Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][N:17]([CH3:22])[C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:43][C:26]([CH3:42])([CH3:25])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:21])([CH3:20])[CH2:18][N:17]([CH3:22])[C:16]5=[O:23])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:24]=2)[CH:30]=[N:29]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CC(C)(C)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C1=O
Product: CN1CC(C)(C)N(c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)C1=O
Yield: 33 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2-one was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol to give 479. Yield 33%. MS (ESI):468.2. 1H NMR (400 MHz, DMSO) δ 8.17 (d, J=8.2, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.36 (dd, J=8.2, 1.8, 1H), 7.22 (d, J=1.7, 1H), 4.73 (s, 1H), 4.31 (t, J=4.9, 2H), 4.03 (s, 2H), 3.35 (d, J=5.6, 2H), 3.19 (t, J=5.0, 2H), 2.83 (s, 3H), 1.72 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14]>C(N(CC)CC)C.[Cu]I>[OH:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CC(C)(C)O
Reactant: OCCCc1cccc(Br)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cccc(CCCO)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a degassed solution of 3-(3-bromophenyl)propan-1-ol (8) (0.95 g, 4.5 mmol) and 2-methyl-3-butyn-2-ol (9) (1.6 mL, 16 mmol) in triethylamine (25 mL) was added PdCl2(PPh3)3 (0.095 g, 0.14 mmol) and CuI (0.027 g, 0.14 mmol). The resulting mixture was degassed and stirred under argon at 70° C. for 15 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL). The solution was filtered through filter paper, washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (10 to 100% EtOAc-hexanes gradient) gave 4-(3-(3-hydroxypropyl)phenyl)-2-methylbut-3-yn-2-ol (10) as a light brown oil: Yield (0.78 g, 80%): 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.18 (m, 4H), 5.46 (s, 1H), 4.48 (t, J=5.2 Hz, 1H), 3.38 (q, J=6.0 Hz, 2H), 2.59 (t, J=7.2 Hz, 2H), 1.66-1.73 (m, 2H), 1.46 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:12][C:13]1C=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:5].Cl.[NH2:28][C@H]1CCC[C@@H]1NC(=O)C1C=CC=CC=1Cl.ClC1N=CC(C(F)(F)F)=CN=1>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:12][C:13]1[N:28]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][N:14]=1)=[O:5]
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1Cl
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1Cl
Agent: Cl
Agent: FC(F)(F)c1cnc(Cl)nc1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cn1)c1ccccc1Cl

Procedure:
Prepared according to the procedure for 2-chloro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 69) from N-[(1S,2S)-2-aminocyclopentyl]-2-chlorobenzamide hydrochloride (Intermediate 19; 100 mg, 0.363 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 80 mg, 0.436 mmol) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C1O[C:14]([CH2:16][CH2:17][NH2:18])([CH3:15])[O:13]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:15][C:14](=[O:13])[CH2:16][CH2:17][NH:18]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: CC1(CCN)OCCO1
Reactant: Cc1cc(F)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1cc(F)ccc1C1CC(=O)CCN1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
4-Fluoro-2-methyl-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluenesulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[O:3][C:4]1([C:10]#N)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].C([Al+]C(C)C)(C)C.CCCCCC.[OH2:28]>ClCCl>[CH3:1][Si:2]([CH3:13])([CH3:12])[O:3][C:4]1([CH:10]=[O:28])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: O
Reactant: C[Si](C)(C)OC1(C#N)CCOCC1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: C[Si](C)(C)OC1(C=O)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
4-(Trimethylsilyloxy)tetrahydro-2H-pyran-4-carbonitrile (1.00 g, 5.02 mmol) was dissolved in dichloromethane (20 mL). To this, a 1 mol/L solution of diisopropylaluminum hydride in hexane (7.76 mL, 7.76 mmol) was added at −78° C. and the mixture was stirred at room temperature for 20 minutes. The reaction was stopped by addition of water (7.76 mL) at 0° C. The mixture was stirred at room temperature for 1 hour and then filtered through Celite. The solvent was evaporated off under reduced pressure and the residue was dissolved in tetrahydrofuran (10 mL). To this, a saturated aqueous ammonium chloride solution was added and the mixture was stirred at room temperature for 30 minutes. Then, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 4-(trimethylsilyloxy)tetrahydro-2H-pyran-4-carbaldehyde (297 mg, yield: 29%).
Reaction SMILES: [Cs].[C:2]1([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][N:20]1[C:24](=[O:25])[C:23]2[C:26]([O:33][CH2:34][CH3:35])=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[CH:29][C:22]=2[S:21]1(=[O:37])=[O:36]>CN(C=O)C>[CH2:34]([O:33][C:26]1[C:23]2[C:24](=[O:25])[N:20]([CH2:19][O:13][C:12]3[N:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:9]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:11]=3)[S:21](=[O:37])(=[O:36])[C:22]=2[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[CH:27]=1)[CH3:35]
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: CCOc1cc(OCC)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [Cs]
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 714.4 %

Procedure:
The cesium salt of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole [prepared from 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole (0.714 g, 0.312 mmol) and Cs2CO3 (0.509 g, 0.156 mmol)] was suspended in DMF (20 ml) and treated with 2-chloromethyl-4, 6-diethoxy-1,2-benzisothiazol-3 (2H)-one 1,1-dioxide (0.5 g, 0.156 mmol). The reaction mixture was stirred at room temperature for 24 hours, then was poured onto ice-water and was extracted with ethyl acetate (300 mL). The organic layer was washed with water, then brine and then was dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography on silica gel eluting with CH2Cl2 to afford 0.57 g (71%) of 4,6-diethoxy-2-[1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =OEt; R5 =6-OEt), m.p. 159°-160° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN1CCOCC1>CN1CCCC1>[N:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncc1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCN(c2ccncc2)CC1
Temperature: 100 °C

Procedure:
Ethyl isonipecotate (6.0 g 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 g mL, 85.00 mmol), were dissolved in N-methylpyrrolidine (50 mL) and the resulting solution was heated at 100° C. for 48 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc and washed with water and brine (2×100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (5% MeOH/CHCl3) to afford 33-1 as a crystalline solid. 1H NMR (CDCl3) δ 8.21 (d, J=6.8 Hz, 2H), 6.78 (d, J=6.8 Hz, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.85 (m, 2H), 3.10 (m, 2H), 2.61 (m, 1H), 2.05 (m, 2H), 1.85 (m, 2H), 1.23 (t, J=7.0 Hz, 3H). ##STR164## 4-Pyridylpiperidin-4-ylcarboxylic acid (33-2)
Reaction SMILES: BrC1C=CC(C(CC2C=CC(Br)=CC=2)C(O)=[O:10])=CC=1.C([Cu])#N.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)#[N:24].CC(C[AlH]CC(C)C)C.CN([CH:53]=[O:54])C>>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH2:31][C:28]2[CH:27]=[CH:26][C:25]([C:23]#[N:24])=[CH:30][CH:29]=2)=[CH:38][CH:37]=1)#[N:40].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH:53]=[O:54])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(O)C(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Agent: N#C[Cu]
Agent: CC(C)C[AlH]CC(C)C
Agent: N#Cc1ccc(CCc2ccc(C#N)cc2)cc1
Product: O=Cc1ccc(CCc2ccc(C=O)cc2)cc1
Yield: 76 %

Procedure:
1,2-Bis-(4-cyanophenyl)ethane was prepared in one step from 2,3-bis-(4-bromophenyl)propanoic acid (Dann, O., (1971) Liebigs Ann. Chem., 749: 68-89) by the action of CuCN in DMF (Das, B. P., et al., (1977) J. Med. Chem., 20: 531-536) in a 50% yield; mp 195-197° C. 1H NMR (DMSO-d6): 7.68 (d, 4H, J=8), 7.40 (d, 4H, J=8), 3.01(s, 4H). 13NMR (DMSO-d6): 146.7, 131.9, 129.3, 118.6, 108.6, 35.8. MS m/e 232 (M++1).1,2-Bis-(4-cyanophenyl)ethane was used without further characterization and on treatment with DIBAL gave a white crystalline solid (CHCl3:ether) 76% mp 121-122° C. of 1,2-bis-(4-formylphenyl)ethane. 1H NMR (DMSO-d6): 9.96 (s, 2H), 7.80 (d, 4H, J=8), 7.44 (d, 4H J=8), 3.05 (s, 4H). 13C NMR (DMSO-d6/D2O): 192.0, 184.0, 134.2, 129.1, 128.8, 36.0. Anal. Calc. for C16H14O2.0.1H2O: C, 80.04; H, 5.96. Found: C, 80.09; H, 5.98. A protocol similar to that described above was employed for the condensation of 1,2-bis-(4-formylphenyl)ethane and 4-(N-isopropylamidino)-1,2-phenylene diamine (18, 35). A 75% yield of a purple solid mp>320° C. 1H NMR (DMSO-d6/D2O): 8.09 (d, 4H, J=8), 8.06 (s, 2H), 7.83 (d, 2H, J=8.4), 7.65 (d, 2H, J=8.4), 7.48 (d, 4H, J=8), 4.03 (br m, 2H), 3.07 (br, 4H), 1.29 (d, 12H, J=6). 13NMR (DMSO-d6/D2O): 162.4, 153.0, 146.6, 138.3, 135.4, 129.8, 127.9, 124.8, 124.1, 123.5, 115.5, 115.0, 45.6, 36.2, 21.2. MS (FAB) 583 (M++1)Anal. calc. for C36H38N8.4HCl.0.5H2O: C, 58.61; H, 5.87; N, 15.19. Found: C, 58.31; H, 5.79; N, 15.02.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>O1CCCC1>[C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2)(=[O:21])[CH3:20]
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
In tetrahydrofuran (100 ml) was dissolved 5-aminophthalide (10 g, 67.05 mmol), and triethylamine (18.64 ml, 134 mmol) was added thereto. To the resulting mixture was added dropwise acetic anhydride (12.61 ml, 134 mmol) under ice-cooling, followed by stirring at room temperature for 3 hours. After addition of a 5% aqueous solution of sodium hydrogen carbonate, the precipitated white solid was separated by filtration, washed several times with water, and then dried to give 5-acetamidophthalide (12.45 g, 97%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[NH:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](O)=O>C(=O)(O)[O-].[Na+]>[NH:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1c[nH]c(-c2nc3ccccc3[nH]2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
A mixture of 1.08 g (10 mmol) of o-phenylenediamine and 20 g of polyophosphate esters was heated gently at 80° C. and was added portionwise 1.11 g (10 mmol) of pyrrole-2-carboxylic acid. After the mixture was stirred at 100° C. for 30 minutes, it was poured into a saturated solution of sodium bicarbonate (500 mL) and stirred until polyphosphate esters was decomposed. It was then extracted with two 400 mL portions of ethyl acetate. the separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. After purification by column chromatography on silica gel with 30% ethyl acetate in hexane, the desired product, 2-(pyrrol-2-yl)benzimidazole (0.50 g, 25%) was obtained as a pale yellow solid, m.p. 250° C.; 1H-NMR (Acetone-d6) 6.25-6.27 (m, 1H, ArH), 6.90-6.92 (m, 1H, ArH), 7.02-7.03 (m, 1H, ArH), 7.14-7.19 (m, 2H, 2xArH), 7.52 (bs, 2H, 2xArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([I:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=C)[CH3:8])=[O:6].ClC1C=C(C=C(Cl)C=1)C(N(C[C@H](C1C=CC(F)=CC=1)CC=C)C)=[O:30]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([I:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=[O:30])[CH3:8])=[O:6]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(I)c1)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(I)c1

Procedure:
The compound was synthesized in an analogous way to that of Method 21b but using 3-bromo-N-[(2S)-2-(4-fluorophenyl)pent-4en-1-yl]-5-iodo-N-methylbenzamide rather than 3,5-dichloro-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide (yield, 100%). 1H NMR (500 MHz, CDCl3): 2.6-3.2 (cm, 4H), 3.4-3.9 (cm, 2H), 4.0-4.2, (cm, 2H), 6.8-8.2 (cm, 7H), 9.8 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.C([Li])CCC.[S].[S:27](=O)(=O)(O)O>CCCCCC.O1CCCC1>[Cl:1][C:2]1([C:5]([OH:20])([CH2:14][N:15]2[C:19]([SH:27])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:3][CH2:4]1
Reactant: OC(Cc1ccccc1Cl)(Cn1cncn1)C1(Cl)CC1
Reactant: O=S(=O)(O)O
Agent: [Li]CCCC
Agent: [S]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
At −20° C., a mixture of 3.12 g (10 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol and 45 ml of absolute tetrahydrofuran is admixed with 8.4 ml (21 mmol) of n-butyl-lithium in hexane and stirred at 0° C. for 30 minutes. The reaction mixture is subsequently cooled to −70° C., admixed with 0.32 g (10 mmol) of sulphur powder and stirred at −70° C. for 30 minutes. The mixture is warmed to −10° C., admixed with ice-water and adjusted to pH 5 by addition of dilute sulphuric acid. The mixture is extracted repeatedly with ethyl acetate and the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 3.2 g (93% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of a solid substance which, after recrystallization, melts at 138-139° C.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][C:18](=O)[C:12]=3[CH:13]=2)[N:8]=1)=[O:4].[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1.[B][B][B][B][B][B][B][B][B][B]>CO.C(Cl)Cl>[CH3:22][C:2]([CH3:23])([CH3:1])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH:18]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=4)[C:12]=3[CH:13]=2)[N:8]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)C(=O)CC3
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc4nc(COC(=O)C(C)(C)C)[nH]c(=O)c4cc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
A suspension of 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione (0.47 g, 1.50 mmol) in anhydrous methanol (33 ml) and anhydrous CH2Cl2 (5 ml) was treated with tert-butyl 4-aminobenzoate (0.34 g, 1.78 mmol) followed by decaborane (0.07 g, 0.58 mmol) and the mixture stirred at room temperature under argon for 18 h. The solvent was removed in vacuo and the residue purified by column chromatography (50 g of silica gel) eluting with 30% ethyl acetate in CH2Cl2 to yield the desired product as a white solid (0.43 g, 58%); m.p. 231° C.; 1H-NMR (CDCl3) δ 1.26 (s, 9H, CMe3), 1.58 (s, 9H, CO2CMe3), 2.00 (m, 1H, 7-H), 2.72 (m, 1H, 7-H), 3.08 (m, 2H, 8-H), 5.10 (s, 2H, 2-CH2), 5.15 (m, 1H, 6-H), 6.67 (d, J=8.8 Hz, 2H, 3′-H, 5′-H), 7.58 (s, 1H, 9-H), 7.87 (d, J=8.8 Hz, 2H, 2′-H, 6′-H), 8.24 (s, 1H, 5-H); MS (FAB, m/z): Found 491 [(M+H)+, 25%], 514 [(M+Na)+, 100%]; Found C, 68.37; H, 6.86; N, 8.35. C28H33N3O5 requires C, 68.41; H, 6.77; N, 8.55%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(Cl)Cl>[CH3:16][C:15]([NH:12][CH2:11][CH2:10][C:9]1[C:13]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[NH:7][CH:8]=1)=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a suspension, cooled in ice, of 5 g (26.3 moles) of 5-methoxytryptamine (in a raw condition) in 100 ml methylene chloride there is slowly added, under stirring, a cold solution of 5 ml (52.6 moles) of acetic anhydride in 50 ml of methylene chloride. Stirring and cooling are continued for 1 hour (the reaction progression can be controlled by TLC), so as to obtain a full solution; then the solution is washed by Na2CO3 2N×2, under strong stirring, and then by water. The organic phase, dried on anhydrous Na2SO4 and evaporated, provides 6 g of raw melatonine, which is purified by chromatography on column (4 cm; diameter/length ratio 1:5) of Merck silica gel (70-230 mesh) (120 g); the solution is eluted by methylene chloride in order to remove the scarcely polar products thereby providing pure melatonine by eluting with methylene chloride-acetone (8:2). There are obtained 4 g of product (purifying yield 65%) which are crystalized from acetone-water. Melting point 116°-7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1>C(Cl)Cl>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[NH:18][C:13]([C:12]1[N:8]([CH2:7][C:6]2[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]=[N:10][N:11]=1)=[O:14]
Reactant: Nc1cnccn1
Reactant: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2nnnc2C(=O)Nc2cnccn2)cc1

Procedure:
1-(4-Methoxybenzyl)-1H-tetrazole-5-carbonyl chloride is reacted in methylene chloride with 2-aminopyrazine to obtain N-(2-pyrazinyl)-1-(4-methoxybenzyl)-1H-tetrazole-5-carboxamide. The protected intermediate is deprotected and worked up by the techniques described in Example 1 to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([C:6]([NH:8][CH2:9][C:10]2([OH:18])[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)=O)=[C:4]([O:22][CH3:23])[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].[S-2].[K+].[K+]>>[NH2:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([C:6]([NH:8][CH2:9][C:10]2([OH:18])[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)=[S:25])=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1(O)CN2CCC1CC2
Agent: [K+]
Agent: [S-2]
Product: COc1cc(N)c(Cl)cc1C(=S)NCC1(O)CN2CCC1CC2

Procedure:
4-Amino-5-chloro-N-(3-hydroxy-1-azabicyclo[2.2.2]octan-3-ylmethyl)2-methoxybenzamide is reacted with phosphorus pentasulfide and potassium sulfide using methods known to those skilled in the art to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][C:9](OC)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Li+].[BH4-].CCOC(C)=O>C1COCC1>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(Br)c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(Br)cccc1CCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl [3-bromo-2-(methyloxy)phenyl]acetate (8.20 g, 31.7 mmol) in 200 mL of dry THF under N2 at room temperature was added LiBH4 (32 mL, 63.32 mmol, 2M THF). After 1.5 hours, the reaction was warmed to reflux for 3 hours, and then cooled to room temperature. The solution was poured into EtOAc/1N HCl solution, and the layers were separated. The organic layer was washed with water, saturated Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated to give 2[3-bromo-2-(methyloxy)phenyl]ethanol
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
4.62 ml (0.03 mol) of ethyl piperidine-4-carboxylate were dissolved in 50 ml of dimethylformamide and treated with 4.98 ml (0.036 mol) of triethylamine. 3.9 ml (0.033 mol) of benzyl bromide were added while cooling with ice and the mixture was stirred for 10 min., warmed to 40° and stirred under an argon atmosphere for 18 hrs. The solvent was then distilled off, the residue was added to 100 ml of water, extracted three times with 100 ml of ether each time and the organic phase was dried over magnesium sulfate. 5.33 g (72%) of ethyl 1-benzyl-piperidine-4-carboxylate were obtained as a yellow oil. MS: me/e=248 (C15H22NO2+).