Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[CH:5]/[O:6][CH3:7].[CH:9](OC)([O:12][CH3:13])[O:10][CH3:11].C[O-].[Na+].[CH3:19][O:20]C>>[CH3:1][O:2][C:3](=[O:8])[CH:4]([CH:9]([O:12][CH3:13])[O:10][CH3:11])[CH:5]([O:20][CH3:19])[O:6][CH3:7]
Reactant: COC
Reactant: CO/C=C/C(=O)OC
Reactant: COC(OC)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C(C(OC)OC)C(OC)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred mixture of 116.0 g methyl-trans-3-methoxyacrylate and 530.0 g trimethyl ortho formate were added 5.0 g FeCl3. The mixture was heated to 35° C. for 30 hours with an additional 1.0 g FeCl3 being added every 6 hours. The mixture was cooled to room temperature and neutralized by addition of 30% sodium methylate solution. After stirring for 2 hours, 30.0 g PEG-dimethylether (mg=1000) were added. The trimethyl ortho formate excess was recovered by fractional distillation. Flash-distillation of the remaining material gave 155.4 g colorless liquid (80% of theoretical based on converted methyl-trans-3-methoxyacrylate) of boiling point 100° C./4 mm Hg. A GC-analysis of the liquid revealed an assay of >99% (FID-detection).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)[S:17][C:10]=12.CCN(CC)CC.[N:51]([CH3:54])=[C:52]=[O:53]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([C:52]([NH:51][CH3:54])=[O:53])[CH2:27][CH2:26]4)=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cc4)sc23)c(F)c1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
Compound 450 (0.367 g, 0.60 mmol) was dissolved in dichloromethane (2 mL) at RT and then Et3N (0.25 mL, 1.803 mmol) was added. The reaction mixture was cooled to 0° C., treated with isocyanatomethane (0. 16 mL, 3.43 mmol) and stirred for 10 min at 0° C. The reaction mixture was then warmed to RT over a 30 min period, and then was quenched with MeOH. It was then concentrated to dryness and the residue was purified by flash chromatography (eluent 9/1/10 MeOH/NH4Cl/DCM) to give title compound 455 as a pale yellow solid (0.16 g, 39% yield). 1H NMR δ (400 MHz, DMSO-d6): 12.48 (s, 1H), 11.83 (s, 1 H), 8.51 (dd, J=1.2, 5.5 Hz, 1H), 8.01 (m, 2H), 7.84 (m, 2H), 7.53 (m, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.23-7.38 (m, 5H) 6.65 (dd, J=0.8, 5.5 Hz, 1H), 6.39 (q, J=4.2 Hz, 1 H), 3.81 (s, 2 H), 3.51 (s, 2H), 3.25 (m, 4H), 2.53 (d, J=4.3 Hz, 3H), 2.31 (m, 4H). LCMS: 669 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1COS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:26]#N.[Na+].C[N:30]([CH:32]=O)C>>[C:32]([CH2:26][C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13]1)#[N:30]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2NC(=O)OC(C)(C)C)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CC#N)C1
Temperature: 80 °C

Procedure:
To a solution of 8.2 g (0.0222 mol) of N-[t-butoxycarbonyl]-2-(p-toluenesulfonyloxymethyl)cyclopentylamine in DMF (250 mL) was added 3.3 g (0.067 mmol) of NaCN and the suspension was heated at 80° C. for 4 h. The solvent was removed in vacuo at 40° C. and the residue was slurried in brine. The aqueous layer was extracted with ethyl acetate, dried and the solvent was removed in vacuo to yield 5.7 g of the title compound. MS(ES+)m/z=225. (one enantiomer)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:23])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:9][CH2:10][CH:11]=1.[NH2:25][O:26][K].C(O)(=O)C>CO.C(OCC)(=O)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][CH:11]=[C:6]([CH2:5][CH2:4][C:3]([NH:25][OH:26])=[O:2])[C:7]1=[O:23]
Reactant: NO[K]
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN2CCC=C(CCC(=O)NO)C2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
46 mg of compound (d) prepared by the above Step 3 was dissolved in methanol solution (0.138 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.122 ml, 0.207 mM) was added thereto at 0° C. and the resulting mixture was stirred for 3 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10 ml of ethyl acetate solution, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:10) solvent mixture as an eluant to give 32 mg of the title compound (e1) (yield: 73%).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH:28]=O)=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH2:28][N:36]6[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]6)=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:34][CH:35]=1
Reactant: C1CCNCC1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C=O)ccc3c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(CN4CCCCC4)ccc3c12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 40.9 %

Procedure:
Step 2 A suspension of 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-formyl-9H-carbazole-1-carboxamide (30 mg, 0.064 mmol) in THF (3 mL) was treated with piperidine (16.46 mg, 0.193 mmol) and sodium triacetoxyborohydride (34.1 mg, 0.161 mmol). The mixture was stirred at rt for 3.5 h, the was treated again with additional piperidine (16.5 mg, 0.193 mmol) and sodium triacetoxyborohydride (20 mg). After stirring overnight, the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by preparative HPLC to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(piperidin-1-ylmethyl)-9H-carbazole-1-carboxamide (14 mg, 39%). 1H NMR (400 MHz, methanol-d4) δ 8.06 (2 H, dd, J=8.7, 5.4 Hz), 7.98 (1 H, d, J=7.8 Hz), 7.63 (1 H, s), 7.52 (1 H, d, J=7.3 Hz), 7.44 (1 H, t, J=7.8 Hz), 7.18-7.31 (3 H, m), 7.07 (2 H, d, J=7.5 Hz), 6.96-7.02 (1 H, m), 3.96 (2 H, s), 2.72-2.88 (4 H, m), 1.99 (3 H, s), 1.63-1.75 (4 H, m), 1.48-1.60 (2 H, m). Mass spectrum m/z 535.2 (M+H)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:24][CH3:25])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18].O[CH2:27][CH:28]1[O:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:37]([O:36][C:34]([N:30]1[CH2:31][CH2:32][O:33][CH:28]([CH2:27][O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH3:25])=[O:23])[CH2:29]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1OCC1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of diisopropyl azodicarboxylate (776 μL; 3.94 mmol; 2 eq.) in THF (5 mL) was added to a cold (0° C.) solution of methyl salicylate (1 g; 6.57 mmol; 1 eq.) and tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (641 mg; 2.95 mmol; 1.5 eq.) and triphenylphosphine (1.03 g; 3.94 mmol; 2 eq.) in THF (15 mL) and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. Purification by column chromatography (EA/heptane) afforded 2-(2-methoxycarbonyl-phenoxymethyl)-morpholine-4-carboxylic acid tert-butyl ester which was dissolved in THF (10 mL) and MeOH (10 mL). 5M NaOH (1.97 mL; 9.86 mmol; 5 eq.) was added and the resulting mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was partitioned between 1M NaOH and DCM and the aqueous layer was washed with DCM. The aqueous phase was made acidic and extracted with DCM (3×). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (411 mg, 34%) as an orange oil which was used without further purification. HPLC (max plot) 89.4%; Rt 3.73 min. UPLC/MS: (MS−) 336.1 ([M−H]−).
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]2.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:12])[CH:6]=[N:7][CH:8]=1)[CH2:18][CH2:17]2
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: O=C1NCCc2cc(Cl)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 150 °C
Yield: 72.6 %

Procedure:
(5-Bromo-pyridin-3-yl)-acetic acid methyl ester (230 mg, 1.0 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (182 mg, 1.0 mmol), CuI (40 mg, 0.21 mmol), Cs2CO3 (650 mg, 2.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.1 mL, 0.8 mmol) were dissolved in dioxane (4.0 ml) and the resulting reaction mixture was heated at 150° C. for 2 hours before it was poured into H2O (20 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (230 mg, 72.5%) as light brown oil. MS: 317.1 (M+H+).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH2:10](Br)[CH2:11][CH2:12][CH3:13].[NH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[CH:32]=[CH:33][S:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1>CN(C)C=O>[CH2:10]([NH:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[CH:32]=[CH:33][S:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCBr
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2ccsc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)no1
Reaction time: 1 h
Yield: 49 %

Procedure:
1.17 ml (6.8 mmol) of N-ethyldiisopropylamine and 0.55 ml (5.1 mmol) of butyl bromide were added to a solution of 0.54 g (1.7 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one in 20 ml of dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). There were obtained 310 mg (47%) of 3-(5-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as a colourless foam, Rf=0.73 (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[K+].[K+].N(C([O-])=O)=NC([O-])=O.C(O)(=O)C>CO>[CH2:1]([O:3][C:4]([C@@:6]1([NH2:11])[CH2:8][C@H:7]1[CH2:9][CH3:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@]1(N)C[C@H]1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-1-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (400 mg, 1.57 mmol) was dissolved in methanol (5 ml) and added to a suspension of azodicarboxylic acid dipotassium salt (1.46 g, 7.5 mmol; cf. D. J. Pasto et al., Organic Reactions 40 (1991), 91-155) in methanol (10 ml). Acetic acid (1.12 g, 18.8 mmol) was added in the course of 10 min and the mixture was stirred for 1 h at room temperature. Azodicarboxylic acid dipotassium salt (1.46 g) and acetic acid (1.12 g) were added once again and the mixture stirred for 1 h. LC/MS analysis then indicated complete conversion. The volatiles were evaporated, the residue was partitioned between EA and a saturated sodium hydrogencarbonate solution, and the combined organic extracts were dried over sodium chloride, decanted over a small plug of silica gel and evaporated to dryness. The obtained intermediate was dissolved in a mixture of DCM (5 ml) and TFA (1 ml) and stirred for 1 h at room temperature. The volatiles were evaporated, and the residue was partitioned between diethyl ether and saturated sodium hydrogencarbonate solution. The combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness to yield the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:9]=[C:10](Cl)[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1>>[Cl:7][C:8]1[N:9]=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: C1COCCN1
Product: Clc1nc(N2CCOCC2)c2sccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Morpholine (87 ml, 1.00 mol, 2.2 equiv.) was added to a solution of 2,4-dichloro-thieno[3,2-d]pyrimidine 3 (93.4 g, 0.456 mol, 1.0 equiv.). The reaction mixture was stirred at ambient temperature for 1 h and the resulting slurry was filtered, rinsed with water (500 ml). The cake was dried in a vacuum oven at 40° C. for 24 hours to give 442-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 4 as an off-white solid (109 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.74 (t, J=4.9 Hz, 4H), 3.90 (t, J=4.9 Hz, 4H), 7.40 (d, J=5.6 Hz, 1H), 8.30 (d, J=5.6 Hz, 1H). LCMS (ESI pos) m/e 257 (M+1).
Reaction SMILES: [CH2:1]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C1C=CC=CC=1>[CH2:1]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[S:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1CCCCCC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Product: CCCCCCCCCCCCN1CCCCCC1=S
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 5 g (17.7 mmol) of 1-n-dodecylazacycloheptan-2-one in 150 ml of benzene was added 4.18 g (9.4 mmol) of phosphorus pentasulfide and the mixture was refluxed for 1 hr. After cooling to room temperature, the mixture was filtered and the solid was washed with chloroform and ethanol. The filtrate was concentrated in vacuo and the residue was subjected to flash chromatography, (silica; (95:5)V/V hexane/ethyl acetate) to give 2.11 g (40%) of 1-n-dodecylazacycloheptane-2thione.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[ClH:12].[F:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1.[CH2:28]=O>C(O)C>[ClH:12].[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:28][CH2:1][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH2:22][CH2:21]2)=[O:19])=[CH:26][CH:27]=1
Reactant: Cc1ncnc2ccccc12
Reactant: C=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCc2ncnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 g of 4-methylquinazoline was dissolved in 20 ml of ethanol. 3.4 g of 4-(p-fluorobenzoyl)piperidine hydrochloride and 1.9 ml of 37% formalin were added to the solution and the mixture was stirred at room temperature for three days. A white precipitate was recovered by filtration and washed with ethanol to obtain the intended product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[S:6].Cl[CH2:12][S:13][C:14]#[N:15]>>[S:13]([CH2:12][O:7][C:5](=[S:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:14]#[N:15]
Reactant: N#CSCCl
Reactant: Cc1cccc(C(O)=S)c1
Product: Cc1cccc(C(=S)OCSC#N)c1
Yield: 79 %

Procedure:
10 g (0.052 mol) of the K salt of 3-methyl-thiobenzoic acid and 5.6 g (0.05 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 9.9 g of an oily liquid having a density of 1.27 (this corresponds to a yield of 79% of the theoretical conversion).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C@H:20]3[CH2:25][N:24]([CH2:26][CH3:27])[CH2:23][CH2:22][NH:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:35]([N:21]1[CH2:22][CH2:23][N:24]([CH2:26][CH3:27])[CH2:25][C@@H:20]1[C:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[O:11])[CH2:17][CH2:16]1)=[O:19])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCN1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN1CCN(C(C)=O)[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
N-(3,4-Dichlorophenyl)-4-{[(2R)-4-ethylpiperazin-2-yl]carbonyl}piperazine-1-carboxamide (70 mg) in chloroform (1 ml) was cooled in an ice bath, triethylamine (19 ul) added, followed by acetyl chloride (10 ul) and the mixture stirred for 2 hours at 0° C. The mixture was diluted with CH2Cl2, washed with saturated aqueous sodium bicarbonate, the organic phase dried (MgSO4), evaporated and the residue purified on a 4 g Redisep® SiO2 column, eluting with 0-50% MeOH/CH2Cl2 to give the title compound as a colourless solid (35 mg, 45%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][C@@H:14]([CH3:16])[NH:13][CH2:12][C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[O:20][CH:21]=[CH:22][C:23]=1[C:24]([Cl:26])=[O:25]>C1C=CC=CC=1>[ClH:26].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][C@@H:14]([CH3:16])[N:13]([C:24]([C:23]3[CH:22]=[CH:21][O:20][C:19]=3[CH3:18])=[O:25])[CH2:12][C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H]1CN(CCCc2ccccc2)[C@@H](C)CN1
Reactant: Cc1occc1C(=O)Cl
Solvent: c1ccccc1
Product: Cc1occc1C(=O)N1C[C@H](C)N(CCCc2ccccc2)C[C@H]1C
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of trans-1-(3-phenylpropyl)-2,5-dimethylpiperazine, 2-methyl-3-furoyl chloride and benzene.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][C@H:4]([NH:21][S@](C(C)(C)C)=O)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.[ClH:29].CCOCC>CO>[ClH:29].[CH3:1][CH:2]([CH3:28])[CH2:3][C@H:4]([NH2:21])[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1
Reactant: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)C[C@H](N)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
(S)-2-methyl-propane-2-sulfinic acid {(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butyl}-amide (38.83 g, 93.90 mmol) was dissolved in methanol and transferred to a 3-necked 1 L flask with overhead stirring and internal temperature. A total of 210 mL methanol was added to give a yellow solution. This was placed in an ice bath and at an internal temperature of 8° C., HCl in ether (188 mL, 2.0 M, 376 mmol) was added over 2 min. The temperature went up to 14° C. The ice bath was removed and the reaction stirred for ˜5 min as a yellow solution than as a white slurry. At 30 min, the reaction was rotovapped to dryness and the solid slurried in diethylether (200 mL) for 1 h. The solid was collected by Buchner filtration, washing with additional diethylether. This was suction dried for ˜1 h and then placed on the vacuum pump to give (S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamine hydrochloride (31.58 g, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6, δ): 9.19 (s, 2 H) 8.78 (br. s., 3 H) 8.61 (d, J=8.2 Hz, 2 H) 7.93 (d, J=8.4 Hz, 2 H) 4.47 (br. s., 1 H) 1.84-2.03 (m, 2 H) 1.41 (m, 1 H) 0.83-0.96 (m, 6 H).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)[C:2]#[CH:3].[CH2:20]=O.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:28][NH:29][CH2:20][C:3]#[C:2][CH2:1][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C#CCN1c2ccccc2C(=O)Nc2cccnc21
Reactant: NCC1CCCCC1
Reactant: C=O
Product: O=C1Nc2cccnc2N(CC#CCNCC2CCCCC2)c2ccccc21
Yield: 17 %

Procedure:
Prepared analogously to Example (1b) from 5,11-dihydro-11-(prop-2-ynyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, paraformaldehyde and (cyclohexyl)methylamine in a yield of 17% of theory. Colourless crystals m.p. 133°-134° C. (diethyl ether).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Oc1ccc(-c2nc(-c3cccnc3)no2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-fluoro-4-hydroxybenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.09 (t, J=8.7 Hz, 1H), 7.63 (ddd, J=7.9, 5.2, 0.8 Hz, 1H), 7.86-7.93 (m, 2H), 8.53 (dt, J=7.9, 2.0 Hz, 1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 9.27 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 258 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]#[N:12].Br[CH2:14][CH2:15]Br.[OH-].[Na+].[Br-]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1([C:11]#[N:12])[CH2:15][CH2:14]1
Reactant: N#CCc1cc(F)c(Cl)cc1Cl
Reactant: BrCCBr
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2cc(F)c(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2,4-dichloro-5-fluorophenyl)acetonitrile (1 g, 4.9 mmol, Eq: 1.00) was dissolved in toluene (4 mL). 1,2-Dibromoethane (1.38 g, 634 μL, 7.35 mmol, Eq: 1.50), aqueous NaOH-solution (4.31 mL, 12.5 M; 53.9 mmol, Eq: 11.0) and tertrabutylammonium bromide (348 mg, 1.08 mmol, Eq: 0.22) were added to the above suspension and vigorously stirred at RT for 4 h. The reaction mixture was diluted with water and extracted with AcOEt. The organic solution was washed with 1 N aqueous HCl, then with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) to yield example 461a) (1.13 g; 100%) as an off-white solid. 1H-NMR (CDCl3, 250 MHz) δ [ppm]: 7.51 (1 proton, d, 6.7 Hz); 7.16 (1, proton, d; 8.9 Hz); 1.76-1.80 (2 protons, m); 1.31-1.36 (2 protons, m)