Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[S:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=2[C:4]([NH:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)=[O:5])=[CH:22][C:21]=1[S:27][CH3:28]
Reactant: CSc1cc(O)ccc1Cl
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1cc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)ccc1Cl
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxycyclohexyl)nicotinamide (150 mg, 0.55 mmol) was added to a solution of 4-chloro-3-(methylsulfanyl)phenol (96 mg, 0.55 mmol), caesium carbonate (358 mg, 1.1 mmol) in N,N-dimethylformamide (2 ml). The reaction was stirred under nitrogen at 55° C. for 18 h, cooled, and quenched with 1:1 water:sat. ammonium chloride solution and passed through a chemelute™ cartridge. The solvent. The residue was purified by flash column chromatography using dichloromethane:methanol (100:0 to 96:4) as eluant to afford 2-[4-chloro-3-(methylsulfanyl)phenoxy]-5-fluoro-N-(trans-4-hydroxycyclohexyl)nicotinamide as an amorphous glass (37 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:9]1[C:10]2[C:5](=[C:4]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ncc2c1OCC1CCCCO1
Product: COc1ccc2c(Cl)nncc2c1OCC1CCCCO1

Procedure:
Operating analogously to example 7 staring from 6-methoxy-5-(tetrahydropyran-2-yl-methoxy)-2H-phthalazin-1-one (1.48 g, 5.12 mmoles), obtained as described in example 42, and phosphoryl chloride (6 ml) 1.65 g of the title product as a crude were obtained and used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21]2[NH:22][N:23]=[CH:24][CH:25]=2)[CH:14]=1)=[O:11].[Br:26]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[Br:26][C:25]1[CH:24]=[N:23][NH:22][C:21]=1[C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:11])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccn[nH]1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1[nH]ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a cooled and stirred solution of 1-(2,4-Difluoro-phenyl)-3-[4-methoxy-3-(2H-pyrazol-3-yl)-phenyl]urea (0.6 g, 1.74 mmole) in DMF (15 mL) was added N-bromosuccinimide (0.37 g, 2.09 mmole) over a period of 15 minutes. The reaction mixture was warmed slowly to ambient temperature and stirred for another 2 hrs. The reaction mixture was poured into well-stirred ice water containing NaHCO3/Na2S2O3. The resulting solid was filtered and washed with ice water (50 mL). The solid was dried in vacuo to afford off-white solid (0.68 g, 92%). LCMS m/z (%)=425 (M+H, 79Br, 100), 427 (M+H, 81Br, 99). 1H NMR (Bruker, 400 MHz, DMSO-d6) δ: 8.96 (bs, 1H), 8.44 (bs, 1H), 8.02-8.08 (m, 1H), 7.48 (bs, 2H), 7.27-7.32 (m, 1 h), 6.99-7.08 (m, 2H), 3.73 (s, 3H) (major tautomer).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>Cl.CCOCC>[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[O:6])[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[ClH:1]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
4-Chloro-4'-chlorobutyrophenone (2.17 g.) was added to a well-ground mixture of 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) and the mixture heated at 100° C for 1 hour. The solid residue was slurried with hot water (100 ml.) for 3 hours, filtered, washed with ether and dried to give a cream coloured solid. Thissolid was dissolved in ethanolic hydrogen chloride, treated with ether and then cooled to 0° C to give the title compound as its hydrochloride(1.9 g.), m.p. 242°-243° C. (Found: C, 62.8; H, 6.2; N, 6.55.C22H25ClN2O2.HCl requires C, 62.7; H, 6.0; N, 6.65%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].S(=O)(=O)(O)[OH:15]>>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:15])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Yield: 94 %

Procedure:
A mixture of 18.0 gms. pentachlorobenzonitrile and 200 ml concentrated sulfuric acid (97 weight % H2SO4) was heated to 145° C. over a period of approximately 40 min. Complete dissolution of the pentachlorobenzonitrile was observed to occur at 130° C. thereby giving a pale straw solution. When cool, the reaction mixture was poured onto ice and the white solid thereby formed was isolated by filtration. In this manner there was formed 18.0 gms. (94% yield) pentachlorobenzamide. Identity of the product was established with the aid of both analytical and spectral data.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C>[CH2:23]([N:20]1[CH2:19][CH2:18][N:17]([C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:22][CH2:21]1)[CH3:24]
Reactant: c1ccc(-c2cc(N3CCNCC3)nc3ccccc23)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN1CCN(c2cc(-c3ccccc3)c3ccccc3n2)CC1
Yield: 85.1 %

Procedure:
A stirred suspension of 3.0 g of 4-phenyl-2-(1-piperazinyl)quinoline, 1.9 g of ethyl iodide and 1.1 g of sodium carbonate in 30 ml of methyl ethyl ketone was heated under reflux for 12 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with ethyl acetate. The dried extracts were concentrated to give an oily residue, which was chromatographed on silica gel (30 g) using chloroform as an eluent. There was obtained the title compound (2.8 g, 85%), m.p. 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9](Cl)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1.[OH:20][CH2:21][CH2:22][NH2:23]>>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([NH:23][CH2:22][CH2:21][OH:20])[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: NCCO
Product: Nc1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
This compound was prepared analogous to Example 2 from 8-amino-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 270°-272° C.; decomposition) and 2-hydroxyethyl-amine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:17]([CH3:49])[C:18]([N:20]([CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[N:44]([CH3:48])[N:43]=[CH:42]3)CC2C=CC(OC)=CC=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([N:17]([CH3:49])[C:18]([NH:20][CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[N:44]([CH3:48])[N:43]=[CH:42]3)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(Cc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)C(=O)N(C)c2cc(C(C)(C)C)nn2-c2ccc(C)cc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N(C)C(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Intermediate (31t) (85 mg, 0.131 mmol) was dissolved in 5 mL of solution of 2% (v/v) anisole in trifluoroacetic acid and stirred at room temperature for 1.5 hour. After evaporation the crude residue was dissolved in EtOAc (80 mL) and neutralized with saturated NaHCO3, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The obtained crude oil was purified on silica gel with EtOAc/hexane (2:3) to obtain compound (32t) as a white amorphous (68.6 mg, 99% yield). 1HNMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.32 (d, J=9.4 Hz, 1H), 7.25 (d, J=7.8 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.07 (t, J=10.2 Hz, 1H), 7.20-6.96 (m, 1H), 6.93 (td, J=8.6, 3.1 Hz, 1H), 6.85 (td, J=8.6, 3.1 Hz, 1H), 6.68 (dd, J=8.6, 4.7 Hz, 1H), 6.11 (s, 1H), 5.31 (t, J=6.3 Hz, 0.8H), 5.17 (t, J=6.3 Hz, 0.2H), 4.48-4.26 (m, 2H), 4.05 (s, 3H), 3.00 (s, 3H), 2.33 (s, 2.4H), 2.32 (s, 0.6H), 1.36 (s, 1.8H), 1.29 (s, 7.2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:16][C@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18]>>[NH2:19][C@H:17]([CH3:18])[CH2:16][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:14]1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1Cl
Product: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Yield: 17 %

Procedure:
The title compound was prepared with the Mitsunobu reaction using the method of Example 3(c) starting from 2-chloro-4-(1H-pyrazol-5-yl)-benzonitrile (2.00 g, 9.82 mmol) and (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.893 g, 10.80 mmol). After Boc removal and workups 0.434 g (17%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 0.97 (d, 3H), 2.96 (m, 2H), 4.15 (m, 2H), 6.98 (d, 1H), 7.86 (d, 1H), 7.92-8.00 (m, 2H), 8.11 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:22])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C3CCCCO3)[CH:10]=2)[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][OH:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[C:6]([N:8]([CH3:22])[C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][OH:33])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCO)c1
Reactant: CN(c1cccc(OC2CCCCO2)c1)c1nc(Cl)ncc1Cl
Product: CN(c1cccc(O)c1)c1nc(Nc2cccc(CCO)c2)ncc1Cl
Yield: 59 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using 2,5-dichloro-N-methyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine and 2-(3-aminophenyl)ethanol [Bioorg. Med. Chem. 2005, 13, 6703-6712] as the starting materials in 59% yield. LCMS for C19H20ClN4O2 (M+H)+: m/z=371.1.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[O:12][CH3:13])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(I)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
lodomethane (2.5 mL, 40 mmoles) was added to a mixture of 5-iodovanillin (10 g, 36 mmoles), potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water (200 mL), dried over MgSO4 and evaporated in vacuo to afford 9.78 g (93%) of 3,4-dimethoxy-5-iodobenzaldehyde, m.p. 58-63° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)[O:17]C3C=CC=CC=3)=[CH:11][CH:10]=2)[O:3]1.[CH3:26][NH2:27].C1COCC1>C1COCC1>[CH3:26][NH:27][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:25])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]2)=[CH:10][CH:11]=1)=[O:17]
Reactant: CN
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of phenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (26 g, 76.6 mmol)), 2.0M Methylamine/THF (265 mL, 530 mmol) in 150 mL of THF was stirred at room temperature for 6 hours, then excess solvent was distilled off from the reaction mixture; residue was dissolved into water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was purified by silica gel column chromatography by using 5-60% ethyl acetate in pet-ether as an eluent. to give 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (20 g, 88% yield) as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][OH:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][O:17][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1C(=O)OCc1ccccc1
Yield: 90.8 %

Procedure:
A solution of D1 (9.70 g, 0.04 mol), imidazole (1.05 eq., 2.95 g) and tert-butyldimethylsilyl chloride (1.1 eq., 6.22 g) in DMF (dry, 50 ml) was stirred overnight at ambient temperature. Solvent was removed under reduced pressure and the residue partitioned between Et2O and water. The aqueous phase was separated and the organic phase washed with dilute HCl (0.5M, 2×100 ml), followed by water (2×100 ml) and the organic phase was then dried (anhydrous MgSO4), filtered and concentrated under reduced pressure to afford an oil (12.70 g). This was used in the next step without purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([SH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH2:10]([O:17][C:18](ON1C(=O)CCC1=O)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CO>[CH2:10]([O:17][C:18]([NH:1][C@@H:2]([C:6]([SH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(S)[C@H](N)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a round bottom flask was added (R)-2-amino-3-mercapto-3-methylbutanoic acid (5.06 g, 33.9 mmol), N-(benzyloxycarbonyloxy)succinimide (8.87 g, 35.6 mmol), MeOH (50 mL) followed by DIPEA (11.9 mL, 67.8 mmol). The reaction was stirred at rt for 1 hr. The reaction was concentrated and the residue was diluted with EtOAc (120 mL). The organics was washed with water (2×50 mL) and saturated aqueous NaCl (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give (R)-2-(benzyloxycarbonylamino)-3-mercapto-3-methylbutanoic acid (4.78 g, 16.9 mmol, 49.7% yield) as a clear oil. Anal. Calcd. for C13H17NO4S m/z 283.3. found: 282.3 (M−H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.45-7.30 (m, 5H), 6.09-5.84 (m, 1H), 5.20-5.01 (m, 2H), 4.37-4.18 (m, 1H), 1.53 (br. s., 3H), 1.39 (br. s., 3H); 13C NMR (126 MHz, CDCl3) δ ppm 156.43, 136.49, 128.44, 128.28, 128.02, 53.12, 41.51, 30.83, 29.72, 11.64.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:7]=[CH:6][C:5]=1[C:21](=[O:23])[CH3:22]>O1CCOCC1>[Br:1][CH2:22][C:21]([C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:9]([Cl:10])[C:4]=1[Cl:3])=[O:23]
Reactant: CC(=O)c1ccc(Sc2ccccc2C(C)C)c(Cl)c1Cl
Reactant: BrBr
Solvent: C1COCCO1
Product: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Reaction time: 0.17 h

Procedure:
Then 2-bromo-1-(2,3-dichloro-4-(2-isopropyl-phenylsulfanyl)-phenyl)-ethanone 41 was prepared as follows. A solution of Br2 (50 mg) in dioxane (1.0 ml) was added to a solution of compound 40 (100 mg, 0.3 mmole) in 2 ml of dioxane. The solution was then stirred for another 10 minutes and concentrated. The residue was dissolved in EtOAc and purified on a 5-g silica gel cartridge, giving the desired product 41 as a white solid. 136 mg, ˜100%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 3.43 (heptet, J=8.5 Hz, 1H), 4.45 (s, 2H), 6.42 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.25–7.31 (m, 1H), 7.49–7.54 (m, 3H); MS (DCI/NH3) m/z 436 (M+NH4)+.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH2:7][CH2:6]1)=[O:4].O[Li].O>CO.O>[O:16]=[C:14]1[NH:13][C:12]2[CH:17]=[C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)[CH:9]=[CH:10][C:11]=2[O:15]1
Reactant: COC(=O)C1(c2ccc3oc(=O)[nH]c3c2)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2ccc3oc(=O)[nH]c3c2)CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 84.5 %

Procedure:
To a solution of 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid methyl ester (1.9 g, 8.1 mmol) in MeOH (20 mL) and water (2 mL) was added LiOH.H2O (1.7 g, 41 mmol) in portions at room temperature. The reaction mixture was stirred for 20 hours at 50° C. MeOH was removed by evaporation under vacuum before water (100 mL) and EtOAc (50 mL) were added. The aqueous layer was separated, acidified with HCl (3 mol/L) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (1.5 g, 84%). 1H NMR (DMSO, 400 MHz) δ 12.32 (brs, 1H), 11.59 (brs, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 1.44-1.41 (m, 2H), 1.13-1.10 (m, 2H). MS (ESI) m/e (M+H+) 218.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(=O)OCC)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:20][O:21][CH2:22][CH:23]1[CH2:27]O[C:25](=[O:28])[O:24]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[CH3:20][O:21][CH2:22][CH:23]1[O:24][C:25](=[O:28])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]3)=[CH:9][CH:10]=2)[CH2:27]1
Reactant: CCOC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: COCC1COC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COCC1CN(c2ccc(N3CCC(=O)CC3)cc2)C(=O)O1
Temperature: 160 °C
Yield: 8.6 %

Procedure:
A mixture of 6.0 g of ethyl 4-(4-oxo-piperidin-1-yl)-phenylcarbamate, 5.0 g of 4-methoxymethyl-1,3-dioxolan-2-one and 0.6 g of potassium carbonate was heated to 160° C. under argon for 3 h. The reaction mixture was cooled, treated with methylene chloride and water and the phases were separated. The organic phase was dried with magnesium sulfate and concentrated. The residue (7.8 g) was chromatographed over silica gel 60 using ethyl acetate as the eluent. There was obtained 0.6 g of (RS)-5-methoxymethyl-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-oxazolidin-2-one. 1H-nmr (CDCl3) ppm: 7.46 (d, 2H), 6.98 (d, 2H), 4.76 (m, 1H), 3.99 (t, 1H), 3.88 (t, 1H), 3.64 (d, 2H), 3.57 (t, 4H), 3.44 (s, 3H), 2.56 (t, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([CH3:18])=[N:9]2)[C:5]([F:19])=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([CH3:18])=[N:9]2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(-c2nc(Cl)ncc2F)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nn(-c2nc(Cl)ncc2F)cc1CO
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of ethyl 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carboxylate 1 (4.9 g, 17.2 mmol) in 60 mL of anhydrous tetrahydrofuran (THF), was slowly added 38 mL (38 mmol) of 1M solution of di-isobutylaluminum hydride (DIBAL) in toluene with ice bath cooling. After being stirred for 2 hours at the same temperature, the reaction was quenched by slow addition of 1N-NaOH solution. It was diluted with ethyl acetate and washed with brine. The collected organic layer was dried over anhydrous sodium sulfate and then partially concentrated in vacou. To this, n-hexanes were added to form pale yellow precipitates. The resulting solids were collected by filtration and rinsed with n-hexanes and then dried with high vacuum to give 3.7 g (90%) of Intermediate No. 2; 1H NMR (300 MHz, CDCl3) δ 8.57 (1H, d, J=3.3 Hz), 8.52 (1H, s), 7.94 (1H, s), 4.72 (2H, s); MS (ESI) m/z 243 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:29][C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: ClCc1ccncc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccncc3)C2=O)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride (2.4 equivalents) and 4-(chloromethyl)pyridine hydrochloride, to give the desired product as a light yellow solid (74%).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17](I)=[C:16]([CH2:19][CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cu][C:22]#[N:23]>O.ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([C:22]#[N:23])=[C:16]([CH2:19][CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1I
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: O
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C#N

Procedure:
1.8 g (5 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-ethyl-5-iodopyrimidine (Example 1) and 1.0 g of copper(I) cyanide were stirred at 200° C. for 30 minutes without solvent. After cooling, the mixture was taken up in water/dichloromethane, the organic phase was again extracted by stirring with aqueous ammonia solution, and the extract was dried and concentrated. The crude product was purified by chromatography on silica gel using petroleum ether/ethyl acetate (7:3), to give 750 mg (52.4% of theory) of a colorless oil which crystallized on standing.
Reaction SMILES: [Na].[ClH:2].C([O:10][CH2:11][C@@H:12]1[CH2:14][C@H:13]1[N:15]([CH3:17])[CH3:16])C1C=CC=CC=1.N.Cl>C(O)C.CCOCC>[ClH:2].[CH3:16][N:15]([CH3:17])[C@@H:13]1[CH2:14][C@H:12]1[CH2:11][OH:10]
Reactant: CN(C)[C@@H]1C[C@H]1COCc1ccccc1
Agent: Cl
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)[C@@H]1C[C@H]1CO
Reaction time: 3 h

Procedure:
1.2 g of sodium are added, in portions, to a solution of 4 g of the compound of Example 5 in 200 ml of condensed liquid ammonia. After 3 hours, 100 ml of ether and then 5 ml of ethanol are added. Stirring is carried out for 16 hours and the mixture is then concentrated and taken up in dichloromethane. The organic phase is treated in conventional manner and then evaporated. Chromatography over silica gel (dichloromethane/methanol: 90/10) allows the expected product to be isolated, which is converted into its hydrochloride form.