Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].NC1C=CC(Br)=CC=1S(N)(=O)=O.[CH2:24]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([OH:41])=[C:33]([C:42](OCC)=[O:43])[C:32]1=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:11][S:8]([C:3]1[S:4][C:5]([Cl:7])=[CH:6][C:2]=1[NH:1][C:42]([C:33]1[C:32](=[O:47])[N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:40]2[C:35]([C:34]=1[OH:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:43])(=[O:9])=[O:10]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Nc1ccc(Br)cc1S(N)(=O)=O
Product: NS(=O)(=O)c1sc(Cl)cc1NC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O

Procedure:
The title compound is prepared according to the procedure of Example 84C substituting the product of Example 174A for the product of Example 84A and substituting the product of Example 99A for the product of example Example 84B.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:30])[C:14]1[N:19]=[CH:18][C:17]([C:20]2([CH2:28][NH2:29])[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22][CH2:21]2)=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:28][C:20]1([C:17]2[CH:16]=[N:15][C:14]([CH:13]([F:30])[F:12])=[N:19][CH:18]=2)[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22][CH2:21]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine. LCMS (MH+): m/z=450.1, tR (minutes, Method F)=2.98
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[OH:14])[N:6]2[N:5]=1)=O.[CH2:21]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[N:26]1([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([CH:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[OH:14])[N:6]4[N:5]=3)=[CH:31][CH:32]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)c1ncc2ccc(C(O)c3ccccc3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: OC(c1ccccc1)c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Yield: 4.7 %

Procedure:
(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol (86.0 mg, 0.299 mmol), 4-(4-morpholino)aniline (107 mg, 0.598 mmol) and N,N-Diisopropylethylamine (0.156 mL, 0.898 mmol) were suspended in 1-Methoxy-2-propanol (0.750 mL, 7.67 mmol) and the reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced under nitrogen. The crude reaction mixture was purified via Gilson reverse phase chromatography to afford 5.69 mg of [2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl-methanol as a lyophilized powder. (M+H)=402.1. 1H NMR (400 MHz, DMSO, d6) δ 9.49 (s, 1H), 9.16 (s, 1H), 7.79 (d, 2H, J=7.12 Hz), 7.67 (m, 1H), 7.58 (m, 2H), 7.50 (d, 2H, J=7.89 Hz), 7.11 (m, 1H), 6.89 (m, 1H), 6.75 (d, 2H, J=8.44 Hz), 3.73 (m, 4H), 3.30 (m, 1H), 3.02 (m, 4H).
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17]2[CH2:18][C@@H:19]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH:23]=2)[CH2:21][CH2:20]3)[CH:9]=1.C1C(=O)N([I:49])C(=O)C1>CC#N>[CH3:39][Si:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][O:33][CH2:32][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:40])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:49])=[C:12]2[N:11]=[C:10]([C:17]2[CH2:18][C@@H:19]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH:23]=2)[CH2:21][CH2:20]3)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1C=C(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)C2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1C=C(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Reaction time: 1 h

Procedure:
To a solution of (1R,5S)-tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (6.32 g, 10.5 mmol, preparation described previously) in CH3CN (50 mL) was added NIS (2.60 g, 11.5 mmol). The resulting solution was stirred at it for 1 h. The reaction quenched with Na2SO3 and CH3CN was evaporated. The aqueous residue was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by a SiO2 column (0-15% EtOAc/Hexanes, Rf=0.4 in 20% EtOAc) to afford the titled compound as a pale yellow oil (6.94 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13]C(=O)C)=[CH:4][CH:3]=1.[C:19]([C:23]([CH2:25][C:26](OCC)=[O:27])=O)([F:22])([F:21])[F:20].O.[OH-].[Na+]>C1(C)C=CC=CC=1.OS(O)(=O)=O>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:5]1[CH:17]=[C:18]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:26](=[O:27])[CH:25]=[C:23]2[C:19]([F:22])([F:21])[F:20]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC(=O)Nc1ccccc1Cc1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccccc1Cc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 45.5 %

Procedure:
A solution of N-[2-(4-nitrobenzyl)phenyl]acetamide (6.80 g, 25.2 mmol) in EtOAc (700 mL) was treated with Pd (10% on C, 0.53 g, 0.5 mmol). The mixture was stirred under a H2 atmosphere for 5 h. The reaction mixture was filtered through Celite, before being concentrated to yield N-[2-(4-aminobenzyl)phenyl]acetamide (6.00 g, 99%): δH ((CD3)2SO)=2.00 (s, 3H), 3.75 (s, 2H), 4.80 (s, 2H), 6.45 (d, 2H), 6.80 (d, 2H), 7.00–7.15 (m, 3H), 7.35 (d, 1H), 9.20 (s, 1H). A PhMe (75 mL) suspension of this aniline (5.00 g, 20.8 mmol) was treated with a solution of CF3COCH2CO2Et (3.83 g, 20.8 mmol) in PhMe (50 mL), before being heated under reflux for 1.5 h. The PhMe was evaporated off under reduced pressure, then the residue was dissolved in EtOAc (400 mL), before being washed with 0.2 M HCl (50 mL) & brine (50 mL). After drying (MgSO4), the EtOAc solution was filtered & concentrated to give a foam that was dissolved in H2SO4 (40 mL). The mixture was heated at 90° C. for 1.5 h, before being cooled & poured onto crushed ice. H2O was added to adjust the volume to 400 mL, then the off-white precipitate produced was collected by filtration & air-dried. The precipitate was treated with AcOH (8 mL) & 12 M HCl (40 mL), & the resulting suspension was heated under reflux. The solid gradually dissolved & heating was stopped after 4 h. The cooled reaction mixture was poured onto crushed ice (50 g), then H2O (200 mL) was added. The aqueous phase was basicified with solid NaOH, then the mixture was extracted with EtOAc (200 mL). The EtOAc layer was dried (MgSO4), filtered, & concentrated to provide the title compound (3.01 g, 45%): δH ((CD3)2SO)=3.85 (s, 2H), 4.85 (s, 2H), 6.50 (t, 1H), 6.60 (d, 1H), 6.85 (d, 1H), 6.90–7.00 (m, 2H), 7.35 (d, 1H), 7.50 (d, 1H), 7.55 (s, 1H); m/z (ES+)=360.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[C:6]([O:15]C)=[N:5]2.Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[C:6]([OH:15])=[N:5]2
Reactant: COc1nc2cc(F)ccc2n2cnnc12
Agent: Cl
Solvent: CC(=O)O
Product: Oc1nc2cc(F)ccc2n2cnnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 11.3 g. (0.52 mole) of 7-fluoro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 115 ml. of 1N hydrochloric acid and 345 ml. of glacial acetic acid was refluxed for a period of three hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice/water. The resulting mixture was then stirred for a period of 30 minutes and thereafter filtered to remove the precipitate, which was subsequently washed with water and air-dried to ultimately afford 8.9 g. (84%) of pure 7-fluoro-4-hydroxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >300° C. Mass Spectrum: m/e, 204 (P).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:13]([O:15][C:16]([C:18]#[C:19][C:20](OCC)=[O:21])=[O:17])[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16]([C:18]1[N:6]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][S:3][C:2]2=[N:1][C:20](=[O:21])[CH:19]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Nc1nc(-c2ccccc2)cs1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(=O)nc2scc(-c3ccccc3)n12
Temperature: 15 °C
Reaction time: 72 h

Procedure:
17.6 g of 2-amino-4-phenylthiazole are dissolved in 100 ml of tetrahydrofuran, the resulting solution is cooled to approximately 15° C. and 17.5 g of acetylene dicarboxylic acid diethyl ester are slowly added to it with stirring at that temperature. The mixture is left standing for 3 days, after which the crystals formed are filtered off the quantity of which was increased by concentrating the mother liquor to approximately half its original volume and recrystallized from ethanol. 3-Phenyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester is thus obtained in a yield of 16.9 g, corresponding to 56.3% of the theoretical.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[C:6]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1)[CH3:2].[H][H]>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Yield: 99.3 %

Procedure:
10% palladium on carbon (about 50% wet) (170 mg) was added to a mixture of tert-butyl 3-(2-ethoxy-2-oxoethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g) and EtOH (34 mL), and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere at 3 atm. The reaction mixture was separated by filtration using Celite, and the filtrate was concentrated under reduced pressure, whereby tert-butyl 3-(2-ethoxy-2-oxoethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g) was obtained as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([NH:20][NH2:21])=[O:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=S)OC2C(F)=C(F)C(F)=C(F)C=2F)[CH:29]=[CH:30][CH:31]=1)[CH3:24].C1N=CN(C(N2C=NC=C2)=O)C=1>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:18]3[O:19][C:33]([NH:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=4)=[N:21][N:20]=3)=[O:22])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: CCOc1cccc(NC(=S)Oc2c(F)c(F)c(F)c(F)c2F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCOc1cccc(Nc2nnc(C(=O)Nc3ccc(N4CCN(C(C)=O)CC4)cc3)o2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
N-[4-(4-Acetylpiperazin-1-yl)phenyl]-2-hydrazino-2-oxoacetamide (Intermediate 21, 153 mg, 0.5 mmol) was added to a solution of O-(pentafluorophenyl) (3-ethoxyphenyl)thiocarbamate (Intermediate 48, 182 mg 0.5 mmol) in DMF (7 mL). The mixture was stirred at 60° C. for 30 min then PS-CDI (500 mg 1.0 mmol) was added and stirring was continued for a further 2 hours. The mixture was allowed to cool then filtered to remove the resin, which was washed with a further 2×10 mL DMF. The combined filtrates were concentrated by evaporation to give a solid that was then triturated with 1:1 acetonitrile:water to give the title compound (220 mg) as a solid; 1H NMR δ 10.95 (1H, s), 10.85 (1H, s), 7.67 (2H, d), 7.33-7.22 (2H, m), 7.12 (1H, d), 6.97 (2H, d), 6.64 (1H, d), 4.04 (2H, q), 3.65-3.51 (4H, m), 3.11 (4H, d), 2.07 (3H, s), 1.35 (3H, t); MS m/e MH+ 451.
Reaction SMILES: [C:1](OC(C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)C(N1[C@@H](CC2C=CC=CC=2)COC1(C)C)=O)(=[O:3])[CH3:2].[CH2:39]([C@H:46]1[CH2:50][O:49][C:48]([CH3:52])([CH3:51])[N:47]1[C:53](=[O:73])[CH:54]([C:56]1[O:60][C:59]([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)=[CH:58][CH:57]=1)[OH:55])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:1]([O:55][CH:54]([C:56]1[O:60][C:59]([C:61]2[CH:62]=[CH:63][C:64]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:65][CH:66]=2)=[CH:58][CH:57]=1)[C:53]([N:47]1[C@@H:46]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:50][O:49][C:48]1([CH3:52])[CH3:51])=[O:73])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Product: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccc(-c2ccc(-c3ccccc3)cc2)o1

Procedure:
According to the procedure described in Example 13 for the preparation of 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-ethanone, 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-2-hydroxy-ethanone was acylated to furnish in quantitative yield 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-ethanone as an off white solid, mp 120-8° C., which was used without further purification. 1H NMR: δ 7.75 (d, 2H, J=8.5 Hz), 7.66-7.62 (m, 4H), 7.46 (t, 2H, J=7.4 Hz), 7.39-7.22 (m, 6H), 6.70 (d, 1H, J=3.7 Hz), 6.62 (d, 1H, J=3.3 Hz), 6.39 (s, 1H), 3.86-3.79 (m, 2H), 3.64-3.60 (m, 1H), 3.39 (d, 1H, J=14.0 Hz), 2.96 (dd, 1H, J=11.4, 14.0 Hz), 2.25 (s, 3H), 1.78 (s, 3H). Anal. Calculated for C32H31NO5 : C, 75.42; H, 6.13; N, 2.75. Found: C, 75.27; H, 6.22; N, 2.65.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[H-].[Na+].O>C1COCC1>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[C:2]=[S:3]
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1ccc(N=C=S)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
4-Isothiocyanato-benzenesulfonamide (750 mg, 3.5 mmol), and tert-butyldimethylsilyl chloride (528 mg, 3.5 mmol) stirred in dry THF (20 mL) at 0° C. Sodium hydride (210 mg, 60% in mineral oil, 5.25 mmol) was added, and the reaction stirred for 1 h before it was poured over H2O (50 mL) and extracted with ether (2×50 mL). Organics were washed with brine (25 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 920 mg (80%) of 4-isothiocyanato-N-(TBDMS)-benzenesulfonamide as a white solid. 1H NMR (300 MHz, CDCl3) δ7.86 (d, 2H, J=6.9 Hz), 7.31 (d, 2 H, J=6.9 Hz), 4.40 (s, 1H), 0.90 (s, 9H), 0.22 (s, 6H). Anal. (C13H20N2O2S2Si) C, H, N, S. Calculated C=47.53; H=6.14; N=8.53; S=19.52; found C=47.47; H=6.25; N=8.46; S=19.49.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:13]1)=[O:11]>CO.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][N:19]=[CH:18][N:17]=2)[CH2:13]1)=[O:11]
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nc(Cl)ncc2-c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2ncncc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of (1H-Benzoimidazol-2-yl)-[3-(2-chloro-5-phenyl-pyrimidin-4-yl)-azetidin-1-yl]-methanone (102 mg, 0.28 mmol) in MeOH (10 mL) was added Pd/C (100 mg). The reaction solution was stirred at RT overnight under H2 atmosphere. The mixture was filtered and concentrated to give the product (51 mg, 0.16 mmol, yield: 55%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Pd]
Solvent: CO
Product: Nc1c(O)cccc1O
Yield: 74.5 %

Procedure:
A solution of 2-nitrobenzene-1,3-diol (5.00 g, 32.2 mmol) in MeOH (100 mL) was stirred under H2 atmosphere (balloon) in the presence of 10% Pd/C (200 mg) for 16 h at room temperature. The reaction mixture was filtered and the filtrate was concentrated to render a residue characterized as 2-aminobenzene-1,3-diol (3.0 g, 95% yield), used as such for the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(F)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COc1c(C(=O)O)ccc(F)c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
To 4-fluoro-2-methoxybenzoic acid (0.96 g) was added concentrated sulfuric acid (6 mL) under ice-cooling, and the mixture was stirred for 15 minutes. To the mixture was added concentrated nitric acid (0.6 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added ice, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To the residue was added a mixed solvent (n-hexane/ethyl acetate=2/1), and the insoluble material was collected by filtration, and dried under reduced pressure to give the title compound (0.78 g).
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.C[O:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:36][CH2:35]2)=[C:30]([CH:33]=1)[C:31]#[N:32]>>[OH:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:36][CH2:35]2)=[C:30]([CH:33]=1)[C:31]#[N:32]
Reactant: COc1ccc(N2CCN(CCc3ccccc3)CC2)c(C#N)c1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: N#Cc1cc(O)ccc1N1CCN(CCc2ccccc2)CC1
Yield: 50.5 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 5-methoxy-2-(4-phenethylpiperazin-1-yl)benzonitrile (257 mg), and the resulting crude product was purified on TLC (developer, chloroform: methanol=12:1) to provide 5-hydroxy-2-(4-phenethyl-piperazin-1-yl)benzonitrile (124 mg).
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[O:6])[CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH:15]=[O:16]>>[CH:1]1([NH:4][C:5](=[O:6])[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[F:7])[CH:15]=[O:16])[CH2:3][CH2:2]1
Reactant: O=CNc1ccccc1F
Reactant: O=C=NC1CC1
Product: O=CN(C(=O)NC1CC1)c1ccccc1F
Temperature: 100 °C
Reaction time: 48 h

Procedure:
An equimolar mixture of 1A and 1B in tetrohydrofuran was stirred for 2 days at 100° C. The solvent was evaporated, and the residue was recrystallized from ether to give 1, as a white solid, m.p.: 104°-105° C.
Reaction SMILES: [N:1]1([CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])OCC)=[C:9]([CH:19]=[N:20][CH3:21])[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)C.[BH4-].[Na+]>CO>[N:1]1([CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[CH:8]=[C:9]3[C:10](=[CH:11][CH:12]=2)[NH:13][C:14](=[O:18])[N:20]([CH3:21])[CH2:19]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1C=NC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CN1Cc2cc(C(c3ccccc3)n3ccnc3)ccc2NC1=O
Reaction time: 7 h
Yield: 20.1 %

Procedure:
To a stirred mixture of 1.7 parts of ethyl [4-[(1H-imidazol-1-yl)phenylmethyl]-2-[(methylimino)methyl]phenyl]carbamate and 31.6 parts of ethanol were added 1 part of sodium tetrahydroborate (portionwise) and 55.3 parts of methanol. After stirring for 7 hours at 40°-50° C., the reaction mixture was evaporated. The residue was taken up in water (to which 0.29 parts of acetic acid were added) and the whole was basified with NH4OH. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from ethyl acetate, yielding 0.3 parts (20.1%) of 3,4-dihydro-6-[(1H-imidazol-1-yl)phenylmethyl]-3-methyl-2(1H)-quinazolinone; mp. 173.8° C. (comp. 23).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[N:9](CC2C=CC(OC)=CC=2OC)[C:8](=[O:21])[C@H:7]1[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P(O)([O-])([O-])=O.[K+].[K+]>O.C(#N)C>[C:1]([NH:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:21])[C@H:7]1[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CNC(C)=O)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)NC[C@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1

Procedure:
A mixture of 298 mg of cis-4-acetamidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine, 576 mg of potassium persulfate and 183 mg of dipotassium phosphate in 15 ml of water and 15 ml of acetonitrile is heated under reflux for 1.5 hours. The reaction mixture is concentrated in vacuo. The residue is taken up in ethyl acetate and the solution is washed successively with an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution. The ethyl acetate solution is dried over magnesium sulfate and the solvent is then distilled off in vacuo. Ethyl acetate is added to the residue and the precipitated crystals are collected by filtration to give cis-4-acetamidomethyl-3-phenylacetamido-2-oxoazetidine, m.p. 200°-202° C.
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:30])[CH:10]([CH2:14][C:15]1[C:16]([CH3:29])=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][CH:20]=1)[C:11](O)=O)[CH3:7].C=O>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:30])[C:10]([CH2:14][C:15]1[C:16]([CH3:29])=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:19][CH:20]=1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)O
Agent: C=O
Solvent: CCNCC
Solvent: ClCCl
Product: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)OCC
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Diethylamine (359 mg, 4.90 mmol) was added dropwise to a solution of 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.44 g, 4.09 mmol) and formaldehyde (464 mg, 5.72 mmol, 37% in water) in methylene chloride (35 mL) at 0° C. under argon. The mixture was stirred at room temperature over night. Methylene chloride was added and the solution was washed with Na2CO3 and brine, dried and concentrated under reduced pressure to give 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (1.03 g, 79%).