Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:26])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19](S(C)(=O)=O)[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C[N:28]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[Br:1][C:2]1[N:3]([CH3:26])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:28])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)-7-(methylsulfonyl)[1,3]thiazolo-[5,4-d]pyrimidine (Intermediate 38) in place of 6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 17). Yellow solid (52 mg, 61%);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[O:29][C:7]1([CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]4[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:33].[Cl:34][C:35]([O:37][CH3:38])=[O:36].CC(OC(C)=O)=O.Cl>>[ClH:34].[CH3:26][O:25][C:23]1[C:22]2[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:13]([N:10]2[CH2:11][CH2:12][C:7]3([CH2:6][C:5](=[O:33])[C:4]4[C:30](=[CH:31][CH:32]=[C:2]([NH:1][C:35]([O:37][CH3:38])=[O:36])[CH:3]=4)[O:29]3)[CH2:8][CH2:9]2)=[O:14])[CH:24]=1
Reactant: COC(=O)Cl
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N)ccc2O3)nc2c(OC)cccc12
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(OC)c4cccc(OC)c4n3)CC1)O2

Procedure:
The free form of the compound was prepared according to the procedure described in Example 30 but using 6-amino-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one and methyl chloroformate instead of 6-(piperazin-1-yl)-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one and Ac2O. Then the material was converted to HCl salt according to the procedure described in Example 2. 1H-NMR (400 MHz, DMSO-d6) δ: 9.65 (1H, s), 7.84 (1H, s), 7.73-7.53 (3H, m), 7.36-7.25 (2H, m), 7.06 (1H, d, J=9.0 Hz), 4.34-4.18 (1H, m), 4.10 (3H, s), 3.97 (3H, s), 3.69-3.26 (3H, m), 3.64 (3H, s), 2.86 (2H, s), 2.10-1.71 (4H, m). MS [M+H]+=506.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:25](=[CH2:26])[C:24]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Reactant: C=CC(=O)OCC
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C(=O)OCC)C(O)c1cc(-c2ccccc2)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and DABCO (10 mmol. 1.12 g) was added an methy/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜5 min.) was diluted with diethyl ether (300 ml) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (316.5 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][C@@H:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:29]=[C:30]([C:34](N(C)OC)=[O:35])[N:31]([CH3:33])[CH:32]=3)=[CH:24][CH:23]=2)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:40][Mg]Br>C1COCC1>[C:34]([C:30]1[N:31]([CH3:33])[CH:32]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:15]([NH:14][C:12]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=3)=[O:13])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)[N:29]=1)(=[O:35])[CH3:40]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1nc(-c2ccc(C[C@@H](CCC(=O)O)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Solvent: C1CCOC1
Product: CC(=O)c1nc(-c2ccc(C[C@@H](CCC(=O)O)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude (4R)-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(1-methyl-2-{[methyl(methyloxy)amino]carbonyl}-1H-imidazol-4-yl)phenyl]pentanoic acid (3.18 mmol) in anhydrous THF (16 mL) under nitrogen at 0° C. was added methylmagnesium bromide (10.6 mL, 10 equiv, 3.0 M in ether) dropwise by syringe. The reaction was stirred for 30 minutes at 0° C. and then carefully quenched with sat. aq. NH4Cl solution (10 ML), followed by 1 N HCl solution (60 mL) such that the pH of the aqueous layer ˜5.5. The product was extracted with EtOAc (4×40 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound, which was used directly in the next reaction. ESMS [M+H]+=512.4.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:7][C:6]=1[O:12][C:13]([F:14])([F:16])[F:15])[CH3:19]
Reactant: CCN(CC)C(=O)c1ccc(O)cc1OC(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a stirring solution of N,N-diethyl-4-hydroxy-2-(trifluormethoxy)benzamide (1876 mg, 6.8 mmol) and diisopropylethylamine (1747 mg, 13.5 mmol) in dry DMF (60 mL) was added chloro(1,1-dimethylethyl)dimethylsilane (1123 mg, 7.5 mmol). The reaction was stirred for 16 h and then quenched with 1M HCl. The reaction was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, 0–40% EtOAc in hexanes) to give 1941 mg of the desired product as a colorless oil. MS (ESI) 392 (M+H).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[N:2]1.[F:10][C:11]1[CH:12]=[C:13]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:1]1([CH2:6][C:7]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:40])=[C:11]([F:10])[CH:12]=3)[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(O)Cn1ccnn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)c(F)c2)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)c(F)c2)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid and (2S,4R)-4-(3,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 226, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(3,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.56 (d, 2H), 7.42-7.31 (m, 2H), 7.24-7.06 (m, 3H), 7.04-6.91 (m, 4H), 5.44 (q, 2H), 4.55-4.49 (m, 1H), 3.88-3.78 (m, 1H), 3.42-3.33 (m, 2H), 2.80-2.68 (m, 3H), 2.02-1.94 (m, 2H). MS (EI) for C28H24F3N5O3. found 536.2 (MH+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[S:9]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH2:8])=[CH:3][CH:4]=1)([OH:12])(=[O:11])=[O:10]
Reactant: NCc1ccccc1
Reactant: O=S(=O)(O)O
Product: NCc1ccc(S(=O)(=O)O)cc1
Yield: 40 %

Procedure:
p-Sulfobenzylamine was synthesized in 40% yield from benzylamine and fuming sulfuric acid, by an adaptation of the method described in Jacobson et al., J. Med. Chem., 35, 4143-4149 (1992), and was recrystallized from a solution in ammonium hydroxide, upon neutralization with hydrochloric acid. NMR DMSO, d6 δ8.10 (br.s, 3H, NH3+), 7.62 (d, J=8.1 Hz, 2H, o- to sulfo), 7.38 (d, J=8.1 Hz, 2H, m- to sulfo), 4.02 (s, 2H, CH2).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:44])[C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:44])[C:13]1[N:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCOCc1ccccc1)c1ncc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cn1
Agent: [Br-]
Agent: [Zn+2]
Product: CN(CCCOCc1ccccc1)c1ncc(C2CCNCC2OCc2ccc3ccccc3c2)cn1

Procedure:
In an analogous manner to that described in Example 125 (h), from tert-butyl (3RS,4RS)-4-[2-[(3-benzyloxy-propyl)-methyl-amino]-pyrimidin-5-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of BOC group by means of anhydrous zinc bromide there was obtained (3-benzyloxy-propyl)-methyl-[5-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidin-2-yl]-amine in the form of an amorphous colourless solid; MS: 498 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.[CH3:26]C(C)([O-])C.[K+].CI>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:26])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[N:11]1
Reactant: O=C(Nc1ccn(Cc2cc(O)ccc2Cl)n1)c1c(F)cccc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: COc1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Reaction time: 0.08 h
Yield: 14.9 %

Procedure:
To a solution of N-{1-[(2-chloro-5-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for as preparation see Intermediate 13) (73 mg, 0.20 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (21 mg, 0.187 mmol). The reaction was stirred for 5 min before adding methyl iodide (0.012 mL, 0.201 mmol, Aldrich). The reaction was stirred at ambient temperature, overnight and under nitrogen. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound (10.5 mg); LCMS: (System 4) MH+=378, tRET=2.86 min.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4](Cl)=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[NH:17]1[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:2][C:3]1[C:4]([N:17]2[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1ncncc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(c2ncncc2Br)CC1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a solution of 5-bromo-4-chloropyrimidine hydrochloride 21 (0.10 g, 0.36 mmol) in DMF (2 mL) was added triethylamine (0.51 mL, 3.6 mmol). After stirring for 30 min, a solution of isonipecotamide (0.14 g, 1.1 mmol) in DMF (2 mL) was added and the mixture was stirred at r.t. for a further 16 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 98:2) to furnish the title compound as a white solid (60 mg, 58%), m.p. 188-190° C.; umax (CHCl3)/cm−1 3012, 2853, 1682, 1566, 1447, 1359, 1144, 1017, 950; m/z (ESI) C10H14BrN4O requires 285.0346, found [M+H]+ 285.0344.
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[BH4-].[Na+].O.C(OCC)C>C(O)C>[CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9]
Reactant: CC(C)=CCc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(C)=CCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
170 mg of the aldehyde compound was dissolved in 20 ml of ethanol, and 100 mg of sodium borohydride was added. The mixture was stirred at room temperature for 1 hour. Water and ethyl ether were added to the reaction mixture to dilute it, and it was then worked up in a customary manner to give 158 mg (yield 92%) of 3-(3-methyl-2-butenyl)benzyl alcohol.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[CH2:31]([O:38][C:39]([N:41]1[CH2:47][C:46]2[CH:48]=[C:49](/[CH:52]=[CH:53]/[C:54]([OH:56])=O)[CH:50]=[N:51][C:45]=2[NH:44][C:43](=[O:57])[CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH2:31]([O:38][C:39]([N:41]1[CH2:47][C:46]2[CH:48]=[C:49](/[CH:52]=[CH:53]/[C:54](=[O:56])[N:2]([CH3:1])[CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([CH3:13])[CH:5]=3)[CH:50]=[N:51][C:45]=2[NH:44][C:43](=[O:57])[CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CNCc1cn(C)c2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Yield: 73 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(1-methyl-1H-indol-3-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-7-(2-carboxy-vinyl)-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepine-4-carboxylic acid benzyl ester hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.29 g, 73%) was prepared as an off-white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.51 (s, 1H), 8.11-8.25 (m, 1H), 7.53-7.64 (m, 2H), 7.30-7.42 (m, 5H), 7.12-7.20 (m, 4H), 6.98-7.03 (m, 1H), 5.03-5.08 (m, 2H), 4.75-4.93 (m, 2H), 4.62 (s, 2H), 4.41 (s, 2H), 3.73-3.77 (m, 3H), 2.91-3.06 (m, 3H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: N[C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C=O.[C:33](#N)C.[C:36]([BH3-])#[N:37].[Na+]>C(O)(=O)C>[CH3:33][N:37]([CH3:36])[C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1ccccc1S2
Reactant: [BH3-]C#N
Reactant: CC#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1ccccc1S2
Reaction time: 1.5 h

Procedure:
7 g of 3-[2-[4-(2-amino-10,11-dihydro-dibenzo[b,f]-thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone, 13.1 ml of 40% formaldehyde and 61 ml of acetonitrile are treated with 3.32 of sodium cyanoborohydride and the resulting mixture is treated dropwise over period of 10 minutes with 1.5 ml of acetic acid. The mixture is stirred for a further 90 minutes, treated dropwise with a further 1.5 ml of acetic acid and again stirred for 15 minutes. The mixture is now extracted with 200 ml of ether and the organic phase washed three times with 1-N aqueous potassium hydroxide solution, dried over sodium sulphate and evaporated. There is obtained 3-[2-[4-(10,11-dihydro-2-dimethylamino-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which melts at 168°-170° C. After recrystallisation from ethanol, this compound melts at 171°-173° C. By treatment with maleic acid there is obtained the corresponding maleate which melts at 143.5°-144.5° C after recrystallisation from acetonitrile.
Reaction SMILES: [C:1]([C:4]1O[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)(=O)[CH3:2].[CH2:15]([NH2:18])[CH2:16][NH2:17].O.[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:2][C:1]1[C:4]2[N:17]([CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:8]=2)[CH2:16][CH2:15][N:18]=1
Reactant: CC(=O)c1cc(-c2ccccc2)co1
Reactant: NCCN
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CCO
Product: CC1=NCCn2cc(-c3ccccc3)cc21
Yield: 31 %

Procedure:
2-Acetyl-4-phenylfuran (0.7 g) was heated at 100° C. for 1 hour under argon with 0.8 ml of 1,2-ethanediamine and 0.1 ml of water. After cooling 50 ml of water were added and the mixture was extracted three times with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 0.7 g of brown oil, was chromatographed on 60 g of silica gel with methylene chloride/methanol (19:1) as the eluent. The crude product, 0.4 g of brown solid, was dissolved in a 50-fold amount of hot ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.4 g (31%) of 3,4-dihydro-1-methyl-7-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 181° C. (dec.)
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)=[O:7])([O-:3])=[O:2].CO.[BH4-].[Na+]>O.C(OCC)(=O)C>[N+:1]([CH2:4][CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:13]=1)[OH:7])([O-:3])=[O:2]
Reactant: CCCCCCCCc1ccc(C(=O)CC[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc(C(O)CC[N+](=O)[O-])cc1
Temperature: 6 °C
Reaction time: 0.17 h

Procedure:
3-Nitro-1-(4-octylphenyl)propan-1-one (75 g) and methanol (750 mL) are charged into a round bottom flask equipped with a condenser and guard tube, stirred to 10 minutes and the mixture is cooled to 6° C. Sodium borohydride (20.2 g) is added in portions over 30 minutes. Allowed the mixture to room temperature, stirred for 3 hours and solvent is removed under reduced pressure to obtain a solid. The solid is diluted with water (1000 mL), ethyl acetate (1000 mL) is added, the separated solid is filtered. The solid, ethyl acetate (200 mL), and water (200 mL) are charged in a round bottom flask and stirred at room temperature, and 6N HCl (100 mL) is added drop-wise. The organic layer is separated, washed with water (200 mL), dried over sodium sulphate, and concentrated under reduced pressure to give the title compound as a yellow liquid. Yield: 30 g.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12](SSCC)C>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH3:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CSc1ccc(Cl)c(C#N)c1
Reactant: CCSSCC
Product: CCSc1ccc(Cl)c(C#N)c1

Procedure:
The subtitle compound was prepared by the method of example 5 step iv) using the product from step i) and diethyldisulphide. Yield 2.50 g.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13].S(Cl)(Cl)=O>C(Cl)Cl>[F:13][C:7]1[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:6]=1[C:5]1[O:14][CH2:2][CH2:3][N:4]=1
Reactant: O=C(NCCO)c1cc(Br)ccc1F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Fc1ccc(Br)cc1C1=NCCO1
Temperature: 25 °C

Procedure:
A solution of N-(2-hydroxyethyl)-5-bromo-2-fluorobenzamide (956 mg, 3.65 mmol) in methylene chloride was treated with thionyl chloride (0.35 ml, 4.75 mmol). The resulting mixture was stirred at ambient temperature as the progress of the reaction was monitored by thin layer chromatography. After one hour of stirring, no starting material was visible. The reaction mixture was diluted with methylene chloride, and the reaction was quenched by the addition of water and 1 N sodium hydroxide. The organic fraction was dried over sodium sulfate, and concentrated to a white solid. The solid was dissolved in 80% aqueous acetonitrile (25 ml) and an excess of potassium carbonate was added. The resulting mixture was stirred for about 72 hours at ambient temperature, heated to reflux for thirty hours, and worked up as before. The desired title product was then further purified by liquid chromatography, yielding 260 mg as a yellow oil.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][CH:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:19][CH:14]([CH3:13])[C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2]
Reactant: CC(N)C(C)(C)C
Reactant: COC(=NC#N)c1ccccn1
Solvent: CO
Product: CC(N=C(NC#N)c1ccccn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 1,2,2-trimethylpropylamine (0.34 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from dichloromethane diethyl ether to give the title compound (0.67 g, 2.9 mmol, yield: 92%) as colorless needles.
Reaction SMILES: C([S:5][C:6]1[C:11]([CH2:12][NH:13][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:9]([CH2:23][CH3:24])=[C:8]([CH3:25])[N:7]=1)(C)(C)C.Cl.N1C=CC=CC=1>O>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[NH:13][CH2:12][C:11]1[C:6](=[S:5])[NH:7][C:8]([CH3:25])=[C:9]([CH2:23][CH3:24])[CH:10]=1
Reactant: CCc1cc(CNc2nc3ccccc3o2)c(SC(C)(C)C)nc1C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1cc(CNc2nc3ccccc3o2)c(=S)[nH]c1C
Temperature: 150 °C

Procedure:
A mixture of 2-t-butylthio-3-{[(benzoxazol-2-yl)amino]methyl}-5-ethyl-6-methylpyridine (78 mg, 0.22 mmol) and pyridine hydrochloride (325 mg, 2.81 mmol) was warmed in a pre-heated oil bath at 150° C. for 25 minutes. The mixture was cooled, diluted with water and the yellow precipitated product was collected by filtration. This residue was dissolved in methylene chloride, filtered through a pad of charcoal and then hexane was added and the methylene chloride boiled off as the product crystallized out to yield 42 mg (64%), m.p. 238°-240° C. Anal Calcd. for C16H17N3OS: C, 64.18; H, 5.72; N, 14.04. Found: C, 63.86; H, 5.69; N, 13.81.