Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[CH3:10][O:11][N:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19](=[NH:22])[CH2:20][Cl:21])[CH2:15][CH2:14]1.Cl>O>[ClH:21].[CH3:10][O:11][N:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19](=[NH:22])[CH2:20][SH:5])[CH2:15][CH2:14]1
Reactant: [O-]P([O-])([O-])=S
Reactant: CON=C1CCN(C(=N)CCl)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON=C1CCN(C(=N)CS)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
1.03 g of trisodium phosphorothioate was added to a solution of 1.472 g of 2-(4-methoxyiminopiperidin-1-yl)-2-iminoethylchloride hydrochloride in 7 ml of water, kept cooled in ice-water, and the mixture was stirred at room temperature for about one hour. 5.7 ml of 1N hydrochloric acid were then added, followed by heating at 65° C. for 30 minutes. The resulting solution was concentrated under reduced pressure, mixed with ether, filtered to remove insolubles, and the filtrate concentrated under reduced pressure. The concentrate was mixed with isopropanol, and the crystals which separated out were collected by filtration and reprecipitated from a mixture of ethanol and ether, giving 850 mg of 2-(4-methoxyiminopiperidin-1-yl)-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[S:8][C:9]([CH3:16])=[C:10]([C:12](=O)[CH2:13][Br:14])[CH:11]=1)=[O:6])([CH3:3])[CH3:2].[O:17]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[S:32])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[BrH:14].[CH3:16][C:9]1[S:8][C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:11][C:10]=1[C:12]1[N:33]=[C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:29][CH:28]=2)[S:32][CH:13]=1
Reactant: NC(=S)Nc1ccc(Oc2ccccc2)cc1
Reactant: Cc1sc(C(=O)OC(C)C)cc1C(=O)CBr
Product: Br
Product: Cc1sc(C(=O)OC(C)C)cc1-c1csc(Nc2ccc(Oc3ccccc3)cc2)n1
Yield: 74.6 %

Procedure:
Isopropyl 5-methyl-4-{2-[4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate hydrobromide: Isopropyl-4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (91 mg, 0.29 mmol) was allowed to react with 4-phenoxyphenylthiourea (72.6 mg) as described in Example 154, step (a) to give 115 mg (75% yield) of isopropyl 5-methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ 1.28 (d, 6H, J=6.2 Hz), 2.70 (s, 3H), 6.06 (quintet, 1H, J=6.2 Hz), 6.92-7.09 (m, 5H), 7.15 (s, 1H), 7.30-7.37 (m, 2H), 7.56-7.70 (m, 2H), 7.98 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C24H22N2O3S2, 450.6 (M+H), found 451.2, 409.2 [—CH(CH3)2].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][N:6]([CH3:8])[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:4]1.[H-].[Na+].[CH3:24]I.O>O1CCCC1>[CH3:24][O:1][CH2:2][CH:3]1[O:7][N:6]([CH3:8])[C:5]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:4]1
Reactant: CI
Reactant: CN1OC(CO)CC1(Cn1ccnc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CC(Cn2ccnc2)(c2ccc(Cl)cc2)N(C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(Hydroxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine (3: R1 =4-Cl, R2 =H) 2.50 g, 8 mmol) is added to a suspension of 1.32 g (24 mmol) of 50% by weight sodium hydride in 50 ml anhydrous tetrahydrofuran, at 0° C. under a nitrogen atmosphere. After stirring for 1 hour at 0° C., 1.28 g (9 mmol) of methyl iodide is added and the resulting suspension is heated to reflux and stirred for 20 hours. Upon cooling to room temperature, the reaction mixture is poured into 100 ml of water and then extracted with chloroform (3×75 ml). The combined organic extracts are dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The crude residue is flash-chromatographed on neutral silica gel using chloroform-methanol (98:2 by volume) as eluent. Following crystallization from ethyl acetate, 1.67 g (64%) of compound 3 (R1 =4-Cl, R2 =CH3) are obtained, mp 123°-126° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:8]([C@@H:18]([NH:20][C:21]1[N:29]=[CH:28][N:27]=[C:26]3[C:22]=1[N:23]=[CH:24][NH:25]3)[CH3:19])=[CH:7]2.[CH3:30][N:31](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[N:29]1[C:21]([NH:20][C@H:18]([C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[C:30]#[N:31])[CH3:19])=[C:22]2[C:26]([NH:25][CH:24]=[N:23]2)=[N:27][CH:28]=1
Reactant: CN(C)C=O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(C#N)c2nc1-c1ccccn1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of N-((S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (80 mg, 0.2 mmol), Pd(PPh3)4 (23 mg, 0.1 eq) and Zn(CN)2 (117 mg, 5.0 eq) in DMF (5 mL) was purged with N2 for 5 min before heating to 130° C. After 3 h, LCMS showed formation of trace amount of 2. The reaction was then heated to 165° C. over night. After cool to rt, the reaction was filtered through Celite™ and purified by reverse HPLC (MeCN/H2O, 0.1% TFA) to give a white solid. 1H-NMR (400 Hz, DMSO-d6) δ 8.83 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.42-8.37 (m, 3H), 8.14 (d, J=8.0 Hz, 1H), 8.08 (t, J=8.0 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 6.24 (s, 1H), 1.72 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=393 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:18][C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH3:34].[Na+].[I-].[H-].[Na+]>CN(C=O)C.CCOCC.O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:14][CH3:15])[CH2:18][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:34])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CCNc1ccc(OCC(=O)OCC)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(CC)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To an ice-cooled and stirred solution of crude (4-ethylamino-phenoxy)-acetic acid ethyl ester (0.243 g, containing 0.214 g, 0.96 mmol), 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.308 g, 1.05 mmol, WO02/28433) and NaI (0.144 g, 0.96 mmol) in DMF (3 ml) was added NaH (55% in oil, 0.063 g, 1.44 mmol). The reaction was stirred at RT for 4 h, water was added and diluted with Et2O and extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, dried (Na2SO4) and evaporated to give 0.32 g (70%) of crude (4-{ethyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester as an orange oil, MS: 479 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[C:14](N)=[O:15].[OH-:25].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[C:14]([OH:25])=[O:15]
Reactant: [OH-]
Reactant: COc1ccc2ccccc2c1C(Nc1ccccc1C)C(N)=O
Agent: [K+]
Solvent: CCO
Product: COc1ccc2ccccc2c1C(Nc1ccccc1C)C(=O)O
Yield: 35.5 %

Procedure:
A mixture of 13.6 parts of 2-methoxy-α-[(2-methylphenyl)amino]-1-naphthaleneacetamide and 120 parts of a solution of potassium hydroxide in ethanol 1 N is stirred and refluxed for 64 hours. The reaction mixture is evaporated and the residue is taken up in 250 parts of water. The unreacted starting material "A" is filtered off and the filtrate is neutralized with glacial acetic acid. The precipitated product is filtered off and dissolved in 140 parts of 1,1'-oxybisethane. The solution is washed with 100 parts of water, dried, filtered and evaporated. The solid residue is crystallized from 40 parts of 2-propanol at 0° C. The product is filtered off and dried, yielding 4.8 parts (35.5%) of 2-methoxy-α-[(2-methylphenyl)amino]-1-naphthaleneacetic acid; mp. 187.5° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@:8]12[CH2:25][CH2:24][C@H:23]3[C@@H:13]([CH2:14][CH2:15][C:16]4[C@:21]3([CH3:22])[CH2:20][CH2:19][C:18](=[O:26])[CH:17]=4)[C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[C:27](OC)=[O:28]>C1COCC1>[OH:28][CH2:27][C@H:9]1[CH2:10][CH2:11][C@H:12]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:7])[C@:21]1([CH3:22])[C:16](=[CH:17][CH:18]([OH:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(O)CC[C@@]43C)[C@@H]1CC[C@@H]2CO
Temperature: 0 °C
Yield: 103.5 %

Procedure:
Approximately 750 ml of dry THF was added to a 3-neck round bottom flask equipped with a condenser, argon bubbler and mechanical stirrer. The flask was cooled to 0° C. and lithium aluminum hydride (LAH) (11.39 g, 0.3 mol) was slowly added. After all of the LAH was added, the flask was warmed to room temperature. A solution of methyl androst-4-ene-3-one-17β-carboxylate (66 g, 0.2 mol) in 600 ml of THF was very slowly added to the LAH slurry. After the addition of the steroid, the reaction mixture was slowly warmed to reflux. After 2 hours the excess LAH was quenched with 11.4 ml water, 11.4 ml 15% sodium hydroxide (NaOH) and 28 ml water. The salts were removed by filtration and washed with approximately 1 liter of warm THF. Concentration of the combined organic solutions afforded 63 g (94%) of 17β-(hydroxymethyl)-androst-4-ene-3-ol as mixture of α and β isomers.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]3[CH:19]([CH:20](C)C)CC[C@@](C4COC(=O)N4)(C)C3)[CH:12]=2)[NH:7][C:6]=1C(O)=O.[C:34](=[O:36])=[O:35].C(O)(=O)CCC(O)=O.[N:45]1C2C(=CC=CC=2)C=CC=1>>[CH3:33][N:2]([CH2:3][CH2:4][C:5]1[C:13]2[CH:12]=[C:11]([CH2:14][C@@H:19]3[NH:45][C:34](=[O:36])[O:35][CH2:20]3)[CH:10]=[CH:9][C:8]=2[NH:7][CH:6]=1)[CH3:1]
Reactant: CC(C)C1CC[C@](C)(C2COC(=O)N2)CC1c1ccc2[nH]c(C(=O)O)c(CCN(C)C)c2c1
Reactant: O=C=O
Reactant: c1ccc2ncccc2c1
Agent: O=C(O)CCC(=O)O
Product: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Temperature: 200 °C
Yield: 90 %

Procedure:
1 g (3.02 mmoles) of the (S)-3-(2-dimethylaminoethyl)-5-(2-oxo-1,3-oxazolidin-4-ylmenthyl)-1H-indol-2-carboxylic acid was suspended in 10 ml of dry quinoline. 20 mg of cuprous oxide was added and the stirred suspension heated to 200° C. under dry nitrogen stream. The reaction mixture was kept at this temperature until no more CO2 was released (15-20 min.). It was left to cool to room temperature and the reaction mixture filtered through decalite. The filtrate was concentrated by vacuum distillation of the solvent, providing a residue which was dissolved with a succinic acid solution and washed three times with 15 ml of dichloromethane. The washed aqueous phase was cooled, the pH adjusted to 12 with a 40% sodium hydroxide solution and extracted three times with 20 ml of dichloromethane. The combined organic phases were dried on anhydrous sodium sulphate and evaporated to dryness. The residue was recrystallised with isopropyl alcohol to give 780 mg (90%) of zolmitriptan as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])=[N:9][CH:8]=[CH:7]2)([O-])=O.[H][H]>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:15]([C:17]([CH3:19])([CH3:20])[CH3:18])=[O:16])=[N:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1nccc2cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1nccc2cc(N)ccc12
Yield: 104 %

Procedure:
6-Nitro-1-bis(tert-butyl carbonyl)aminoisoquinoline (75.00 g, 0.193 mol) in methanol/THF (500 ml/500 ml) was hydrogenated with a hydrogen balloon in the presence of Pd/C (5%, 5 g) for 2.0 h. Filtration of the Pd/C and concentration gave a solid, which was recrystallized from methanol to give 65.72 g (94.97%) of 1B as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (m, 18H) 4.18 (s, 2H) 6.89 (d, J=2.20 Hz, 1H) 6.99 (dd, J=9.01, 2.42 Hz, 1H) 7.35 (d, J=6.59 Hz, 1H) 7.75 (d, J=8.79 Hz, 1H) 8.22 (d, J=5.71 Hz, 1H). LC-MS: 741 (2M+Na)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[OH:26])#[CH:19]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[OH:26])[CH:3]=1)=[O:17]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC1CCCCC1O
Product: O=C(NCCCc1cccc(C#CC2CCCCC2O)c1)C(F)(F)F

Procedure:
Sonogashira coupling of bromide 3 with 2-ethynylcyclohexanol followed by flash chromatography (5-50% EtOAc/hexanes gradient), gave 2,2,2-trifluoro-N-(3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide as a yellow oil. Yield (1.2 g, 43%): 1H NMR (400 MHz, CDCl3) δ 7.18-7.28 (m, 3H), 7.06-7.30 (m, 3H), 6.33 (brs, 1H), 3.48-3.57 (m, 1H), 3.36 (app q, J=6.8 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.38-2.46 (m, 1H), 2.32 (brs, 1H), 2.02-2.10 (m, 2H), 1.91 (quint, J=7.2 Hz, 2H), 1.74-1.82 (m, 1H), 1.66-1.74 (m, 1H), 1.40-1.52 (m, 1H), 1.16-1.40 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[C:9]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[NH2:21].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:9]1[N:10]([CH3:11])[C:3]2[C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:25][C:26]4[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=4)=[C:18]([CH3:17])[CH:19]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=1
Reactant: Cn1c(-c2ccco2)cc2ncnc(Cl)c21
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccco5)n(C)c34)cc2C)cn1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 64.8 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (92 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (102 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 3.5 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mL×2), and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (105 mg).
Reaction SMILES: [C:1]([C:4]1[NH:5][N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:7](=[O:9])[CH:8]=1)(=O)[NH2:2].C(#N)C.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[NH:5][N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: Cc1ccccc1-n1[nH]c(C(N)=O)cc1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1[nH]c(C#N)cc1=O
Temperature: 0 °C

Procedure:
22.5 g of 3-carbamoyl-1-(2-methylphenyl)-5-pyrazolone and 150 ml of acetonitrile were put into a 300 ml three-necked flask. A mixture solution of 35 ml of phosphorus oxychloride and 100 ml of N,N-dimethylformamide was added dropwise thereto at a temperature of 15° C. or below. After completion of the dropwise addition, the reaction mixture was poured into ice water and the crystals thus deposited were collected by filtration.
Reaction SMILES: C[O-].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][SH:10].Br[CH2:12][CH2:13][CH2:14][Cl:15]>CO.C(#N)C.C(OCC)(=O)C>[Cl:15][CH2:14][CH2:13][CH2:12][S:10][CH2:9][C:5]1[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: SCc1cccs1
Reactant: ClCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: ClCCCSCc1cccs1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.5 ml of a 30% sodium methylate solution in methanol is added in drops to 1.0 g of thiophen-2-yl-methanethiol in 8 ml of anhydrous acetonitrile at 0° C. After 5 minutes, the drop-by-drop addition of 1.1 ml of 1-bromo-3-chloropropane is carried out. Then, the reaction solution is allowed to stir for 5 hours at room temperature. For working-up, the batch is diluted with ethyl acetate, washed with water and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient yields 1.3 g of 2-(3-chloropropylthiomethyl)-thiophene as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15].[C:16]1([CH2:22][CH2:23][C:24](Cl)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1>[C:16]1([CH2:22][CH2:23][CH2:24][N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[CH2:9]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cc(C2CCCNC2)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Yield: 93.1 %

Procedure:
The title compound was prepared by acylation of 209 mg (1 mmole) of the 3-(4-fluoro-3-methoxyphenyl)piperidine from Preparation 8, Part C, with 253 mg (1.5 mmole) of 3-phenylpropionyl chloride in toluene, followed by reduction with 175 mg (4.6 mmole) of lithium aluminum hydride in tetrahydrofuran, substantially according to the procedure of Preparation 3. This afforded 305 mg (93% yield) of the title compound.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH2:50][CH3:51])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH2:50][CH3:51])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(CC)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.7 mg (0.15 mmol) LiOH in 3 mL water was added to a solution of 73 mg (0.10 mmol) (R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(3-ethyl-4-hydroxy-5-methyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 11.2) in 5 mL THF and the reaction mixture was stirred for 2 h at RT. The THF was eliminated i.vac., 1 M HCl was added until an acidic reaction was obtained and the mixture was evaporated down again i.vac. The residue was taken up in DMF and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: NC1CN=C(C2C=CC=CN=2)C2C=C([Br:19])C=CC=2N=1.[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH3:21].BrCC(=O)C(OCC)=O.C(OCC)C>O1CCCC1>[BrH:19].[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH3:21]
Reactant: NC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Agent: CCOC(=O)C(=O)CBr
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Br
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
A suspension of 52 g of 2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine in 1.5 l of tetrahydrofuran was treated in succession with 58 ml of N-ethyldiisopropylamine and 44 ml of ethyl bromopyruvate and the mixture was stirred at 65° C. for 20 min. Then, a further 5.8 ml of N-ethyldiisopropylamine and 44 ml of ethyl bromopyruvate were added and the mixture was stirred at 65° C. for a further 20 min. After cooling in an ice bath 0.5 l of diethyl ether was added and the crystals were filtered off. 49.5 g of N-ethyldiisopropylamine hydrobromide were obtained. The filtrate was evaporated in a vacuum, the residue was taken up in dichloromethane and shaken twice with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over sodium sulphate and chromatographed over 2 kg of silica gel. With dichloromethane/ethanol 197:3 and 196:4 there were firstly eluted small amounts of impurities, then with dichloromethane/ethanol 97:3, 95:5 and 94:6 there were isolated a total of 58.2 g of ethyl 3-[2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-1-yl]pyruvate. This was dissolved in 11 of acetic acid and stirred at 100° C. for 3.5 h. The solution was then evaporated in a vacuum and the residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution (11 of each). The dichloromethane phase was separated, dried over sodium sulphate and chromatographed over 2 kg of silica gel. 17.2 g of ethyl 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate were obtained as dark red crystals by elution with ethyl acetate. This was again chromatographed over 2 kg of silica gel. Strongly coloured impurities were eluted with ethyl acetate/dichloromethane 1:1 and 2:1. The desired ethyl 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate was eluted with ethyl acetate. There were obtained 11.7 g of ethyl 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate of m.p. 227-230° C.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[N+:20]([O-])([OH:22])=[O:21].[K+].[Br-]>C(O)(=O)C>[OH:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19]
Reactant: CC1(C)Oc2ccsc2C(N2CCCCC2=O)C1O
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(N2CCCCC2=O)C1O

Procedure:
The title compound was prepared as described in Example 5 starting with 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran (1.5 g, 5.33 mmol) and 90% nitric acid (2.5 mL) in acetic acid (25 mL) to give the product, 0.837 g (48%), as a yellow solid: mp 210°-211° C.; IR (KBr): 3231, 1613, 1515 and 1492 cm-1 ; MS: m/z 327 (MH+); 1H NMR (CDCl3): δ1.32(s, 3H), 1.51(s, 3H), 1.84(m, 4H), 2.55(m, 2H), 3.20(m, 2H), 3.84(d, J=9.5 Hz, 1H), 4.78(bs, 1H, exchanges with D2O), 5.86(d, J=9.5 Hz, 1H) and 7.40(s, 1H).