained oil in tetrahydrofuran (10 mL) was added dropwise 1.0 M diisobutylaluminum hydride toluene solution (10 mL, 10 mmol) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, sodium sulfate decahydrate was added and the mixture was further stirred at room temperature for 1 hr. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90-60/40) to give the title compound (250 mg, yield 48%) as a colorless oil.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[N:19]1[CH:20]=[N:21][N:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]4[C:45]5[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:47]6[O:48][CH2:49][C:50]([CH2:53][O:54][Si](C(C)(C)C)(C7C=CC=CC=7)C7C=CC=CC=7)([CH3:52])[N:51]=6)[CH:44]=5)[N:39]=[CH:38][N:37]=4)=[CH:31][C:30]=3[CH3:72])=[CH:24][C:23]=12>C1COCC1>[N:19]1[CH:20]=[N:21][N:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]4[C:45]5[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:47]6[O:48][CH2:49][C:50]([CH2:53][OH:54])([CH3:52])[N:51]=6)[CH:44]=5)[N:39]=[CH:38][N:37]=4)=[CH:31][C:30]=3[CH3:72])=[CH:24][C:23]=12
Reactant: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CO4)cc23)ccc1Oc1ccn2ncnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(CO)CO4)cc23)ccc1Oc1ccn2ncnc2c1
Reaction time: 3 h

Procedure:
TBAF (7.799 mmol, 7.79 mL, 1M in THF) was added to a solution of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4-((tert-butyldiphenylsilyloxy)methyl)-4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (2.866 g, 3.900 mmol) in THF (60 mL). The reaction was stirred for 3 hours and then concentrated. The residue was purified by flash chromatography, eluting with EtOAc/Hex/MeOH 9:1:1 with 0.1% H2O to provide the title compound. MS APCI (+) m/z 497.4 (M+1) detected.