Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[CH3:37][C:38]([CH3:42])([CH3:41])[CH:39]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:37][C:38]([CH3:42])([CH3:41])[CH3:39])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C=O
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CC(C)(C)C)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2,2-dimethyl-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using trimethylacetaldehyde (75% in tert butanol) instead of acetone and was obtained as a light brown oil. MS m/e: 594.3 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>[OH-].[Na+]>[C:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(O)ccc1Br
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 4-bromo-3-methylphenol (184.1 g) and aqueous NaOH (850 ml, 2M) at 20° C. is treated with acetic anhydride (136 ml) and stirred at room temperature for 1 h. The suspension is extracted with diethyl ether (3×300 ml) and the combined extracts are washed with aqueous NaOH (2×100 ml 2M), dried (Na2SO4) and filtered. The solvent is evaporated off under reduced pressure to yield the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([Cl:11])=[C:9]([CH3:12])[C:8]([Cl:13])=[CH:7][C:5]=2[N:6]=1.[CH2:14]([O:16][S:17]([O:20]CC)(=[O:19])=[O:18])[CH3:15]>>[CH2:14]([O:16][S:17]([OH:20])(=[O:19])=[O:18])[CH3:15].[CH3:1][CH:2]1[N:6]([CH2:14][CH3:15])[C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([CH3:12])=[C:10]([Cl:11])[C:4]=2[O:3]1
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1nc2cc(Cl)c(C)c(Cl)c2o1
Product: CCN1c2cc(Cl)c(C)c(Cl)c2OC1C
Product: CCOS(=O)(=O)O

Procedure:
The compound was prepared as described in Example 5 using 2,6-dimethyl-5,7-dichloro-benzoxazole and diethylsulfate.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([OH:31])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:31]
Reactant: Cc1nc(N2CCN(Cc3cccc(C(F)(F)F)c3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3cccc(C(F)(F)F)c3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 81 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(3-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 81% yield: mp 175-176° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) 8.58 (s, 1H), 8.50 (d, J=4.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.61-7.54 (m, 1H), 7.53-7.44 (m, 3H), 7.29-7.21 (m, 1H), 6.21 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.51 (s, 2H), 4.14-4.02 (m, 2H), 3.52-3.41 (m, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.2, 155.5, 153.7, 149.3, 149.0, 136.7, 135.6, 133.9, 131.6, 131.5, 131.1, 129.5, 125.0, 124.9, 123.6, 117.1, 47.7, 42.0, 41.9, 41.4, 17.3; MS (ES+) m/z 476.4 (M+1).
Reaction SMILES: OS(O)(=O)=O.[O:6]=[C:7]1[N:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23](OC)[C:24](=C=O)[C:25]3[CH:30]=[C:29]([Br:31])[C:28]([O:32]COCC[Si](C)(C)C)=[C:27]([Br:41])[CH:26]=3)=[O:21])[CH2:16][CH2:15]2)[CH2:12][CH2:11][C:10]2[CH:46]=[CH:47][CH:48]=[CH:49][C:9]=2[NH:8]1>C1COCC1.CO>[O:6]=[C:7]1[N:13]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C@@H:23]([C:20]([O:22][CH3:23])=[O:21])[CH2:24][C:25]3[CH:26]=[C:27]([Br:41])[C:28]([OH:32])=[C:29]([Br:31])[CH:30]=3)=[O:21])[CH2:18][CH2:19]2)[CH2:12][CH2:11][C:10]2[CH:46]=[CH:47][CH:48]=[CH:49][C:9]=2[NH:8]1
Reactant: CO[C@H](OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)C(=C=O)c1cc(Br)c(OCOCC[Si](C)(C)C)c(Br)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere 5.46 mL methanolic H2SO4 (0.5 M) was added to a solution of 4.30 g (5.69 mmol) (R)-2-[3,5-dibromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-methoxy-carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 40 mL THF and 40 mL MeOH and the reaction solution was stirred for 6 h at RT. The reaction mixture was evaporated down i.vac. and the residue was further reacted without purification.
Reaction SMILES: [Cl:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.C(O)C.O.[BH4-].[Na+]>O1CCCC1>[Cl:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2Cl
Temperature: -55 °C
Reaction time: 7 h
Yield: 34 %

Procedure:
A solution of 380 mg of 11β-chloro-7α-methyl-estr-4-ene-3,17-dione (F′) in 7.6 ml of tetrahydrofuran, 4.4 ml of ethanol and 1.15 ml of water was mixed at −55° C. in portions with 596 mg of sodium borohydride and stirred for 7 hours at −55° C. Then, the mixture was added to ice water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 130 mg of pure 11β-chloro-17β-hydroxy-7α-methyl-estr-4-en-3-one (I) was obtained ([α]D20=+136.9° (in chloroform), FD183.2° C.).
Reaction SMILES: C(Cl)Cl.[CH2:4]([CH:11]([NH:15][C:16](=[O:33])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([O:31][CH3:32])[CH:20]=1)[CH:12]([OH:14])[CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:4]([CH:11]([NH:15][C:16](=[O:33])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([O:31][CH3:32])[CH:20]=1)[C:12](=[O:14])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)O)ccc1-n1cnc(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
To a methylene chloride (2.0 mL) solution of (E)-N-(1-benzyl-2-hydroxy propyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (29.0 mg), Dess-Martin reagent (60.7 mg) was added. After agitating the reaction solution at room temperature for 4 hours and 30 minutes, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate ethanol=10:1), and 15.4 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4](O)[N:3]=1.[Cl:19]S(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>P(Cl)(Cl)(Cl)=O>[ClH:19].[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([Cl:19])[N:3]=1
Reactant: Nc1nc(O)cc(-c2cccc3ccccc23)n1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cl
Product: Nc1nc(Cl)cc(-c2cccc3ccccc23)n1
Temperature: 95 °C
Reaction time: 6 h

Procedure:
2-Amino-6-hydroxy-4-(naphth-1-yl)-pyrimidine (900 mg) was added to a solution of chlorosulfonic acid (0.05 mL) in 2.5 mL of phosphorus oxychloride, and the mixture was stirred at 95° C. for 6 hours. The mixture was poured onto ice, neutralized with potassium carbonate, and extracted with ethyl acetate. The crude product (70 mg) was purified by silica gel chromatography, eluting with methylene chloride, and treated with hydrochloric acid-ethanol to give 2-amino-6-chloro-4-(naphth-1-yl)-pyrimidine hydrochloride (25 mg), m.p. 248-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]2[C:29]([O:31][CH3:32])=[O:30])=[CH:17][CH:18]=1
Reactant: COC(=O)C1CCNC(Cc2ccc(Cl)cc2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 110.2 %

Procedure:
To a solution of methyl 2-(4-chlorobenzyl)piperidine-4-carboxylate (3.72 g, 13.2 mmol) and DIPEA (4.85 mL, 27.78 mmol) in DCM (100 mL) was added methyl chloroformate (1.431 mL, 18.48 mmol) in DCM (50 mL) over 30 minutes. The reaction solution was stirred overnight (16 h). The organic phase was washed with satd NaHCO3, dried using a phase separator and evaporated to yield dimethyl 2-(4-chlorobenzyl)piperidine-1,4-dicarboxylate (4.74 g, 110%) as a yellow oil. MS m/z 326, 328 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH:16](OCC)(OCC)OCC.[N-:26]=[N+:27]=[N-:28].[Na+]>CC(O)=O>[CH3:8][C:6]1[C:5]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=[C:2]([N:1]2[CH:16]=[N:28][N:27]=[N:26]2)[N:7]=1
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(C)c1ccc(N)nc1C
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc(-n2cnnn2)nc1C
Temperature: 90 °C
Reaction time: 0.83 h

Procedure:
To a mixture of ethyl 2-(6-amino-2-methylpyridin-3-yl)propanoate (1.6 g, 7.6 mmol), CH(OEt)3 (3.4 g, 22.8 mmol) in AcOH (50 mL) was added NaN3 (0.6 g, 9.2 mmol) at room temperature. The mixture was heated to 90° C. and stirred for 50 min. The mixture was cooled to ambient temperature and stand over night. The mixture was concentrated under reduce pressure. Water was added, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatograph to give compound ethyl 2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]propanoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[NH2:13][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][C:16]([OH:18])=[O:17]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:13]([CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:16]([OH:18])=[O:17])[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: NC(CC(=O)O)c1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=O)N(C(CC(=O)O)c1ccccc1)C2=O
Yield: 54.6 %

Procedure:
A stirred mixture of 4-methylphthalic acid anhydride (1.62 g, 10.0 mmol) and 3-amino-3-phenylpropionic acid (1.65 g, 10.0 mmol) in 15 mL of acetic acid under nitrogen was heated to reflux for 6 hours. The resulting reaction solution was concentrated in vacuo to an oil which was crystallized from 20 mL of a 1/1 mixture of ethyl acetate/hexane to afford 1.69 g (55%) of 3-(4-methylphthalimido)-3-phenylpropionic acid as an off-white powder: 1H NMR (DMSO-d6)δ 12.5 (br s, 1H, COOH). 7.85-7.55 (m, 3H, Ar), 7.55-7.2 (m, 5H, Ar), 5.68 (dd, 1H, J=9, 7 Hz, CH), 3.51 (dd, 1H, J=9, 16.5 Hz), 3.29 (dd, 1H, J=9, 16.5 Hz), 2.47 (s, 3H, CH3). Anal. Calcd for C18H15N1O4. Theory; C, 69.89, H, 4.89, N, 4.53. Found: C, 69.45, H, 4.93, N, 4.55. HPLC: 95%.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2nsc3ccccc23)CC1
Yield: 38.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20.0 mmol), K2CO3 (3.0 g, 21.8 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 5 hours. Most of the solvent was removed in vacuo and the resultant gummy residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried with MgSO4, and concentrated to yield 7.8 g. Purification by preparative HPLC (Waters Associates Prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent) afforded 6.5 g of a damp, off-white solid. The product was recrystallized twice from toluene to provide 3.1 g (39%) of 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=114°-116° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].Cl[S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].ClCCl.C(OCC)(=O)C>N1C=CC=CC=1>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[O:8][S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][CH:21]=1)(=[O:12])=[O:11]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: [O-][n+]1ccccc1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)On2ccccc2=O)cc1
Yield: 30 %

Procedure:
2-Hydroxypyridine-1-oxide (0.21 g, 1.9 mmol) was reacted with 4-(chlorosulfonyl)benzoic acid (0.62 g, 2.8 mmol) in 5 mL pyridine. The solvent was evaporated, leaving a yellow oil. Addition of 5 mL of dichloromethane followed by the addition of 5 mL of ethyl acetate allowed for precipitation of PZBG-1e in 30% yield (0.17 g, 0.57 mmol). 1H NMR (400 MHz, DMSO) δ=8.18 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.4 Hz), 7.88 (dd, J1=7.6 Hz, J2=2 Hz), 7.45 (td, J1=8.2 Hz, J2=2 Hz, 1H), 6.50 (dd, J1=9.2 Hz, J2=1.6 Hz, 1H), 6.26 (td, J1=7 Hz, J2=1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ=166.5, 156.6, 141.5, 138.2, 137.9, 137.3, 131.2, 130.4, 122.8, 106.2. ESI-MS(−): m/z 294.26[M−H]−. Anal. calcd. for C12H9NO6S: C, 48.81; H, 3.07; N, 4.74. Found: C, 48.91; H, 3.37; N, 4.84.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[O:16]1[CH:20]=[C:19](C=O)[N:18]=[CH:17]1.C1C[O:26][CH2:25]C1>>[O:16]1[C:20]([CH:25]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:9][CH:10]=2)[OH:26])=[CH:19][N:18]=[CH:17]1
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Reactant: O=Cc1cocn1
Reactant: C1CCOC1
Product: OC(c1ccc(OC2CCCCO2)cc1)c1cnco1
Temperature: -78 °C
Reaction time: 21 h

Procedure:
4-(2-Tetrahydro-3H-pyranoxy)phenylmagnesium bromide (120 mL, 0.5 M in THF, 60 mmol) was added dropwise to a solution of oxazole-4-carbaldehyde (4.85 g, 50 mmol) in THF (90 mL) at −78° C. After stirring at −78° C. for 21 hours, the reaction was quenched with saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 17 g of the crude product 5.1, which was used in the next reaction without further purification.
Reaction SMILES: BrC[CH2:3][C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CO>[NH2:18][C:16]1[S:17][CH:3]=[C:4]([C:6]2[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[CH3:14])[N:15]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)c(C(=O)CCBr)c(C)c1
Solvent: CO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 70 %

Procedure:
A solution of 80 g of 2,4,6-trimethylphenyl bromoethyl ketone and 35 g of thiourea in 250 ml of methanol is refluxed for 3 hours. After cooling the reaction mixture, the precipitate is filtered off and washed abundantly with diethyl ether. After concentration of the filtrate to a third of the initial volume, a second bath of crystals is recovered. Yield: 70%. m.p.=138° C. The hydrobromide prepared by the action of HBr in ethanol melts at 295° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:15]([C:28](O)=[O:29])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:34]2N(O)N=[N:37][C:35]=2[CH:36]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:35]1([NH:37][C:28]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:29])[CH2:36][CH2:34]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 191.9 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(5-phenylpentyl)-1H-1,2,3-triazole-4-carboxylic acid (392 mg, 0.964 mmol) obtained in Example 101b), HOBt (67.3 mg, 0.482 mmol, 0.5 eq.) and cyclopropylamine (0.090 ml, 1.25 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 6 ml), WSC (226 mg, 1.16 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 13.5 hr. Water (10 ml) was added to the reaction mixture, and the mixture was stirred. The precipitate was collected by filtration, washed with water and methanol-water (1:1) and dried to give the title compound as a white powder (412 mg, 0.925 mmol, 95.9%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:23])[CH:9]=2)[N:4]=1.ClC1C2C(=CC=C(F)C=2)N=C(CCl)[N:26]=1.COC1C=CC(NC)=CC=1>CC(O)C.Cl.C(Cl)Cl>[NH2:26][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:23])[CH:9]=2)[N:4]=1
Reactant: Fc1ccc2nc(CCl)nc(Cl)c2c1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccc(F)cc23)cc1
Agent: CNc1ccc(OC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(CN)nc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
(2-Chloromethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of 4-chloro-2-chloromethyl-6-fluoroquinazoline (265 mg, 1.15 mmol) and (4-methoxy-phenyl)-methyl-amine (175 mg, 1.26 mmol) in i-PrOH (10 mL) was treated with HCl (12 M, 4 drops) and stirred overnight at rt. The reaction was diluted with CH2Cl2 and washed with 5% NaOH. The organics were dried (MgSO4), concentrated and purified by gradient MPLC (SiO2, EtOAc/hexanes, 0-100%, 20 min) to provide 258 mg (68%) of the title compound. 1H NMR (DMSO-d6) δ 7.83 (dd, 1H), 7.62 (ddd, 1H), 7.25-7.33 (m, 2H), 7.02-7.10 (m, 2H), 6.47 (dd, 1H), 4.75 (s, 2H), 3.81 (s, 3H), 3.54 (s, 3H); LC-MS (ESI+; 332 ([M+H]+)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]3[O:20][CH2:19][O:18][C:15]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1.C([O:24][C:25](=[O:27])[CH3:26])(=O)C.[N+:28]([O-:31])([OH:30])=[O:29].[C:32]([OH:35])(=[O:34])[CH3:33]>>[C:25]([OH:24])(=[O:27])/[CH:26]=[CH:33]\[C:32]([OH:35])=[O:34].[N+:28]([O-:31])([OH:30])=[O:29].[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]3[O:20][CH2:19][O:18][C:15]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Agent: OCCCCCNc1nccc2cc3c(cc12)OCO3
Solvent: O=[N+]([O-])O
Product: O=C(O)/C=C\C(=O)O
Temperature: 3 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.835 g. of 1-(5-hydroxypentyl)amino-6,7-methylenedioxyisoquinoline and 1 ml. of acetic acid is added dropwise to a stirred mixture of 1.32 ml. of acetic anhydride and 0.44 ml. of nitric acid at a temperature of minus 3°C. The reaction mixture is stirred for about 20 minutes at about minus 3°C., and then added to an excess of ice-cold aqueous ammonia solution and twice extracted with ethyl acetate. The combined organic extracts are dried, filtered and evaporated in vacuo to an oil which is redissolved in chloroform. The resulting solution is passed through silica gel to obtain 0.965 g. of an oil of the free base of the above title compound. This oil is dissolved in methylene chloride and 0.5 g. of maleic acid is added. The resulting solution is filtered, evaporated to a small volume and diethyl ether added to crystallize a material which is then recrystallized from methanol/diethyl ether to obtain 1-(5-hydroxypentyl)amino-6,7-methylenedioxyisoquinoline nitrate maleate, m.p. 138°-139.5°C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:5]=1.[F:20][C:21]([F:25])([F:24])[CH2:22][OH:23]>CN(C=O)C>[CH:17]1([CH2:16][NH:15][C:6]2[N:5]=[C:4]([O:23][CH2:22][C:21]([F:25])([F:24])[F:20])[CH:14]=[CH:13][C:7]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1ccc(Cl)nc1NCC1CC1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC(F)(F)F)nc1NCC1CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Sodium hydride was added at room temperature to a DMF solution of ethyl 6-chloro-2-[(cyclopropylmethyl)amino]nicotinate and 2,2,2-trifluoroethanol, followed by stirring at 80° C. for 20 hours. By post-treating the reaction liquid, ethyl 2-[(cyclopropylmethyl)amino]-6-(2,2,2-trifluoroethoxy)nicotinate was obtained.