Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:7](=O)[CH3:8])[C:4](=O)[CH3:5])[CH3:2].Cl.[NH:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1)[NH2:12]>>[CH2:1]([C:3]1[C:7]([CH3:8])=[N:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][OH:21])=[CH:17][CH:18]=2)[C:4]=1[CH3:5])[CH3:2]
Reactant: CCC(C(C)=O)C(C)=O
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: CCc1c(C)nn(-c2ccc(CCO)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 3-ethyl-2,4-pentanedione and 2-(4-hydrazinophenyl)ethanol hydrochloride: MS (ESI) m/z 245 [M+H]+, 1H-NMR (CDCl3) δ 7.36-7.26 (4H, m), 3.84 (2H, t, J=6.6 Hz), 2.89 (2H, t, J=6.6 Hz), 2.24 (2H, q, J=7.5 Hz), 2.26 (3H, s), 2.22 (3H, s), 1.12 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].Br[CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH2:1]([N:3]([CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCNCC(O)COc1ccc(C#N)cc1
Reactant: CCCSCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCSCCCN(CC)CC(O)COc1ccc(C#N)cc1

Procedure:
4.7 g of 4-[3-(ethylamino)-2-hydroxypropoxy]-benzonitrile, 4.5 g of 1-bromo-3-(propylthio)-propane and 5.8 g potassium carbonate were mixed in 50 ml isopropanol and refluxed over night. The mixture was filtrated and evaporated. The residual oil 8.3 g was separated by column chromatography. Yield 4.9 g of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([S:22]([NH:21][C:18]2[CH:19]=[CH:20][C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:9]=3[CH:17]=2)(=[O:23])=[O:24])=[CH:30][CH:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1

Procedure:
According to Step 5, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid ethyl ester (1.24 g, 2.5 mmol) from Example 1d) with 1M sodium hydroxide solution in ethanol/water (2:1, 49 mL), the desired compound is obtained at quantitative yield (1.18 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>C(Cl)Cl.O1CCOCC1>[O:1]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C(=O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)C1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of the 1-tert-butyl 4-ethyl 2-oxopiperidine-1,4-dicarboxylate (20 g, 74.45 mmol) in DCM (93 mL) was add 4N hydrogen chloride in dioxane (30 mL). The reaction was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. The resulting residue was dissolved in DCM and water, then adjusted to PH=8 with saturated aqueous Na2CO3 solution. The mixture was extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to afford ethyl 2-oxopiperidine-4-carboxylate (12 g, yield 94.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][NH:7][C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NCCc2cccc(F)c2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 76.6 %

Procedure:
To a solution of 3-fluoro phenethylamine (3.06 g, 22 mmol) and Rhodanine (2.66 g, 20 mmol) in acetonitrile (70 mL) was added DIPEA (7.66 mL, 44 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (5.97 g, 22 mmol) was added in two portions within 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (1.0 L) and ethyl acetate (500 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (100 mL) and water (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the crude residue was dissolved in acetonitrile (25 mL) at hot condition. After cooling in the refrigerator overnight, the solids were collected by filtration and washed with acetonitrile. After drying in air, 3.65 g (76.6% yield) of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one was isolated as a white solid: HRES(+) m/e calcd for C11H11FN2OS (M+H)+ 239.0649. found 239.0647.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[K].Cl[C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1.Cl>O>[CH2:1]([O:3][NH:12][C:10]1[CH:11]=[CH:6][C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:9]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl
Agent: [K]
Solvent: O
Product: CCONc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 96 %

Procedure:
To ethanol (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol, ca. 2.24 equiv) and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (57.74 g, 240 mmol, 1.0 equiv, [CAS RN 35375-74-7]) was added in one portion and the resulting dark red mixture was stirred at 55-60° C. for 4 d. The warm reaction mixture was slowly poured into water (ca. 2000 mL), the pH adjusted with a solution of 1 M HCl to 2, the yellow precipitate filtered off, washed with water and dried in air at 60° C. to give 57.81 g (96%) of the title compound as a yellow solid which was used without further purification. MS (ISN): 249.0 [M−H]−.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2>>[C:1]1([S:7][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C1CCc2cc(OCCCl)ccc2N1
Product: O=C1CCc2cc(OCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from thiophenol and 6-(2-chloro-ethoxy)-3,4-dihydro-carbostyril (m.p. 152.5° to 153.5° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([OH:11])=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[NH2:8][C:6]1[C:5]([OH:11])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c(N)n1
Reaction time: 72 h
Yield: 98678.5 %

Procedure:
A mixture of 6-methyl-2-nitro-pyridin-3-ol (18.5 g, 0.120 mmol), 10% palladium on activated carbon (1.35 g), and ethyl acetate (240 mL) was hydrogenated for 3 days. The mixture was filtered through Celite and washed with methanol/ethylacetate (5%). The filtrate and washing were combined and concentrated to give the title compound (14.7 g, 99% yield) as a pale brown solid. 1H NMR (DMSO-d6) δ 9.19 (bs, 1H), 6.73 (d, 1H, J=7.6 Hz), 6.12 (d, 1H, J=7.6 Hz), 5.36 (bs, 2H), 2. 15 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.Cl[CH2:27][C:28]1[O:29][C:30](=[O:34])[O:31][C:32]=1[CH3:33]>>[CH3:27][C:28]1[O:29][C:30](=[O:34])[O:31][C:32]=1[CH2:33][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1
Reactant: Cc1oc(=O)oc1CCl
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2cn(Cc3oc(=O)oc3C)c3ccccc23)cc(OC)c1OC
Yield: 6 %

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (2.37 g) obtained in Example 1 and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (1.63 g) except that the obtained crude crystals were further purified by preparative high-pressure liquid chromatography (HPLC), to give Compound 11 (188 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(=O)C)[CH2:23][CH2:22]2)[N:3]=1.FC(F)(F)C(O)=O.[CH3:37][S:38](N1CCC(N)CC1)(=[O:40])=[O:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1cccc(OC)c1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(OC)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with 1-[4-[4-amino-5-(2,6-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone (Example 333) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,6-dimethoxy-phenyl)-methanone. MS (M+H)+, 436
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:23]([O:24][C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[C@@H:22]([OH:36])[C@@H:21]([CH2:37][OH:38])[O:20][C@@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](OC)=[O:17])(=[O:3])[CH3:2].O.[NH2:40][NH2:41]>>[C:1]([NH:4][C@@H:5]1[C@@H:23]([O:24][C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[C@@H:22]([OH:36])[C@@H:21]([CH2:37][OH:38])[O:20][C@@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:40][NH2:41])=[O:17])(=[O:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H]1NC(C)=O
Solvent: O
Product: CC(=O)N[C@H]1[C@@H](OCCCCCCCCC(=O)NN)O[C@H](CO)[C@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
Compound (6) was dissolved in hydrazine hydrate and left to stand for 2 h. At that time, the solvent was removed by co-evaporation with butanol-water 1:1 (v/v) 3×5 mL) to provide the hydrazide (7) used in preparing artificial antigens and immunoadsorbents as described below.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]3)=[O:16])[NH:12][C:9]2=[N:10][CH:11]=1.Cl.[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:23][C:20]1([F:24])[CH2:21][CH2:22][N:17]([C:15]([C:13]2[NH:12][C:9]3=[N:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]4[CH2:29][CH2:30][CH2:31][C@H:27]4[CH3:26])[CH:7]=[C:8]3[CH:14]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: O=C(c1cc2cc(OCCCCl)cnc2[nH]1)N1CCC(F)(F)CC1
Reactant: C[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1cnc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from [5-(3-chloro-propoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, (R)-2-methyl-pyrrolidine hydrochloride (commercially available) and potassium carbonate in acetonitrile to give the desired product as a light brown solid (53%).
Reaction SMILES: [CH3:1]ON(C)C(=O)CC(C)C.[F:11][C:12]([C:17]1[CH:18]=[C:19]2[NH:25][CH2:24][C:23]([CH3:27])([CH3:26])[C:20]2=[N:21][CH:22]=1)([F:16])[CH2:13][CH2:14][CH3:15]>>[F:11][C:12]([C:17]1[CH:18]=[C:19]2[NH:25][CH2:24][C:23]([CH3:26])([CH3:27])[C:20]2=[N:21][CH:22]=1)([F:16])[CH2:13][CH:14]([CH3:1])[CH3:15]
Reactant: CON(C)C(=O)CC(C)C
Reactant: CCCC(F)(F)c1cnc2c(c1)NCC2(C)C
Product: CC(C)CC(F)(F)c1cnc2c(c1)NCC2(C)C

Procedure:
Prepared starting from N-Methoxy-3,N-dimethyl-butyramide in an analogous fashion to 6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (see Preparations 264 and 116. MS: [M+H]+=255.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([CH:17]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH3:19])[CH3:16].[CH3:34][CH:35]([CH3:39])[CH2:36]C=O.C(O)(=O)C>ClCCl>[CH2:15]([CH:17]([N:20]([CH2:34][CH:35]([CH3:39])[CH3:36])[CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CC(C)CC=O
Reactant: CCC(CC)NCCNC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)N(CCNC(=O)OCc1ccccc1)CC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
Sodium triacetoxyborohydride (1.87 g, 8.84 mmol) was added to a solution of benzyl 2-[(1-ethylpropyl)amino]ethylcarbamate (1.8 g, 6.8 mmol) (Preparation 50), 3-methylbutanal (0.8 ml, 7.5 mmol) and acetic acid (1 ml, 8.85 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with dichloromethane (50 ml) and then washed with saturated aqueous sodium hydrogen carbonate solution (100 ml). The organic phase was dried over anhydrous magnesium sulphate and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume). This gave the title compound as an oil (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CC(C)=O.O>[C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:2]([F:1])[CH:3]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 28.91 g of 3-fluoro-4-morpholinyl-aniline and 27.88 g of sodium bicarbonate in 500 mL of acetone and 250 mL of water at 0° C. was added 28.68 g of benzyl chloroformate. After stirring the mixture for 1.5 hours, the mixture was poured onto 1000 cc of ice and water, and the ice allowed to melt. The precipitated solid was collected by filtration and washed with 3×250 ml of water, and then dried in a vacuum oven at 75° C. to give a gray-purple solid. This was recrystallized from acetone-water to give a cream-colored solid, mp=123°-124° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[C@H:4]2[C:8]([O:10]CC)=[O:9].[OH-].[Na+]>C(O)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[C@H:4]2[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)[C@H]1C2CCC(=O)C21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCC2C1[C@H]2C(=O)O
Reaction time: 1.33 h

Procedure:
To a solution of crude ethyl (6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate (30.2 g, 180 mmol, uncorrected) in 30 mL of ethanol at room temperature is added 89 mL (178 mmol) of 2N sodium hydroxide. Upon stirring for 80 minutes, the reaction mixture is washed with tert-butyl methyl ether (1×90 mL) and the aqueous layer is treated with conc. hydrochloric acid (18 mL) to reach a pH=1.0. The mixture is treated with 15 g of sodium chloride followed by washing with ethyl acetate (3×90 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated in vacuo to give 23.8 g (94%, uncorrected) of the title compound as an off-white solid.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N[C@H]1CCNC1)c1cccc2ccccc12
Reactant: Brc1ncccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](N[C@H]1CCN(c2ncccn2)C1)c1cccc2ccccc12
Yield: 70.4 %

Procedure:
To a suspension of 156.6 mg of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride in 5 ml of dioxane were added 87.4 mg of 2-bromopyrimidine and 207 mg of diisopropylethylamine, and the mixture was stirred under reflux for 16 hours. The reaction mixture was evaporated, and to the residue were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→0:1) to obtain 112 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine. (2) In 10 ml of ethyl acetate was dissolved 112 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine, and 1 ml of a solution of 4M hydrochloric acid in ethyl acetate was added to the mixture and the resulting mixture was stirred. The reaction mixture was concentrated under reduced pressure, to the residue was added diethyl ether, precipitates were collected by filtration and washed with ethyl acetate, to obtain 68.3 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine dihydrochloride (the following Table A2, Example 2.010).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:17]=2[N:16]=1>C(O)C>[N+:24]([C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:15]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[N:16][C:17]=2[CH:23]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc3cc([N+](=O)[O-])ccc3[nH]2)CC1
Temperature: 135 °C

Procedure:
In a 20 mL sealed tube under nitrogen, a mixture of tert-butyl piperazine-1-carboxylate (0.943 g, 5.06 mmol), 2-chloro-5-nitro-1H-benzo[d]imidazole (0.5 g, 2.53 mmol) and ethanol (9.5 mL) was heated at 135° C. for 2 hours. The reaction was concentrated and the residue was purified by reverse-phase chromatography to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13]O)[CH:11]=[CH:12][C:4]=2[O:3]1.C(N(CC)CC)C.CS([Cl:26])(=O)=O>C(Cl)Cl>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][Cl:26])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1Oc2ccc(CO)cc2NC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1Oc2ccc(CCl)cc2NC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4.59 g (23.8 mmol) of (±)-2-methyl-3-oxo-6-hydroxymethyl-3,4-dihydro-2H-1,4-benzoxazine is mixed with 5.53 g (54.6 mmol) of triethylamine after being dissolved in 900 ml of methylene chloride. At 0° C., 4.08 g (35.6 mmol) of methanesulfonic acid chloride is added in drops, and the batch is then stirred at room temperature for 5 hours. Another 3.8 ml of triethylamine and 1.4 ml of methanesulfonic acid chloride are added and stirred again for 20 hours at room temperature. A portion of methylene chloride (600 ml) is spun off. After dilution with 1 l of diethyl ether, the organic phase is washed twice with 50 ml of water each, once with 50 ml of saturated sodium bicarbonate solution and again with 50 ml of water. The organic phase is spun in after drying, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol). 2.95 g (58.7%) of the desired product in addition to 1.1 g (16.6%) of the corresponding mesylate are obtained, melting point 162-169° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:21])[C@@:15]([F:20])([CH3:19])[C:16]([OH:18])=O)[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]2=3)[CH2:3][CH2:2]1.[F:30][C:31]([F:38])([C:34]([F:37])([F:36])[F:35])[CH2:32][NH2:33]>>[CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:21])[C@@:15]([F:20])([CH3:19])[C:16]([NH:33][CH2:32][C:31]([F:38])([F:30])[C:34]([F:37])([F:36])[F:35])=[O:18])[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]2=3)[CH2:3][CH2:2]1
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: C[C@@](F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid was coupled with 2,2,3,3,3-pentafluoropropylamine in analogy to the procedure described for RJR 7 to yield (R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5](Cl)[N:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CCC>[CH3:1][S:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1
Reactant: Nc1ccccc1
Reactant: CSc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CSc1nc(Nc2ccccc2)c2[nH]cnc2n1
Reaction time: 8 h

Procedure:
2-methylthio-6-chloropurine (10 g, 50 mmol), aniline (7.7 g, 63 mmol) and triethylamine (35 ml, 250 mmol) were refluxed in butanol (400 ml) for 2 h. Butanol was removed in vacuo and water (290 ml) added to the cooled residue. pH was adjusted to 8.0, the mixture was left at −16° C. overnight. Filtration and drying over phosphorus pentoxide in vacuo gave 10 g crude yellow-green product. The product was chromatographically purified (250 g silica, Fisons, chloroform); eluted with chloroform/methanol (97/3, v/v). Appropriate fractions were dried in vacuo, re-crystallised from ethanol with decolourisation by active carbon. After drying to constant weight over P2O5, yield 5.76 g, (46%), HPLC purity >98%. TLC: chloroform/methanol (9/1, v/v), no contaminants.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19].CO>>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][N:19]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CN(C)CCN
Solvent: CO
Product: CN(C)CCn1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (1.83 g, 0.00957 mol) and N,N-dimethyl-1,2-ethanediamine (3 g, 0.03 mol) were refluxed in methanol (20 mL, 0.5 mol) for 1 hour. The volatiles were removed via rotovapor. The residue was purified via flash chromatography (40 g of silica gel, 50% EtOAc/CH2Cl2) and gave a light yellow solid.