Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[C:8](=O)[NH:9][CH:10]=[N:11][C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:8]1[C:7]2[CH:6]=[C:5]3[O:1][CH2:2][O:3][C:4]3=[CH:13][C:12]=2[N:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cnc2cc3c(cc12)OCO3
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2cc3c(cc12)OCO3
Yield: 69 %

Procedure:
A mixture of 7H-[1,3]dioxolo[4,5-g]quinazolin-8-one (0.550 g, 2.78 mmol) and phosphorus pentachloride (0.800 g, 3.84 mmol) in 3 mL phosphorus oxychloride was heated to a gentle reflux for 2.5 hours. Solvent was removed in vacuo, and azeotroped with toluene. Residue was dissolved in ethyl acetate and washed with 5% sodium bicarbonate solution and then filtered, and then solvent was removed in vacuo to give 8-chloro-[1,3]dioxolo[4,5-g]quinazoline (0.400 g, 74%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:15]=[C:16]([CH:19]=[O:20])[NH:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:22]1COCC1.[H-].[Na+].IC>O>[CH3:22][N:17]1[CH:18]=[C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:21])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[CH:15]=[C:16]1[CH:19]=[O:20]
Reactant: C1CCOC1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3c[nH]c(C=O)c3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1C=O

Procedure:
1.3 g (4.6 mmol) of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-pyrrolecarboxaldehyde and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 300 mg (10 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. 640 μl (10 mmol) of iodomethane are then added and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and heptane (70/30). After evaporation of the solvents, 600 mg (44%) of the expected product are collected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](/[C:12](/[F:29])=[C:13](\[F:28])/[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](/[C:12](/[F:29])=[C:13](\[F:28])/[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)[CH2:9][CH:10]=[O:11])=[CH:6][CH:7]=1
Reactant: OCCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Reaction time: 4 h
Yield: 98.1 %

Procedure:
To a stirred solution of (4E)-3-(4-chlorophenyl)-4,5-difluoro-6-(3-phenoxyphenyl)-4-hexen-1-ol (0.332 g, 0.80 mmol) in methylene chloride (20 ml) at room temperature under nitrogen was added pyridinium chlorochromate (PCC; 0.268 g, 1.24 mmol), and the resulting mixture was stirred for four hours. The reaction mixture was diluted with methylene chloride, washed sequentially with 10% hydrochloric acid, water, saturated sodium bicarbonate and water, and dried over anhydrous sodium sulfate. Concentration in vacuo afforded the title compound as a brown oil (0.324 g) which was characterized by 1HNMR, 19FNMR and mass spectral analysis, and used without further purification.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[S:54][S:53][C:52](=[S:55])[CH:51]=2)=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C:44]3[CH:45]=[CH:46][C:47]([C:50]4[S:54][S:53][C:52](=[S:55])[CH:51]=4)=[CH:48][CH:49]=3)=[O:16])[CH:12]=2)[CH:7]=1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)C(=O)Oc3ccc(-c4cc(=S)ss4)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To the solution of 1 (naproxen, 595 mg, 2.58 mmol) in 20 mL of dimethylformamide, hydroxybenzotriazole (388 mg, 2.87 mmol) and DCC (593 mg, 2.87 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 5-p-hydroxyphenyl-1,2-dithiole-3-thione (2; 650 mg, 2.87 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product was loaded on a silica gel open column and eluted with dichloromethane, from which 4-(5-thioxo-5H-1,2-dithiol-3-yl)phenyl 2-(2-methoxynaphthalen-6-yl)propanoate (3) was obtained (406 mg, 36% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[NH:7][CH2:6][CH2:5]2.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=1)[N:7]([C:39]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:40])[CH2:6][CH2:5]2
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Fc1ccc2c(c1)CCNC2c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2cc(F)ccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
A solution of 6-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.3 g, 1.0 mmol) and diisopropylethylamine (0.2 mL, 0.919 mmol) in anhydrous dichloromethane (6 mL) was treated with 4-fluorophenyl isocyanate (0.14 g, 1.0 mmol) and stirred at RT for 16 h. Formation of a white precipitate was observed which was collected by filtration. The solid was dried under high vacuum to give 6-fluoro-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (0.35 g, 80%). MS (ESI pos. ion) m/z: 433 (M+H).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:23]=[CH:22][C:9]([O:10][C:11]2[CH:12]=[C:13]([C:17]#[C:18][CH:19](O)[CH3:20])[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1>>[Br:2][CH:19]([C:18]#[C:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:9]2[CH:22]=[CH:23][C:6]([F:5])=[CH:7][CH:8]=2)[CH:12]=1)[CH3:20]
Reactant: CC(O)C#Cc1cccc(Oc2ccc(F)cc2)c1
Reactant: BrP(Br)Br
Product: CC(Br)C#Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
The solution of 4-[3-(4-fluorophenoxy)phenyl]-3-butyn-2-ol in methyl t-butyl ether prepared in step 1 was cooled to 0°-10° C. and PBr3 (7.6 kg) was added slowly to maintain the reaction temperature under 15° C. The reaction mixture was agitated for 2 hours and then was quenched by the addition of chilled distilled water (25 kg). The layers were separated and the organic phase was diltuted with methyl t-butyl ether, washed with distilled water and 5% aqueous NaHCO3, and concentrated in vacuo to give 2-bromo-4-[3-(4-fluorophenoxy)phenyl]-3-butyne.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1)([O-])=O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)oc1ccccc12
Reaction time: 0.25 h

Procedure:
3-nitrodibenzofuran (6.2 g, 29.08 mmol) was dissolved in 360 mL ethyl acetate and was degassed 5 minutes by passing nitrogen gas through the solution. 500 mg of Pd/C was added to the solution and the content was hydrogenated at 60 psi pressure. Reaction was let go until pressure in hydrogenation apparatus stabilizes at 60 psi for 15 minutes. Reaction content was then filtered through a small celite pad and off white color product was obtained. (5.3 g, 28.9 mmol)
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[Cl:11][C:12]1[C:21]([NH2:22])=[C:20]([NH:23][CH2:24][C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[Cl:11][C:12]1[C:21]2[N:22]=[CH:1][N:23]([CH2:24][C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH:26]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cc(Cn3cnc4c(Cl)nc5ccccc5c43)on2)cc1
Temperature: 110 °C
Yield: 58.7 %

Procedure:
Pyridine hydrochloride (3 mg, 0.02 mmol) and triethyl orthoformate (0.3 mL, 1.7 mmol) were added to a solution of 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (0.4294 g, 1.164 mmol) in toluene (10 mL), and the reaction was heated at 110° C. for 16 hours. A solid was present and was isolated by filtration. The filtrate was concentrated under reduced pressure and triturated with diethyl ether to provide a solid. The two solids were combined and purified by column chromatography on silica gel (eluting with 1:1 ethyl acetate:hexane) to provide 0.259 g of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinoline as a white solid, mp 219.0-220.0° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:63])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:26]([O:57][CH3:58])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:55][CH3:56])[C@@H:36]([CH3:54])[C:37]([NH:39][C@@H:40]([CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)[C:41]([NH2:43])=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:3])=O.[O:64]=[C:65]1[CH:69]=[CH:68][C:67](=[O:70])[N:66]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][C:76]([NH:78][NH2:79])=[O:77]>>[O:70]=[C:67]1[CH:68]=[CH:69][C:65](=[O:64])[N:66]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][C:76]([NH:78][NH:79][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:63])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:26]([O:57][CH3:58])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:55][CH3:56])[C@@H:36]([CH3:54])[C:37]([NH:39][C@@H:40]([CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)[C:41]([NH2:43])=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:77]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157, from N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH2:9](Br)[C:10]#[CH:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[N+:1]([C:4]1[N:5]([CH2:11][C:10]#[CH:9])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a round bottom flask was added 2-nitroimidazole (500 mg, 4.42 mmol), propargyl bromide (631 mg, 5.31 mmol), potassium carbonate (733 mg, 5.31 mmol) and DMF (5 mL). The reaction was stirred overnight at RT. TLC (EtOAc) indicated complete reaction. The reaction was poured onto water (20 mL) and extracted into EtOAc (3×20 mL). The combined organics were washed with water (5×20 mL). The organic layer was then concentrated in vacuo and purified on a silica gel cartridge using EtOAc:Hex as the eluent to afford 571 mg (85% yield) of 10 as a pale yellow solid. 1H NMR (CDCl3, 400 MHz), δ: 2.63 (1H, d, J=5.6 Hz), 5.23 (2H, d, J=2.4 Hz), 7.20 (1H, d, J=1.2 Hz), 7.46 (1H, s). Mass Spec (lo-res): Calc'd for C6H5N3O2: 151.04; found: 152.10 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](Br)=[CH:4][N:3]=1.CCO[C:13]([S-:15])=[S:14].[K+].O.OS(O)(=O)=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:15][C:13](=[S:14])[NH:8][C:6]=2[N:7]=1
Reactant: Nc1ncc(Br)c(N)n1
Reactant: CCOC(=S)[S-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc2sc(=S)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 2,4-diamino-5-bromo-pyrimidine (9.5 g, 50 mmol, 1.0 eq) and potassium ethyl xanthogenate (16 g, 100 mmol. 2 eq) in DMF (300 ml) was heated up to reflux for 10 hours under N2. The reaction solution was cooled down to room temperature and water (600 ml) was added. The pH of the solution was then adjusted to about 5 using H2SO4 (2 ml) and the resulting suspension was stirred at 50-60° C. for 30 min., cooled to about 30° C., filtered and washed with water. The product was dried under vacuum at 50-60° C. to give 8.2 g (89%) of 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-thione as a yellow solid. 1H NMR (400 MHz, d6-DMSO). δ 6.91 (s, 2H, ex. D2O), 8.34 (s, 1H), 12.3 (br, 1H, ex. D2O); MS (+)-ES [M+H]+ m/z 185.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]2[O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]3[O:52][CH2:51][C:50](=[O:53])[N:49]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[C:48]=3[CH:59]=2)=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])O.[Na+]>ClCCl>[CH3:58][O:57][CH2:56][CH2:55][CH2:54][N:49]1[C:48]2[CH:59]=[C:44]([CH2:43][O:42][CH:30]3[CH:29]([C:26]4[CH:27]=[CH:28][C:23]([C:21]([N:10]5[CH2:11][CH2:12][CH:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[CH2:8][CH2:9]5)=[O:22])=[CH:24][CH:25]=4)[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)[CH:45]=[CH:46][C:47]=2[O:52][CH2:51][C:50]1=[O:53]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)Cl)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)N4CCC(c5ccccc5)CC4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 0.122 g of 4-phenylpiperidine in 2 ml of dichloromethane is admixed with 0.101 ml of triethylamine. The reaction solution is cooled to 0° and a solution of tert-butyl 4-(4-chlorocarbonylphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 4 ml of dichloromethane is added dropwise. The reaction mixture is stirred at 0° C. over 40 minutes and subsequently poured onto 25 ml of saturated sodium hydrogencarbonate solution. The mixture is extracted with 80 ml of dichloromethane, the phases are separated and the organic phase is washed with 40 ml each of water and brine, dried over sodium sulphate, filtered and concentrated. The residue is purified by means of flash chromatography (SiO2 60F). The title compound is obtained as a colourless oil. Rf=0.20 (3:1 EtOAc-heptane); Rt=5.44.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2CCC[C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=CC=1.Cl.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][CH:17]1[NH2:21]>>[ClH:1].[NH:13]1[CH2:9][CH2:8][CH2:2][CH2:7][CH2:6][C:5]1=[N:21][CH:17]1[CH2:18][CH2:19][CH2:20][C:16]1([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:15]
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: NC1CCCC1(O)c1ccccc1
Agent: Cl
Product: OC1(c2ccccc2)CCCC1N=C1CCCCCN1

Procedure:
Following the procedure described in Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of 2-hydroxy-2-phenylcyclopentylamine hydrochloride and employing a reaction time of 47 days the desired product was obtained, M.P.261°-262° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:33]([C@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]1)[CH3:34]>C1(C)C=CC=CC=1>[CH2:33]([C@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH3:34]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Reactant: CC[C@H]1CCCCN1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[C@H]1CCCCN1C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 86.8 %

Procedure:
Operations are carried out as for Example 7, starting from 2.5 g of 1-phenyl isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.2 g of 2(S)-ethyl piperidine in 100 ml of toluene. After chromatography, 3 g of 2(S)-ethyl 1-[(1-phenyl 3-isoquinolyl) carbonyl]piperidine in the form of oil are obtained. αD23 =-2.4° (2% in ethanol).
Reaction SMILES: CO[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH3:3])[CH2:6][CH2:7]3)=[N:12][NH:13]2)=[CH:18][CH:17]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Yield: 68.8 %

Procedure:
To a stirred solution, under nitrogen, of 13.0 g of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboxylic acid methyl ester in 150 ml of tetrahydrofuran was added, dropwise, 48 ml of a 1M solution of lithium aluminum hydride (0.048 mole) in tetrahydrofuran. The solution was stirred under reflux for 1 hr. The reaction mixture was cooled in an ice-bath and water was added slowly. The reaction mixture was filtered, the filter cake washed with tetrahydrofuran and methanol, and the filtrate was concentrated. Recrystallization of the residue from ethanol-water yielded 7.6 g (69%) of product, mp 211°-213° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@H:6]1[C@@H:9]([N:10]=[N+:11]=[N-:12])[C:8](=[O:13])[NH:7]1)(=O)=O.[Br-:21].[Li+].CN(C)C=O>C(OCC)(=O)C>[N:10]([C@H:9]1[C:8](=[O:13])[NH:7][C@H:6]1[CH2:5][Br:21])=[N+:11]=[N-:12]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2N=[N+]=[N-])cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@H]1CBr
Yield: 94.1 %

Procedure:
A mixture of 0.413 g (1.40 mmol) of cis-3-azido-4-oxo-2-azetidinylmethyl tosylate, 0.434 g (5.0 mmol) of anhydrous lithium bromide and 5 ml of anhydrous dimethylformamide is heated to 100° under argon for one hour. The solution is allowed to cool to 25°, poured into ethyl acetate and extracted copiously with water. The ethyl acetate layer is dried and evaporated to give 0.270 g (94%) of the title product.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9])(=O)C.CO[C:16]1C=CC(CN2N=NC(CC(OCC)=O)=N2)=C[CH:17]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([O:10][CH2:16][CH3:17])=[O:9]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: CCOC(=O)Cc1nnn(Cc2ccc(OC)cc2)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(N)c1
Temperature: 105 °C

Procedure:
2-(Acetylamino)isonicotinic acid (13 g, 73.60 mmol) synthesized by the method of Example 7, (A) was added with ethanol (50 ml) and toluene (150 ml) and heated to 100-110° C. The mixture was added dropwise with concentrated sulfuric acid (7 ml) and heated for 11 hour with stirring. The reaction solution was returned to room temperature and poured into saturated aqueous sodium hydrogencarbonate cooled with ice. The mixture was extracted with chloroform and the collected organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 7.6 g (23% for the two steps) of the title compound as pale yellow crystals without purification.
Reaction SMILES: C([O:8][C:9]1[C:42]([CH3:43])=[CH:41][C:12]([C:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:33][CH2:32][C:31]5[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=5[NH:29][C:28]4=[O:40])[CH2:23][CH2:22]3)[CH:16]=2)=[O:14])=[CH:11][C:10]=1[CH3:44])C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C:9]1[C:42]([CH3:43])=[CH:41][C:12]([C:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:33][CH2:32][C:31]5[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=5[NH:29][C:28]4=[O:40])[CH2:25][CH2:26]3)[CH:16]=2)=[O:14])=[CH:11][C:10]=1[CH3:44]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c(OCc5ccccc5)c(C)c4)ncn3)CC1)C(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c(O)c(C)c4)ncn3)CC1)C(=O)N2

Procedure:
70 mg (0.10 mmol) 3-{1-[6-(4-benzyloxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one and 20 mg palladium on charcoal (Pd/C 10%) in 10 mL MeOH were hydrogenated for 30 min at RT in a hydrogen atmosphere of 10 psi. After filtration of the reaction mixture the solvent was eliminated i. vac. and the residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][S:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=2)[C:12]([C:26](OCC)=[O:27])=[CH:11][N:10]=1>O1CCCC1>[CH3:7][S:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=2)[C:12]([CH2:26][OH:27])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(SC)ncc2CO)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (4.15 g) in tetrahydrofuran (150 ml) is added a solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (38.32 g) in tetrahydrofuran (100 ml) under ice-cooling at 5° C. to 10° C. over a period of one hour. After the addition, the ice bath is removed, and the reaction mixture is stirred at room temperature for one hour. To the reaction mixture is added water (4.15 ml) under ice-cooling, and thereto is further added 3N aqueous sodium hydroxide solution (4.15 ml). To the mixture is added water (4.15 ml) three times, and the mixture is stirred at room temperature for one hour. The reaction mixture is treated with magnesium sulfate, and the solid precipitates obtained are filtered. The precipitates are washed with tetrahydrofuran. The filtrate and the washings are combined, and concentrated under reduced pressure, and triturated with a mixture of ethyl acetate and isopropyl ether. The resulting crystals are collected by filtration, and washed well with isopropyl ether to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine as a pale yellow crystalline powder.